Nepotrebno je, 
da bolezen spremlja bolecina 

tramadol 

Moc opioidnega analgetika brez opioidnih stranskih ucinkov 
. 
centralno delujoci analgetik za lajšanje zmernih in hudih bolecin 

. 
ucinkovit ob sorazmerno malo stranskih ucinkih 


Indikacije: Srednje mocne do mocne akutne ali kronicne bolecine. Po trt,topenjski shemi Svetmme 
ulraustwne orgcmizaetJe za i<\ff<mje l>olecin pri bolnikih z mkuvim obolenjem tramadol odpmu{f(1 
srednje hudo boleUrw alt bolebno druge stopnje. Kontraindikacije: Zdravila ne smemo dajati otrokom, 
mlajšim od 1 leta. Tramadola ne smemo uporabljati pri akutni zastrupitvi z alkoholom, uspavali, analgetiki in 
drugimi zdravili, ki delujejo na osrednje živcevje. Med nosecnostjo predpišemo tramadol le pri nujni indikaciji. Pri 
zdravljenju med dojenjem moramo upoštevati, da 0,1 o/o zdravila prehaja v materino mleko. Pri bolnikih z zvecano 
obcutljivostjo za opiate moramo tramadol uporabljati zelo previdno. Bolnike s krci centralnega izvora moramo 
med zdravljenjem skrbno nadzorovati. Interakcije: Tramaclola ne smemo uporabljati skupaj z inhibitorji MAO. 
Pri socasni uporabi zdravil, ki delujejo na osrednje živcevje, je možno sinergisticno delovanje v obliki povecane 
sedacije, pa tudi ugodnejšega analgeticnega delovanja. Opozorila: Pri predoziranju lahko pride do depresije dihanja. Previdnost je potrebna pri bolnikih, ki so preobcutljivi za opiate, pri starejših osebah, pri miksedemu in hipotiroidizrnu. Pri okvari jeter in ledvic je potrebno odmerek zmanjšati. Bolniki med zdravljenjem ne smejo upravljati strojev in motornih vozil. Doziranje in nacin uporabe: Odrasli in otroci, starejši od 14 let: Injekcije: 
50 do 100 mg i.v.,i.m.,s.c.; intravensko injiciramo pocasi ali infundiramo razredceno v infuzijski raztopini. 
Kapsule: 1 kapsula z malo tekocine. Kapljice: 20 kapljic z malo tekocine ali na kocki sladkorja; ce ni zadovoljivega ucinka, dozo ponovimo cez 30 do 60 minut. Svecke: 1 svecka; ce ni ucinka, dozo ponovimo po 3 do 5 urah. Otroci od 1 do 14 let.· 1 do 2 mg na kg telesne mase. Dnevna doza pri vseh oblikah ne bi smela biti višja od 400 mg. Stranski ucinki: Znojenje, vrtoglavica, slabost, bruhanje, suha usta in utrujenost. Redko lahko pride do palpitacij, ortostatske hipotenzije ali kardiovaskularnega kolapsa. Izjemoma se lahko pojavijo konvulzije. Oprema: 5 ampul po 1 ml (50 mg/ml), 5 ampul po 2 ml (100 mg/2 ml), 10 ml raztopine (100 mg/ml), 20 kapsul po 50 mg, 5 sveck po 100 mg. 
Podrobnejše informacije so na voljo pri proizvctjalcu. 

...KRK. 
SLOVENIJA 
Radiology and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, rnagnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, radiophysics and radiation protection. 



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Ljubljana, Slovenia  
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Gregor Serša  
Ljubljana, Slovenia  
Viljem Kovac  
Ljubljana, Slovenia  
Editorial board  Bela Fornet  Maja Osmak  
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lndexed and abstracted by 
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CONTENTS 
ULTRASOUND 
Transesophageal echocardiograplly -a new diagnostic metllod in cardiology Koželj M  97  
Age-related changes of renal vascular resistance in normal native kidneys: color duplex Doppler ultrasound assessment Brkljacic B, Drinkovic I, Delic-Brkljacic D, Hebrang A  102  
Color-Doppler ultrasound evaluation of renal celi carcinomas Drinkovic I, Brkljacic B, Zeljko ž  107  
COMPUTERISED TOMOGRAPHY AND NUCLEAR MEDICINE  
Role of CT gnidance in the biopsy of the spine and paravertebral soft tissue Puskas T  114  
Evaluation of hypertrophic pulmonary osteoarthropathy by bone scintigraphy in patient witll carcinoma of tile lung Huic D, Dodig D, Huic M, Škorak I, Poropat M  118  
EXPERIMENTAL AND CLINICAL ONCOLOGY  
lmproved tllerapeutic effect of electrocllemotllerapy witll cisplatin by intratumoral drug administration and cllanging of electrode orientation for electropermeabilization on EAT tumor model in mice Cemažar M, Miklavcic D, Vodovnik L, farm T, Rudolf Z, Štabuc B, Cufer T, Serša G  121  
Early stage Hodgkin's disease: tile remaining cllallenge after a "success story". An overview of tllirty year's experience of tile Florence Radiotllerapy Department Magrini SM, Cellai E, Papi MG, Ponticelli P, Sulprizio S, Pertici M, Bagnoli R, Biti G  128  






Survival of stage I Jung cancer patients with previous or subsequent primary malignant neoplasms Vasiljev OA, Khartchenko VP, Kouzmine IV 148 

RADIOPHYSICS  
The air kerma-rate constant of high dose-rate Ir-192 sources  
Podgorsak MB, DeWerd LA, Paliwal BR  153  
REPORT  
Report on the meeting of the EAR executive bureau held in Munich 4 February 1995  
Blery M  163  
NOTICES  165  


The publication of the journal is subsidized by the Ministry of Science and Technology of the Republic Slovenia. Contributions of Institutions: Fundacija doc. dr. J. Cholewa, Ljubljana; Inštitut za diagnosticno in intervencijsko radiologijo, KC Ljubljana; Klinika za otorinolaringologijo in maksilofacialno kirurgijo, KC Ljubljana; Klinicki zavod za dijagnosticku interventnu radiologiju, KBC Rebro, Zagreb; Onkološki inštitut, Ljubljana 
Transesophageal echocardiography -a new diagnostic method in cardiology 
Mirta Koželj 
Department of Cardiovascular Disease, University Medica! Centre, Ljubljana, Slovenia 
Transesophageal echocardiography (TEE) is a rapidly expanding diagnostic procedure in cardiology. Limitations of transthoracic approach caused by pulmonary emphysema, obesity, thoracic deforma­tion and dyspnea have been overcome by using the transesophageal approach. TEE has a higher resolution, because higher frequency transducers can be used and there is no thorax interposition between the heart and transducer. There are strong and relative indications for this procedure. The TEE examination is a safe method and has very limited contraindications. 
Key words: echocardiography transesophageal, diagnostic method, carcliology 
Introduction 

After the introduction of echocardiography, it soon became apparent that scanning of the heart is sometimes hinderecl by inadequate pe­netration of ultrasound through the thoracic wall and ribcage. This stimulated many investi­gators to search for alternative approach. Wit­hin only a few years, transesophageal echocar­cliography (TEE) has become established as an important new imaging technique in cardiology. TEE has opened a unique »new win<low« to the heart. The immediate proximity of oesopha­gus ancl the posterior heart permits exceptio­nally high resolution images, particularly of the left atrium, mitral valve, and interatrial septum, 
Correspondence to: Mirta Koželj, MD, PhD, Depart­ment of Cardiovascular Disease, University Medica! Centre, Zaloška 7, 61000 Ljubljana, Slovenia. Phone: 
+ 386 61 317 057. Fax: + 386 302 455. 
and thoracic aorta. Aclclitionally, from the sto­mach, the ventricles can be clepcndably imagecl. 
Technological developments and cnrrent TEE probes 
The technique of TEE imaging was first intro­duced on an experimental basis in the late 1970s.1 Since then, rapicl advances in ultrasouncl technology have greatly changecl the practice of TEE imaging. Miniaturisation of transducers size, the development of phased array systems housed in flexible endoscopes, and the ability to perform pulsed and colour Doppler flow imaging have made TEE a valuable diagnostic 
3 

tool.2• Until recently, transesophageal endo­scopes have had a single set of transclucer orments attachecl to the probe tip. Using this transducer, images are acquired in serial trans­verse imaging planes. Recently Omoto et al.4 
UDC: 616.12-073:534-8 have introduced a biplane transesophageal pro­
be. Two phased-array transducers, one imaging in transverse and one in longitudinal planes, are mounted side-by-side at the tip of the gastroscope. This additional sagittal plane trans­ducer allow imaging of the heart in two ortho­gonal planes, and enable a more complete biplane examination of cardiac and aortic ana­tomy. Much more sophisticated systems opera te with multiplane probes, which allow to observe the heart in even multiple sections. 
The basic construction of all transesophageal transducers is similar. A commercially available gastroscope is adapted by fitting a phased-array transducer at its tip for imaging in the transverse axis. The fiberoptics, together with the channels used for suction and biopsy, are removed to provide space for electronic connections for the transducer, but normal guidance controls are retained (Figure 1). The probes have the capa­city for two-dimensional imaging at 5 to 7 MHz and 3.5 MHz for Doppler sampling. 
TEE echocardiography is presently utilised in two environments: intraoperatively and for outpatient examinations. Intraoperatively, TEE is utilised to monitor cardiac function and detect intracardiac air or debris, to diagnose or quan­titate cardiac pathology and to assess operative results. 

Patient preparation for TEE examination 
TEE is unpleasant for most patients. Prior to the TEE examination, the possibility of gastro­esophageal disease must be excluded, specifi­cally oesophageal varices, diverticula, spasm and strictures, and intraesophageal masses. To prevent aspiration the patient should abstain from all oral intake for at least 4 hours, and during the introduction and examination the patient lies in the left decubitus position. Anti­biotic prophylaxis is recommended only for a group of patients at high risk of infectious endocarditis such as those with prosthetic heart valves, severe native mitral regurgitation, and congenital heart disease.5 Choice of anti micro­bial agent is made in accordance with the guidelines of the American Heart Association.6 


Lidocain spray is given for local anaesthesia to all patients. In our experience other premedica­tion is not necessary. We perform TEE with sedatives and spasmolytics only in patients, in whom the aortic dissection is suspected. The patient is asked to swallow and the probe is advanced into the oesophagus with the aid of gentle pressure. Under no circumstances should oesophageal intubation be attempted against resistance. Por the unconscious for example at intraoperative TEE, anaesthetised patients, no preparations are needed other than those for the operative procedure itself. The TEE probe is introduced into the oesophagus following of anaesthesia. 

TEE: anatomic correlations 

A comprehensive transesophageal examination entails a sequence of transducer positions and tomographic planes of sections. A step-by step approach that can be altered on the basis of the clinical situation is suggested. During TEE, two distinct tomographic examinations are per­formed -namely, that of the heart and that of the thoracic aorta. 
Complete TEE imaging of the heart is perfor­med from transducer locations in the stomach and various levels of the oesophagus. Views from the distal and proximal fundus of the stomach, gastroesophageal junction, lower and 

Figure l. Biplane probe (5 MHz). Note dual cables and connectors ("vertical, horizontal") for two trans­ducers. 
middle oesophagus, and upper oesophagus are included in a standard TEE study of the heart. Although these locations serve as a general guide, the exact location of the transducer should be guided by the acquired image and not by the position in the stomach or oesopha­gus. If the probe is rotated anticlockwise, all of the thoracic descending aorta can be visuali­sed adjacent to the transducer. 7 
The main clinical indications for a TEE study in adults 
The oesophagus is adjacent to the left atrium and descending aorta. The high resolution and the shorter distance to the transducer make possible high quality images of the left atrium, mitral valve, interatrial septum and aortic valve. Flow patterns in the heart can be studied in detail. With transthoracic echocardiography, shi./ding of the left atrium by prosthetic valves 
.

often prevents evaluations of insufficiencies. TEE with colour flow Doppler provides magni­ficent evaluation of (para) valvular mitral insuf­ficiency. Biplane TEE provides better evalua­tion of all cardiac valves and of valve insuffi­ciencies in the longitudinal sections. Longitudi­nal sections are superior for the evaluation of the right ventricular outflow tract. With TEE, the interatrial septum is about perpendicular to the transducer and also the detection of a very small atrial septal defect is easy now. A diffe­rent and often better evaluation of the aortic valve and right atrium is possible with TEE. 
Major indications for ambulatory ( outpatient and inpatient) TEE include defining the aetio­logy and severity of native valve disease, espe­cially mitral regurgitation; detecting vegetations and other sequels of endocarditis (Figure 2); assessing prosthetic valve function and regurgi­tation; and identifying a potential cardiac embo­lic source (Figure 3). TEE has been shown to be an excellent method for detecting atrial septal defects, atrial septal aneurysm (Figure 4), and patent foramen ovale. In regard to cardiac tumours, although the <lata are prelimi­nary, certain tumour locations and morphologic aspects are better evaluated with TEE than with other techniques. Important advantages of TEE over transthoracic echocardiography are the high resolution images of cardiac cavities for tumour Iocation and the visualisation of the 

Figure 2. Transcsophagcal cchocardiogram at thc Je­vci of thc lcft atriovcntricular junction. A bilcaflct prosthetic valvc is in mitra! position, which casts a shadow within thc lcfl vcntriclc (LV). Thcrc is a vcgctation (arrow) of the lcft atrial sidc of thc prost­hesis. LA 

left atrium. Thc vcgctation was not scen at transthoracis study becausc of shadowing of mitra! prosthcsis in thc lcft atrium. 


Figure 4. Transesophagcal image of an atrial septal aneurysm (arrow). LA = left atrium, RA = right atrium. 
myocardial wall and great veins for recognition of impingement, containment, migration and 
8 
infiltration of diverse turnours types. A new fieki in ultrasound diagnosis is the thoracic aorta. Good information about the prcsence of dissection and plaques can be obta­
ined (Figure 5). The true and false lumen can 
bc distinguished with colour flow Doppler. Thc aortic arch and ascending aorta are not always visible because of intcrposition of trachea. 
TEE is of limited value in the evaluation of 
lcsions within thc coronary arterics. Even whcre the quality of the images is excellent, only limitcd segments of the proximal vessels can be visualised. It is our opinion that the only prac­tical value is in the idenfication of left main coronary stenosis or the involment of coronary arteries in dissection of ascending aorta. 


Safety and complications of TEE 
Clear indications for TEE are necessary because side effects are rare but can be harmful. The complications include intolerance of the proce­dure, bronchospasm, spasm of oesophagus, vo­miting, cardiac rhythm disturbances, angina, pharyngeal bleeding. The ECG monitoring is mandatory during the procedure. Nevertheless 

Figure 5. Cross-sectional transesophagcal imagc of the aortic arch (AO) in a patient with acutc dissection. The arrow shows the intima! tear. The color flow Doppler study confirms the flow at this sitc. Subse­quent surgical inspcction confirmed that this was the sitc of an intima] tear. 
a careful history concerning upper gastrointesti­nal problems should be taken before TEE stu­d y 9 
. 

Conclusion 

TEE has indeed opened a new and exciting window to the heart. TEE has now become a logical extension of a complete transthoracic echocardiographic examination. Predictable high-quality irnages obtained frorn the trans­esophageal examination have fostered wide ap­plication of this new technology. With newer multiplanar scanning devices becorning availa­ble, whole sets or farnilies of short-and long­axis and four chamber views of the heart will be obtained. 

References 

l. Frazin L, Talano J, Stephanides L, Loeb HS, Kopel L, Gunnar RM. Oesophageal echocardio­graphy. Circulation 1976; 54: 102-8. 
2. Hisanaga H, Hisanaga A, Nagata K, Ichie Y. Transesophageal cross-sectional echocardiography. Am Heart J 1980; 100: 605-9. 



3. 
Hisanaga H, Hisanaga A, Nagata K, Yoshida S. A new transesophageal real-tirne twodimensional echocardiographic system using a flexible tube and its clinical application. Proc Jpn Soc OJ Ultrasonics in Med 1977; 32: 43-4. 

4. 
Omoto R, Kyo S, Matsumura M, Recent technolo­gical progress in transesophageal colour Doppler flow imaging with special reference to newly deve­loped biplane and paediatrie probes. In: Erbel R, Khanheria, Brennecke R, Mcyer J, Seward JB, Tajik AJ eds. Transesophageal echocardiography. A new window to the heart. Heidelberg, Berlin: Springer-Verlag, 1989: 21-6. 

5. 
Foster E, Redberg RF, Schiller NB. Transesopha­geal echocardiography. Indications and technical considerations: In: Schiller NB, Foster E, Redberg RF cds. Transesophagcal echocardiography. Car­diology Clinics. 1993; 11: 355-60. 

6. 
Dajani AS, Bisno AL, Chung KJ, Durack DT, Freed M, Gerber MA. Prevention of bactcrial 



endocarditis. Rccommendations by The American Heart Association. JAMA 1990; 264: 2919-22. 

7. 
Schneider AT, Hsu TL, Schwartz SL, Pandian NG. Single, biplane, multiplane, and thrce dimensional transesophageal echocardiography. Echocardio­graphic-Anatomic corrclations. In: Schiller NB, Fo­ster E, Redberg RF eds. Transesophageal echocar­diography. Cardiology Clinics. 1993; 11: 361-87. 

8. 
Seward JB. Cardiac tumours and thrombus: trans­esophageal echocardiographic experience. In: Erbel R, Khanheria, Brennecke R, Meyer J, Seward JB, Tajik AJ eds. Transesophageal echocardiography. A new window to the heart. Heidelberg, Berlin: Springer-Verlag, 1989: 120-8. 

9. 
Fraser AG, Anderson RH. The normal examina­tion: teclrnique, imaging planes, and anatomical features. In: Sutherland GR, Roeland JRTC, Fra­ser AG, Andercrson RH eds. Transesoplzageal echocardiography in clinical practice. Gower Medi­ca! Publishing, 1991: 3.1-3.32. 










Age-related changes of renal vascular resistance in normal native kidneys: color duplex Doppler ultrasound assessment 
Boris Brkljacic,1 Ivan Drinkovic,1 Diana Delic-Brkljacic,2 Andrija Hebrang1 
1 Department of Radiology, Ultrasonic Center, University Hospital "Merkur" and 2 Department of Medicine, University Hospital "Sestre Milosrdnice", Croatia. 
Purpose: To evaluate age-related changes of renal vascular resistance (RVR) in normal native kidneys. Materials and methods. lntrarenal arteries were insonated in 180 kidneys of 90 examinees and Doppler sonographic resistive indexes (Ris) were measured. Examinees were classified into three age groups: the first consisted of subjects < = 30 years old, the second of subjects between 31 and 54 years and the third of subjects 55 years of age and older. Results: Mean Ris were 0.57 in the first group, 0.598 in the second group, and 0.621 in the third group. Ris were found to be age dependent, with significant elevation observed with increasing age 
(group I vs. group II, P < .01; group II vs. group III, P = .03; group I vs. group III, P < .01). Conclusion: Doppler sonographic resistive indexes reflect elevation of RVR with aging. 
Key words: kidney, blood, renal artery-ultrasonography; ultrasonography, supply, Doppler, color; age factors. 
Introduction 

Extensive research has been performed during the last decade in Doppler assessment of intra­
3 

renal blood flow in transplanted kidneys.1-In the last few years Doppler studies were perfor­med in native kidneys, as well. 4-6 Normal values have been established in a few studies and Doppler indexes have been correlated with renal functional tests and blood pressure values 
Correspondence to: Boris Brkljacic, M. D., Ph. D., Department of Radiology, Ultrasonic Center, Univer­sity Hospital "Merkur", Zajceva 19, Zagreb, Croatia. Phone/Fax: + 385-1-2331440. 
UDC: 611.611:611.136.7:534-8 
in severa! renal diseases.7-13 In most of these studies age-dependent changes of renal vascular resistance were neglected, although some authors referred to age-related changes of Dop­pler inexes in large series of patients.10 The purpose of this study was to evaluate age-rela­ted changed of renal vascular resistance, reflec­ted in values of Doppler sonographic resistive indexes (Ris), in normal native kidneys. 

Materials and methods 

Between November 1991 and November 1994 color-duplex Doppler sonography of intrarenal arteries was performed in 180 kidneys of 90 


subjects without renal impairment. There were 39 men, and 51 women, aged 18-55 years (mean 44.6 ± 14.6 years). Twenty six were heal­thy volunteers and 64 were studied in the course of nonrenal abdominal, thyroid or breast US examinations. The inclusion criteria for the examination were abscence of a history of kid­ney disease; absence of systemic, chronic or malignant diseases that might affect renal fun­ction; absence of hypertension; absence of hi­story of congenital or acquired heart disease; normal conventional US finding of kidneys; and normal urinalyisis findings prior to Doppler US examination. Twenty eight subjects had findings of normal serum creatinine, tested wit­hin 30 days prior to Doppler US examination. Informed consent was obtained from all exami­nees. All subjects were older than 18 years, to avoid variations in Rls values noted in child­hood.14·15 The examinees were arbitrarily classi­fied into three age groups ( < = 30 years old, 31-54 years, > = 55 years) to evaluate age dependence of RI values in healthy adult su­
bjects. 
Real-tirne and color duplex-Doppler US exa­minations were performed with a Radius CF color Doppler scanner (GE-CGR, Buc, Fran­ce), with a curved-array 3.75-MHz transducer. After color-Doppler identified flow in intrare­nal vessels, a sample-volume was positioned in segmenta!, interlobar and arcuate arteries in their typical positions. Spectral analysis was performed and Rls measured using existing software capabilities of the scanner. Mean RI values for each kidney were calculated from all measurements. Wall-filter of 50 Hz and minimal PRFs were used to obtain optimal spectral waveforms in all cases. Sample-volume was set at 2-4 mm. Examination was technically successful and adequate spectra obtained in all subjects. The RI was measured with the formula (peak systolic frequency shift -minimum diasto­lic frequency shift)/mean frequency shift during the cardiac cycle.16 Subjects were examined in supine and decubitus positions; the duration of the examination per person was 30-40 minutes. All the examinations were performed by the first author (B. B). 

Mean RI values were compared between different age groups of examines. "Goodness­of-fit test" (Kolmogornov-Smirnov) was used to test whether the distribution of RI values was normal. The statistical significance of obser­ved differences was calculated with the Mann­Whitney U test. The Pearson method was used to estimate the correlation between Ris and age of the age of the whole group of examinees. 

