Radiol Oncol 1994; 28: 3.51-8.
Importance of surgery in the multimodality treatment for small cell
Jung cancer (SCLC)
Andreas Schamanek and Karl Karrer for the International Society of Chemotherapy (ISC)-Lung Cancer Study Group
Institute for Cancer Research of University of Vienna, Borschkegasse 8a, A-1090 Vienna,
Austria
Until November 1990 186 unselected patients received first surgery for cure at 23 cooperating departments of thoracic surgery in 9 different countries. All patients had improved SCLC with clinical stage Ti,2NqjMq and were postoperatively randomized to aggressive standard chemotherapy (cyclophosphamide, doxorubicin, vinblastin) or to alternating chemotherapy which went on for 6 months. Thereafter they recieved prophylactic cranial irradiation (PCI) according to the prospective ISC protocols 1 and II.
Since December 1990, more than 90 additional patients received surgery and postoperative adjuvant chemotherapy according to the simplified, still on going, ISC protocol V/VI at the above mentioned , and 8 additional departments. In February 1994 the preliminary evaluation showed that, after 28-30 months after the surgery, the curves indicating long-time survivals (cures) takes a plateau-like shape. The survival rate 30 months after the surgery is 61 % (45 patients) for stage pTi_3N0M0 and 37% (27 patients) far stage
pT,_3N2R()Mo.
We would like to conclude that a preference should be given to the surgery with the curative intent as the first step of multimodality treatment. A complete resection is indicated for SCLC as for the other nonsmall cell subtypes of lung cancer, even if mediastinal lymphonodes are involved, provided, they can still be resected completely according to the Naruke's system. Based on the feasibility of the aggressive chemotherapy used, we suggest to further engaged thoracic surgeons to perfarm similar studies, using first surgery far SCLC fallowed by aggressive postoperative chemotherapy.
Key words: lung neoplasms-surgery, surgery with curative intent; small-cell lung cancer (SCLC); combined modality therapy, postoperative adjuvant chemotherapy
Introduction
The differences of efficacy of adjuvant chemotherapy after surgery for cure on patients with
Corrcspondence to: Univ. Prof. Dr. med. Karl Karrer, Facharzt fur Onkologie, Anton-Renk-Str. 2, 6330 Kufstein, Austria. Phone: +34.5372 63228.
UDC: 616.24-006.6-08
SCLC versus patients with non-small cell lung cancer (NSCLC) were discussed in Paris in 1979.1 Consequently, we discontinued chemotherapy for NSCLC and made preparations for, together with Stjernswaerd, cooperative immu-notherapeutical studies. At the time of surgery the immunostimulation was made by intrapleu-ral applications of coryne-bacterium parvum by
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patients with NSCLC at early stages.2 At the same time we continued cooperative trials, using the agressive combined adjuvant chemotherapy after surgery for patients with SCLC at early stages. The results of this latter randomized studies were discussed at the 13 th International Congress of Chemotherapy (I.C.C.) in Vienna.3'4 With the help of Prof. Orel, these discussions led to the further enlargement of the multinational cooperation; we formed the International Society of Chemotherapy - Lung Cancer Study Group (ISC - LCSG).5 The 2nd Central European Conference on Lung Cancer in Ljubljana is dedicated to the 40ieth anniversary of the Austrian Cancer Research Institute in Vienna, whose first director, the late surgeon Prof. Wolfgang Denk, started on adjuvant chemotherapy for lung cancer in 1954. 6'7 The results have stagnated during the last decade despite of new and more intensive treatment regiments. Moreover, the duration of chemotherapy and the integration of radiotherapy and surgery in the multimodality management of SCLC are stili controversial.8-10 One of the most important controversies is related to the indication for radical surgery with curative intent: (a) Indication for surgery treatment is the same as in NSCLC. It is the first choice for treatment - as long as the chance for the complete resection of the primary tumour (T), together with its lymph drainage area (N), seems possible. It works when the stage pTNR0 is set up. (b) Indications for surgery treatment are only small peripheral coin lesions. (c) Chemotherapy is the first option for the beginning of the treatment, regardless, of the stage, eventually followed by adjuvant surgery.
