Radiol Oncol 2019; 53(3): 348-356. doi: 10.2478/raon-2019-0043 348 research article Inquiry and computer program Onko-Online: 25 years of clinical registry for breast cancer at the University Medical Centre Maribor Darja Arko1,2, Iztok Takac1,2 1 University Medical Centre Maribor, Maribor, Slovenia 2 Faculty of Medicine, University of Maribor, Slovenia Radiol Oncol 2019; 53(3): 348-356. Received 17 February 2019 Accepted 16 May 2019 Correspondence to: Prof. Iztok Takač, M.D., Ph.D., Adviser; Division of Gynaecology and Perinatology, Maribor University Medical Centre, Ljubljanska 5, 2000 Maribor, Slovenia. Phone: +386 2 321 2445; E-mail: iztok.takac@ukc-mb.si Disclosure: No potential conflicts of interest were disclosed. The authors acknowledge the project Identification of molecular biomarkers for prognosis of clinical outcome and metastasis in triple nega- tive breast cancer patients, ID J3-9272, was finacially supported by the Slovenian Research Agency. Background. High-quality routine care data collected in the clinical registry play a significant role in improving the management of cancer patients. Clinical cancer registries record important data in the course of cancer diagnosis, treatment, follow-up and survival. Analyses of such comprehensive data pool make it possible to improve the quality of patients care and compare with other health care providers. Methods. The first inquiry at the Department of Gynaecologic and Breast Oncology of the then General Hospital Maribor to follow breast cancer patients has been introduced in 1994. Based on our experience and new approaches in breast cancer treatment, the context of inquiry has been changed and extended to the present form, which served as a model for developing a relevant computer programme named Onko-Online in 2014. Results. During the 25-year period, we collected data from about 3,600 breast cancer patients. The computer pro- gram Onko-Online allowed for quick and reliable collection, processing and analysis of 167 different data of breast cancer patients including general information, medical history, diagnostics, treatment, and follow-up. Conclusions. The clinical registry for breast cancer Onko-Online provides data that help us to improve diagnostics and treatment of breast cancer patients, organize the daily practice and to compare the results of our treatment to the national and international standards. A limitation of the registry is the potentially incomplete or incorrect data input by different healthcare providers, involved in the treatment of breast cancer patients. Key words: clinical registry; computer program; breast cancer Introduction In Slovenia, we have one of the oldest population- based cancer registries in Europe named the Cancer Registry of Republic of Slovenia. It was founded at the Institute of Oncology in Ljubljana in 1950. This registry monitors the population burden for all ma- lignant and non-malignant oncological diseases.1 Clinical registers in Slovenia are needed for collect- ing additional information on certain cancers.2 The Clinical Register of Skin Melanoma was founded in 2017 as the first special clinical registry for Slovenia.3 At our Department of Gynaecologic and Breast Oncology we introduced seven different inquir- ies for gynaecological (vulvar, vaginal, cervical, endometrial, ovarian, fallopian tube cancer) and breast cancer in 1994. For all of them, a computer program running in Microsoft Access has been de- signed and we published two articles on the use of this software for follow-up of patients with ovarian malignancies in 1996 and 1999.4,5 Methods In the last decades, treatment of the most com- mon female carcinoma, breast cancer, changed dramatically in terms of surgery and systemic Radiol Oncol 2019; 53(3): 348-356. Arko D and Takac I / Clinical registry for breast cancer 349 treatment. Regarding previous experience with collecting data of cancer patients and including relevant data, the context of the inquiry for breast cancer has been changed and extended to achieve the form, which we use nowadays. The updated inquiry served as a model for developing an ad- equate computer program named Onko-Online in 2014, which records data during diagnostics, treat- ment and follow-up. The paper inquiry was completed during diag- nostic and treatment procedures. Included in the program were all breast cancer patients at first presentation who started treatment at our institu- tion irrespective of the disease stage. If a patient underwent diagnostic procedures at a different in- stitution, it was possible to collect data based on medical records. Therefore, these patients were al- so included to the program in case their first treat- ment was initiated at our institution. General data were