Results 

The mean RI ± SD in 180 kidneys of 90 
subjects with normal native kidneys was 0.596 ± 0.038 (range 0.535 -0.685). Ali Ris were below 0.70. 
There were 23 examinees 30 years old or younger (group 1), 46 subjects were in the range of 31 -54 years of age (group II), and 21 examinees were 55 years old or older (group III). The distribution of Ris by these three age groups is shown in Figure l. 
The age distribution, as well as distribution of Ris within each age group was normal. Statistical significance of differences of Rls bet­ween different age groups (Mann-Whitney U­test) was observed between the age groups I and II (P < .01), between the age groups II and III (P = .03; 95 % confidence leve!), and bet­ween the age groups I and III (P < .01). 
RI 

0.7 -------------­
f--J--E} MEAN 0.621 

0.65 
MEAN 0.570 

0.6 
0.55 
0.5c__ -.-------.­----"------­
n= 23 n•46 
>• 55 YEARS 
n=21 

Figure 1. The distribution of mean RI values and 1 
S. D. in three age-groups of examinees with normal native kidneys. n = number of patients within the particular age-group. 
The typical Doppler spectra from intrarenal arteries with high continuous diastolic flow and low resistive index are shown in the Figure 2. 
The Pearson lienar correlation method show­ed high and statistically significant correlation between Rls and age of the whole group of examinees with normal native kidneys. The Pearson correlation coefficient (r) between age of examinees and RI was 0.5172 (P< .001). 
The Pearson method showed lack of correla­tion between Ris and renal length and between Rls and renal parenchymal thickness in subjects with normal native kidneys. Correlation coeffi­cients between Rls and renal lenght were: r = ­
0.053 for the right kidney (P 

NS) and r = 

0.061 for the left kidney (P = NS). Coefficients between Rls and renal parenchymal thickness were: r = --0.078 for the right kidney and r = 
0.086 (P = NS) for the left kidney (P = NS). 
Disc11ssion 

Doppler sonographic studies of renal vascular resistance in renal parenchymal diseases have shown comp!ex interrelations of severa! para-meters affecting values of Doppler sonographic 
indexes. A few studies have analyzed rela­tion between RI and renal biopsy findings. It appears that the site of the pathologic altera­tions within the kidney is very important in measurement and interpretation of Doppler so­

18 

nographic indexes.13· Doppler analysis seems to be particularly useful in disease affecting tubulointerstitial and vascular compartments of kidneys. In diabetic nepropathy Doppler index­es reflect elevated renal vascular resistance.10 . In unilateral pyelocalicectasis Doppler seems to be very accurate in distinguishing between obs­tructive and non-obstructive collecting system dilatation.1 1• 12 In addition to pathologic altera­tions within the kidney and hypertension, age has emerged in large studies as a significant covariable, affecting RVR and Doppler indexes values. 10• 17 The present study has shown a high and significant correlation of Doppler sonogra­phic resistive index and age of examinees with normal native kidneys. It has also shown age­dependance of Ris values, which tend to in­crease with aging. 
In a literature a RI value of 0.70 has been generally accepted as a threshold value for pathological renal vascular resistance, and Ris of 0.70 and higher are considered abnormally elevated. This threshold RI value has been 
51718 

introduced by Platt• • and other groups · of investigators have accepted it.10-13 This study has shown that it is reasonable to take into account age-related dependence of Doppler in­dexes in interpretation of their values and in comparison with the control groups. 
Statistically significant differences of Ris va­lues were observed in the present study between arbitrarily chosen age-groups of examinees. It was noted that all the examinees had Rls below 0.70, and even in the oldest age-group the mean RI of 0.621 was far below the threshold value of O. 70. The mean RI value of 
0.596 ± 0.038 observed in this study was similar to other studies where mean intrarenal Rls in normal native kiclneys ranged from 0.58 to 0.64. 5, 7, 9, 10 
There are severa! limitations in the golden standard reference method for normal renal 
status. It is known that serum creatinine levels may be normal while even a 50 % decrease in renal function may exist simultaneously. 19 The­refore, it is hard to prove normal renal status when a study is performed in a usual clinical setting. An analysis of creatinine clearance rates has to take in account potential error from inaccurate urine collection.19 In the present study, small proportion of control subjects had serum creatinine levels tested and we had to rely in the majority of subjects on absence of history of renal disease, normal conventional US findings and urin analysis findings for inclu­sion of examinees in the control group. Al­though some persons with renal functional im­pairment may have been included in the control group using such criteria, we believe that the relevance of obatined data is not essentially decreased. 


This study shows that elevation of Rls with aging does not represent false variations or variability of these values. A few studies about physiology of aging suggest that the loss of renal function related with aging is hemodina­mically mediated ( elevated renal vascular resi­stance). 20-23 The prescnt study confinns those results. Some authors think that elevation of Doppler indexes that occurs with aging reflects the loss of functioning nephrons, observed in the senescent kidney, that is not reflected by 
1924 

serum creatinine elevation. 5• • In pediatric population higher Rls were observed in compa­
5 

rison with adults. 14• Only subjects older than 18 years were included in the present study, so the changes of Ris in childhood need not to be accounted for. Ris values did not show signifi­cant correlation with renal length and parenchy­mal thickness of our examinees, which is not surprising for normally functioning kidneys. 
Doppler US imaging has the most important potential for the diagnosis of parenchymal renal diseases in the longitudinal follow-up of patients with renal disease to provide predictive clinical information on the recovery of renal function or the progression of renal disease. Results of the present study indicate that elevation of Rls with increasing age has to be taken into account in such longitudinal studies, and that it is accep­table to consider RT of 0.70 as a threshold value for pathologic elevation of renal vascular resi­stance. 

References 

l. Pelling, M, Dubbins PA. Doppler and color Dop­
pler imaging in acute transplant failure. J Ciin Ultrasound 1992; 20; 507-11. 

2. 
Deane C. Doppler and color Doppler ultrasono­graphy in renal transplants: chornic rejection . .l Ciin Ultrasound; 20: 539-42. 

3. 
Becker JA. Role of radiology in evaluation of the failing renal transplantation. Radio! Ciin Norih Am 1991; 29: 511-5. 


4. 
Sauvain JL, Bourschcid D, Picrrat V, et al. Du­plex Doppler ultrasonography of intra-renal arte­ries. Normal and pathological aspects. Ann Radio/ 1991; 34; 237-46. 

5. 
Platt JF. Duplex Doppler evaluation of native kidney dysfunction: obstructive and nonobstruc­tivc disease. A.!R 1992; 158: l035-42. 

6. 
Scheidegger .JR, Werlen S. Spektra! und Farbdop­plcrsonographie: Teclmik, Moglichkeit und Gren­zen in der Uroradiologie. Schweiz Med Wo­chenschr; 1991; 121 (9): 292-8. 

7. 
Gottlieb RH, Luhmann K IV, Oatcs RP. Duplcy ultrasouncl evaluation of normal nalive kidneys and nalive kidneys with urinary tract obstruction. J Ultrasound Med 1989; 8: 609
--11. 

8. 
Rodgers PM, Batcs JA, lrving HC. Intrarcnal Doppler ultrasound studics in normal and aeutely obstructed kidncys. Br J Radio/ 1992; 65: 207. 

9. 
Kirn SH, Kim WH, Choi BI, et al. Duplcx sono­graphy of the native kidncy Resistive index vs. serum creatininc. J Ultrasound Med 1990; 9: 25-9. 

10. 
Brkljacic B, Mrzljak V, Drinkovic I, Soldo D, Sabljar-Matovinovic M, Hcbrang A. Rena! vascu­lar rcsistancc in cliabetic nephropathy: duplex Doppler US cvaluation. Radiology 1994; 192: 549­54. 


ll. Brkljacic B, Drinkovic I, Sabljar-Matovinovic M. et al. Intrarenal duplcx-Doppler sonographie cva­luation of unilateral native kidney obstruction. J Ultrasound Med 1994: 13: 197-204. 
12. 
Brkljacic B, Drinkovic I, Soldo D, Vidjak V, Odak D, Hebrang A. Pulsedwavc and color-Dop­plcr in the assessmcnt of nalive kidneys with urinary tract obstruction. Radio! Oncol 1993: 27: 21-6. 

13. 
Mostbcck GH, Kain R, Mallck R, ct al. Duplcx Doppler sonography in rcnal parenchimal disease. Histopathologic correlation. J Ultrasound Med 1991; 10 (4): 189-94. 




14. 
Wong SN, Lo RNS, Yu ECL. Renal blood flow pattern by non-inv.sive Doppler ultrasound in normal children and acute renal failure patients. J Ultrasound Med 1989; 8: 135-43. 

15. 
Keller MS. Renal Doppler sonography in infants and children. Radiology 1989; 172: 603-4. 

16. 
Pourcelot L. Applications cliniques de l'examen Doppler transcutane. In Peronneau P ed Veloci­metrie ultrasonare Doppler Seminaire INSERM. 

Paris, 1974; 34: 213-30. 


17. 
Platt JF, Rubin JM, Ellis JH. Diabetic nephropa­thy: evaluation with renal duplex Doppler US. Radiology 1994; 190: 343-6. 

18. 
Platt JF, Ellis JH, Rubin JM, Di Pietro MS, Sedman AB. Intrarenal arterial Doppler sono­graphy in patients with nonobstructive renal disea­se: correlation of resistive index with biopsy fin­dings. AJR 1990; 154: 1223-7. 




19. 
Becker JA Evaluation of renal function. Radiology 1991; 179: 337-8. 

20. 
Hollenberg NK, Adams DF, Solomon HS, Rashid A, Abrams HL, Merrill JP. Senescence and the renal vasculature in normal man. Circ Res 1974; 34: 309-14. 

21. 
Epstein M. Effects of aging on the kidnes. Fed Proc 1979; 38: 169-72. 

22. 
Anderson S, Brenner BM. Effects of aging on the renal glomerulus. Am J Med 1986; 80: 435-42. 

23. 
Cody RJ, Torre S, Clark M, Pondolfino K. Age­related hemodynamic, renal and hormona! diffe­rences among patients with congestive heart failu­re. Arch Intern Med 1989; 149: 1023-8. 

24. 
Riehl J, Clasen W, Schmitt H, Kierdorf H, Siebert HG. Altersabhaengige veraendenrungcn der renal haemodynamik. Untersuchungen untells duplex­sonographie (DS). Ultraschall Klin Prax 1989: 4(1): 129. 






Color-Doppler ultrasound evaluation of renal celi carcinomas 
Ivan Drinkovic, Boris Brkljacic, Žarko Zeljko1 
Department of Radiology, Ultrasonic Center and · Department of Surgery, Division of Urology, 1 University Hospital "Merkur", Medica! School, University of Zagreb, Croatia 
Color-duplex Doppler US (CDDUS) evaluation was performed in 39 patients with renal celi carcinomas (RCC). Intrarenal arteries within the tumor, on the margin of the tumor, and in the unaffected part of the kidney were insonated. Spectral analysis was performed, peak-systolic frequencies recorded, and Doppler-sonographic resistance-indices (Ris) calculated. Intrarenal arteries of 44 normal examinees were studied as a control group, in which a mean RI of 0.597 ± 0.035 (1 SD) was found. Spectral features of vessels on the margin of the malignant tumor consisted mostly of high frequency Doppler shifts (mean systolic peak 3.89 ± l.06kHz), while vessels within the tumor had very low vascular resistance, with low RI values (mean RI 0.498 ± 0.059), which were significantly lower in comparison with the control group (P < .01). These features are simi/ar in RCC regardless of their size. The overall sensitivity of CDD US in detection of at least one of abnormal flow features in RCC was 92.3 %, while the specificity was 93.2 %. CDD US can aid significantly in the noninvasive diagnosis of RCC, with exception of relatively rare hypovascular and avascular tumor types. 
Key words: kidney neoplasms-ultrasonography; carcinoma, renal celi; ultrasonography, Doppler, color 
Introduction 
Malignant renal tumors make up to 3 % of all human malignant tumors and renal cell carci­noma (RCC) is the most common primary malignancy of the kidney. These are generally tumors with the slow growh rate, late manifesta­tion of clinical symptoms and, consequently, often late discovery. Despite the slow growth 
Correspondence to: Doc. Dr. Ivan Drinkovic, Depart­ment of Radiology, Ultrasonic Center, University Ho­spital "Merkur", Zajceva 19, Zagreb, Croatia. 

rate the prognosis is poor, with an overall survival rate of 20-25 % 10 years after nephrec­tomy. However, if the carcinoma is confined to the kidney there is a 50 % 10-year survival. Therefore, the early diagnosis of this lesion is very important. 1• 2 
The widespread use of ultrasound and CT has increased the detection of small renal neo­plasms, often found incidentally in patients without renal simptoms. Still, diagnostic diffi­culties are often encountered with excretory urography, CT, conventional US and renal an­giography in the diagnosis of small renal tu­
UDC: 616.61-006-073:534-8 mors. 3· 4 


The introduction of color-Doppler US has enabled the visualisation of intrarenal vasculari­zation and has considerably facilitated the quan­tification of Doppler signals from intrarenal arteries and arteries within various pathological lesions. 5• 6 The purpose of this study was to evaluate the color-Doppler US in the detection of renal cell carcinomas, particularly of smaller tumors which are more difficult to be diagnosed with conventional US and other imaging moda­lities. 

Patients and methods 

Between December 1991 and June 1994, CD US and spectral analysis was perfonned in 39 patients with RCC. 26 patients were referred from the Divisions of Urology and Nephrology with the suspicion for renal tumor, and 13 tumors were discovered incidentally in asympto­matic patients on conventional US examina­tions. Twenty seven patients were male and 12 female. They were aged 45-79 years (mean, 
58.1 years). Intrarenal arteries of 44 normal examinees (mean age 49.5 years) were studied as a control group. All the subjects were exami­ned in the morning, usually after an eight hour fast. In all patients urography, CT and selective DSA were also performed. Doppler study was performed after conventional US in 17 patients, after urography and conventional US in 11 patients, after CT and conventional US in 8 patients, after CT and selective DSA in 2 patients and after DSA in 1 patient. Patho­hystologic findings produced definite diagnosis in 34 patients who were operated and fine­needle biopsy specimens analysis in 5 patients who were not subjected to operation because of poor general condition, disseminated disease and high surgical risk. On the conventional US examinations the largest diameter of tumors was 6.2 ±3.3 cm (mean ±lSD). Fourteen tu­mors were up to 4 cm large in the largest diameter, while 25 tumors were larger than 4cm. 
Conventional and CD US examinations were performed with a color-Doppler scanner (Ra­dius CF, GE-CGR, Buc, France) with a curved array 3.75 MHz transducer. Ali patients and control subjects were examined in supine and semioblique positions by two experienced radio­logists. The duration of examination per patient was 30-45 minutes. In patients with renal mas­ses, vessels were as a rule insonated in at least 3 spots in the kidney -arteries within the tumor, arteries on the margin of the tumor, and at least one artery in the morphologically normal part of the kidney, unaffected by the tumor. Intrarenal arteries (interlobar and arcua­te) of the opposite kidney were studied in all patients and in the control subjects in 2-3 different parts of the kidney. In all insonated arteries spectral systolic frequency peaks were recorded (in kHz), and resistance indices (Ris) calculated with the following formula: (peak systolic frequency shift -minimum diastolic frequency shift / peak systolic frequency shift). Mean Rls were calculated for normal kidneys from multiple measurements from different intrarenal arteries. The wall filter was set usually at 50 Hz, and the sample volume was 2-4 mm. Only optimal spectral waveforms were used for all measurements. 
The statistical significance of observed diffe­rences was calculated with the Mann-Whitney U test. Descriptive statistical parameters were also used. 

Results 

CD US showed prominent vascularization with­in the tumor and on the margin of the tumor in 34 patients and adequate spectral waveforms were obtained in these spots in all of these patients. Vascularization was not observed within the tumor in 5 patients and spectral waveforms could not have been obtained from these tumors. All these patients had hypovascu­lar or avascular types of renal cell carcinomas, as shown by selective DSA. However, in 3 of these 5 patients clearly visible vessels on the margin of the renal mass were observed by color-Doppler and in 2 cases high systolic spect­ral peaks (> 3 kHz) typical for tumor neovascu­





larization were obtained from these arteries. Sensitivity of color-Doppler US for obtaining adequate signals from arteries within the tumor was 87 .2 % and for obtaining signals from arte­ries on the tumor margin 94.9 % . Spectral systo­lic frequency peaks in arteries on the margin of the tumor, obtained in 37 patients, were ranging from 2.1 kHz to 6kHz (mean 3.89 ± 1.06). In 4 of 37 patients spectral peaks in these arteries were below 3 kHz (which corresponds to velocity of cca. 80 cm/s for our transducer of 
3.75 MHz). Spectral systolic peaks in all intrare­nal arcuate, interlobar and segmenta! arteries in normal kidneys (control group) and contrala­teral normal kidneys of patients with renal tumors were below 2.5 kHz. Systolic peaks were below 3 kHz in all main renal arteries in the control group. If systolic peak of 3 kHz for our transducer is used as a cutoff value for abnor­mally high frequency shifts in the artery on the margin of the tumor, indica ti ve of malignant neovascularization, the sensitivity of CD US and spectral analysis for detecting pathologic vessels in RCC was 89.2 % (33 of 37 patients). If all 39 patients with renal carcinoma are taken into account, including those 2 with completely avascular malignancies, the sensitivity of CD US and spectral analysis in the detection of abnormally high frequency shifts indicative of A-V shunts in vessels on the tumor margin was 84.6% (33 of 39 patients). The specificity of 3 kHz cutoff value for our scanner was 100 % . 
Mean RI in intrarenal arteries in the control group of examinees was 0.597 ± 0.035 (mean ± SD). Mean RI measured in arteries within the tumor obtained in 34 patients was 0.498 
± 0.059, with the range from 0.38 to 0.65. The difference betwen RI values in these 34 patients and RI values in intrarenal arteries of normal examinees was statistically significant (Mann­Whitney U-test, P < 0.01). We propose mean RI value ± 1 SD as a cutoff value for abnor­mally low RI value. In our study it would be RI value below 0.56. Out of 34 patients with RCC who had flow detectable by CD US in arteries within the tumor, 31 patients had RI values below 0.56. Therefore, the sensitivity of spectral analysis for detecting abnormally low 
renal vascular resistance characteristic for ma­lignant neovascularization in those patients was 
91.2 % (31 of 34 patients). When all patients are taken into account, including those where arteries within the tumor could not have been visualized by CD US, the overall sensitivity of RI value below 0.56 in detecting malignant neovascularization within the tumor was 79 .5 % (31 of 39 patients). 
The proportions of patients with vasculariza­tion observed on the margin of the tumor and within the tumor, as well as proportions of observed pathological frequency peaks ( > 3kHz) in marginal vessels and Rls < 0.56 in vessels within the RCC are presented in Table l. 
Table 1. Proportions of patients with vascularization on the margin of the tumor and within the tumor, and proportions of pathological frequency peaks ( > 3 kHz) in marginal vesscls and Rls < 0.56 in ves­sels within the RCC. 
PTSwithRCC  
N = 39  %  
vascularization  
on TM margin  37/39  94.9  
pcaks > 3 kHz in  
vesscl on TM margin  33/39  84.6  
vascularization  
within tumor  34/39  87.2  
RI < 0.56  
within tumor  31/39  79.5  

The mean RI values ± 1 SD in vessels within tumors and in the intrarenal arteries of control subjects are shown in Figure l. 
RI 

0.7 
MEAN 0.597 

0.65" 
0.6 
MEAN 0.498 

0.55 
o.s•· 
0.45 
0.4 
CONTROL GROUP RCC PATIENTS 

Figure 1. Mean Rls ± l SD in vcssels within RCC and in control group of normal examinees. 
In the intact part of the kidney with the tumor we did not observe any differences of Ris in comparison with the control group. The mean RI value below 0.56 was observed in 3 young patients (mean age 23.2 years) in the control group. So, this cutoff value has the theoretical specificity for detecting malignant neovascularization of 93. 2 % . However, since generally no abnormalities can be seen in the normal subjects on conventional US, the CD US findings have to be evaluated together with conventional US findings. Therefore, the speci­ficity of low Ris associated with abnormal con­ventional US finding indicative of renal mass is in practice 100 % . 
Figure 2. Conventional US finding of hypoechoic, solid, exophytic renal mass renal celi carcinoma. 
Figure 3. Very high systolic spectral frequency peaks, higher than 3 kHz, with phenomenom of aliasing, obtained in the vessel on the margin of a renal celi carcinoma. 

Figure 4. Color-Doppler US imagc of abundant vascu­larization within and on the margin of the renal mass -renal celi carcinoma. 
Figure S. Spectral analysis of the vessel within the RCC -low pulsatility waveform, with high diastolic flow and low resistance index (RI = 0.47). 
Thirty-six out of 39 patients had at least one abnormal Doppler finding, either peak systolic shift in the artery on the margin of the tumor higher than 3 kHz or the RI of 0.55 or lower in the artery within the tumor. Therefore, the overall sensitivity of CD US and spectral analy­sis in the detection of pathologic flow in RCC, using one of two proposed criteria was found to be 92.3 %. 
Fourteen patients with small renal tumors with the largest diameter below 4 cm were ana­lyzed as a separate group, using two proposed 
criteria for abnormality. At least one of two abnormal Doppler findings were observed in 13 patients. Therefore, the sensitivity of CD US and spectral analysis for detection of pathologi­cal flow characteristic for RCC was 92.9 % in , patients with small renal tumors. In one case without detectable abnormality the tumor was 
avascular on selective DSA examination. 
Discussion 

RCC is most commonly seen in the sixth and 
seventh decades of life, with a 3 to 1 male to 


female ratio. Patients most frequently present 
with hematuria, palpable mass and flank pain. 
Widespread metastases are also common, espe­
cially to lungs, bones, lymph nodes, !iver, adre­
nal glands and brain. 7 
RCC presents with a wide spectrum of US 

findings that range from a predominantly cystic 
to a solid mass. The most common sonographic 
pattern is echo-complex. However, approxima­
tely 30 % of RCC appear as hypoechoic lesions 
and there is possibility of mistaking carcinoma 
for a benign cyst. 8 When a lesi on is big and has 
infiltrated renal vein, IVC or lymph nodes, 
conventional US diagnosis of malignancy is 
relatively simple. However, small RCC are 
often difficult to diagnose and differentiate from 
benign lesions (hypertrophied column of Bertin, 
angiomyolipoma, oncocytoma, inflammatory 
mass, complex cyst) with conventional US, as 
well as other imaging modalities.9 
-11 

Doppler US of intrarenal arteries has been extensively used for analysis of flow in trans­planted kidneys and in native kidneys, for diag­nosis of renal artery stenosis, renal obstruction 
12 15 

and parenchymal kidney diseases.5•-Dop­
pler US has been also suggested as a way of 
further chraracterizing malignant from benign 
lesions.16 The advent of color-Doppler, in our 
experience, further enhances the value of Dop­
pler in evaluating malignant neovascularization. 
A few studies have shown high Doppler shift 

frequencies in vessels along the margin of renal 
17 19 

tumors.-Our results confirm these findings. The recorded peak frequencies are dependent on the transducer frequencies and cannot be compared between scanners with different transducers. The cutoff value of 3 kHz that we have used in this study is equivalent to the velocity of 80 cm/s, which is higher value than in normal intrarenal arteries and main renal arteries. The usage of even higher cutoff value of 4 kHz would have reduced our sensitivity for approximately 20 % , without increase in specificity when normal examinees from the control group are considered. High frequency shifts in arteries along the tumor margins have been generally attributed to arteriovenous shunts, found in hypervascularized RCCs.11-19 Our results confirm these findings. In addition, we have observed very low vascular resistance in arteries within the tumor itself, and we were able to visualize these vessels in very high proportion of patients. RI index values reflect renal vascular resistance and, Ris were statisti­cally significantly lower in arteries within the tumor (mean 0.498) in comparison with intra­renal arteries of normal examinees (mean 0.597). These pathological vessels in RCC lack muscular elements in their walls, which is the presumed cause of low resistance.20 However, there is a relatively small, but significant pro­portion of hypovascular or avascular RCCs (cca 15 % ) and in these tumors CD US signals could not have been found. However, it is hard to diagnose these tumors with CT and DSA, as well. 
With continuous improvements in US, CT and MRI the dilemma of what to do with the small, less than 3 cm, renal parenchymal lesion has become prevalent. Frequently, a small renal mass is discovered incidentally during routine US or CT abdominal examination. These le­sions are frequently of indeterminate nature, as they are hypoechoic on US and measure 25 HU or more on CT.21 Bosniak suggested that in the elderly or those with terminal disease, these small lesions can be ignored.22 However, in others the use of a multimodality approach including gadolinium-enhanced MRI may be indicated. We have shown that CD US and spectral analysis yield high sensitivity and speci­ficity in the diagnosis of pathological vasculari­

zation in the RCC smaller than 4cm in size. 
With the exception of avascular or hypovas­cular RCC, CD US and spectral analysis have high sensitivity and specificity in detecting pat­hologic vascularization of RCC, regardless of its size. Since it is a noninvasive and relatively simple method we believe it should be included in the diagnostic algorithm as a first method for suspected renal mass after conventional US. This method has same or higher sensitivity and specificity in detecting pathologic vasculariza­tion in RCC in comparison with conventional CT and selective DSA.23• 24 
We are conducting further investigation for differentiation of benign and malignant renal masses with CD US. It seems that angiomyo­lipoma and oncocytoma lack Doppler spectral findings observed in RCC. Also, the differentia­tion of column of Bertin from hypervascularized tumor is quite straightforward. The problem in differential diagnosis are inflammatory masses that may also have abnormal vascularity along the margin of the mass. In these cases fine­needle aspiration biopsy is very useful in the differentiation of these conditions. Also, some other malignancies that are not hypervascu­larized, like transitional-cell tumors of renal pyelon seem to be hard to diagnose with CD US and spectral analysis. 
Although further studies are necessary to assess the clinical usefulness of this method in differentiating benign and malignant renal mas­ses, it is obvious that CD US has a very high sensitivity in detecting pathologic vasculariza­tion in RCC, since these tumors are in the majority of cases hypervascular. Regardless of possibility of false-positive diagnosis in the case of inflammatory mass, Doppler findings of high frequency shifts along the kidney mass margin and/or low resistance in arteries within the mass should alert the clinician for a very high proba­bility of RCC. 