Material and methods
Until 1990 the ISC-LCSG conducted 4 prospective randomized multinational cooperative ISC Studies for the optimum of the treatment of SCLC regarding their different stages. ISC Study I for operable patients with SCLC at clinical stages I or II (cT1,2NoNo, 1 Mo). ISC Study II for patients with received surgical
resection for an underfined lung tumour. After the resection, the patho histological examination of the operation specimen defined the histological sub-type of a SCLC. ISC Study III for patients with SCLC at N2 stage to receive preoperative neoadjuvant chemotherapy followed by surgery with a curative intent.
ISC Study IV for inoperable patients with palliative chemotherapy
Ali patients were randomized to receive the standard chemotherapy CAV or another combination of chemotherapy. The standard chemotherapy consisted of Cyclophosphamid 1000 mg/ m2, Adriamycin 50mg/m2 and Vincristin 1.4mg/ m2. It was administered in 500 ml saline per i.v. infusion on the day of the onset of the chemotherapy, 1-2 weeks after the surgery and again at 3 weeks interval for a total of 8 such cycles within the first half of postoperative year. Another sequential chemotherapies (combination A, B, C) consisted of 3 different drug-combina-. tions, given intermittetly in a timing as the former mentioned chemotherapy.
Combination A: Cyclophosphamid 1500mg/ m2, CCNU 100mg/m2 and MTX 15mg/m2. Combination B: Cyclophosphamid 1000mg/m2, Adriamycin 40mg/m2 and Vincristin 1 mg/m2. Combination C: Ifosfamide 1600mg/m2, Mesna 400mg and VP-16 120mg/m2.
The above mentioned chemotherapy was given at 4 intervals, so that 6 cycles were administered within the first half year after the surgery.
Four weeks after the end of chemotherapy the prophylactic cranial irradiation (PCI) was performed by patients without the symptoms of brain metastases in Study I and II. Tumour dose was 30 Gy in 10 fractions and 3(5 Gy in 18 fractions.
The input of patients for the Study I and II was closed in November 1990. Since December 1990 the consequent continuation is stili going on as ISC-Studies V and VI with simplified protocols: All patients undergo the same chemotherapy, using first a new combination A: Adriamycin 50mg/m2 on day 1; Ifosfamide 2g/ m2 on day 1 and 4; Mesna 400mg/m2 at 4h,
Importance of surgery in the multimodality treatment for SCLC
353
8h- After 3 weeks interval a new combination B is given: Cisplatin 90 mg/m2; Etoposid 150 mg/ m2- These 2 combinations are repeated so that 4 cycles in total are administered within the first 3 postoperative months. PCI is not obligatory any more, but brain irradiation is given if it is indicated by symptoms.
The aims of our studies
The study participants agreed to the following tasks:
-	Comparison of survival of groups of patients resected for SCLC at different pTNM stages and at different chemotherapy.
-	Differences of clinical (cTNM) versus pathological (pTNM) staging after histological examination of the operation specimen and the impact of prognosis.
Distribution of different histological subtypes of SCLC.
-	Pattern of first local recurrence and distant metastases.
-	Incidence of side effect caused by treatment and secondary malignancies.
The "local" pathologists agreed to send tumour samples and histo slides to 2 review pathologists to be additionally examined and to confirm the final classification.
Follow up forms
The evaluations are based on data given by the follow up forms which consist to:
-	Registration, randomisation, diagnostic procedures for staging.
-	Patients characteristics, age, sex, home physician.
-	Laboratory data, performance stage.
-	Surgery report, extent, localisation of primary tumour and lymphonodes.
-	Chemotherapy administered, blood counts, side effects.
-	Pathologist's report, tumour extension, lymphonodes labelled by the surgeon prove the final pTNMR classification.
-	Report of death, tumour status preferably with autopsy report.
The follow-up forms must be filed at each
treatment cycle and at every 6 weeks for the 1st and 2nd year, thereafter at every 3 months and after 30 months following the surgery once per year until death.