References 

l. Kaufmann JJ. Reasons for nephrectomy: paliative and eurative . .TAMA 1958; 204: 607-11. 

2. 
Thompsom IM, Peek M. Improvement in survival of patients with renal celi carcinoma: the role of the serendipitously detected tumor. J Ural 1988; 140: 487-90. 

3. 
Smith SJ, Bosniak MA, Megibow AJ, Hulnick DH, Horii SC, Raghavendra BN. Renal celi car­cinoma: earlier discovery and increased detection. Radiology 1989; 170: 669-703. 

4. 
Curry NS, Schabel SI, Betsill WL. Small renal neoplasms: diagnostic imaging, pathologic features and clinical course. Radiology 1986; 158: 113-7. 

5. 
Platt JF, Ellis JH, Rubin JM. Examination of native kidneys with duplex-Doppler ultrasound. Seminars in Ultrasound, CT and MRI 1991; 12: 308-18. 

6. 
Ramos 1, Taylor KJW, Kier R, et al. Tumor vascular signals in renal masses: detection with Doppler US. Radiology 1988; 168: 633-7. 

7. 
Neiman HL. The urinary system In: Goldberg BB, ed. Textbook of abdominal ultrasound, Wil­liams & Wilkins, Baltimore, 1993; 330-91. 

8. 
Coleman BG, Arger PH, Mulhern CB Jr, et al. Gray-scale sonographic spectrum of hypernephro­mas. Radiology 1980; 137: 757-65. 

9. 
Levine E, Huntrakoon M, Wetzel LH. Small renal neoplasms: clinical, pathologic and imaging features. A.TR 1989, 153: 69-73. 

10. 
Amendola MA, Brce RL, Pollack HM, et al. Small renal celi careinomas: resolving a diagnostic dilemma. Radiology 1988; 166: 637--41. 

11. 
Porena M, Vespasiani G, Rosi P, et al. Tnciden­tally detected renal celi carcinoma: Role of ultra­sonography. J Ciin Ultrasound 1992; 20: 395--400. 

12. 
George EA, Salimi Z, Wolverson MK, Garvin PJ. Assessment of renal allograft pathology by scintigraphic and ultrasound index-markers. Ciin Nucl Med 1991; 16: 394-8. 

13. 
Sievers KW, Loehr E, Werner WR. Duplex Dop­pler ultrasound in determination of renal artery stenosis. Ural Radio[ 1989; 11: 142-7. 

14. 
Brkljacic B, Drinkovic I, Sabljar-Matovinovic M, et al. lntrarenal duplex-Doppler sonographic eva­luation of unilateral native kidney obstruction. J Ultrasound Med 1994; 13: 197-204. 

15. 
Brkljacic B, Mrzljak V, Drinkovic I, et al. Renal vascular resistance in diabetic nephropathy: du­plex-Doppler US evaluation. Radiology 1994; 192: 549-54. 

16. 
Taylor KJW, Ramos I, Morse SS, Fortune KL, Hammers L, Taylor CR. Focal Iiver masses: diffe­rential diagnosis with pulsed Doppler US. Radio­logy 1987; 164: 643-7. 

17. 
Taylor KJW, Ramos I, Carter D, Morse SS, Snower DP, Fortune KL. Correlation of Doppler US tumor signals with neovascular morphologic features. Radiology 1988; 166: 57-62. 




18. 
Kier R, Taylor KJW, Feyock AL, Ramos IM. Rena! masscs: characterization with Doppler US. Radiology 1990; 176: 703-7. 

19. 
Kuijpers D, Jaspers D. Rena! masses: diffcrential diagnosis with pulsed Doppler US. Radiology 1989; 170: 59-60. 

20. 
Folkman J. How is blood vessel growth regulatcd in normal and neoplastic tissue? G.H.A. Clowes memorial award Iecture. Cancer Res 1986; 46: 467-73. 

21. 
Yamashita Y, Takahashi M, Watanabe O, et al. Small renal celi carcinoma: pathologic and radio­Iogic correlation. Radiology 1992; 184: 493-8. 




22. 
Bosniak MA. The small ( < = 3.0 cm) rcnal pa­renchymal tumor: detcction, diagnosis and contro­vcrsies. Radiology 1991; 179: 307-17. 

23. 
Warshaucr DM, Me Carthy SM, Street L, et al. Detection of rcnal masses: sensitivities and speci­ficitics of excrctory urography/lincar tomography, US and CT. Radiology 1988; 169: 363-5. 

24. 
Frohmuller HG, Grups JW, Hellcr V. Compara­tive valuc of ultrasonography, computerized tomo­graphy, angiography and excretory urography in the staging of rcnal celi carcinoma. J Ural 1987; 138: 482-4. 








Role of CT guidance in the biopsy of the spine and paravertebral soft tissue 
Tamas Puskas 
Department of Radiology, Markusovszky Teaching Hospital, Szambathely, Hungary 


CT is the only imaging system which can visualise the vertebral bodies and the adjacent soft tissues at the same tirne. Contrary to conventional fluoroscopy-guided skeleta! biopsy, CT guidance results in more accurate and safer performance of the intervention. Thereby, the complication rate of these procedures can be diminished. 
Key words: spinal diseases -radiography; biopsy; computed tomography, x-ray 
Introduction 
Earlier two-directional radiography and con­ventional tomography were the only possible imaging modalities in the diseases of the verte­brae. In this way the paravertebral soft tissues could not be identified with safety. Among the modern imaging systems, CT and MR can vi­sualise the vertebrae and the adjacent soft tis­sues at the same tirne. Representing the axial plane, CT seans have defined the exact position of the lesion, resulting in better guidance of diagnostical approach. 


Materials and methods 
The first paper about CT-guided intervention was issued in 1976.1 From that tirne on a lot of publications have emphasised the advantages of 
Correspondence to: Tamas Puskas MD, Department of Radiology, Markusovszky Teaching Hospital, Szombathely, Hungary, H-9701. 
UDC: 616.711-073.756.8 

CT guidance, and development of interventio­nal procedures.2• 3 We have performed CT exa­minations in our hospital by a 3rd generation Siemens Somatom DRH equipment since 1989. The CT-guided intervention was introduced in 1991. The total number of procedures in the last 3 years have amounted to 136, including 16 biopsies in patients affected by diseases of vertebrae and paravertebral soft tissue. We are the first among Hungarian radiologists who have performed CT-guided biopsies in vertebral and paravertebral diseases. Por the biopsy of bone structures we use a Jamshidi needle, in case of soft tissue biopsy, it is carried out by a 14 G Uro-cut needle. Before intervention the position and extent of the lesion, and the exact point of biopsy are determined. The patient is in prone position. We use local anaesthesia in adults, a short general anaesthesia is needed in children. 

Results 

As to the site of 16 interventions we performed the biopsy of soft tissue in 7 ,' and of vertebral 


body in 9 patients. We had to repeat the intervention in 2 patients, because the speci­mens were not sufficient for histology. In ali other cases the first procedure proved to be successful. We present the patients, the types of biopsy and the fina! diagnosis in Table 1. We marked the repeated biopsies with an aste­risk (*). 
Case reports 
l. A 56-year-old female patient suffered from lumboischialgia. On myelography the contrast material stopped at the leve! of LIII-IV. The emergent CT examination revealed a large soft tissue mass at the Jevci of LIV, destroying the vertebral arch, and invading to the spina! canal. The CT-guided biopsy verified a metastatic lesion of a malignant thyroid tumour (Figure 1). 
2. A 55-year-old female patient was admitted to our hospital because of weight loss and 
Table l. Types of biopsy and fina] diagnosis. 
abdominal pain. ln her history an ovarian tu­mour and a gynaecological surgcry were men­tioned. Ultrasonography showed a large cystic 

Number scx agc Sitc of biopsy Result 
l F 
bodyof LIV unsucccssful 

2 F 56 paravcrtebral metastatic soft tissue thyroid tumour 3* F 50 body of LIV tuberculous inflammation 4 M 45 body of LII metastatic tcsticular tumour 
5 F 
body ofLIV mctastatic brcast tumour 
6 M 
paravertebral 

sarcon1a 

soft tissue 7 F 81 paravertebral unsucccssful soft tissue 8* F 81 paravertcbral inflammation-soft tissue absccss 9 F 55 paravertebral mctastatic soft tissue ovarian tumour 10 F 11 body of ThXII tuberculous inflammation 11 F 54 body ofThX metastatic breast tumour 
M 

paravertebral metastatic 
soft tissue testicular tumour 13 M 72 bodyofCVII mctastatic colon tumour 14 F 64 bodyofLI mctastatic Jung tumour 15 M 38 body ofThXI tuberculous inflammation 16 M 71 paravcrtcbral mctastatic soft tissue pancreas tumour 





Evaluation of hypertrophic puhnonary osteoarthropathy by bone scintigraphy in patient with carcinoma of the Jung 
Dražen Huic, 1 Damir Dodig, 1 Mirjana Huic, 2 Ivan Škorak, 2 Mirjana Poropat1 
1 Department of Nuclear Medicine and Radiation Protection, 2 Department of Interna! Medicine, University Hospital Rebro, Zagreb, Croatia 
The authors described a case of a 61-year-old heavy smoker with some symptoms of hypertrophic pulmonary osteoarthropathy (HPO) and suspected pulmonary malignancy. The bone scan demonstrated diffuse bony involvement of the long bones of the lower limbs raising question about possible metastatic bone disease. The knees and ankles were not affected. The plain radiographs of the bones were normal but the chest radiograph showed right hilus deformation. Transpleural biopsy revealed a bronchogenic adenocarcinoma. Typical radionuclide finding of HPO without bone destruction on radiographs ruled out metastatic bone disease. 
Key words: secondary hypertrophic osteoarthropathy, radionuclide imaging, bronchogenic carcino­ma, bone scintigraphy 
Case report 

The 61-year-old man was admitted complaining of worsening cough, rapid weight loss, digital clubbing, but without joint swelling or tender­ness. The terminal phalanges were enlarged, and there was loss of the normal nail-to-cuticle angle (Figure 1). The sedimentation rate, white blood cell count and alkaline phosphatase level were slightly elevated. 
The whole body scintigraphy was performed 

Correspondence to: Dražen Huic, M.D., Department of Nuclear Medicine and Radiation Protection, Uni­versity Hospital -Rebro, Kišpaticeva 12, 41000 Za­greb, Croatia. Fax: + 385 41 23 57 85. 
UDC: 616.71-002-033.2-073:534-8 
because of suspected metastatic malignant di­sease. Seans, obtained 3 hours after injection of 740 MBq of Tc-99m pyrophosphate, showed 



Figure 2a. Thc whole body scan, obtaincd 3 hours 
after radionuclide injection, shows diffusc increased 

radiotracer uptake in ali long boncs of the lower limbs. Figure 3a, b. Thc racliographs of thc lower limbs do not show thc charactcristic pcriostcal elevation of hypcrtrophic osteoarthropathy .3 
t 



Figure 2b. The delayed static images of both lower extremities reveal prominent uptake pericorticaly in the distal parts of the long bones, which is typical for hypertrophic osteoarthropathy and differentiates it from metastatic bone disease.1• 2 
diffuse increased radiotracer uptake in all long bones of the lower limbs (Figure 2a). The knees and ankles were not affected. 
The detailed static images of both lower extremities revealed most prominent uptake pericorticaly in the <listal parts of the long bones (Figure 2b). 
The radiographs of the lower limbs did not demonstrate any bone destruction or abnorma­lities suggestive of hypertrophic pulmonary osteoarthropathy (HPO) (Figure 3a, b). 


The chest radiograph revealed right hilus deformation and a lesion in right upper lobe was suspected. Finally, transpleural biopsy re­vealed a bronchial adenocarcinoma. 
Discussion 

Detection of HPO with 99 m-Tc-phosphate complexes has been often reported in the 
15 

past.­
The incidence of HPO in patients with bron­chogenic carcinoma is approximately 10 % and it is particularly important to distinguish HPO and metastatic bone disease in radionuclide images. Most prominent uptake pericorticaly in the distal parts of the long bones, as obtained in our patient, is typical for HPO and differen­tiates it from metastatic bone disease.4 
The radiographs of the lower limbs did not show the characteristic periosteal elevation of HPO,6 not either bone destruction, what is typical for metastases. 
Unusual radionuclide seans of HPO are not uncommon, 3 but we found our patient inte­resting because of non-affected joints, which are almost always affected. Probably we can say this is the case of hypertrophic osteopathy. 
Unfortunately, patient had metastases in a few other organs and he was not suitable for an operation. That was the reason why a bone biopsy was not performed, but the typical radio­nuclide finding without bone destruction on radiographs ruled out metastatic bone disease. 

References 

l. Donnelly B, Johnson PM. Detection of hypertro­phic pulmonary osteoarthropathy by skeleta! ima­ging with 99m-Tc-labeled diphosphonatc. Radio­logy 1975; 114: 38 9-91. 
2. 
Kay CJ, Rosenberg MA. Positive 99m-Tc-poly­phosphate bone scan in a case of secondary hyper­trophic osteoarthropathy. J Nucl Med 1974; 15: 

312-3. 

3. 
Freeman MH, Tonkin AK. Manifestations of Hy­pertrophic Pulmonary Osteoarthropathy in Patients with Carcinoma of the Lung. Radiology 1976; 120: 36 3-6. 

4. 
Rosenthall L, Kirsh J. Observations on Radionuc­lide Imaging in Hypertrophic Pulmonary Osteoart­hropathy. Radiology 1976; 120: 35 9-6 2. 

5. 
Rubini G, Lauriero F, Rubini D. 99m-Tc-MDP globa! skeleta! uptake and markers of bone metabo­lism in patients with bone diseases. Nucl Med Commun 1993; 14: 56 7-72. 

6. 
Burton MD, Wain JC. Clubbing and Hypertrophic Ostcoarthropathy. N Engl I Med 1993; 329: 1861. 





Improved therapeutic effect of electrochemotherapy with cisplatin by intratumoral drug administration and changing of electrode orientation for electropermeabilization on EAT tumor 




model in mice 
Maja Cemažar,1 Damijan Miklavcic,2 Lojze Vodovnik,2 Tomaž Jarm,2 Zvonimir Rudolf, 1 Borut Štabne, 1 Tanja Cufer1 and Gregor Serša1 
1 Institute of Oncology, Ljubljana, 2 University of Ljubljana, Faculty of Electrical and Computing Engineering, Laboratory of Biocybernetics, Ljubljana, Slovenia. 


Antitumor effectiveness of cisplatin can be improved either by intratumoral administration of the agent or by increased drug delivery into the cells by exposing the tumor to short intense electric pulses. Electric pulses increase plasma membrane permeability (electropermeabilization) of tumor cells and thus allow the chemotherapeutic agent intracellular access. This combined use of electric pulses and chemotherapy is termed electrochemotherapy. Also, we recently demonstrated that efficacy of electrochemotherapy can be improved by changing of electrode orientation for electropermeabili­zation. Therefore, the aim of this preliminary study was to determine whether intratumoral cisplatin administration and changing of electrode orientation for electropermeabilization can improve therapeutic effect of electrochemotherapy. For this purpose electrochemotherapy with intratumoral versus intravenous cisplatin administration and electrochemotherapy with train of 8 electric pulses versus two trains of 4 pulses, given perpendicularly to each other (4 + 4 pulses), were tested on EAT subcutaneous tumors in mice. Electrochemotherapy with intratumoral cisplatin administration was more effective than electrochemotherapy with intravenous cisplatin administration. In addition, antitumor effectiveness of electrochemotherapy with intratumoral cisplatin administration was improv­ed with changing of electrode orientation (4 + 4 pulses), since with this treatment 18 % of mice were cured in contrast to other treatment combinations tested, where only some partial responses were 
observed. Key words: neoplasms, experimental-therapy; cisplatin; electric stimulation therapy; cell membrane permeability 
Correspondence to: Gregor Serša, Ph.D., Institute of Oncology, Department of Tumor Biology, Zaloška 2, 61105 Ljubljana, Slovenia. Tel.: + 386 61 323 063 ext. 2933; fax.: +386 61 131 41 80; E-mail: gsersa@ mail.onko-i.si 
UDC: 616-006.6-085.84-092.9 

Introduction 

. Cisplatin is chemotherapeutic agent widely used against variety of malignancies. Like ali chemo­therapeutic agents, its effectiveness is limited by normal tissue toxicity .1 One of the ways to reduce toxicity to normal tissues is local, intra­tumoral (i.t.) cisplatin administration. By this 
route of administration higher cisplatin concen­tration in the tumor and lower concentration in the organism is achieved, and thus thera­peuti. gain is increased.2 
Also, one of the ways of potentiating cytoto­xic action of chemotherapeutic drugs is increas­ed drug delivery into the tumor cells. This can be done by use of short intense electric pulses, which nonselectively increase plasma mem­brane permeability ( electropermeabilization), without impairing cell viability and thus allow­ing chemotherapeutic drugs to diffuse into the cells and act on their intracellular targets.3-10 This principle of increased drug delivery was termed electrochemotherapy. Electrochemo­therapy with bleomycin and cisplatin was elab­orated in vitro, in vivo and in clinical trials. 8• 
11-22 
In all of the studies on electrochemotherapy reported electric pulses were delivered in one direction.11· 12 • l4-J?, 19• 21• 22 However, according to our observations on electrochemotherapy with bleomycin, therapeutic response to treat­ment can be improved if train of 8 electric pulses used for electropermeabilization is split into two and the second train given perpendicu­larly to the first one (4 + 4 pulses).23 By this changing of electrode orientation whole tumor mass is encompassed by electrodes and more tumor cells are exposed to electric field over critical threshold value for effective electroper­meabilization. 
The aim of this preliminary study was to determine whether intratumoral administration of cisplatin and changing of electrode orienta­tion for electropermeabilization can improve therapeutic effect of electrochemotherapy with cisplatin on EAT tumor model in mice. For this purpose we compared electrochemotherapy with i.t. versus intravenous (i.v.) cisplatin administration and electrochemotherapy with train of 8 electric pulses given in one direction versus two trains of 4 pulses given perpendicular to each other for electropermeabilization. Tu­mor response to electrochemotherapy was as­sessed by tumor growth delay and therapeutic responses to treatment. 
Materials and methods 

Drug formulations 
Cisplatin (Platimit) was obtained from Pliva (Zagreb, Croatia) as crystalline powder and dissolved in sterile H20 at a concentration 1 mg/ml. The fina! cisplatin dose (1 mg/kg) was prepared in 0.9 % NaCl solution. The cisplatin solutions were injected systemically, i. v. into the lateral tail vein of the mice or locally, i. t .. Injection volume was 0.02 ml/g body weight for 
i.v. administration and 0.lml/tumor for i.t. administration. For i.t. cisplatin administration "fan" pattern was used which facilitates drug distribution throughout the tumor. 2 Cisplatin solution was injected while the needle was slowly withdrawn. For each experiment fresh cisplatin solution was prepared. 
Animals 
In the experiments CBA mice of both sexes, 8-12 weeks old, weighing 20-30 g, in good condition, without fungal or other infections were used. Mice were purchased from fae Insti­tute of Pathology, University of Ljubljana and were kept at constant room temperature (24 °C) under natura! day/night light cycle, fed with standard mouse chow and tap water ad libitum. 
Tumor model 
Ehrlich ascites tumor (EAT)· cell suspension, syngeneic to CBA mice was prepared from ascitic form of the tumor. Solid subcutaneous tumors were initiated in the right flank of the mice by injection of 5 x 106 EAT cells. The viability of the cells injected was over 95 % as determined by trypan dye exclusion assay. After 6-8 days when the tumors reached approxi­mately 40 mm3 , mice were randomly divided into experimental groups comprising 5-11 mice and subjected to specific treatment protocol. 
Electrochemotherapy protocol 
Electric pulses were delivered through two par­allel plate electrodes 8 mm apart (two stainless 


B 

A 



Figure l. Schematic presentation of the electrode orientation at the two electric pulses treatment proto­cols. A. Electric pulses were given by two electrodes positioned on the two opposite margins of the tumor in the train of 8 consecutive pulses; B. In the protocol B the 8 pulses were split into two trains of 4 pulses with one second interval (4+4 pulses). Each train of 4 pulses was given to the tumor by the placement of the electrodcs at thc oppositc margins of the tumor in the two perpendicular directions. 
steel strips with rounded corners, 7 mm in width) placed at the opposite margins of the tumor. Conductive gel was used to assure good contact between electrodes and the skin. Eight square wave pulses; 100 µ,s pulse width, repeti­tion frequency 1 Hz and 1040 V amplitude were generated by electropulsator Jouan GHT 1287 (St. Herblaine, France). Tumor bearing mice were treated either with 8 square wave pulses given in one direction or with 8 pulses split into two train of 4 pulses. In this experimental group second train of 4 pulses was given perpen­dicularly to the first one (Figure 1). Cisplatin was injected either i.v. or i.t. In electrocliemo­therapy with i.v. cisplatin administration mice were treated with electric pulses 3 min after cisplatin injection and in electrochemotherapy with i.t. injection mice were treated with elec­tric pulses 10 min after i.t. cisplatin injection. Mice in control group and in electric pulses groups were injected with 0.9 % NaCl solution instead of cisplatin solution. 
Tumor response and statistical analysis 

Tumor growth was followed every 2 days by measuring three mutually orthogonal diameters (e1, e2, e3) with vernier calliper and tumor vol­ume calculated by the formula e1 xe2 xe3 x1r/6. From the measurements, the arithmetic mean (AM) and standard error of the mean (SE) were calculated for each experimental group, pooled from two separate experiments. Tumor doubling tirne (DT) was determined as fone in days for tumors to double their volume from the beginning of the treatment. For each indi­vidual tumor in ali experimental groups DT and tumor growth delay from the DT of each indi­vidual tumor in experimental groups minus mean DT of control group were calculated. 
Therapeutic response was scored according to WHO guidelines as progressive disease (PD) if tumor volume increased, no change (NC) if tumor volume reduced less than 50 % , partial response (PR) if tumor volume reduced more than 50 % and complete response (CR) if tumor became unpalpable. Mice, tumor free 100 days after the treatment, were termed as cured and were not included in tumor growth curves and tumor growth delay calculations. 
The significance of the differences between the mean DT and tumor growth delay of the experimental groups was evaluated with New­man-Keuls method for multiple comparison after one way analysis of variance was per­formed and fulfilled. Levels of P less than 0.005 were taken as statistically significant. 
Results 

In this study electrochemotherapy with i.t. cis­platin administration was compared to electro­chemotherapy with i.v. administration. In addi­tion, electrochemotherapy with train of 8 elec­tric pulses given in one direction was compared to electrochemotherapy with two trains of 4 pulses given perpendicularly to each other (4 + 4 pulses). 
Cisplatin treatment alone as single treatment was more effective after i.t. administration than after i.v. administration. Intratumoral cisplatin administration had marked antitumor effect, tumor growth delay was significantly prolonged compared to i.v. cisplatin treated group (Table 1, Figure 2). 
Electric pulses treatment alone as single treat­ment, in both orientations (8 pulses and 4 + 4 
Table l. Antitumor effectiveness of electrochemotherapy with 1 mg/kg cisplatin. Comparison of i.t. versus i.v. cisplatin administration and train of 8 pulses given in one direction versus two times of 4 pulses (4 + 4 pulses) given perpendicularly to each other for electropermeabilization. 
Experimental groups  n  DT2 (days)  Tumor growth delay3 ( days)  Therapeutic response4 (n)  Cures (n, %)  
Control  21  4.1 ± 0.3  o  
Cisplatin i.v.  14  5.1 ±0.3  1.0 ± 0.3  PD(14)  o  
Cisplatin i.t.  10  13.5 ± 1.6  9.4 ± 1.6  PD(8)/NC(2)  o  
Electric pulses 8 p.  15  6.5 ±0.5  2.4±0.5  PD(15)  o  
Electric pulses 4+4 p. ECT1 8p.-i.v. cisplatin  10 16  6.4 ±0.8 8.1 ± 0.6  2.3 ± 0.8 4.0 ± 0.6  PD(lO) PD(14)/NC(2)  o o  
ECT 4+4p.-i.v. cisplatin  10  10.4 ± 1.0  6.3 ± 0.8  PD(4)/NC(6)  o  
ECT 8p.-i.t. cisplatin  11  17.8 ± 1.4  13.7 ± 1.4  NC(7)/PR(4)  o  
ECT 4+4p.-i.t. cisplatin  11  20.5 ± 1.1  16.4 ± 1.1  NC( 4)/PR(5)/CR(2)  2 (18 %)  


1 ECT electrochemotherapy 

2 DT -tumor doubling tirne (AM ± SE) 
3 Tumor growth delay compared to control group (AM ± SE). 

4 Therapeutic response to treatment was scored according to the WHO guidelines as PD-progressive disease; NC -no change; PR -partial response; CR -complete response. 
pulses), was equally effective and had moderate effect on tumor growth (Table 1, Figure 2). 

Electrochemotherapy treatment with i.v. cis­platin administration was more effective than treatment with i.v. cisplatin alone as single treatment, demonstrated by significantly pro­longed tumor growth delay (Table 1, Figure 2). Changing of electrode orientation (4 + 4 pulses) for electropermeabilization did not potentiate antitumor effectiveness of i.v. cisplatin admin­istration compared to treatment with 8 electric pulses given in one direction. The small differ­ence between the two electrochemotherapy treatment protocols with i.v. cisplatin admini­stration was observed only in the first 4 days after the treatment. Electrochemotherapy with 
i. v. cisplatin administration and 4 + 4 pulses arrested tumor growth in the first 4 days after the treatment, while after electrochemotherapy with i. v. cisplatin administration and 8 pulses no arrest of the tumor growth was observed. 
Electrochemotherapy with i. t cisplatin admin­istration was more effective than treatment with i. t. cisplatin treatment alone as single treatment, demonstrated by significantly pro­longed tumor growth delay (Table 1, Figure 2). Changing of electrode orientation for electro­permeabilization (4 + 4 pulses) was more effect­ive than treatment with 8 pulses in one direct­ion. Electrochemotherapy with 8 pulses resulted in 36 % of PR, whereas changing of electrode orientation ( 4 + 4 pulses) resulted in higher percentage of PR ( 45 % ) and also in 18 % of cured mice. 

Electrochemotherapy with i. t. cisplatin administration was more effective than electro­chemotherapy with i.v. cisplatin administration (Table 1, Figure 2). Specifically, tumor growth delay after electrochemotherapy with i. t. cis­platin administration was significantly prolong­ed compared to tumor growth delay after ele­ctrochemotherapy with i. v. cisplatin administra­tion. Also, electrochemotherapy with i.t. cispla­tin administration resulted in high percentage of PR and CR, in contrast to electrochemothe­rapy with i. v. cisplatin administration where only NC therapeutic response was recorded. 


Discussion 

This study shows that i.t. cisplatin administra­tion and 4 + 4 pulses given perpendicularly to each other for electropermeabilization improve therapeutic effect of electrochemotherapy with 1 mg/kg cisplatin on EAT tumor model in mice. 
In our previous study on three different tu­mor models in mice (EAT, SA-1 fibrosarcoma and B 16 melanoma) antitumor effectiveness of electrochemotherapy with i.v. cisplatin admin­istration was tested with respect to electric pulses amplitude, cisplatin dose and sequencing and timing of cisplatin administration relative to electric pulses application. 22 In that study 
, 8 pulses-cisplatin i.v. 4+4 pulses-cisplatin i.v. 
400 
200 
100 
@ control 

,,--.. 
60 
1111 electric pulses 
E 

A 1 mg/kg cisplatin E · 'V electrochemotherapy 
40 

(l) 20 

E 
::::; 

400 l 8 pulses-cisplatin i.t. 4+4 pulses-cisplatin i.t. 
o 
O 200 
E 

1-100 
60 
40 
20 '------'----'---'------'----'------' 

o 10 20 30 O 10 20 30 



Days after treatment 
Figure 2. Growth curves of EAT tumors after treatment with lmg/kg cisplatin administered either i.v. or i.t. and/or electric pulses (8 pulses or 4 + 4 pulses; pulse Jength 100 µ,s, repetition frequency 1 Hz, pulse amplitude 1040V, electrode distance 8 mm). In electrochemotherapy group with i.v. cisplatin administration mice wcre treated with cisplatin 3 minutes before electric pulses application and in electrochemotherapy with i.t. cisplatin administration 10 minutes before electric pulses. Valucs are AM ± SE for 9-21 mice. 
antitumor effectiveness of electrochemotherapy with i. v. cisplatin administration was demon­strated by prolonged tumor growth delay compared to cisplatin treatment alone. Also, electrochemotherapy with 8 mg/kg ( the highest dose tested) resulted in 14 % of cured mice bearing B 16 melanoma tumors. However, no mice bearing EAT or SA-1 tumors were cured. In addition, in our previous study on EAT tumor model we have demonstrated that changing of electrode orientation for electroper­meabilization improves therapeutic effect of electrochemotherapy with bleomycin.23 There­fore, in this preliminary study both i.t. cisplatin administration and changing of electrode orien­tation for electropermeabilization were tested for ability to improve therapeutic effect of electrochemotherapy with cisplatin. 
For electrochemotherapy with i. v. cisplatin administration 3 minute tirne interval between the cisplatin administration and electric pulses 
application was chosen. In our previous study we demonstrated that at this tirne interval the most pronounced antitumor effect of electro­chemotherapy with cisplatin is achieved.22 Also, for electrochemotherapy with i.v. bleomycin it was demonstrated that the best antitumor effect is achieved when bleomycin is injected 3 min­utes before electric pulses application.21 There­fore, it seems that both chemotherapeutic drugs have similar accumulation properties in tumors of mice. According to the experiments perform­ed on electrochemotherapy with i.t. bleomycin administration, where the best antitumor effect was achieved with 10 minute interval (Heller, personal communication), the same tirne inter­val (10 minutes) was used for electro­
chemotherapy with i.t. cisplatin administration. However, a tirne response relationship studies for electrochemotherapy with i.t. cisplatin ad­ministration need to be performed to confirm the choice of timing. 

The <lose of cisplatin used in our preliminary study was a subtoxic <lose (toxic <lose 10-15 mg/kg), well tolerated by the animals, which injected systemically did not induce significant antitumor effect. The results demonstrate that electrochemotherapy with i.v. cisplatin admin­istration was moderately effective and suggest that cisplatin concentration achieved in the tu­mor is not sufficient for pronounced antitumor effect. However, electrochemotherapy with i. t. cisplatin administration was more effective than electrochemotherapy with i.v. cisplatin admin­istration at the same <lose of the drug. Antitu­mor effectiveness of electrochemotherapy with 
i.t. administration is comparable to electroche­motherapy with i.v. administration, but in 8­fold higher dose. 22 In addition, electrochemo­therapy with i. t. cisplatin administration and 4 + 4 pulses for electropermeabilization resulted in some cured mice with long lasting CR (18 % ), indicating that with increased cisplatin concen­tration in the tumor and changing of electrode orientation more clonogenic tumor cells are electropermeabilized and thus also sterilized by the chemotherapeutic drug. 
ln conclusion, electrochemotherapy with i.t. cisplatin administration and 4 + 4 pulses given perpendicularly to each other for electroper­meabilization improves therapeutic effect of electrochemotherapy on EAT tumors in mice. Therefore, electrochemotherapy with i.v. cis­platin administration can be used as adjunct to ongoing cisplatin-based chemotherapy in pa­tients who have tumor lesions accessible to application of short intense electric pulses, so that antitumor effectiveness of chemotherapy is potentiated locally. On the other hand, since electrochemotherapy with i. t. cisplatin admin­istration is more effective than electrochemo­therapy with i. v. cisplatin administration, it could be used as a single treatment modality. 

References 
l. Haskell CM. Principles and modalities of canccr treatment. Cancer treatment, WB Saunders, Phi­ladelphia, PA, 1990. 


2. 
Begg AC, Bartelink H, Stewart FA, Brown DM, Luck EE. Improvcment of differential toxicity between tumor and normal tissues using intratu­moral injection with or without a slow-drug-release matrix system. Natl Cancer Jnst Monogr 1988; 6: 133-6. 

3. 
Weaver JC. Molecular basis for celi membrane electroporation. Ann Ny Acad Sci 1994; 720: 141-52. 

4. 
Rols MP, Teissie J. Electropermeabilization of mammalian cells. Quantitative analysis of the phe­nomenon. Biophys J 1990; 58: 1089-98. 

5. 
Tsong TY. Electroporation of celi membranes. Biophys J 1991; 60: 297-306. 

6. 
Potter H. Electroporation in biology: methods, applications, and instrumentation. Ana! Biochem 1988; 174: 361-73. 

7. 
Orlowski S, Mir LM. Celi electropermeabilization: a new tool for biochemical and pharmacological studies. Biochim Biophys Acta 1993; 1154: 51--63. 

8. 
Poddevin B, Orlowski S, Belehradek Jr J, Mir LM. Very high cytotoxicity of bleomycin introduc­ed into the cytosol of cells in culture. Biochem Pharmacol 1991; 42: S67-75. 

9. 
Orlowski S, Bclehradek Jr J, Paoletti C, Mir LM. Transient electropermeabilization of cells in cultu­re. Increase in cytotoxicity of anticancer drugs. Biochem Pharmacol 1988; 37: 4727-33. 

10. 
Melvik JE, Pettcrsen EO, Gordan PB, Selgen PO. Increase in cis-dichlorodiammineplatinum (II) cytotoxicity upon revesible electropermeabiliza­tion of the plasma membrane in cultured human NHIK 3025 cells. Eur J Cancer Ciin Oncol 1986; 22: 1523-30. 

11. 
Mir LM, Orlowski S, Belehradek Jr J, Paoletti C. Electrochemotherapy potentiation of antitumor effect of bleomycin by local electric pulses. Eur J Cancer 1991; 27: 68-72. 

12. 
Belehradek Jr J, Orlowski S, Poddevin B, Paoletti C, Mir LM. Electrochemotherapy of spontaneous mammary tumours in mice. Eur J Cancer 1991; 27: 73-6. 

13. 
Mir LM, Orlowski S, Belehradek J Jr, Tessie J, Rols MP, Serša G, Miklavcic D, Gilbert R, Heller 

R. Biomedical applications of electric pulses with special emphasis on antitumor eleetrochemothera­py. Bioelectroch Bioener 1995 in press. 


14. 
Okino M, Esato K. The effects of a single high voltage eleetrical stimulation with an anticancer drug on in vivo growing malignant tumors. Jpn J Surg 1990; 20: 197-204. 

15. 
Okino M, Mohri H. Effects of a high-voltage electrical impulse and an anticancer drug on in vivo growing tumors. Jpn J Cancer Res 1987; 78: 1319-21. 

16. 
Okino M, Tomie H, Kanesada H, Marumoto M, Esato K, Suzuki H. Optimal electrical conditions 



in electrical impulse. chemotherapy. Jpn J Gancer Res 1992; 83: 1095-101. 

17. 
Salford LG, Persson BRR, Brun A, Ceberg CP, Kongstad PCh, Mir LM. A new brain tumor therapy combining bleomycin with in vivo electro­permeabilization. Biochem Bioph Res Go 1993; 194: 938-43. 

18. 
Belehradek M, Dom_enge C, Luboinski B, Orlow­ski S, Belehradek Jr J, Mir LM. Electrochemothe­rapy, a new antitumot treatment. First elinical phase I-II tria!. Cancer 1993; 72: 3694-700. 

19. 
Heller R, iaroszeski M, Leo-Messina J, Perrot R, Van Voorhis N, Reintgen D, Gilbert R. Treat­ment of B16 mouse melanoma with the eombina­tion of electropermeabilization and chemotherapy. Bioelectrochem Bioenerg 1995; 36: 83-7. 




20. 
Mir LM, Belehradek M, Domenge C, Orlowski S, Poddevin B, Belehradek Jr J, Schwaab G, Luboinski B, Paoletti C. Electrochemotherapy, a novel antitumor treatment: first elinical tria!. C R Acad Sci Paris 1991; 313: 613-8. 

21. 
Serša G, Cemažar M, Miklavcic D, Mir LM. Electrochemotherapy: variable anti-tumor effect on different tumor models. Bioelectrochem Bioe­nerg 1994; 35: 23-7. 

22. 
Serša G, Cemažar M, Miklavcic D. Potentiation of cisplatin antitumor effect by in vivo electroper­meabilization. XIIth international symposium on bioelectroehemistry and bioenergetics, Sevilla 1994, Book of abstracts, OIII-5. 

23. 
Serša G, Cemažar M, Šemrov D, Miklavcic D. Changing electrode orientation improves the effi­cacy of elcetrochemotherapy of solid tumors in mice. Bioelectrochem Bioenerg (accepted). 




Early stage Hodgkin's disease: the remaining challenge after a 


"success story" An overview of the thirty years' experience of the Florence Radiotherapy Department 
Stefano M. Magrini,1 Enrico Cellai,1 Maria G. Papi,1 Pietro Ponticelli, 2 Susanna Sulprizio,1 Maurizio Pertici, 1 Rita Bagnoli, 1 Gianpaolo Biti1 
1 Radiotherapy Unit of the Clinical Physiopathology Department of the University of Florence, ltaly 2 Radiotherapy Department, Arezzo, ltaly 
The experience of the Florence Radiotherapy Department with early stage Hodgkin's disease (HD) is reviewed, along with an analysis of the literature on this subject. In particular, the issue of the reduction of the diagnostic and therapeutic "burden" in the more favourable cases and of the identification of "high risk" cases, to be submitted to more aggressive treatment, is discussed. 
Key words: Hodgkin's disease-radiotherapy 

Introduction 
Even if the impact of the present tirne oncology on cancer mortality in adults is rather unsatis­factory for the majority of malignant neoplasms, including the more frequent ones, clear-cut progresses have been made as far as Hodgkin's 
2 
disease is concerned.1• The cause specific sur­vival rate for all the patients with Hodgkin's 

Corrcspondcncc to: Stcfano M. Magrini, M.D., Ra­diothcrapy Unit of thc Clinical Physiopathology, De­partment of the Univcrsity of Florence, Policlinico di Carcggi, Viale Morgagni 85, 50134 Florence, Italy. 
Acknowledgments: This papcr was partly supported with MURST 60 % grants and with CNR grant no. 
92.024.88.4. and with a grant of the III Hcalth Re­search Programmc of thc Tuscan Rcgion. 

disease (HD) treated in Florence after 1970 is much higher than that, relative to patients treated before 1970 (20-year survival: 74 % vs 46 % ) . Similar gains in survival have been obtai­ned in almost ali major Institutions and have been attributed to a better understanding of the natura! history of the disease, to a more accu­rate staging (lymphangiography, laparotomy, with splenectomy) and to rational use of radio­therapy and chemotherapy. 
On the other hand, many patients have been exposed to a variety of possible long term complications of the treatment given, even if they were cured of their disease. The data collec­ted by the International Database on Hodgkin's Disease (IDHD), regarding over 14000 patients treated in many Institutions, show that about 6 % of the deaths are directly attributable to the complications of the treatment. Moreover, 
UDC: 616-006.442:615.849 some of the deaths caused by other diseases 
(24 % of the to tal number of deaths) might also be linked with the therapy given for HD ( e.g., second neoplasms, cardiovascular events).2 Therefore, a remarkable effort has been devo­ted, in the last years, to the study of the late effects of the treatment; as a consequence of these studies, some major Institutions are pre­sently aiming at a reduction in the "therapeutic burden", whenever possible without hampering 
the good survival results already obtained. 
However, the IDHD data also show that almost 70 % of the deaths after the treatment of HD are caused by the disease itself. There­fore, an effort is also needed to identify the subsets of patients to be treated more aggressi­vely to obtain the cure of the disease. The attempts to reach this second goal are based on the study of "old" and "new" prognostic factors and also on the research on new therapeutic tools. 
Along with an analysis of the literature, we will present in this review data derived from the Florence Radiotherapy Department expe­rience, regarding about 1300 HD patients, con­secutively treated with radical aim since 1960. Long term data coming from a single Institution may help to clarify the questions how to success­fully address the ultimate challenge: to increase the overall survival rates of patients treated for HD. A reduction in the incidence of treatment related deaths and an increase in the proportion of the "high risk" patients who can be cured are, in fact, two faces of the same problem. 
Questions regarding prognostic factors, staging procedures and therapy: tailoring the diagnostic and therapeutic "burden" according to the different clinical features of the disease 
Sixty to seventy per cent of the patients with HD are defined, after a thorough clinical sta­ging, as having Stage I and II disease. The proportion of Clinical Stage (CS) I and II patients in different hospital series is shown in Table 1.2-5 
The majority of these patients are treated with radiotherapy (RT) alone. However, diffe-
Table 1. Proportion of patients with Clinical Stagc I-II disease in diffcrent scrics from thc literature. 
Institution, N. of N. with CS % Rcf. paticnts 1-II disease 
Stanford,3 1660 1014 61 % Princcss 790 466 60% Margarct,4 Royal Marsdcn,5 732 455 61 % 
2 

IDHD,14225 9041 64% 
Florence 1121* 66% 
* trcated 1960-88 
rent treatment philosophies stand behind this fact. The choice of the treatment modality depends also from the staging procedures adop­ted. 
In fact, some lnstitutions submit ali the CS I-II patients to surgical staging, then treating with RT alone those without occult abdominal involvement and, in some cases, those with only splenic and/or upper paraaortic nodes in­volvement (pathological stage IIII). For exam­ple, Mauch and co-workers reported the expe­rience of the Joint Center for Radiation The­rapy in Boston with 315 Pathological Stage (PS) IA and IIA HD patients: overall cause specific survival at 14 years was 93 % , primary treat­ment having been mantle (M) plus lumbar bar (LA) radiotherapy alone.6 Similar results have been observed in 232 PS I-IIA patients treated at our Institution approximately in the same period (1970-1988) and with the same modality (M+ LA radiotherapy): actuarial overall cause specific survival was 88 % at ten years and 85 % at 20 years. 
Others prefer to rely on the identification of different prognostic groups to select patients to be treated with RT alone, thus avoiding laparo­tomy with splenectomy. For example, the Prin­cess Margaret Hospital group suggested that the proportion of CS I-II patients given radio­therapy alone ( about 80 % ) will not change by selecting patients for this treatment according to a prognostic grouping in three categories rather than with laparotomy and splenectomy. The clinical factors defining the three groups include clinical stage, presence or absence of general symptoms, histology, age.4 These clini­



cal investigators observed that their results are in line with those one could expect from a policy of surgical staging followed by the appro­priate therapeutic choice; they report a 78 % ten-year overall cause specific survival for a group of 252 CS I-IIA patients treated with radiation alone over a decade (1968-77). 
A third option is based on the combination of radiotherapy and chemotherapy for all CS I-II patients, again avoiding surgical staging, in the belief that chemotherapy will obviate for the need of treating with radiotherapy the abdo­minal sites of disease, if present. Survival figu­res do not seem to be different from those reported for patients treated with radiation alone. In fact, randomized studies comparing patients treated with RT alone with those trea­ted with RT plus chemotherapy, evidenced often better relapse free survival rates for pa­tients treated with the addition of chemotherapy (CT), but overall cause specific survival was never significantly different. For example, the Manchester group (Anderson, Crowther et al.) randomized patients with PS I-IIA and I-II B to RT or Rt plus CT;7 the overall 10-year survival, after correction for intercurrent deaths, was 90 % for the RT alone group (n = 56), as opposed to 95 % for the RT plus CT group (n = 59). An attempt has been recen­tly made to analyse togheter all the numerous randomized clinical studies comparing radiation alone vs radiation and chemotherapy for early stage HD. The results of this meta-analysis showed, again, that the addition of chemothe­rapy produces higher relapse free survival rates, but no significant advantage in terms of cause specific survival. 8 
No randomized clinical trial is available to give a definitive answer about the possible superiority of one of these three approaches the others. Therefore to some authors conclude that there is not a "treatment of choice", but "a choice of treatments" for early stage Hodg­kin's disease.9 
Our policy largely depends from surgical sta­ging of CS I-II patients, because: 
l. it allows the use of RT alone in a large proportion of early stage patients, selection being based on the. most important prognostic factor (presence or absence, and extent, of abdominal disease); 

2. 
it obviates the need for splenic irradiation and might result in a further reduction of the treated volumes, according to other prognostic factors, in PS I-IIA cases; 

3. 
it entitles to a clear distinction between Illl and III2 substages, thus allowing treatment with RT alone of the IIIl cases ( or of part of them); 

4. 
it clearly defines the subdiaphragmatic ex­tent of the disease, and therefore the sites to be treated with radiotherapy, also in cases submitted to combined modality treatment. 


Furthermore, we prefer the use of RT alone for early stage patients, because it reduces the "therapeutic burden", combined modality treat­ment being the only viable alternative. In fact, CT alone has proved inferior to RT alone in the randomised trial we conducted, with the Hematology and Radiotherapy Departments of the Universities of Florence and Rome, compa­ring M+ LA radiotherapy with MOPP chemo­therapy in the treatment of PS I-IIA patients.10 With a median follow up in excess of 9 years, overall cause specific survival resulted in 93 % in the RT alone group (n = 45) and in 56 % in the MOPP group (n = 44). The difference in overall survival was mainly due to a more difficult rescue of relapsed patients treated ini­tially with CT, whose survival probability 80 months after relapse was of 15 % , the corre­sponding figure for patients relapsed after RT alone being 85 % . The percentage of "true" relapses ( occurring at initially involved sites) was much higher (8/12 vs 1/12, p < 0.001) in the MOPP group; which underscores the need for adequate radiotherapy of initially involved sites also in the context of combined modality treatment. It should be mentioned that a similar study of early stage HD, conducted in the United States by the National Cancer Institute on 136 patients, yielded somewhat different results, the difference between the MOPP and the RT arms being not significant, when the 13 PS IIIAl cases, also randomised, were excluded from the analysis. It should be noticed, howe­


Table 2. Incidencc of cases with CNHD in some reportcd scrics. 
lnstitution,  N. with  Period  N. with  N. with  
Ref.  CS !-II HD  of accrual  CS I  CS II  
Royal Marsdcn,12 Stanford,3  225 915  1970-79 1968-86  78 (34.6 % ) l04  25 (ll.6 % ) 52  
(11.3%)  (5.7%)  
Florence  703  1960-88  77  21  
Joint Center, 13  552  1969-86  (10.9%) 108  (3.0%) N.R.  
(19.5 % )  

N.R. 

Not reported; only patients with supradiaphragmatic HD considered. The Royal Marsden scries includes only patients subsequcntly submittcd to staging laparotomy; ali the other serics consider ali thc CS 1-11 patients. 
ver, that in this study 30 cases with "favourable" presentations, out of 34 with PS IA, were treated with radiotherapy alone, but not rando­mized; conversely, 22 patients with PS 1-IIB were randomised and evaluated.11 Moreover, in the NCI study, higher proportion of the relapses observed after RT alone were "true" (in field) relapses (7/17, 41.2 % , vs 1/12, 8.3 % , as observed in the ltalian study). 
The retrospective analysis of our results with Clinical Stage 1-11 patients (743 cases treated 1960-1988) seems to confirm the general state­ment that, for early stage HD, radiotherapy alone is as effective as combined modality treat­ment. Five-, ten-and fifteen-year disease speci­fic survival rates are respectively of 85 % , 77 % and 74 % for the 578 cases treated with radio­therapy alone; the corresponding figures for the 129 cases treated with RT and CT are respectively 84 % , 78 % and 78 % . However, some clinical presentations of the disease could not be easily forced in a schematic subdivision by clinical or pathological stage only. These presentations should be analysed separately. 
Clinical stage I-11 Hodgkin's disease invol­ving cervical nodes only ( CNHD) should be considered as a rather uncommon presentation of this neoplasm, accounting for an average of 20 % of the supradiaphragmatic CS 1-11 patients 
1213 

(Table 2). 3, ' 
Distinctive clinical, pathologic and biologic features are reported for this subset. Firstly, an excess of cases with a histologic diagnosis of lymphocytic predominance HD (LPHD) has been observed (in comparison with the much larger group of the other stage I-11 patients). Therefore, the peculiar clinical characteristics linked with this hystological subtype are fre­q uently present among CNHD patients: male preponderance, an age peak in the fourth de­cade, a single site of disease, a long tirne lapse between the appearance of a cervical adeno­pathy and the definitive diagnosis, a chronic relapsing course, an excess of second tumors and an allegedly better prognosis. 14• 15 Secondly, the entire group of cases with CNHD has been studied in detail, as far as the results of laparos­plenectomy are concerned, aiming at the avoi­dance of surgical staging, at least in some patients. The high incidence of cases with LPHD among CNHD patients is confirmed also in our series: 33 % of the 98 cases with CNHD treated between 1960 and 1988 show this histologic subtype, as opposed to only 12 % of the remaining supradiaphragmatic CS I-11 patients (P = 0.001). A higher proportion of male patients among cases with LPHD histology has been observed in our CNHD series (M/ F = 3.0). The age at diagnosis peaks in the fourth decade for the LPHD patients of the CNHD group. More than 10 % of our CNHD cases (13/98) had a long history ( > 2 years, 4.5 years on average) of adenopathy in the same site subsequently biopsied, reaching the diagno­
sis of HD. 
Forty-four out of the 98 patients studied have been submitted to staging laparotomy with sple­nectomy. The overall incidence of occult abdo­
Table 3. Incidence of splenic involvement in CNHD patients, according to differcnt clinical features. 
Clinical feature  N. with spleen involved  %  
Males  2/24  8.3%  
Females  0120  
Clinical Stage I  1/38  2.6%  
Clinical Stage II  1/6  16.6%  
High neck disease  0/15  
Low neck disease  2/32  6.3%  
Bulky nodal masses  l/8  12.5%  
No bulky nodal  
masses  1/36  2.7%  

minal involvement is low ( 4.5 % ) . Factors appa­rently related with a higher frequency of splenic involvement are shown in Table 3. 
Therefore, the need for surgical staging may be questioned in a fraction of the patients with CNHD (namely, female patients with high neck disease, CS I, without bulky nodal masses). 