Statistics
Every patient has to be evaluated. All records are available for extramural review. The observed overall survival rates are calculated by the Kaplan-Meier method. Surgical and postoperative mortality is not excluded. Tests for p-values of biostatistical significance are used according to the generalised Wilcox method.11
Ethics and patients' consent
The approval of the ethical committee at the investigators hospital is sought according to their country's rules. The informed consent is gained from each patient prior to randomisation and is field in the hospital.
Consecutive, unselected, untreated patients enter the ISC-Study I/II if the minimum requirement for clinical staging as cTNM I or II is achieved. The clinical staging is based on physical examination, radiology such as chest film, CT scans of chest, brain, liver and bone and on invasive studies as mediastinoscopy and bone marrow examination. There are no contraindications against surgery.
Results
The following results are based on the preliminary evaluation of February 1994, after the average follow-up time of 70 months after the surgery as the beginning of treatment. 186 patients have been enrolled into the ISC-Studies I and II at the 23 cooperating departments of thoracic surgery and they are associated with the departments of medical oncology, radiology as well as pathology as it is listed in Table l.
The numbers of patients are subdivided by the ISC-Study I or II, sex and pTNM stages (Table 2). The distribution by age and sex is as follows: 39 males and 12 females under 50 years old, further 99 males nad 21 females
Table 1. Participants of the Cooperative ISC. Studies I, II, III, V			, VI, VII.			
Country/City		Surgery	Medical Oncology	Radiology		Pathology
A	Vienna	N. Pridun	M. Neumann, N. Vetter	G.	Alth	E. Lintner
PL	Gdansk	Z. Paplinski	H. Karnicka. J. Jassem	A. Jungowska, A. Sokol		K. Doerr
D	Rohrbach	J. Vogt-Maykopf	P. Drings	M	. Wannenmacher	K.-M. Müller
SLO	Ljubljana	J. Orel, J. Erzen, B. Hrabar	M. Klevisar	M	. Debevec	T. Rott
RC	Shanghai	O.Wang, X. CHow	M. Liao, J. Zhao	M. Lin		Z. Lin
RC	Beijing	G. Huang	Y. Sun	W. Yin		F. Liu
RC	Shenyang	H. Li, d. Chen, L. Han				
D	Bielefeld	M. Thermann	M. Körte	L.	Arndt	U. Raute-Krensen
I	Forli	A. Lattuneddu, D. Dell' Amore	A. Galassi, A. Campanini	G.	Giorentini	F. Padovani
A	Gaisbiihel	G. Zimmermann	J. Rothmund, M. Amann	Oser		G. Breifellner
TR	Istanbul	A. Sayin	B. Berkarda, S. Serdengecti	R. Ucel		G. Glirisken
Jp	Kawasaki	H. Osada	M. Koike	M.	, Endoh	Kakimoto
A	Vienna	E. Wolner, F. Eckersberger	W. Schlick	K.	Kärcher	H. Holzner
RA	B. Aires	A. Imposti	M. Bruno, N. Brocato	N.	Ruggeri	
Jp	Tokyo	E. Hata, R. Matsuoka				
PL	Krakow	L. Kolodziejski	M. Pawlicki, M. Ziobro	S. Dyczek		a. Niezabitowski
RC	Guangzhou	H. Zhou	Z. Guan	G.	Zheng	
A	Salzburg	O. Boeckl	H. Hausmaninger	D.	Kogel ni k	J. Thurner
A	Vienna	E. Zwintz	G. Baumgartner, O. Kokron	G.	Alth	J. Mühlbauer
A	Linz	H. J. Böhmig	K. Aigner, J. Wiirtz	F.	Mieß, J. Hammer	H. Regele
I	Firenze	C. Crisci	N. Nozzoli, S. Nutini			N. Dini, N. Santucci
I	Milano	I. Cataldo, A. Bedini, G. Ravasi		F.	Milani	C. Patriarca
RA	B. Aires	R. Grinspan, H. Hoyos	D. Levy	B.	Dosoretz	a. Ferrari
I	Cosenza		V. Zottola, S. Barbera			G,. Galippi
JP	Tayama	Y. Kusajima	Y. Mizukami	M.	Sugihara	N. Takayanagi
RA	Buenos Aires	H. Delia Torre	A. Pepe, L. A. Tabarews			
I	Bologna	P. Sette		L.	Cacciari	
D	Donaustauf	F. v. Bültzinglöwn				
Byelar/Minsk		V. Zharkov, Y. Demidchik	V. Kurchin. P. Moiseev. N. Shishko		A. Furmanchuck	