In our series, all patients were treated with RT alone. Cause specific survival is very good (87 % ); disease free survival is in the region of 80 % . Therefore, other therapeutic modalities do not appear to be a viable alternative. In­stead, an attempt should be made to identify the cost/benefit ratio for the use or different treated volumes. Waldeyer's ring (WR) involve­ment bas been frequently detected in these patients (17/98, 24 % ), but prophylactical irra­diation of this anatomic region does not seem warranted. According to our experience, in fact, biopsy of clinically negative WR always gave negative results.16 Not surprisingly, the use of wide field radiotherapy determines an increase in relapse free survival when compared with that of involved field (IF) irradiation. 

Taking into account the types of relapse obser­ved in the group of patients treated with IF and their treatment, we judge that the use of "mini mantle", avoiding the irradiation of the media­stinum, would be the best choice for many CNHD patients. In our series, the use of "mini mantle" would have probably avoided 3 of the 7 relapses observed in the IF treated group (the marginal ones). Appropriate salvage chemothe­rapy ( and the possibility of cure) is now availa­ble, but could not be offered to 3 of the 4 remaining patients, with other types of relapse, at the tirne when they were treated. 

Patients with subdiaphragmatic presentations of HD (SDHD) represent a small fraction of the cases with Stage I-II A disease (5-10 % , in the more relevant series of the literature; 5 o/o in our series). 'fhey also have distinctive clini­cal-pathological features, shared in part with CNHD patients. Among our 41 cases (treated 1960-1990) we observed a relatively high M/F ratio (3.1), a high proportion of cases with the LP histotype (25 % ), an older median age at presentation ( 46 years). However, it is possible to subdivide this small group of cases: those with "central" (abdominal) presentation have more often systemic symptoms, a mixed cellu­larity (MC) histotype, Stage II disease and a worse prognosis. On the contrary, those with "peripheral" (inguinal) presentation have more often a LP histotype, no systemic symptoms, Stage I disease and a better prognosis. Por Stage IA patients, lymphangiography is 100 % accurate and the results after radiotherapy only (the treated volume being almost always the "inverted Y") are very good (100 % cause spe­cific survival in our series). As far as IIA cases are concerned, laparotomy with splenectomy identifies a subset with pathological Stage I disease, and therefore could not be omitted, to avoid "overtreatment" of the downstaged cases ( Table 4). In fact, pathologically staged IIA cases and all the IIB cases should be treated more aggressively, because the relapse rate is otherwise unacceptably high. 
In conclusion, CNHD and SDHD cases ac­count for about a quarter of our series of CS I-II patients; in a not negligible fraction of them, laparotomy with splenectomy could be 
Table 4. Stage variations among 27 SDHD patients after laparotomy with splenectomy. 
Clinical Stage / CSIA CSIIA CSIIB Pathologic al Stage 


PSIA 6 8 PSIIA 7 
-PSIIAS -2 PSIIB PS IIBS 
Table 5. Prognostic factors and actuarial 5,10-and 15-year discasc specific (DS) and relapse-free survival (RFS). 743 Clinical Stage 1-II HD patients treated 1960-1988. 
Factor (n. of cases) 5-year 10-year 15-year 5-year 10-year 15-year DS DS DS RFS RFS RFS 
ALL CASES (743) 85% 77% 74% 64% 58% 56% Ciin. Stage II (582) 84% 75% 73% 60% 54% 51 % Ciin. Stagc I (161) 89% 86% 82% 79% 74% 71 % "B" symptoms (105) 70% 65% 65% 45% 38% 36% No "B" symptoms (638) 87% 80% 76% 67% 61 % 59% 
avoided and/or the treated volumes reduced, apparently without hampering the good results obtained with radiation alone. 
Another group of patients with CS I-II HD seems, conversely, to have a worse prognosis after treatment with radiation alone. 
According to our data and to the results from the literature, advanced age and male sex are significantly related with a worse prognosis. 17 In addition, the effect of the "biologic" progno­stic factors outweights that of the factors linked with the so called "tumor burden". 
Among the 743 Clinical Stage I and II HD patients treated at our Institution (1960-88), the presence of "B" symptoms confers an un­favorable prognosis (univariate analysis, p < 0.001, Table 5). Among the different prog­nosticators linked with the "tumor burden", only stage seems to be equally relevant (Table V), mostly however, as far as relapse free survival is concerned. In line with these re­marks, it is of 
some interest that in our expe­rience, the presence of a "bulky" mediastinal mass (transverse mediastinal diameter larger than one third of the thoracic diameter) is not linked with a significantly worse prognosis. 
The subset of patients with "B" symptoms is in fact the only one seemingly deriving survival advantage from the addition of chemotherapy to radiotherapy as primary treatment (Table 6). Therefore, our treatment policy for I-IIB pa­tients (representing about 15 % of the CS I-II cases of our series) is different from that, adopted for the other CS I-II HD patients and the primary treatment includes chemotherapy. The addition of chemotherapy to radiotherapy seems to eliminate the prognostic disadvantage of the "B" cases. 
Questions regarding long term, treatment related damage: tailoring the diagnostic and therapeutic "burden" according to the risk of sequelae 
The fact that a large fraction of patients cured of HD has been already exposed to a variety of long term sequelae of the treatment attracted the interest of many clinical investigators. 
A relatively high incidence of second malig­nant neoplasms, the occurrence of cardiac or pulmonary damage and of infections and the 
Table 6. Disease specific (DS) and relapse free survival (RFS) after different treatment types for CS I-II B patients (105 cases, 1960-1988, Florence Radiotherapy Departement). 
Treatment modality 
5-year 10-year 15-year p 5-year 10-year 
(n) DS DS DS RFS RFS RFS 
ALL"B" 70% 65% 65% 45% 38% 36% 
RTALONE 60% 56% 56% 33% 29% 26% (tj = 61) 
RT+ CT 85% 76% 76% 63% 49% 49% (n = 39) 
CT(n = 5) 


P (Logrank) = 0.03 for DS and 0.006 for RFS 


risk of infertility are among the most feared "consequences of survival". We studied extensively the problem of second malignancies (SM). 
It is known from the literature and from our own data that the risk of SM and of acute leukemia in particular, is higher among patients treated for Hodgkin's disease than in the gene­
ral population.18 Among our patients (1121 
cases treated 1960-88), the observed/expected (0/E) ratio for SM resulted to be 2.27 (95 % confidence intervals, C.I., 1.8-2.9) with respect to a comparable sample of the general popula­tion (data from the Tuscan Tumor Registry). 
Table S. Relative risks of second solid tumors (SST) in different age classes and therapeutic subgroups (Multivariate analysis, Cox model, 1121 patients treat­ed in Florence 1960-1988, relapsed patients censored at relapse). Factor RR of SST p Age at diagnosis <20 1 
20-40 0.075 
40-60 8.2 0.006 
>60 Trcatment intensity IF/M STNI/TNI IF/M + CT STNI/TNI + CT 27.9 <0.001 

1 1.9 0.12 1.5 0.49 4.4 0.01 

For acute leukemia, the 0/E ratio resulted to CT 
0.03 

be 30.3 (C.I. 14.5-55.8). We therefore studied the cumulative probability of having a SM in different clinical and therapeutic subgroups of our series. 
The 15-year cumulative probability of acute leukemia (AL) is equal to 1.6 % ; the risk of AL resulted to be mucb higber after cbemotbe­rapy, alone or in combination witb radiothera­py, than after radiotberapy alone (Table 7). 
Anotber interesting remark is that tbe risk of acute leukemia (AL) is apparently bigher wben cbemotherapy and radiotherapy are given togheter, at presentation, tban when radiotbe­rapy is given at presentation and chemotberapy for relapse (4/185 cases vs 0/142, RR = 10, P = 0.03). 
In our experience, splenectomy does not in­crease tbe risk of AL. Overall cumulative probability of second so­lid tumors (SST) is bigber than that of AL (9 % 
IF = Involved field; M = Mantle; STNI, TNI Subtotal-and Tota! nodal irradiation; CT = Chemo­therapy. RR = relativc risk. Likelihood ratio statistics, P<0.001. 


at 15 years). Tbe risk of SST is linked mainly witb age at diagnosis of HD. However, cbemo­therapy, alone or associated witb extended field radiotherapy, seems to be linked also witb an increased incidence of SST (Table 8). 
Wbile a remarkable excess of cases of AL in HD patients treated with cbemotberapy bas been observed also in tbe large majority of the otber publisbed series, an excess of second solid tumors in tbe same group of HD patients bas been less frequently reported. However, two large recent studies, from tbe M.D. Ander­son Cancer Center and from the British Natio­nal Lympboma Investigation Group, reacbed conclusions very similar to ours.19• 20 In conclu-
Table 7. 15-year cumulative probability and relative risks (RR) of acute leukemia (AL) in 1121 patients treated in Florence (1960-88), according to the therapy given at presentation (relapsed patients have been censored at · relapse; comparisons of different Kaplan Meier cumulative probability curves have been made with the Logrank test). 


presentation cases cumulative 
probability Radiation alone 745 0.2% 1 Radiation + 272 4.3% 13.4 0.02 Chemotherapy Che.otherapy alone 104 11.1 % 9.9 0.10 


Therapy at 
15-year AL RR 



Table 9. Relative risk (RR) of respiratory complica­tions according to age groups and radiation <lose Icvels to mcdiastinum: multivariate analysis, Cox model, 1060 paticnts trcatcd in Florence until 1986. 


Factor  RR  p  
Dosc to mediastinum  
<20Gy  1  <0.001  
20-30Gy  7.3  
>30Gy  18.0  
Age  
<20  1  <0.001  
20-60  1.9  
>60  <1  
Extent of Mediastinal  
Involvement  
None  1  <0.005  
Nonbulky  1.6  
Bulky  2.8  
Nonbulky and hylum  2.3  
Bulky and hylum  2.1  

sion, the risk of developing a SM is not negli­gible and seen,3 to be at least in part treatment­related: therefore, it should be taken into ac­count when choosing primary treatment for early stage HD. 
According to an analysis conducted on a series of 1060 cases treated at our Institution until 1986, about one third (34 % ) of the com­plications observed are respiratory; however, mild paramediastinal fibrosis (rarely accompa­nied by mild symptoms) account for about 90 % of the episodes; in the remaining 10 % symp­toms were more severe or protracted. Multiva­riate analysis shows that the age of the patients and the dose to the mediastinal structures are directly relat.d to the incidence of respiratory complications (Table 9), along with the extent of the mediastinal mass (and therefore of the lung volume exposed to radiation). To perspec­tively evaluate these data, however, functional evaluation of radiation damage to the lung should be considered. 
In a s.ries of 43 patients consecutively treated at our Institution with radiotherapy alone bet­after radiotherapy, with complete recovery the­reafter; in patients with abnormal RFf before therapy ( with large mediastinal adenopathies), all parameters improved after mantle irradia­tion. 21 Similar results have been reported by other investigators.22 

Treatment with chemotherapy by itself may produce respiratory damage; however, the addi­tion of regimens containing bleomycin or adria­mycin to mediastinal irradiation greatly increa­ses the risk of severe respiratory impairment. In particular, a significant increase in the pro­portion of patients experiencing moderate to severe respiratory toxicity and two lethal pul­monary insufficiencies have been observed in patients enrolled in the H6F trial of the Euro­pean Organization for Research and Treatment of Cancer and randomized to treatment with the ABVD regimen plus mantle and lumbar bar radiotherapy, when compared with those treated with radiation and MOPP chemothera­PY. 23 A recent pilot study of the British N ational Lymphoma Investigation testing the value of involved field radiotherapy plus a chemothe­rapy regimen including vinblastine, methotre­xate and bleomycin (VEM) in early stage HD was prematurely discontinued also because of severe pulmonary toxicity. 24 
Age and dose to mediastinum (Table 10) appear to be the factors more directly related also to the occurence of cardiac complications, that are much less frequent of the respiratory ones (5 % of the total number of complications observed in our series). Of the various types of cardiac damage we observed, ischemic heart 
Table 10. Relative risk (RR) of cardiac complications according to age groups and radiation <lose levels to mediastinum: multivariate analysis, Cox model, 1060 patients treated in Florence until 1986. 
Factor RR p 
Age (years) 

ween 1978 and 1980, respiratory function tests 
1 <0.01 

30-50 1.22 
>50 3.65 
(RFf) were performed before mantle irradia­
tion and 6, 9, 15 or more months thereafter. 

Dose to mediastinum 
Small variations in the different functional para­<30Gy 1 <0.05 >30Gy 2.3 
meters explored were observed 3 to 6 months 


disease is the prevailing one ( 60 % of the cases). Cardiac damage has been studied only recently also in comparison with adequate control groups of the general population. Glanzmann and colleagues identified 6 patients with fatal coronary heart disease (CAD) in a series of 339 HD cases who received mediastinal radiothera­PY, with or without chemotherapy. 25 The cases with fatal CAD were equally distributed in the groups treated with or without chemotherapy. Standardised mortality rate in comparison with the general population resulted to be 5.6 (C.I. 2.6-10.7.). However, the excess risk was Iimited to HD patients with known risk factors for CAD (high cholesterol Ievels, smoking, hyper­tension). 
On the whole, infectious complications ac­count for about one third of the episodes of iatrogenic <lamage observed in our series (30 % ). According to our experience, zoster infections represent more than two thirds of the infectious episodes and their occurrence ap­pears to be related with splenectomy, with the extent of the treated volume and with the combination of radiotherapy and chemotherapy (Table 11). 
Similar relationships have not been observed for bacterial infections and for the other vira! infections. We observed two cases of sepsis, but only one following splenectomy. 
Table 11. Relative risk (RR) of zoster infections according to the use of splenectomy, to the extent of the treated volume and to the treatment modality: multivariate analysis, Cox model, 1060 patients treated in Florence until 1986. 

Factor  RR  p  
Splenectomy  
No  1  <0.01  
Yes  2.4  
Treated volume  
IF  1  <0.05  
M-STNI  1.6  
TNI  2.6  
Treatment Modality  
Radiation alone  1  <0.05  
Radiochemotherapy  1.9  
Chemotherapy alone  1  

IF = Involved field; M = Mantle; STNI, TNI Subtotal-and Tota! nodal irradiation. 
More aggressive chemotherapy regimens may result in prolonged neutropenic episodes, occa­sional septic deaths having been reported. 
In conclusion, respiratory and cardiac compli­cations appear to be related to the age of the patient and to mediastinal irradiation. 
Radiation pneumopathy is relatively fre­quent, but rarely symptomatic. It may be more severe and occasionally fatal when chemothe­rapy ( especially with drugs as bleomycin or adriamycin) is added to radiotherapy. 
Cardiac damage is much Iess frequent, but more often severe; it is Iinked also with the other well known risk factors. 
Infections caused by the herpes zoster virus are the most frequent; their incidence is increa­sed among patient submitted to splenectomy and in those treated with radiation ( especially on Iarger volumes) and chemotherapy. Other vira! or bacterial infections are Iess frequent; their incidence is increased after combined mo­dality treatment. Infections in patients rendered neutropenic by combination chemotherapy may be occasionally fatal. 
The risk of gonadal damage is particularly worrying, owing to the young mean age of the HD patients. Consequences of the treatment given of fertility are particularly difficult to "measure"; psychosocial problems in HD survi­vors may in fact alter the sexual behaviour (and therefore fertility) even more than the physical damage from radia ti on and/or chemotherapy. Moreover, in 30-70 % of HD male patients, defects in spermatogenesis are present before any treatment. Finally, the fact that 30-50 % of HD patients already had a child before the diagnosis of HD may well influence their beha­viour after treatment. In a recent paper from the Memorial Sloan Kettering Cancer Center, Kornblith and coworkers26 reported the results of a comparison of psychosocial adaptation and sexual function in 150 Iong term survivors of advanced HD treated with three different, che­motherapy regimens (MOPP, ABVD and MOPP/ABVD). They conclude that there are no differences between the different treatments as far as the measured outcomes are concerned, even though differences among the "physical" 


effects of MOPP and ABVD on gonadal funct­ion may well exist. Therefore, other factors, unrelated to therapy ( as the perceived negative effect of having had a cancer on the socioeco­nomic status of the patient or on his sexual life) may exert a profound influence on the probabi­lity of having children of HD survivors. 
For male patients, the use of total nodal irradiation (TNI) might produce long lasting azoospermia, because of the scattered radiation to the testes; also very low fractional doses seem effective in damaging spermatogenesis. The irradiation of less extended volumes is much less dangerous in this respect. The scatter­ed dose to the testes has been determined by researchers at the National Cancer Institute and resulted to be between 0.2 % and 1 % of a midline dose of 40 Gy for mantle or paraaortic fields; when a pelvic field is added, the total dose to the testes rises up to 140-300 cGy.27 In fact, the scarce clinical data on this subject seem to confirm that male HD patients treated on volumes smaller than TNI can preserve their fertility, if not already compromised before treatment. In our series, TNI was included in the primary tratment mostly until 1980, while it was very rarely used thereafter (139/776 cases -18%-vs 26/500 -0.5%-); this is particularly trne for early stage disease. 
Chemotherapy induced gonadal damage is very frequent in male patients treated with the MOPP regimen: after such treatment infertility is the rule. Apparently, the ABVD regimen seems to exert a less pronounced effect on spermatogenesis. Thirty-six per cent of 25 male patients treated by Santoro and colleagues in Milan with ABVD plus radiotherapy (STNI) had azoospermia and 20 % oligospermia after chemotherapy; full recovery of spermatogenesis was evident in the 13 patients who had a repeated sperm count within 18 months.28 Al­ternating regimens (like the MOPP/ABVD or the COPP/ABVD ones) seem to affect fertility in a percentage of male patients similar to that observed after MOPP chemotherapy.29 
For female patients, another critical factor is age; women younger than 20-30 years have a higher probability of preserving fertility both after radiotherapy and after chemotherapy. Ra­diotherapy to mantle and lumbar bar seems to be relatively "safe"; on the contrary, when radia ti on to pelvis (TNI) is necessary, many authors suggest to perform an oophoropexy along with staging laparotomy and splenectomy. In this way, a central pel vic shield may protect ovaries and more than 70 % of the treated women continue to have or resume, shortly after treatments normal menses. As far as che­motherapy is concerned, the Milan group claims that also for females the ABVD regimen is less toxic for gonadal function than the MOPP one. Out of 24 females treated with STNI and ABVD, none had "prolonged" amenorrhea as opposed to 5/10 of those over thirty years of age treated with MOPP and STNI.28 As for the effect of alternating regimens, the same obser­vations reported for males apply also to female patients. 
In conclusion, the issue of gonadal damage is complicated by the effect of various psycho­logic and social factors; however, chemotherapy with the MOPP regimen seems to produce sterility in nearly ali the male patients and in a substantial number of the female ones; similar conclusions can be drawn for other MOPP-like regimens (as the MVPP one). Even if long term data with ABVD are more scarce, it seems that gonadal damage is less frequent after treatment with this regimen. For both male and female patients, radiotherapy seems to be much less damaging for the gonads than chemotherapy (with the possible exception of total nodal irra­diation in males, nowadays rarely used). 
Discussion and concluding remarks 

The evidence from the literature and our own data show that the knowledge of a few easily identifiable prognostic factors, coupled with the awareness of the potential risks of each thera­peutic modality, may allow to design a reason­able treatment strategy for early stage HD. The Florence Radiotherapy Department policy of treatment has been built on the "gold standard" represented by subtotal nodal irradiation in 
laparotomy staged patients. This choice granted both acceptable survival rates and a sufficiently low cumulative probability of major complica­tions. High, and reproducible, cause specific survival rates are reported after STNI in lapa­rotomy staged patients, no significant survival differences having been reported in comparison with patients treated with radiation and chemo­therapy; the cumulative probability of second malignancies (acute leukemia in particular) is lower for these radiotherapy treated patients than for those treated with chemotherapy, par­ticularly of the MOPP type, alone or combined with radiation. After radiotherapy alone, gona­dal function appears to be preserved in a much higher proportion of cases. 
The fact that about 30 % of the patients treated with radiotherapy alone will relapse (therefore requiring salvage chemotherapy) does not seem to obscure the picture. The majority of the relapsed patients will be cured; moreover, the risk of leukemia does not seem to be raised in this subgroup; in fact, the risk of AL is much higher when chemotherapy and radiation are given concurrently rather than separately, one ( RT) at presentation and the other (CT) at relapse. 
Cardiac and respiratory sequelae seem, how­ever, mainly linked with age and with the radiation dose to the mediastinum. Unfortuna­tely, this form of iatrogenic damage cannot be eliminated with combined modality treatment (because of the need of treating with radiothe­rapy the initially involved sites, that most often include the mediastinal nodes); moreover, the addition of chemotherapy regimens containing bleomycin or adriamycin may significantly in­crease the frequency and severity of radiation related lung damage. 
From the large group of CS I-II patients, two groups can be identified, requiring a diffe­rent therapeutical approach. 
For the "favourable", or "peripheral", cases (with high neck disease, or with limited sub­diaphragmatic disease), the use of less extended treated volumes ( avoiding mediastinal irradia­tion in a not negligible fraction of cases) and a less frequent recourse to staging laparotomy with splenectomy do not seem to hamper the excellent survival figures previously reported. Conversely, patients with "B" symptoms should be treated with combined modality treatment, that seems to produce better survival results when compared with radiation alone. 

While this is a reasonable state-of-the-art policy, ongoing studies aim at two major end results: 
l. The further reduction of the therapeutic burden, mainly attempting the combination of the irradiation of less extended volumes with novel chemotherapeutic regimens, presumably less leukemogenic and/or less toxic to lung and gonads, in clinically staged patients; or the reduction in the treated volume in a fraction of the laparotomy-staged cases; 
2. The identification of "very high risk" cases (both at diagnosis and after relapse) to be submitted to very aggressive treatment (for example, "supramaximal" chemotherapy with or without different types of radiation therapy and with some from of bone marrow support). 
As far as the use of new, less toxic, chemo­therapy regimens associated with small field radiotherapy is concerned, the more relevant example of this strategy is represented by the use of the VBM schema (vinblastine, 6 mg/m2 , bleomycin, 10 mg/m2 , methotrexate, 30 mg/m2 , given i.v. on days 1 and 8 of a 28-day cycle for 6 cycles) plus involved field radiotherapy, as proposed by the Stanford group and tested by American and British investigators.24• 30 In the Stanford experience, survival results were sub­stantially the same with this treatment protocol and with extended field radiotherapy alone, in early stage patients. 30 Gonadal toxicity was very low after VBM; moreover, the individual drugs of the schema have been selected for their allegedly lower carcinogenicity. However, a relatively higher incidence of abnormal pul­monary function test was recorded in these VBM-treated patients. A more recent paper from the British National Lymphoma Investiga­tion group reports that 47 % of the 30 patients treated with the VBM schema suffered from pulmonary toxicity (as opposed to 31 % of the patients treated at Stanford), defined as "unex­
pectedly severe". Moreover, a septic death was recorded. Therefore, the BNLI g,toup prematu­rely interrupted the study. Of course, the search for new effective che­motherapy regimens for HD continues, and probably some of them will be tested also in this clinical setting. Considering the issue of the reduction of the treated volume in surgically staged patients, the EORTC experience should be mentioned. Treated volume was limited to the "mantle" in the PS I-II patients with favourable prognostic factors enrolled in the H6F EORTC trial.19 Patients were characterized by the absence of bulky mediastinal masses, less than 3 involved sites, absence of B symptoms with an ESR lower than 50 or B symptoms, but with an ESR lower than 30. Six year cause specific and relapse-free survival higher than 90 % and 80 % respectively -have been reported. 



In this very favourable subset of patients, therefore, a strategy of laparotomy followed by radiotherapy limited to "mantle" alone in PS I-II cases might be justified. A retrospect ana­lysis of the 439 cases with CS I-II treated in Florence 1975 through 1988 showed that 93 of the PS I-II patients treated with radiotherapy alone presented with the same features of the H6F patients. For this subset, overall 6-year cause specific (CSS) and relapse free survival (RFS) rates were respectively of 94 % and 85 % . Patients treated with mantle radiotherapy alone (n = 19) fared as well as those treated on larger volumes (n = 74): CSS and RFS rates in the two groups were respectively 93 % vs 94 % and 85 % vs 86 % . However, the Physician Data Query information sheet, released by the National Cancer Institute, in its July 1994 upda­te, recommends strict follow up, including care­ful surveillance of abdominal nodes, for the favourable PS 1-II cases treated with mantle radiotherapy only. 
As far as the treatment of high risk cases is concerned, the presence of B symptoms and advanced stage correlate with a worse prognosis in patients failed after radiation therapy alone for early stage HD, for example in the Stanford experience.31 Patients not responding, progre-sing or relapsing after primary treatment and belonging to one of the unfavourable prognostic groups listed above have been relatively often submitted to "supramaximal" chemotherapy with marrow support.32• 33 However, even this very aggressive therapeutic effort will obtain acceptable survival results only if there is resi­dual sensitivity of the disease to the therapeutic modalities already used during primary treat­
ment. This is the main reason of the somewhat deluding results obtained. Mature data on allo­geneic, syngeneic and autologous marrow trans­plantation after "supramaximal" therapy for HD come from the Seattle group.28 These in­vestigators report an overall 5-year survival probability of 21 % , with a median follow up of two years; 40 % of the patients died for causes unrelated to active HD (pulmonary or multiorgan failure being the prevailing ones). The proportion of patients with less advanced disease treated according to such (or similar) policy has been relatively higher in some other reported series: the results have been in some cases better (survival rates up to 30-40 % , but generally after a much shorter median follow up period). 
The Transplant Unit of the Hematology De­partment of the University of Florence, a Cen­ter collaborating with our Institution as far as the care of HD patients is concerned, perfor­med about 200 autologous bone marrow trans­plants since 1988. Nineteen of these transplants (2 allogeneic, 17 autologous) have been perfor­med in HD patients, ali but two treated initially with chemotherapy for advanced disease. Ele­ven of these cases had refractory disease (mainly relapsing HD, a few with primarily refractory disease). Eight cases had partial re­sponses after primary treatment (3 cases) or after treatment for first (4 cases) or second (1 case) relapse. Ali the patients were submitted to supramaximal chemotherapy only before the transplant. Until now, five patients relapsed after transplant, 5 died because of progressing disease, 3 for treatment-related causes. Six ca­ses have been followed for less than one year. Our excperience, therefore, seem to be aligned with the results obtained elsewhere.32• 33 


References 
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2. 
Henry Amar M, Somers R. Survival outcome after Hodgkin's disease: a report from the Interna­tional Data Base on Hodgkin's disease. Semin Oncol 1990; 6: 758-68. 

3. 
Leibenhaut MH, Hoppe RT, Efron B, Halperm J, Nelsen T, Rosenberg SA. Prognostic indicators of laparotomy findings in clinical stage 1-II supra­diaphragmatic Hodgkin's disease. J Ciin Oncol 1989; 7: 81-91. 

4. 
Sutcliffe SB, Gospodarowicz MK, Bergsagel DE, Bush RE, Alison RE, Bean HA, et al. Prognostic groups for management of localized Hodgkin's disease. J Ciin Oncol 1985; 3: 393-401. 

5. 
Horwich A, Easton D, Nogueira-Costa R, Liew KH, Colman M, Peckham MJ. An analysis of prognostic factors in early stage Hodgkin's disease. Radiother Oncol 1986; 7: 95-106. 

6. 
Mauch P. Tarbell N, Weinstein H, Silver B, Goffman T, Osteen R, et al. Stage IA and IIA supradiaphragmatic Hodgkin's diseasc: prognostic factors in surgicall y staged patients treated with mantle and paraaortic irradiation. J Ciin Oncol 1988; 6: 1576-83. 

7. 
Anderson H, Crowther D, Deakin DP, Ryder WD, Radford JA. A randomiscd study of adjuvant MVPP chemotherapy after mantle radiotherapy in pathologically staged IA-IIB Hodgkin's disease: 10-year follow up. Ann Oncol 1991; 2(8): 49-54. 

8. 
Specht L, Gray R. Overview of randomised trials of adjuvant combination chemotherapy (CT) and of extended field radiotherapy (RT) in nodal Hodgkin's disease (HD). European J Cancer 1991; 27(S): 236. 

9. 
Hoppe RT. Early-stage Hodgkin's disease: A 

choice of treatments or a treatment of choice? J Ciin Oncol 1991; 6: 897-901. 

10. 
Biti GP, Cimino G, Cartoni C, Magrini SM, Anselmo AP, Maurizi Enrici R, et al. Extended­field radiotherapy is superior to MOPP chemothe­rapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study. J Ciin Oncol 1992; 3: 378-82. 

11. 
Longo DL, Glatstein E, Duffey P, Young RC, Hubbard P, Urba WJ, et al. Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year re­sults of a prospective randomized study. J Ciin Ono/ 1991; 6: 906-17. 

12. 
Brada M, Easton DF, Horwich A, Peckham MJ. Clinical presentation as a predictor of laparotomy findings in supradiaphragmatic stage I and IOI Hodgkin's disease. Radiother Oncol 1986; 5: 15­22. 



13. 
Mauch P, Larson D, Osteen R, Silver B, Yeap B, Canellos G, et al. Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Ciin Oncol 1990; 8: 257-65. 

14. 
Trudel MA, Krikorian JG, Neiman RS. Lympho­cyte predominance Hodgkin's disease. A clinico­pathologic reassessment. Cancer 1987; 59: 99-106. 

15. 
Tefferi A, Zellers RA, Banks P, Therneau TM, Colgan JP. Clinical orrelates of distinct immuno­phenotypic and histologic subcategories of lym­phocyte-predominance Hodgkin's disease. J Ciin Oncol 1990; 8: 1959-65. 

16. 
Cionini L, Bastiani P, Biti GP, Mungai V, Ponti­celli P, Di Lollo S. Waldeyer's ring (WR) involve­ment in Hodgkin's disease. Radiother Oncol 1985; 3: 299-302. 

17. 
Oza AM, Ganesan TS, Leahy M, Gregory W, Lim J, Dadiotis L, et al. Patterns of survival in patients with Hodgkin's disease: Long follow up in a single centre. Ann Oncol 1993; 4: 385-92. 

18. 
Biti GP, Cellai E, Magrini SM, Papi MG, Ponti­celli P, Boddi V. Second solid tumors and leuke­mia after treatment for Hodgkin's disease: an analysis of 1121 patients from a single institution. Int J Radiat Oncol Biol Phys 1994; 29: 25-31. 

19. 
Rodriguez MA, Fuller LM, Zimmermann SO, Allen PK, Brown BW, Munsell MF, et al. Hod­gkin's disease: Study of treatment intensities and incidences of second malignancies. Ann Oncol 1993; 4: 125-131. 

20. 
Swerdlow AJ, Douglas AJ, Vaughan Hudson G, Vaughan Hudson B, Bennett MH, Mac Lennan KA. Risk of second primary cancers after Hod­gkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 1992; 304: 1137-1143. 

21. 
Cionini L, Pacini P, De Paola E, Corrado A,_De Luca Cardillo C. Mungai V, et al. Respiratory function tests after mantle irradiation in patients with Hodgkin's disease. Acta Radio/ Oncol 1984; 23: 401-9. 

22. 
Horning SJ, Adhikari A, Rizk N, Hoppe RT, Olshen RA. Effect of treatment for Hodgkin's disease on pulmonary function: results of a pro­spective study. J Ciin Oncol 1994; 12: 297-305. 

23. 
Carde P, Hagenbeek A, Hayat M, Monconduit M, Thomas J, Burgers MJV, et al. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treat­ment of Cancer Lymphoma Cooperative Group. J Ciin Oncol 1993; 11: 2258-72. 

24. 
Bates NP, Williams MV, Bessell EM, Vaughan Hudson G, Vaughan Hudson B. Efficacy and toxicity of Vinblastine, Bleomycin and Metho­trexate with involved field radiotherapy in clinical stage IA and IIA Hodgkin's disease: a British National Lymphoma Investigation Pilot Study. J Ciin Oncol 1994; 12: 288-96. 





25. 
Glanzmann C, Huguenin P, Lutolf UM, Maire R, Jenni R, Gumppenberg V. Cardiac Iesions after mediastinal irradiation for Hodgkin's disease. Ra­diothr Oncol 1994; 30: 


26. 
Kornblith AB, Anderson J, Cella DF, Tross S, Zuckerman E, Cherin E, et al. Comparison of psychosocial adaptation and sexual function of survivors of advanced Hodgkin disease treated by MOPP, ABVD or MOPP alternating with ABVD. Cancer 1992; 70: 2508-16. 

27. 
Kinsella FJ, Fraas BA, Glatstein E. Late effects of radiation therapy in the trcatment of Hodgkin's diseasc. Cancer Treat Res 1982; 66: 991-1001. 

28. 
Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, ct al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Ciin Oncol 1987; 5: 27-37. 

29. 
Kreuser ED, Felsenberg D, Behles C, Seibt-Jung H, Mielcarek M, Diehl V, et al. Long-term gona­dal disfunction and its impact on bone mincraliza­






tion in patients following COPP/ABVD chemo­
therapy for Hodgkin's discase. Ann Oncol 1992; 
3(S): 105-10. 
30. 
Horning S, Hoppe RT, Hancock SL, Rosenbcrg SA. Vinblastine, bleomycin and methotrexate: an effeetive adjuvant in favorable Hodgkin's disease. J Ciin Oncol 1988; 6: 1822-31. 

31. 
Roach III M, Brophy N, Cox R, Varghese A, Hoppe RT. Prognostic factors for patients relaps­ing after radiotherapy for early-stage Hodgkin 's disease . ./ Ciin Oncol 1990; 8: 623-9. 

32. 
Anderson JE, Litzow MR, Appelbaum FR, Schoch G, FisherLD, Buckner CD, ct al. Allogc­neic, syngeneie and autologous marrow transplan­tation for Hodgkin's discasc: the 21-ycar Seattle experience. J Ciin Oncol 1993; 11: 2342--50. 

33. 
Bierman PJ, Bagin RG, Jagannath S, Vose JM, Spitzer G, Kessingcr A, et al. High dose chemo­therapy followed by autologous hematopoietic res­cue in Hoclgkin's disease: long term follow-up in 128 patients. Ann Oncol 1993; 4: 767-73. 







Postoperative adjuvant chemotherapy with 5-fluorouracyl, adriamycin and cisplatin (F AP) in resectable gastric cancer 
Saša Markovic, Zvezdana Hlebanja, Borut Štabuc 
Institute of Oncology, Department of Medica! Oncology, Ljubljana, Slovenia 
The effectiveness of combined chemotherapy F AP as an adjunct to surgery was investigated in resected gastric cancer patients. OJ 40 pts, 33 were evaluable. All patients were randomly assigned to surgery plus adjuvant F AP or surgery alone. The results have shown no benefit of adjuvant F AP in overall and disease free survival of patients with resectable gastric cancer. In addition, gastro­intestinal intolerance presented a severe drawback and compromised the patients' quality of lije. 
Key words: stomach neoplasms -drug therapy; postoperative period 
Introduction 
Gastric cancer remains a major health problem in Slovenia, despite its decrease during the last decades. The prognosis in patients is poor; the overall five year survival rates are modest and have not increased over 5 % to 12 % .1 The only chance of cure is still offered by surgery, al­though at the tirne of diagnosis only 20-30 % of patients will be amenable to operation.1• 2 Up to two thirds of patients, who have undergone curative resection, present with a recurence and die due to locoregional failure or metastatic disease. In the Western countries there has been no improvement in the prognosis over the past 40 years. The Japanese have however documented both better resectability and im­proved survival rates during the past 30 years. 
Correspondence to: Assist. Prof. Saša Markovic, 
M. D., Ph. D., Institute of Oncology, Zaloška 2, 61105 Ljubljana, Slovenia. 
UDC: 616.33-006.6-089.168.1 

Extended lymphadenectomy has been reported to modify the survival in Stage II gastric cancer, while in stage III only 15 % patients can be cured by surgery alone.3-5 
The failure of surgery to control the disease 
14 

has led to several trials on adjuvant therapy.5­The combination of the drugs used is often the one that has shown satisfactory results in the treatment of advanced gastric cancer. The com­bination of 5 FU, adriamycin and cisplatinum (F AP) is one of the several chemotherapeutic 
. regimens that have proved active against ad­vanced disease and have yielded 50 % response rate.15 This paper, presents the results of a prospective randomized controlled study of adjuvant chemotherapy using F AP combination in operable gastric cancer. 

Materials and methods 

Patients included in the study had undergone resection for histologically proven gastric ade­nocarcinoma. The UICC TNM classification 


was used to define the stage of the disease. Histological subtyping of tumors was done by means of Lauren classification. The patients were randomized either to surgery plus chemo­therapy or to surgery alone. Chemotherapy was started within 6 weeks following surgery. The chemotherapy consisted of 5 fluorouracil (5-FU) 500mg/m2 by rapid i.v. infusion on day 1 through day 5, doxorubicin 30mg/m2 i.v. on day 1, CDDP 20mg/m2 in 15 00ml of 0.5 normal saline i.v. over 2 hours on day 1 through day 
5. The cycle was repeated every 4 weeks. Six consecutive cycles were planned to be given to each patient. Antiemetic therapy was admini­stered routinely. Chemotherapy related toxicity was evaluated using WHO score. Appropriate dose adjustment or discontinuation of therapy was made if extensive toxicity was experienced during the proceeding course or if the patient refused further treatment. In addition, any hi­
stologically proven evidence of local recurrence 
Tota!  FAP  Corrtrol  
Number of patients  33  22  l1  
Sex: male/female  16/17  
Age (years): median (range)  50 (37-62)  
Site of primary tumor  
Pylorus or antrum  20  10  10  
Body  9  9  o  
Cardia or fundus  4  3  l  
Histological type  
Intestinal  12  9  3  
Diffuse  21  13  8  
Surgical procedure  
Subtotal gastrectomy  24  14  10  
Tota! gastrectomy  9  8  1  
Surgical margins status  
Negative  26  16  10  
Positive  7  6  1  
TNMstage  

 7  4  3  
T3A  17  10  7  
T3B  7  7  o  
T4  2  l  1  
N stage  
NO  7  4  3  
Nl  17  9  8  
N2  8  8  o  
N3  1  1  o  
Stage  
II  11  7  4  
IIIA  12  5  7  
HIB  8  8  o  
IV  2  2  2  

or metastatic disease necessitated cessation of FAP treatment. Criteria for recurrence were histological proof or X-ray evidence of metasta­ses. 
Before entry to trial and after completed chemotherapy staging was carried out using chest radiology, ultrasonography or/and CT scan, hepatic and renal function tests and blood count. The patients were followed up in three month intervals; the check comprised a com­plete physical examination and blood chemistry, while repeated staging including gastroscopy was performed every six months in the first two postoperative years, and thereafter in 6 -month intervals. 
The end point of the protocol was to deter­mine the impact of adjuvant F AP on the survi­val and disease-free interval in patients treated by chemotherapy compared to those treated by surgery alone. 
Survival and disease-free interval were calcu­lated using Kaplan-Meier's method. The survi­val was assessed from the day of surgery until death or the most recent visit. The differences between groups were evaluated using log-rank test. 

Results 

The trial was conducted between January 1985 and January 199 0. Fourty patients were entered into the trial; of these 33 were evaluable while 7 patients were !ost to follow up. Patients' characteristics are shown in Table l. There were 17 females and 16 males. Of 33 patients, 9 underwent total gastrectomy and 24 had sub­total gastrectomy. Seven patients underwent gastrectorny with incomplete removal of the prirnary (infiltrated tumor rnargins). For 11 patients surgery was the sole therapy, 21 cases received surgery plus F AP chemotherapy. 
During 5-year observation period, 20 patients 
Table l. Charactcristics of cvaluable paticnts. 
FAP = 5-FU, adriamicin, cisplatinum 


Table 2. Causes of death. 
Clinical causc of death  Tota!  FAP  
No.  No.  No.  
Metastatic disease  11  8  3  
Local recurrence  9  7  2  
Not recorded  3  3  o  
Tumor unrelated  3  2  l  
Tota! deaths  26  20  6  

FAP 5-FU, adriamycin, cisplatinum 
in the treated arm and 6 in the control have relapsed and died. The causes of are shown in Table 2. 
At five years, 7 patients have been alive patients treated by chemotherapy and 5 con­trols. The overall survival for the whole group was 70 % at two years, and 24 % at 5 years (Figure 1), the corresponding numbers for NED being 52 % and 24 % respectively (Figure 2). 
N = 33 
.o 
.-.----.­
12 24 36 48 60 72 84 96 
.Cl'JTHS Figure 1. Overall survival of 33 patients with resectable gastric cancer. 
N = 33 
.500 
o ....,_ __.-.-­
__ -.-.----.--....-, 
O ll . 36 . 00 72 M % 
.=s 


Figure 3. Survival without evidence of disease in 22 patients treated by adjuvant FAP (5-FU, adriamycin, cisplatinum) and 11 patients treated by surgery alone. 
The comparison of the survival between both groups revealed statistically significant (p < 0,0133) difference in disease-free survival in favour of the untreated arm (Figure 3). 
·••fW;»Cllq> ... 25 
-NOTR40!C,II_OP=7 

.750 
.500 
250 
o˝-----.--.-.-' 
.-.-----.-­
12 24 36 48 00 72 84 96 

.Cl'JTHS Figure 4. The influence of radical surgery on survival without evidence of disease. 
A group analysis showed that patients who unde1went radical surgery managed significant­ly better (p < 0,0015) than those who had incomplete resection (Figure 4). Adjuvant the­rapy worsened the survival in radically operated gastric cancer patients (Figure 5). The diffe­rence was however of borderline significance (p = NS). The histological type of the tumor bas not exerted any influence on the survivals (P = NS) (Figure 6). 
Side effects experienced by patients on che­

Figure 2. Survival without evidence of disease in 33 patients with resectable gastric cancer. motherapy are summarized in Table 3. Chemo­


.750. 
.500 
250 
Figure 5. The influence of adjuvant chcmotherapy on thc survival without evidence of discase in 26 radically opcratcd gastric cancer paticnts. 
.750 
.500 
250 

MONTHS 

Figure 6. The influence of histology (Laurcn classifica­tion) on the survival without evidence of discasc in 
33 rcsccted gastric cancer patients. 
therapy was discontinued after two or three courses in 9 ( 46 % ) patients because of poor gastrointestinal tolerance. Only 12 patients ( 54 % ) completed the planned therapy. There were no deaths related directly to chemotherapy in this study. 
Table 3. Side effects of treatment with FAP (5-FU, adriamycin, cisplatinum). 
Side effect _{_Grade 3-4) No(%) 
Nausea/vomiting 15 (68%) Alopecia 16 (72 %) Nephrotoxicity 2(9%) Neurotoxicity 1 (4,5%) Hemotoxicity 6 (27%) 
MONTHS 

Discussion 

The role of systemic combination chemotherapy in the standard treatment for stomach cancer is limited to palliation. The most popular regi­mens used in gastric cancer treatment in Europe and the United States, such as FAB, FAM and F AP induce an objective response rate of 30­40 % . 12• 13• 15· 16 The F AP combination has been shown to be the most promising chemotherapy schedule at the beginning of the study, with a 50 % response rate in advanced gastric cancer patients. 15 These results have suggested that FAP should be tested in patients with resectable gastric cancer. 
The discussion of whether adjuvant chemo­therapy is of any benefit in the treatment of gastric cancer is stili open. Conflicting results have been obtained so far.6 ·7· 9 -12·15 Therefore this kind of chemotherapy is used in resectable gastric cancer solely in randomized clinical trials. Severa] studies of adjuvant chemotherapy using different drug combinations have been conducted but have failed to demonstrate any benefit in improved survival.3• 6• 7• 9• 12 There was however a suggestion that patients with T3 ­T4 tumors do benefit from such treatment. Even though no statistically significant differen­
ces in the survival were established, a lower number of recurrences was found in the treated 
6 

arms. 
The Japanese5 have however reported a sig­nificant beneficial effect of combined chemo­immunotherapy in 1805 resected gastric cancer patients followed up for 5 years. Patients given immuno-chemotherapy survived longer than those treated by surgery alone. A curatively operated stage III subgroup seems to benefit the most from postoperative immuno-chemo­
5• 17 

therapy, 4· 
the beneficial effect was related to tumor infiltration by dendritic cells.17 A combination of mitomycin, tegafur and PSK has become the most popular regimen for adju­vant treatment of gastric cancer in Japan. 5• 1 6 
In adjuvant studies the stage of the disease (TNM), was shown to be the most important prognostic factor; this was followed by subtype 
using Lauren classification, and site of the pri­mary tumor.1· 17· 18 

The results of this study have shown that the overall survival of all patients from both arms is not inferior to the survival data reported in patients with potentially curative resection for gastric cancer. 1· 2 The finding of a significantly higher survival in nontreated arm compared to the treated arm, however, disagreed with other reports. By additional analysis of subgroups with different prognostic factors, it was shown that despite the random selection of operated patients, the unfavorable prognostic factors were all more prominent in the treated group. The treated group comprised six nonradically resected cases and all cases with N2 and N3 nodal involvement, vs. one nonradically resect­ed and none N2 and N3 case in the control arm. In the German Gastric study, the survival was shown to be mainly dependent19 on the absence of residual tumor. Non-radical resec­tion shortened the survival. The results of the present study are in accordance with that fin­ding. However the Gastrointestinal Tumor Study Group have found a 5 year survival rate of 17 % obtained by chemotherapy plus radio­therapy in patients with microscopic locally recurrent or residual gastric cancer after surge­ry. 20 In our treated group none of the patients survived 5 years and all were dead within the first postoperative year. 
Diffuse type carcinoma has been connected with worse prognosis in gastric cancer pa­
18 
tients.17 · Statistically insignificant difference was shown also in the present study. Diffuse type was found to be the predominant histolo­gical type in the whole observed group with no difference between the two arms. The result shows that the worse outcome in the treated group was not related to the difference in tumor histology. 
Adverse effects of the drug combination, especially gastrointestinal toxicity, posed a se­vere problem and required cessation of therapy in 46 % of patients. Nausea and vomiting grade 3 and 4 were the reasons for patients' refusal of further therapy. 
The results reported here indicate that as 

best this regimen can not be of benefit to patients with operable gastric cancer. In fact, there was a decreasing trend in the survival of the FAP treated patients. In view of the nega­tive impact on survival, it would be reasonable not to conduct any further trials with this drug combination in adjuvant settings. However, the study included only 33 patients, and group evaluation revealed that despite randomisation, the differences between arms were very promi­nent. In future, studies of adjuvant therapy must comprise a sufficient number of cases to enable satisfactory evaluation. 
References 

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2. 
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3. 
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4. 
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5. 
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6. 
Lise M, Nitti D, Buyse Met al. Adjuvant FAM2 in resectable gastric cancer. Anticancer Res 1989; 9: 1017-22. 

7. 
Bleiberg H, Gerard B and Deguiral P. Adjuvant therapy in resectable gastric cancer. Br J Cancer 1992; 66: 987-91. 

8. 
Wu YF. Adjuvant chemotherapy of gastic carcino­ma: A pilot study of oral administration of inject­able 5-fluorouracil. J Surg Oncol 1985; 28: 227-9. 