CIS Moscow		M. Danydov, Al-Ansari,	V. Gorbunova. N. Smirnova N. Orel			
D Düren		R. Rios-Pooley	J. Karow			
Latv. Riga		H. Basko, R. Zaleskis	G. Purkalne, D. Lega, J. Berzins		A. Veinbergs	I. Rone
Lith.	Vilnius	A. Jackevicius	V. Jakeleviciene P. Nzujokaitis		e. Aleknavicius	A. Felinskaite
CIS Kiev		E. Konovalov, Y. Kogoso	J. Smolanko, B. Radionov		V.Saphonov	e. Suslov
I Siena		g. Gotti, G. Biagi, P. Paladini	E. Tucci		L. Volterrani	V. Sforza
ISP Valencia		A. Canto	V. C. ALerola		v. Cervera	S. Navarro
ISC-Study Center: K. Karrer, N. Pridun, E. Ulsperger A. Schamanek Inst, for Cancer Research of the Univ. Vienna/A
M. Schemper, Institut für Medizinische Comprites - Wissenschaften Univ. Vienna/A.
T. Shields, Northwestern Univ. Chicago/USA, O. Selawry, Rileyville, Virginia/USA;
Reference-Pathologists: J. H. Holzner, Institute for Pathology of the University of Vienna/A
K.-M. Müller, Institute for Pathology of the Univ. of Bochum/D
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Table 2. Distribution of Patients per ISC-Studics 1, II, Scx and pTNM-stagcs.
Study scx I II	IIIA	IIIB IV
Tl,2	T3	T4
N2	NO NI	N2 NI N2
ISC-1 f 10 7 2	1
m 58 31 15 4	2 1	5
ISC-II f 23 7 7 4	2	1 1 1
m ' 95 28 32 23	l 4	4 1 1 1
TOTAL f+m 186 73 56 31	3 7	10 2 2 2
patients, there were more reductions of a dose used.13 Generally, the palliative effect was poor but similar after chemotherapy 1 and 2. Therefore, we also discontinued the ISC Study IV and recommended the individual chemotherapy according to the most up-to-date recommendations, for instance the recommendations of international Association for the Study of Lung Cancer (IASLC).14
Discussion
The hypothesis to consider SCLC as a systemic disease regardless the stage and to suggest that there is no place for surgery in SCLC, seems unjustified in the light of reports and our demonstrated results. The pTNM stage N0M0 in SCLC as well as in other histological subtypes of Jung cancers and in other carcinomas is a reality. There were 38 patients with such a stage involved in the ISC Study I, and 36 patients in the ISC Study II, treated at 23 independent cooperating hospitals in 9 different countries. These patients are still alive and 47 of them are long term survivors of more than 5 years. These are reliable figures.
The importance of surgery seems convincingly substantiated by the relatively high level of the 5 year survival of 30 % patients (of 27 patients) who were completely resected for SCLC and reached to stage pTN2R0M0. With the development of more effective chemotherapy it becomes apparent that in patients treated with chemo- and radiotherapy a frequent site of failure was the tumour bed or regional lymph nodes. Thus, a more effective treatment
of local control it appeared to be needed. The multimodality treatment starting with the resection for the cure of SCLC can be seen as another example of the concept that has led to major progress in curing malignant diseases during the last three decades. This concept of combined treatment from the time of diagnosis is of general importance, even though the number of suitable patients with SCLC may be relatively small in one hospital, as the result of limited activities in early diagnostic procedures. Surgery with attention to cure at very early stages is not enough because of the danger of clinically undetectable micrometastases. Postoperative chemotherapy appeared more effective than surgery alone.