9. 
Coomber RC, Schein PS, Chilvers CED, Wils J and International Collaborative Cancer Group. A randomized tria! comparing adjuvant fluorouracil, doxorubicin, and Mitomycin with no treatment in operable gastric cancer. J Ciin Oncol 1990; S: 1362-9. 





10. 
Douglass HO, Stabclin DM, Marsh J ct al. Adju­vant therapy after curativc resection of gastric cancer. Gastrointcstinal tumor study group (GITSG). [Abstr] Proc Annu Meet Am Soc Ciin Oncol 1991; 10: A439. 

11. 
MacDonald JS, Gagliano R, Fleming T et al. A phasc II tria! of FAM chemotherapy vs control as adjuvant treatment for resected gastric cancer: A Southwest Oncology Group tria! (SWOG 7804). [Abstr] Proc Annu Meet Am Soc Ciin Oncol 1992; 11: A488. 

12. 
Figoli F, Galligioni E, Crivellari D et al. Evalua­tion of two consecutive regimens in advanced gastric cancer. Cancer In vest 1991; 9: 257-62. 

13. 
Carter SK. Adjuvant chemotherapy of canccr. A review of its currcnt status. Drugs 1986; 31. 337­67. 

14. 
Lise M, Natti D, Marchet A and Fornasiero A. Adjuvant treatment for gastric cancer. Anti Cancer Drugs 1991; 2: 433-45. 

15. 
Moertel C, Rubin J, O'Connell MJ, Schutt AJ and Wieand HS. A phase II study of combined 




5-fluorouracil, doxorubicin, and dsplatin in the treatmcnt of advanced uppcr gastrointestinal adc­nocarcinomas. J Ciin Oncol 1986; 4: 1053-7. 

16. 
Wils J and Bleiberg H. Current status of chcmo­thcrapy for gastric canccr. Eur J Cancer Ciin Oncol 1989; 25: 3-8. 

17. 
Schmitz-Moormann P, Hcrmanck Pand Himmel­mann GW. Morphological predictors of survival in early and advanccd gastric carcinoma. I Cancer Res Ciin Oncol 1992; 118: 296-302. 

18. 
Jakesz R, Dittrich C, Funovics J et al. The effect of adjuvant chcmotherapy in gastric carcinoma is depcndent on tumor histology: 5-ycar rcsults of a prospective randomizcd tria!. Recent Results Can­cer Res 1988; 110: 44-51. 

19. 
Rodhe H, Gebbensleben B, Bauer Pet al. Staging gastric cancer; is there any improvement? Cancer 1989; 64: 2465-81. 

20. 
Thc Gastrointestinal Tumor Study Grouyp: A combination chemotherapy and combined moda­lity therapy for locally advanced gastric carcinoma. Cancer 1982; 49: 1771-7. 










Survival of stage I Jung cancer patients with previous or subsequent primary malignant neoplasms 
Oleg A Vasiljev, Vladimir P Kartchenko, Igor V Kouzmine 
Moscow Research Institute of Diagnosis and Surgery, Moscow, Russia 
Fram 1965 to 1990 2161 patients underwent the complete resection for lung cancer. In 910 cases stage I was histologically proved. pTI -375 (4! %), pT2 -532 (58,7%). There were 90,9% cases observed more then 5 years, 60,2 % -10 years. Ninetysix (10,6 %) patients were found to have second primary neoplasms before or after the curative treatment of stage I lung cancer. 13 (13,5 %) patients died due to subsequent primary malignancy, 17 (17%) -of other causes. Crude 5-year survival of stage I lung cancer patients was 65 %, 10-year survival was 53 %. In the group of 96 cases with multiple neoplasms accordingly 73 and 53 %. Our data confirm that the relative probability of the second primary malignancy increases in time of monitoring after the curative surgery or the combined treatment and depends on the spread of tumor (TNM factors) in connection with indirect influence on the survival. In early lung cancer second primary neoplasms after the curative treatment do not influence forma! indices of survival. The paper discusses the results of adjuvant methods of treatment in connection with multiple primaries. 
Key words: lung neoplasms -mortality; survival rate; neoplasms second primary 
Introduction 

Every item of multiple'cancer with lung prima­ries (MCLP) has been intensively discussed for many decades but some of them haven't been studied properly. One of the inadequately stu-
Corrcspondence to: Olcg A, Vasiljev, M.D., Moscow Research Institute of Diagnosis and Surgery, 117837, GSP7, Profsojuznaya str. 86, Moscow, Russia. Fax: 
+ (095) 334-79-24, Email: DIRECTOR mniidih, MSK, SV. 
The paper was prescnted at the 2nd Central European Confercnce on Lung Cancer; Ljubljana -Slovcnia, April 13-16, 1994. 
UDC: 616.24-006.6-036.8 
died problems is the survival of patients with early lung cancer. In the first place stage I patients have the curative treatment more fre­quently. Secondly, the survival is significantly longer. On the other hand, after organ-preser­ving surgery, a large vol ume of spare lung tissue with precancer changes rests the poten­tial source of multiple growth. Moreover, there are many more possibilities for the realization of the curative surgery for the second and even third tirne. A repeated radical treatment is based on the certainty of pathologic determina­tion of the new primary and the stage of its development. 
The problem of MCLP plays the important role in the estimation of long-term results of 
radical treatment. Generally, in order to leave out the influence of MCLP on survival, this kind of patients is not included in the analysis of clinical material. But this group of patients is the most important part of treatment program and constitutes up to 10-12 % of cases. At the same tirne, in most publications only mean duration of life in years and months was repor­ted. According to general statistics, the crude 5-year survival of MCLP was near 30 % with the consideration of ali stages of the disease. 
Material and methods 

During the years 1965-1990 2161 patients were operated in Moscow Research Institute of Diag­nosis and Surgery. Stage I of the disease was stated histologically in 910 cases. TIS -3, TlNO -375, T2NO -532 patients. Remote results were estimated to 05.05.92 (Kaplan­Meyer method). There are 827 (90,9 % ) pa­tients who have been observed for five years and 551 (60,3 % ) patients for 10 years. In 96 (10,6 % ) patients of 910 cases MCLP was de­tected. There are 48 patients who are stili alive (Table 1). For the verification of multiple pri­maries generally accepted criteria were used.1 

Results and discussion 

Among 234 patients with central type of cancer the incidence of MCLP was 16,2 % , in periphe­ral (297) 

14,4 % ( p > .05). It is important to underline the similar incidence of central and peripheral multiple Jung cancer. It concerns extrathoracic primaries as well. The risk of second primary in TlNO patients is twice grea­ter than in T2NO patients. The difference is significant (p < .02) without any connection with clinico-pathologic forms of Jung cancer. 
Table l. Alive after curative trcatment of stagc I Jung cancer. 
Tota!  No recurrence  With progr.  MCLP  
415  336  29  48  
100%  81,4%  7%  11,6%  


The mean diameter of ·the primary pulmonary tumor in MCLP patients was 34 mm, in solitary lung cancer -30 mm (p > . 05). 
The incidence of MCLP has been studied for comparison in 90 operated TlNl 

2 lung cancer patients. In this group 6,8 % of MCLP patients were found. 
Age and sex 
The mean age of MCLP patients (Stage I) was 57,9 years, of others 

55,6 (p< ,005). In pa­tients of 60 years old and younger the incidence of MCLP was 8,3 % , in an elderly group of patients -15,3 % (p < .05). The direct correla­tion of MCLP was not found but the annual relative risk of second malignant tumor was on average 2 % . During postoperative monitoring of patients two picks of increasing of multiple lesions of respiratory tract in 1-2 and 4-5 years after the radical treatment were observed. The same data have been already mentioned in the literature. 2 
Seventeen (18 % ) MCLP patients were wo­
men. In the group of multiple cancer of respir­
tory tract patients women represent 7,1 % ca­
ses. In the entire group MCLP was observed 
in 12 % of women and in 10 % of men. The 
difference is not significant. 
So the possibility of MCLP development is connected with the stage of the lung cancer and the period of monitoring: factors with direct influence on the survival of cancer patients. The risk of a new primary tumor seems to be equal for ali stages, however, the incidence of MCLP is lower due to the shorter follow-up period. The majority of new cancers would appear only a few years after the primary treatment, i.e. only after the patients with advanced tumors already died. 
Localization of MCLP 
In 52 (55,8 % ) patients the second cancer was found in lung, in 6 (6,3%) 

larynx, in 4 ( 4,3 % ) -stomach, 3 (3,2 % ) -esophagus, 2 
both diseases, every new malignant tumor does not significantly impact the formal survival of stage I lung cancer patients. 
3. 
The adjuvant irradiation of curatively trea­ted patients does not produce the essential influence on the incidence of MCLP respiratory and extrathoracic localization and does not cor­relate with the long term results. 

4. 
The influence of the modem chemothe­rapy (neoadjuvant including) could not be defi­nitely proved. But according to our limited experience (without randomization) we could assume that chemotherapy decreases the risk of second primary cancer with stage I lung cancer patients. 




References 

1. 
Martini N, Mclamcd M. Multiplc primary lung canccrs. J Thorac Cardiovasc Surg 1975; 70: 606­12. 

2. 
Razzuk MA, Rockcy M, Urschcll HC, Paulson DL. Dual primary bronchogcnic carcinoma. Ann Thorac Surg 1974; 17: 434-43. 

3. 
Peloquin A, Poljicak M, Falardcau M, ct. al. Survival of breast canccr paticnts with prcvious or subscqucnt ncoplasms. Canad J Surg 1992; 35: 481-85. 

4. 
Margolese RG. Survival of brcast cancer patients with previous or subsequcnt neoplasms. Canad J Surg 1992; 35: 476-80. 






The air kerma-rate constant of high dose-rate Ir-192 sources 
Matthew B. Podgorsak,1 Larry A. DeWerd, and Bhudatt R. Paliwal 
Departments of Medica! Physics and Human Oncology, University of Wisconsin, Madison, Wisconsin, 53792. 1 Present address: Department of Radiation Medicine, Roswell Park Cancer Institute Buffalo, New York 14263 
The current value of the air kerma rate constant used in dosimetry calculations for high dose-rate (HDR) lr-192 sources is based on photon spectral information obtained with low activity lr-192 sources clifferent in size and encapsulation from the HDR lr-192 sources used today. Since source configuration has been shown to affect the photon spectrum emitted by a radionuclicle, the purpose of this work is to measure the photon spectrum emitted by an HDR lr-192 source. To simplify the spectral measurements and increase the accuracy of the resulting spectrum, an Ir-192 source identical dimensionally to a clinical source but activated to as low an activity as technically possible was obtained from the manufacturer. Spectral measurements were made with a high purity germanium detector interfaced to a multichannel analyzer. It was found that the HDR source capsule attenuates photons with energies below 500 ke V. In fact, no photons with energy below 60 ke V can be identified in the HDR lr-192 photon spectrum, even though the decay of Ir-192 results in severa! characteristic x-rays in this energy range. As a result, the fluence-weighted and energy-fluence-weighted average energies of the HDR lr-192 spectrum were found to be 371 and 402keV, respectively, higher than the average energies of a bare lr-192 source. A calculation of the HDR lr-192 air kerma-rate constant 
18 2 1 

based on the measured photon spectrum gives a value of (29.02 ± 0.26) x w-Gy m Bq-1 s-, -5 % lower than the value currently associated with HDR lr-192 sources. The serious potential clinical implications resulting from this cliscrepancy in air kerma rate constant strongly support the abolishment of source activity in Javor of reference air kerma rate for HDR lr-192 source strength specification. 
Key words: brachytherapy; iridium radioisotopes; radiotherapy dosage; spectrum analysis; photons 






Introduction 
Presently, the most commonly used high dose­rate (HDR) remote afterloader in North Ame­rica is the Microselectron (Nucletron Corpora-
Correspondence to: Matthew B. Podgorsak, Ph.D., Department of Radiation Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263. 
UDC: 615.849.2:539.12.08 

tion, Leersum, Holland). This unit houses a single iridium (Ir-192) source with a nominal activity of 370 GBq (10 Ci) attached to a stain­less steel cable. The source is driven by remote· control between the storage safe located at the unit and user-programmed positions within the lumen of applicators implanted inside a patient. Treatment planning algorithms calculate the <lose distribution in these implants using a for­malism which includes several variables that describe the radiation properties of the HDR 
Ir-192 source.1• 2 Currently, it is predominately low dose-rate (LDR) Ir-192 decay data that is used in HDR Ir-192 dosimetry calculations. Recent characterizations of the HDR Ir-192 source, however, have shown that some radia­tion parameters are highly source-type speci­fic, 3· 4 suggesting that the use of LDR Ir-192 decay data in dosimetry calculations for HDR Ir-192 implants may be inappropriate. 
One radiation parameter that has not yet been specifically determined for HDR Ir-192 sources in the air kerma-rate constant (r6)K. This quantity, in units of Gy m2 s-1 Bq-1, is defined by the photon spectrum emitted by a source and is related to the exposure rate constant (r0)x. Assuming a value 33.97 J/C for (W/e)ain it can be shown that the ratio of (r0)K to (r0)x is 6.58 x 10-17 Gy R-1 h s-1 Ci Bq-1. There have been many publications that have reported values of (r6)x for Ir-192 sources 
2 
ranging from 0.400 to 0.496 R mCi-1 11-1 ((ro)K = 26.3 x 10-18 to 32.6 x 10-18 Gy m2 
1 

s-Bq-1). 5-7 Recently, Ninkovic and Raicevic8 reported a value of 30.0 x 10-18 Gy m2 s-1 Bq-1 for the air kerma rate constant of an unfiltered Iow dose rate Ir-192 source. For an Ir-192 source encapsulated in 0.15 mm of platinum, 
1 
they quoted a value of 27.8 x 10-18 Gy m2 s­Bq-1, approximately 7 % lower than for the unfiltered source. 

The Iarge variation in the air kerma rate constant for Ir-192 sources in different configu­rations clearly demonstrates a strong depen­dence of this quality on source design, particu­Iarly the type and thickness of encapsulation surrounding the active source material. Because the design of an HDR Ir-192 source is different from any other Ir-192 source, it is not apparent which of the previously reported values of (r o)K should be used in HDR Ir-192 dosimetry calcu­Iations. A value of 30.66 x 10-18 Gy m2 s-1 Bq-1 
(0.466 Rm2 Ci-1 h-1) has been adopted by ma­nufacturers of the source and severa! brachythe­rapy treatment planning systems, while standar­dized calibration Iaboratories use a value of 
30.24 X 10-18 Gy m2 s-1 Bq-1 (0.4596 Rm2 Ci-1 h-1). This latter value is calculated from a theoretical modeling of the HDR Ir-192 spec­trum based on attenuation in the source encap­sulation of known photons emitted from Ir-192. Although both these values are well within the range of those previously reported, they are significantly different from each other and, fur­thermore, the methodology used in their deter­mination is not in ali cases entirely clear. It is the purpose of this paper to describe a measu­rement of the HDR Ir-192 photon spectrum and a subsequent evaluation of the air kerma­rate constant for these sources. 


Materials and methods 

HDR Ir-!92 source driven by the Microselectron 
The activation of an HDR Ir-192 source requi­res approximately 6 weeks of irradiation by the typical thermal neutron fluxes in most reactors used to produce these sources.9 Prior to place­ment inside a reactor, the major component of the source material is expected to be Ir-191. The most likely activation therefore follows the Ir-191 (n, y) Ir-192 reaction. Once activated to an activity of ~ 370 GBq, the source is removed from the reactor and carefully encapsulated in a stainless steel capsule. Even though techni­cally more difficult, encapsulation of the source must be done only after activation. This is because some components of stainless steel (mostly iron-58, chromium-50, and cobalt-59) have non-negligible neutron activation cross­sections and could themselves be activated by thermal neutrons and contaminate the HDR source photon spectrum. 10• 11 The source manu­facturing process is completed by welding a stainless steel cable to the source capsule. The manufacturer (Mallinckrodt Diagnostica, Pet­ten, Holland) then waits approximately one week before releasing the source for clinical use. This delay allows the Ir-194 contaminant, produced alongside Ir-192, to decay to the point where it will not contribute significantly to the energy spectrum of a clinical HDR Ir-192 source. 
The most recent HDR Ir-192 source, shown 

schematically in Figure 1, 2 was introduced in 
1

June 1991. In this design, the source capsule is 
5.0 mm long with a diameter of 1.1 mm and a wall thickness of 0.25 mm. The active source material inside the capsule is 3.5 mm long and 
0.6 mm in diameter. The center of source acti­vity is 2 mm from the tip of the capsule. 
Photon spectroscopy system: Description 
Photon pulse-height spectra (PHS) were measu­red with a system consisting of a high-purity germanium (HPGe) detector (Canberra Indu­stries, Inc., Meriden, CT) interfaced to a 4096 channel analyzer (MCA). The detector element was a coaxial germanium crystal (p-type) moun­ted in a cryostat consisting of a vacuum chamber thermally coupled to a liquid nitrogen heat sink. The impurity concentration in the germa­nium crystal was on the order of 1010 atoms/cm3 The crystal was held in place inside the cryostat . by an aluminum holder 0.5 to 1.0 mm thick. The outer vacuum jacket was also made of aluminum, 1.5 mm thick on the sides and 
0.5 mm thick at the entrance window. The HPGe crystal face was located 5 mm from the inside wall of the entrance window. A bias of 1000 V was applied to the crystal during acqui­sition of pulse height spectra. 
Photon spectroscopy system: Detector 
calibration 
Calibration of the spectroscopy system was done using standard Cobalt-60 (Co-60) and Europium-152 (Eu-152) sources (set no. 1718, Amersham International, Arlington Heights, IL). For acquisition of pulse-height spectra, the Eu-152 and Co-60 sources were positioned 50 cm from the front surface of the detector element (49.5 cm from the detector faceplate). The acquisition times were 4200 and 900 se­conds, respectively. Any scattering surface was at least 1 m from both the source and detector crystal. A background spectrum was collected over a period of 1628 seconds, and was prorated 
to either 4200 or 900 seconds. The number of . counts N(c) in the vicinity of eack peak in the background-corrected Co-60 and Eu-152 pulse height spectra was then fitted with the following 
equation: 
C -a3)2a4 

N(c) = a1 + a2exp [ -( ·· ] + a5(a3-c), (1) 
where c is channel number. Equation (1) inclu­
des terms for the following four components of 
the pulse-height spectrum in the vicinity of each 
peak: (1) a smoothly varying background signal 
produced by Compton interactions of higher 
energy photons in the detector crystal followed 
by escape of a scattered photon, (2) a Gaussian 
contribution from photoeffect interactions 
where the photon energy is entirely deposited 
in the detector with ali resulting charge collec­
ted, (3) a low energy tail on the Gaussian 
distribution arising from imperfect charge collec­
tion in some regions of the detector or secondary 
electron or bremsstrahlung escape from the ac­
tive volume, and (4) a step-like rise or fall in 
the Compton continuum due to Compton pro­
cesses where the recoil electron receives almost 
ali of the transferred energy. 
Next, the parameters of Eq. (1) were used to 
derive two calibration models. The first was a 
second order polynomial in channel number 
relating the energy of a photon to the center of 
its Gaussian distribution. The correlation coeffi­
cient for the fit was 0.99999998, demonstrating 
an excellent fit. The second model, initially 
proposed by Singh, 13 related the efficiency for 
a full-energy event to the energy of the photon 
interacting in the detector. The maximum devia­
tion of the model-predicted efficiency and the 
experimental values used in its determination 
was 3.4 % , although most deviations were 
< 1 % . The magnitude of these deviations is 
typical for a calibrated HPGe detector. 3 
1

Lower activity HDR Ir-192 source 
To simplify the spectral measurements and in­crease the accuracy of the resulting spectrum, an Ir-192 source activated to as low an activity 
as technically possible was obtained from the manufacturer (Mallinckrodt Diagnostica, Pet­ten, Holland). The source was physically identi­cal to the clinical HDR Ir-192 source shown in Figure 1, except its activity was much lower, 
Stainlcss stccl 
Iridium cnblc 
Drive metni 
J 
0.6mm 
T 

Figure l. Schematic diagram showing a cross-scction through the center of an HDR Ir-192 sourcc remotely afterloaded by the Nucletron Microselcctron. Thc diagram shows the most recent source design. The source is encapsulated in a 0.25mm thick stainless steci capsule and a stainless steel cable connects the source capsule to the mechanical drivers inside the afterloader. 
thus minimizing the effects of pulse pile-up and detector saturation on the measured pulse height spectrum. An initial calibration of the source was done with an HDR-1000 well ionization chamber (Standard Imaging, Middleton, WI), itself calibrated with a clinical HDR Ir-192 source whose air kerma strength had been deter­mined using the inverse-square method. 14• 15 The signal to noise ratio for ionization current rea­dings with this source was > 600. The air kerma strength of the source was found to be 
1.929 x 10--0 Gy m2 h-
1. According to the HDR­1000 calibration certificate, the uncertainty in this value is ± 2 % . In practite, though, the error is most likely very much less than 1 % , and will be neglected in the remainder of this paper. A second calibration done approximately two weeks later and just before acquisition of the pulse height spectrum gave an air kerma strength of 1.692 x 10--0 Gy m2 h-1• Over the 14 day period of tirne between calibrations, the source decayed with a half-life of 73.833 days, in excellent agreement with the recently repor­ted half-life for decay of clinical HDR Ir-192 
16 
sources. A schematic diagram of the set-up used for the measurement of the HDR Ir-192 pulse 

height spectrum is shown in Figure 2. The source was suspended in air at a height of 120cm above the ground at a distance of 130 cm from the front end of the detector element 
(129.5 cm from the detector faceplate). This extended source-detector distance was necessary to reduce the effects of pulse-pileup and detec­tor saturation. The detector was placed at the end of a table at a height that centered the source on the detector faceplate. Only air was between the source and the detector faceplate. The operating parameters of the spectroscopy system were identical to those used for system calibration. 
/ 
HPGe dctector HDR Ir-192 ',
Wood table source 1 I Steel 
support 
111111 
\ 1 . 


.I[---129.5cm ------. .. .! 
0.55 cm 
120cm 
..L 

Figure 2. The experimental set-up for the mcasure­mcnt of the HDR Ir-192 pulse height spectrum. The walls in the room were ali at least 100 cm either the detector or the source . 