Nevertheless, the initial complete surgical resection of the localised stage of SCLC, followed by intensive postoperative chemotherapy, is not the only viable option for patients with an early stage of SCLC, since some of the patients with incomplete surgical resection are still alive (Figure 1). However, the results of the initial complete surgical resection are much better, both if compared with non surgical treatments or the results of neoadjuvant preope-rative chemotherapy.13 The results obtained in patients with pT3N0M0 SCLC appear to be satisfactory, even though only 3 such patients are under observation, but 2 of them are still alive 5 years after surgery.
Although the International Association for the Study of Lung Cancer (IASLC) published the consensus report about the positive role of surgery for the patients with cTNM stage I, II or IIIA, 15 the use of initial surgical complete resection followed by intensive postoperative
Importance of surgery in the multimodality treatment for SCLC
357
chemotherapy is still not in common use. Only a small number of reports have been published during the last 5 years. 16-19
The indication of surgery for pTN2 has been extensively discussed for all lung tumours, since this group of patients is quite large and involves a great variety of prognoses. There are patients without detected macroscopically but histologically praven discrete tumour cell infiltration in mediastinal nodes. On another handthere are patients with real bulky N2 disease. The result presented in literature, as well as our own results, lead to the conclusion that the indication for surgery should be handled for patients with SCLC in the same way as for other histological subtypes of lung cancers. As long as the primary tumour and regional lymph nodes -also N2 - can be completely resected, such surgery with curative intent should be performed whenever possible. Extended surgical procedures to allow complete resection of the mediastinal lymph nodes should be followed by aggressive chemotherapy. This contention is supported by our observation of the 37 % 30-month survival rate of the 27 patients whose SCLC stage pTN2 was completely resected. The inclusion of patients with operable N2 tumours should increase the number of evaluable patients for more future studies. The incidence of local recurrence at first relapse was 11/47 in our pTNO patients and 8/39 in pTN2. It indicates the low influence of the surgical procedures on local relapse rate.
Regarding the so called neoadjuvant preoperative chemotherapy, severa) critical aspects have to be considered, namely, if the primary tumour is localised at the very beginning of the treatment. That may present a problem, the case of fast growing tumours, which require preoperative chemotherapy. The time lost cannot be compensated through chemotherapy. Most of the reports show that the proportion of patients without any viable tumour cell after initial chemotherapy is small. The rate of still operable patients has also decreased. Patients with mixed tumours, including non-small cell elements, need surgery in any case. From the psychological point of view it seems more en-
couraging for the patients to undergo initial surgery, if the tumour is considered to be operable. The tumour heterogenity seems to be an important factor for treatment failures in patients with SCLC. Further biological studies might offer a better understanding of the fact that most of the patients with SCLC do relapse after initial effective treatment. For such investigations fresh tumour samples from surgical specimens are needed, which is another advantage of surgery as the first treatment modality.
Of 156 patients enrolled in our ISC Study III, only 82 showed a response after the preoperative chemotherapy. Secondly, a high proportion of responders have not received post-chemotherapy surgery. It seems to be most important that there is a relatively low survival rate of the patients receiving surgery for pTN2M0 stages after preoperative chemotherapy. This seems quite similar to the results presented by Lad.20 Therefore, we nolonger recommend preoperative neoadjuvant chemotherapy for SCLC and close the input for our ISC Study III.
We conclude that presented data imply that 30 months- and 5-year survival rate of patients with SCLC at pTNM stage 1, II and pT3N0M0 becomes substantially improved by initial complete surgical resection and intensive postoperative chemotherapy. The results are superior to preoperative chemotherapy followed by adjuvant surgery. As long as pTN2M0R0 SCLC can be completely resected, surgery with an intent to cure should be performed as the first step of multimodality treatment. The indication for surgery for SCLC should be the same as for NSCLC. As surgery is not yet generally accepted as the crucial first step of multimodality treatment of SCLC, the intensification of cooperation and/or independent studies are necessary to confirm our promising results. Finally, our results should be convincing enough to stimulate future cooperation to get a substantial number of patients in each of the different prognostic subgroups, necessary for general recommendations. We strongly recommend full attention to be paid to diagnostic procedures, as these have been effective in Japan.21 At
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least, such efforts are indicated for high risk groups, which can be defined. With an increased therapeutic efficacy and with an increased number of longterm survivours, including cures, measures for early diagnosis became even more justified.
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