Results 

HDR Ir-192 pulse height spectrum 
The background corrected pulse-height spec­trum for the lower activity HDR Ir-192 source is shown in Figure 3. The acquisition tirne was 1254 seconds. The spectrum is comprised of 16 peaks superimposed on a varying Compton background. Analysis of the spectrum consisted of fitting Eq. (1) to the number of counts in the vicinity of each peak ( approximate peak center ± 38 channels). In the case of a doublet, where the events from one gamma ray could contribute to the distribution of a nearby peak created primarily by a different gamma ray, the sum of two such equations was fit to the pulse height spectrum in the vicinity of the two peaks comprising the doublet. In this work, the crite­
-----. Table l. Fitting and efficiency data for the HPGe 

detcctor used in this work. The numbcrs in brackets are the unccrtainty in the value above each bracket. 
Position of Photon Efficicncy arca(E) Pcak maximum encrgy E (count* 
TJ(E) 
(channcl) (keV) (xl0-4) channel) 

(a) 179.83 64.72 2.8000 118836.11 (0.12) (0.05) (3976.51) (b) 206.33 74.29 2.8000 58822.17 (0.21) (0.08) (3567.71) 
(c) 558.69 201.55 2.0035 13941.29 (1.73) (0.62) (4665.31) 5000 (d) 570.37 205.77 1.9006 80685.99 
(0.23) (0.08) (4143.62) (e) 820.12 295.96 0.9767 549015.61 
Figure 3. Backgound-corrected pulse hcight spectrum 
measured with an HDR Ir-192 sourcc. The acquisition 
(f) 
tirne was 1254 seconds. 
(0.02) (0.01) (3155.69) 
854.75 308.46 0.9250 539980.08 
(0.02) (0.01) (2888.58) 877.03 316.50 0.8951 1455272.55 

rion for a doublet was the. existence of two 
peaks within 30 channels of one another. Simi­(h) larly, a triplet would be identified if there were
(0.01) (0.01) (4305.75) 
1037.25 374.35 0.7278 10258.73 
(0.27) (0.10) (834.69) 

three peaks within 60 channels. In the HDRIr-192 pulse height spectrum shown in Figure3, peaks (a) and (b), (c) and (d), (f) and (g),
(k) and (1), and (n) and (o) were considereddoublets; there were no triplets.
The position of each peak's center and thecorresponding photon energy calculated fromthe calibration curve described above are listed in Table l. The full-energy peak efficiencymodel derived with the calibration sources can­not be used directly with the Gaussian peakareas listed in Table l. This is because the HDR Ir-192 pulse height spectrum was obtainedwith the source at a distance of 130 cm from the detector element, while the calibrationcurve was evaluated with pulse-height spectrameasured at a source-detector distance of 50 cm. The measured peak area was correctedwith a simple multiplicative correction factorbased on geometrical considerations: 
[130

area(E) = a(E) 50 ] 2 exp{µ(E)[l30-50]}, (2) 
where µ,(E) is the linear attenuation coefficientin air (in cm-1) for a photon of energy E,17 a(E)is the area of the Gaussian distribution corres­ponding to that photon in the measured pulse­height spectrum (source-detector distance = 130cm), and area(E) is the area that would 
(i) 1154.60 416.72 0.6376 8997.67 (0.42) (0.15) (1127.94) G) 1296.86 468.07 0.5502 531067.19 (0.01) (0.01) (1974.23) (k) 1342.63 484.59 0.5260 34556.46 (0.06) (0.02) (669.86) (1) 1355.55 489.25 0.5195 3662.26 (0.44) (0.16) (579.75) (m) 1630.74 588.58 0.4066 38703.94 (0.04) (0.01) (466.05) (n) 1674.67 604.43 0.3934 67144.46 (0.04) (0.02) (860.98) (o) 1696.91 612.45 0.3855 42126.47 (0.06) (0.02) (813.53) (p) 2450.51 884.30 0.2402 1723.80 (0.24) (0.09) (121.64) 
have been measured were the source-detector distance equal to that in the calibration geome­try (50cm). The equivalence of energy calibra­tion curves measured at different distances with identical detector operating characteristics hasbeen demonstrated by Kamboj et al. 18 They measured the full-energy peak efficiency for an HPGe detector with radium-226 (Ra-226) sour­ces placed at distances of 53.5 and 164cm fromthe detector, and they found identical calibra­tion curves once inverse square fall-off photonfluence and photon attenuation in the air bet­ween the two measurement points were accoim-ted for. Table 1 lists each identified photon inthe HDR Ir-192 pulse-height spectrum along 
with its efficiency for a full-energy interactionwith the detector and the corrected area under the peak evaluated using Eq.(2). 
Air k.erma rate constant 
The air kerma strength Kair of the HDR Ir-192 source at the beginning of the acquisition ofthe pulse height spectrum was 1.689 x 10-6 Gy 
m2 
h-1 (4.692 X 10-10 Gy m2 s-1) ± 2 % It can be shown that over the acquisition tirne of the HDR Ir-192 pulse height spectrum (t = 1254 seconds) the total air kerma was 5.883 X 10-7 Gy m2 ±2%. 
The emission frequency f(E) of each identi­fied photon of energy E in the HDR Ir-192pulse height spectrum, given in units of numberof photons emitted per parent decay, is givenby: 
Substituting Eq. ( 4) into Eq. (3) gives area(E)· ]-1 

[ K f(E) 


(5) ri(E) (ro)K 
Solving Eq. (5) for (I'1i)K results in the followingequation for the air kerma rate constant: 
f(E) ri(E) Kair (ro)K = ----.(6) 
area(E) 
The necessary information to evaluate (r 0)K using Eq. (6) for the HDR Ir-192 source has either been determined in this work (ri(E), Kair, area (E)) or can be estimated from the litera­ture (f(E)). The full energy peak efficiencyri(E) and the corrected area area(E) are listedin Table 1. The uncertainty in the correctedareas listed in Table 1 vary greatly dependingon the peak. Not surprisingly, the four lowestfractional uncertainties occur with the four most prominent peaks in the pulse-height spectrum.These uncertainties range from 0.3 to 0.6 % forpeaks representing the following energies:295.96, 308.46, 316.50, and 468.07 keV. The uncertainties in the corrected area of the other peaks are ali > 2 % , too high to suggest useof data from these peaks in Eq. (6).

To approximate f(E) for a photon of energyE in the HDR Ir-192 photon spectrum, theemission frequencies for a bare Ir-192 source19 can be corrected for photon attenuation in thestainless steel encapsulation surrounding the
area(E) 
f(E) 
ri(E)N 
where area(E) in the corrected area under eachfull energy peak, ri(E) is the full-energy peakefficiency, and N is the to tal number of decaysof the parent atom. Calculating the number ofHDR lr-192 decays from the pulse height spec­trum shown in Figure 3 is imprecise since theCompton continuum upon which the full-energyevents are superimposed is not negligible, andthe true detector crystal collecting volume isnot known. It is, howewer, possible to relateN to the air kenna Kair as follows: 

HDR Ir-192 source. Assuming stainless steel tobe equivalent to iron in attenuation characteri­stics and using attenuation coefficients found inthe literature, 17 the correction for attenuation in the encapsulation represents a 1. 7 % decreasein f(E) for the 468.07 ke V photon and a 2.1 %decrease in f(E) for the 295.96, 308.46, and 316.50keV photons. The corrected emissionfrequencies to be used in Eq. (6) are therefore0.277, 0.287, 0.813, and 0.469 for the followingphotons, respectively: 295.96, 308.46, 316.50,and 468.07 keV. Using Eq. (6) with pulse heightspectrum data from each distribution correspon­ding to these four photons and the air kerma
K· 
(ro)K 

calculated above gives the following respectivevalues of (r6)K: (29.02±0.53)x10-18, (28.95 ± 0.46)x10-18, 
(29.41 ± 0.20)x10-18, and 

(28.62 ± 0.53)x10-18 Gy m2 Bq-1 s-1• These values are ali equal within experimental error.The average value is (29.02 ± 0.26)x10-18 Gy 
m2 
Bq-1 s-1 (0.441 ± 0.004 R m2 Ci-1 11-1). 

Discussion 

Table 2 lists the energy and emission frequencyof each photon component of the Ir-192 decayscheme described above alongside those of the 
Table 2. HDR Ir-192 photon spectrum components comparcd to unencapsulatcd Ir-192 spectral 
Photon  Emission  Emission  
Photon energy  energy  frcqucncy  frequency  
Peak  (HDR Ir-192)  (rcf. [19])  (HDR Ir-192)  (ref. [19])  
(keV)  (kcV)  (y's/dccay)  (y's/decay)  
7.822  0.00027  
8.266  0.00076  
8.904  0.0060  

 9.337  0.000083  
9.435  0.0164  
9.975  0.000270  
10.469  0.0063  
11.174  0.0177  
12.213  0.00113  
13.025  0.00317  
61.485  0.0116  
(a)  64.72 ±0.05  63.000  0.021 ± 0.002  0.0200  
65.122  0.0266  
66.831  0.0456  
71.313  0.0069  
(b)  74.29±0.08  73.643  0.010 ± 0.001  0.00174  
75.634  0.0159  
78.123  0.00415  
136.34347  0.00181  
177.00  0.000073  
(c)  201.55 ± 0.62  201.3805  0.003 ± 0.0005  0.00455  
(d)  205.77 ± o.os  205.79581  0.021 ± 0.001  0.0318  
219.221  0.000016  
283.2671  0.00252  
(c)  295.96 ± 0.01  295.9582  0.277±0.011  0.283  
(f)  308.46 ± 0.01  308.45689  0.287 ± 0.012  0.293  
(g)  316.50 ± 0.01  316.50789  0.801 ± 0.033  0.830  
329.348  0.00016  
(h)  374.35±0.10  374.5204  0.007 ± 0.001  0.00709  
(i)  416.72±0.15  416.4714  0.007 ± 0.001  0.00667  
420.601  0.00064  
(j)  468.07 ± 0.01  468.07151  0.476 ± 0.021  0.477  
(k)  484.59 ± 0.02  484.6473  0.032 ± 0.001  0.0313  
485.60  0.000022  
(1)  489.25 ± 0.16  489.0626  0.003 ± 0.001  0.00432  
(m)  588.58 ± 0.01  588.5845  0.047 ± 0.002  0.0447  
593.48  0.000438  
(n)  604.43 ± 0.02  604.41463  0.084 ± 0.004  0.0823  
(o)  612.45 ± 0.02  612.46561  0.054 ± 0.002  0.0534  
703.867  0.000058  
(p)  884.30 ± 0.09  884.5418  0.004 ± 0.001  0.00284  
1061.55  0.000523  
1090.01  0.000011  
1378.05  0.000016  

HDR Ir-192 spectrum determined in this work. ton spectra reported by several authors for 
The emission frequencies of the photons emit­ted by the HDR Ir-192 source were calculated using Eq. (5) with parameter values taken from Table l. Figure 4 is a bar plot of the HDR Ir-192 photon spectrum compared with the pho-
8• 19• 20 

unencapsulated Ir-192 sources. All pho­tons, including y-rays and characteristic x-rays, with emission freguencies greater than 0.003 
(0.3 % ) were identified in the HDR Ir-192 pulse-height spectrum, with the following ex­
ceptions. First, Table 2 shows that the decay of Ir-192 produces several characteristic x-rays with energies between 7.822 and 13.025keV. The HDR Ir-192 pulse height spectrum, how­ever, shows no peaks below channel 180 ( corre­sponding to an energy of -63 ke V) where one would expect Gaussian distributions for each for these photons. Complete absorption of pho­tons with energies below -60 ke V in encapsula­ted Ir-192 sources has been suggested by Ninko­vic and Raicevic:8 in evaluating the air kerma rate constant for an Ir-192 source encapsulated in 0.15 mm of platinum, they assumed a cutoff photon energy 6 of 136.6 keV. Second, the four characteristic x-rays in the energy range of 61 
to 67 ke V emitted by Ir-192 could not be resol­ved in the HDR Ir-192 pulse-height spectrum with the current spectroscopy system. Instead, a single photon of energy roughly equal to the average of the four (64.72 keV) is suggested. Similarly, the two x-rays in the energy range of 71 to 76 ke V are treated as one photon of energy equal to 74.29 keV. 
1.0.--------------. 
II  this woik  
0.8  0  Kochcr(1981) Ninkovic and  
f:'.J  Raiccvic (1993) Browne and  
Fircslonc (1986)  
0.6  

;;::: 0.4 
0.2 
0.0JG ,PU, • II ltJr1,R1H, l:IDIVH1fltnl em_,,JUJ,UI ,Vld,U:11#1 j 
....N.....O.N...OOM.O 
...N.N...·.M.O.N.··M 
....q..-..000.000..00.N. 
o-M..oo.o-.-.0000000-00 
--NNNMMM····...OO 
Encrgy (ke V) 
Figure 4. Photon spectrum for the HDR Ir-192 sourcc cvaluatcd in this work comparcd to the components of thc photon spcctra for bare Ir-192 sources with emission frcquencies grcater than 0.003. The energies Iisted are those determined in this work. 
As shown in Table 2, the emission frequen­cies of high energy photons (E > 500 ke V) emit­ted by the HDR Ir-192 source are essentially equal to those form a bare source. Lower 

energy photons, however, have em1ss1on fre­quencies which are consistently Iower than those emitted by a bare source. The magnitude of the difference increases with decreasing pho­ton energy. A direct result of attenuation of lower energy photons in the stainless steel en­capsulation is an increase in the average energy of the HDR Ir-192 photon spectrum. Por the spectrum shown in Figure 4, the fluence­weighted and energy-fluence-weighted average energies are 371 and 402 keV, respectively. These are higher than the respective average energies calculated for the unencapsulated Ir­192 source spectrum (-346 and 395keV) (20). Furthermore, the air kerma-rate constant calcu­lated above is -5 % Iower than the value currently used by the HDR Ir-192 source manu­facturer and severa! brachytherapy planning systems to relate apparent source activity and reference air kerma rate. The apparent source activity is calculated from the measured refe­rence air kerma rate and the air kerma rate constant only to facilitate understanding of the amount of radioactivity present in the source. Based on the apparent activity, a planning algorithm calculates the corresponding air kerma strength using an air kerma rate constant and then continues with the evaluation of the dose distribution. The clinical implications of a discrepancy in the air kerma rate constant now become clear. If the values of (r6)K used by a physicist (in calculating apparent activity from measured air kerma strength) and a planning system ( doing the reverse calculation) are not the same, then the value of the source reference air kerma rate calculated by the treatment planning system will not equal the measured value. Inaccuracy in the calculated dose distri­bution with a subsequent dose delivery error will result directly from this discrepancy. The magnitude of the error will depend on the ratio of the two air kerma rate constants. The value of the air kerma rate constant has no effect on the dose distribution and subsequent dose deli­very provided a consistent value is used throughout the source calibration and dose cal­culation procedures. As a result, the air kerma rate constant is a "dummy" constant in dose 




calculation algorithms for sources calibrated in units of reference air kerma-rate. 
The use of reference air kerma rate in place of activity for brachytherapy sources has been suggested severa! times in the recent literatu­
21-23 

re. Surprisingly, activity remains the domi­nant unit used for specification of HDR sour­ces. In view of the potentially serious dose delivery errors resulting from the use of either air kerma rate or exposure rate constant in conjunction with source activity, we strongly encourage manufacturers of brachytherapy sources and treatment planning systems to eli­minate activity as the measure of source strength and instead use reference air kerma rate. Since all HDR Ir-192 sources are calibra­ted in terms of reference air kerma rate, it makes little sense to use a quantity other than reference air kerma rate to describe the strength of these sources. While familiarity of the mag­nitude of the activity unit allows for a "feeling" of the amount of radioactivity present in a source, the radiation therapy community will 
eventually discover the same "feeling" from the magnitude of the reference air kerma-rate. 
Conclusions 

An estimate of the photon spectrum emitted by a clinical HDR Ir-192 source was made based on the pulse-height spectrum measured with a lower activity version of the source. The half-life for decay of this lower activity source was equal, within experimental error, to the value reported for clinical sources. This similar decay rate, coupled with the fact that the lower activity HDR Ir-192 source was manufactured to the same dimensional specifications as the clinical version, suggests that the low activity source had decay properties similar to a clinical source. Therefore, any radiation parameters evaluated from these properties will also pertain to clinical sources. Qualitatively, the photon spectrum showed that photons with an energy less than 60 ke V do not escape the source capsule. Those most notably absent are the relatively abundant 9 and 9 .44 ke V photons that are a result of the decay of Ir-192. Overall, ali photons with energies below 500 ke V are attenuated. The emission frequencies of higher energy photons, though, were identical to those from a bare Ir-192 source, suggesting negligible attenuation of these high energy photons in the stainless steel encapsulation. 
A direct result of the difference in photon 
spectra is an increase in the fluence-weighted 
and energy-fluence-weighted average energies 
of the HDR Ir-192 source relative to the respec­
tive average energies of a pure Ir-192 source. 
Consequently, the air kerma rate constant eva­
luated from the measured HDR Ir-192 photon 
spectrum was ~5 % lower than the value for a 
bare Ir-192 source. The air kerma rate constant was also lower than the value currently used by treatment planning systems. The serious potential clinical implications resulting from this discrepancy in air kerma rate ( and exposure rate) constant strongly support the abolishment of source activity in favor of reference air kerma-rate for HDR Ir-192 source strength specification. This would make use of a modi­fying constant such as the air kerma rate or exposure rate constant unnecessary, and thus prevent dose delivery errors that could result from a misunderstanding of the value of either constant. 

Acknowledgments 

We are grateful to Dr. Edgar Loeffler of Nuc­letron Corporation for commissioning the lower activity version of the HDR Ir-192 source used in this work. Also appreciated are numerous helpful discussions with Drs. Loeffler, Paul DeLuca, Jr., Rock Mackie, and Wayne New­hauser. 

References 

l. Killian H, Baicr K, Loefflcr E, Sussenbach K, Dorner K. A comparison of differcnt planning algorithms used in interstitial radiotherapy with iridium-192 wircs. In: Mould RF, ed., Brachythe­rapy 2. Holland: Nuclectron, Lecrsum: 1989: 92­100. 
2. van dcr Laarse R. The Selectron treatment plan­ning system. Proceedings of the 7-th Jnternational Conference on the 7-th Jnternational Conference 
5. Joint Commission UEMS -EAR 

Three main points were tabled: 
The Charter on Training of Medica! Specia­lists. UEMS published in 1992 a compendium on medica! specialist training in the E.U. For the tirne being it intends to publish an updated compendium regarding ali medica! specialities recognized by the E.U. Authorities. To prepare this document, UEMS set up a charter that defines that specialists have to list their specific requirements. The matters under discussion by UEMS are the same as those discussed by the EAR Working Group EUCORE/Education Committee, such as: the Core of Knowledge, the Guidelines for Training in Radiology (Gene­ral) and the Requirements for Training Facili­ties. They have been adopted by both the Joint Commission and the Executive Bureau. 
Charter for Continuing Medica! Education (CME) for specialists in E.U. countries. The charter was issued by UEMS and sets up guide­lines and rules to be discussed by the respective UEMS sections. 
A draft of EAR guidelines for CME reached the Executive Bureau. This document is to make circulating among the various EAR bo­dies involved in educational matters in order to harmonize the work of the European Board of Radiology. 


European Society of Breast Imaging and Forensic Imaging 

During the ECR'95 a group involved in Breast Imaging will meet with the aim of setting up for the future a European Society of Breast Imaging. A group involved in Forensic lmaging will also meet with the same objective. 
7. Preparation of the EAR General Assembly (Vienna 9 March 1995) 
The new articles to be voted at the General Assembly concern the Interna! Regulations of the Committee for Computer Science Applica­tions in Radiology and the Professional Organi­sation Committee. Furthermore research and cost effectiveness will be included in the Aims of the Association. 
The Executive Bureau accepted Georgia and the Republic of Belarus as full members of the Association. This decision will be submitted for approval to the General Assembly. 













[10U[]WDJJB 0[10V[]CJ DJJ[] 

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Contact European School of Oncology, Via Ripa­monti 66, 20141 Milan, Italy; or call + 39 25730 5416; Fax: + 39 25730 7134 ; or contact ESO Vienna, c/o Arztekammer fuer Wien, Fortbildungsreferat, Weihburggasse 10-12, 1010 Vienna; or call 
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Contact the ESTRO Secretariat, Radiotherapy De­
partment, University Hospital St Rafael, Capucijnen: 


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• ucinkovit pri avtoimunih boleznih in boleznih, kjer je udeležena avtoimuna komponenta, kot so psoriaza1 revmatoidni artritis, atopicni dermatitis in endogeni uveitis 
Sandostatin ® (oktreotid) 
• 
sinteticni oktapeptldni derivat somatostatina 

• 
pomemben v gastroenterologiji, endokrinologiji in intenzivni medicini 


Sirrdalud ®(tizanidin) 
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mišicni relaksant s centralnim delovaniem 

• 
za zdravlienie bolecine v križu, mišicnih spazmov in spasticnosti 


Syntocinon ® (oksitocin) 
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sinteticni oksitocin za spodbujanje maternicnih kontrakcij 

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. Dunajska 51, Ljubljana 

Instructions 
The journal Radiology and Oncology publishes ori­ginal scientific papcrs, profcssional papcrs, review ar­ticlcs, case reports and varia (rcviews, short communi­cations, profcssional information, ect.) pcrtincnt to diagnostic and intervcntional radiology, computcriscd tomograpny, magnetic resonance, nuclcar medicine. radiotherapy, clinical and expcrimcntal oncology, ra­diobiology, radiophysics and radiation protection. 
Submission of manuscript to Editorial Board implies that the papcr has not becn published or submitted for publication elsewhere: thc authors are rcsponsiblc for all statements in their papers. Accepted articlcs bccome the propcrty of thc journal and thcreforc cannot be publishe<l clscwhere without written permis­sion from the Editorial Board. 
Manuscripts written in English should bc sent to the Editorial Office: Radiology and Oncology. Institute of Oneology, Vrazov trg 4, 61000 Ljubljana, Slovenia: Phone: + 386611320068, Fax: + 386611314180. 
Radiology and Oncology will consider manuscripts prepared according to the Vancouver Agrecment (N Engl J Med 19t91; 324: 424-8t.; BMJ 1991; 302: 6772.). 
All articles are subjected to editorial review and review by two independent refcrees selccted by the Editorial Board. Manuscripts which do not comply with the tcchnical rc4uircments stated herc will be returned to the authors for corrcction before thc review of the referees. Rejected manuscripts are gene­rally returncd to authors, howevcr. the journal cannot be hcld responsiblc for their loss. Thc Editorial Board rcservcs thc right to re4uire from thc authors to _make appropriatc changes in the content as wcll as gramma­tical and stylistic corrcctions whcn necessar.y. Thc expcnses of additional editorial work and re4ucsts for reprints will be charged to the authors. 
General instructions: Typc the manuscript double spa­ced on one sidc with a 4 cm margin at thc top and lcft hand side of the sheet. Write thc paper in grammati­cally and stylistically corrcct language. Avoid abbrcvia­tions unlcss previously cxplained. The technical data should confirm to thc SI system. Thc manuscript. including thc rcfercnces may not cxceed 15 typewritten pages, and the number of figures and tables is limited to 4. lf appropriatc, organise the text so that it includes: lntroduction, Material and methods, Results and Discussion. Exceptionally, thc results and discus­sion can be combincd in a singlc section. Start cach section on a ncw page and number thesc consecutively with Arabic numerals. Authors are encouraged to submit their contributions besides three typewritten copies also on diskcttcs (5 1/4") in standard ASCII format. 

to autbors 
First page: 
-name and family name of ali authors. 
-a brief and specific titlc avoiding abbreviations 
and colloquialisms. 
-compkte addrcss of institution for cach author. 
-in thc abstract of not more than 200 words cover 
the main factual points uf the article, and illustrate 
them with the most relcvant data. so that the rcader 

may quickly obtain a general view of the material. 
lntroduction is a bricf and concise scction stating the purposc of thc articlc in relation to other alrcady published papers on the same subjects. Do not present extcnsivc reviews of the literature. 
Material and methods should provide cnough informa­tion to cnable experiments to be rcpcatcd. 
Write the Results clearly and conciscly and avoid rcpcating thc data in thc tablcs and figures. 
Discussion should cxplain thL: results. and not simply rcpcat them. interpret thcir significance and draw conclusions. 

Graphic material (ligures and tables). Each item should be sent in triplicate, one of thcm marked original for publication. Only high-contrast glossy prints will be acccpted. Line drawings. graphs and charts should be done profcssionally in lndian ink. Ali lcttering must be legiblc after reduction to column size. In photo­graphs mask the idcntitics of paticnts. Label the figures in pencil on thc back indicating author's name. the first few words of thc title and figure number: indicatc thc top with and arrow. Writc legend to figurcs and illustrations on a scparatc shcet of papcr. Omit vcrtirnl lines in tables and writ<: thc next to tables overhcad. Labe! the tablcs on thcir rcverse side. 
Rererences shoul<l bc tapcd in accordancc with Van­couver stylc. double spaccd on a scparate sheet or' papcr. Numbcr thc rcfcn:nccs in the order in wh1eh thcy appear in the text and quotc thcir corrcsp,rnding numbers in thc text. Following are some cxampks of refcrcnccs from articlcs. books and book ch_aptcrs: 
1. 
Deni RG. Cole P. /11 1·i1m maturation of monocy­tes in squamous carcinoma of thc lung. Br J Cancer 19t81; 43: 486-95. 

2.t
Chapman S. Nakielny R. A guide /O rwliologirnltprncedures. London: Baillicre Tindall. 1986. 

3. 
Evans R. Alexander P. Mcchanisms of extraccllu­



lar killing of nuclcatcd mammalian cclls by macropha­gcs. In: Nelson DS cd. /111111w10biology oj' macrnphage. New York: Acadcmic Press. 1976: 45-7--1. 
For reprint in/t1r111a1io11 in North Amerirn C,mtact: ln11•m111io1111/ reprim Corpora1io11 96H Admiral Callag­lwn l.1111<', # 16H 1'. O. Box /](}04, Vallejo, CA 94590, TI'!.: 017/ 553 9130, fox: (707) 55] 9514. 



POOPERATIVNA SLABOST IN BRUHANJE 
NELAGODJE IN STISKA OGROŽATA USPEH OPERATIVNEGA POSEGA 
ondansetron 
PREPRECEVANJE Ena sama intravenska injekcija po 4mg pri uvajanju v anestezijo ZDRAVLJENJE Ena sama intravenska injekcija 
po 4mg 
G/axo 
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6111 5 Ljubljana, p.p. 17, Slovenija 
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