partly collected when the diagnosis of breast malignancy was established. After completing primary treatment, data were recorded using the computer program Onko- Online, which allowed for processing and analys- ing of the obtained data. Hard copies were com- pleted by the doctor in charge. The data from hard copies were put into the computer program by a clerk with adequate training. The documentation was also kept in the form of printed copies as part of health records. Results The inquiry for breast cancer covered 167 different information, divided into 11 sections: general data (G), medical history (MH), clinical examination (CE), mammography (M), ultrasound (US), preop- erative investigations (PI), surgery (S), radiother- apy (RT), histopathology (H), systemic treatment (ST), and follow-up (FU). General data consisted of the identification data and data regarding treatment collected at the end of primary treatment (Figure 1). The data were recorded using the computer pro- gram when patients completed their primary treat- Figure 1: General data. BREAST CANCER G1 year/no.: G2 NAME AND G3. FAMILY NAME: G4 GENDER: G5 PERSONAL IDENTIFICATION NUMBER: G6 AGE: G7 DATE OF BIRTH: G8 CARD NO. OF CBD (BREAST DISEASE CENTER): G9 CARD NO. GIN: PC NO.: G10 DATE OF LAST EXAMINATION (or EX): _______________ (last check-up, field S1.) G11 STATUS AT LAST FOLLOW-UP (or EX): (last check-up, field S8.) 0 alive, no symptoms 1 alive, partial remission (PR) 2 alive, stable disease (SD) 3 alive, relapse 4 alive, progressive disease (PD) 5 alive, condition unknown 6 ex due to breast malignancy 7 ex during treatment 8 ex due to other disease, no breast cancer symptoms 9 ex due to other disease, breast cancer symptoms present 10 ex, cause unknown 11 condition unknown G12 DG: ________________ G13 DATE OF DG: _____________ 1 DCIS 2 ductal carcinoma 3 LCIS 4 lobular carcinoma 5 medullary carcinoma R R R R R  L  L  L  L  L 6 mucinous carcinoma 7 tubular carcinoma 8 other (please, specify) _____________ R R R  L  L  L G14 STAGE: TX T0 TIS T1 T1mi T1a T1b T1c T2 T3 T4a T4b T4c T4d NX N0 N1 N2 N2a N2b N3 N3a N3b N3c MX M0 M1 G15 DIFFERENTIATION: 1 G1 2 G2 3 G3 G16 INTRINSIC TUMOR SUBTYPE: 1 luminal A 2 luminal B, HER2 negative 3 luminal B, HER2 positive 4 HER2 positive non-luminal 5 triple negative G17 TREATMENT: 0 no 1 tumorectomy 2 mastectomy 3 SNB 4 axillary clearance R  L  R  L R  L R  L 5 complete/full chemotherapy 6 non-complete chemotherapy 7 non-adjuvant chemotherapy 8 beam radiation 9 hormone therapy 10 other (please, specify) G18 DATE OF 1st RELAPSE ________________________ G19 SITE OF 1st RELAPSE 1 bones 7 same breast 2 axilla 8 other breast 3 lungs 9 soft tissues 4 liver 10 chest wall 5 brain 11 other 6 local relapse G21 DATE OF 2nd RELAPSE __________________________ G22 SITE OF 2nd RELAPSE 1 bones 7 same breast 2 axilla 8 other breast 3 lungs 9 soft tissues 4 liver 10 chest wall 5 brain 11 other 6 local relapse G24 DATE of 3rd RELAPSE _____________________________ G25 SITE of 3rd RELAPSE 1 bones 7 same breast 2 axilla 8 other breast 3 lungs 9 soft tissues 4 liver 10 chest wall 5 brain 11 other 6 local relapse G27 DATE of 4th RELAPSE ___________________________ G28 SITE of 4th RELAPSE 1 bones 7 same breast 2 axilla 8 other breast 3 lungs 9 soft tissues 4 liver 10 chest wall 5 brain 11 other 6 local relapse G20 1st LINE TREATMENT 0 no 1 surgical 2 systemic chemotherapy 3 systemic-targeted 4 systemic hormone therapy 5 beam radiation 6 other (please, specify) G23 2nd LINE TREATMENT 0 no 1 surgical 2 systemic chemotherapy 3 systemic-targeted 4 systemic hormone therapy 5 beam radiation 6 other (please, specify) G26 3rd LINE TREATMENT 0 no 1 surgical 2 systemic chemotherapy 3 systemic-targeted 4 systemic hormone therapy 5 beam radiation 6 other (please, specify) G29 4th LINE TREATMENT 0 no 1 surgical 2 systemic chemotherapy 3 systemic-targeted 4 systemic hormone therapy 5 beam radiation 6 other (please, specify) FIGURE 1. General data. Figure 2: Medical history. MEDICAL HISTORY MH1 FAMILY HISTORY 0 none 1 tuberculosis 2 diabetes 3 allergies 4 mental disorders 5 STDs 6 other (__________________) MH18 MENOPAUSE 0 not yet (go to A20) 1 natural 2 artificial/triggered MH13 AGE AT MENOPAUSE (years) _______________ MH20 HORMONE THERAPY (PERI- OR POSTMENOPAUSE) 0 never (go to A23) 1 estrogen 2 estrogen-progesterone 3 other (__________________) MH21 NUMBER OF YEARS of HRT USE _______________ MH22 NUMBER OF YEARS since DISCONTINUED HRT _______________ MH23 SMOKING 0 never (go to A25) 1 before 2 now MH24 NUMBER OF PACKAGES-YEARS (number of years x no. of packages daily) _______________ MH25 ALCOHOL CONSUMPTION 0 never 1 moderate (< 20g [1 unit] per day) 2 excessive (> 20g per day) MH26 PREVIOUS OR PRESENT CONDITIONS 0 none 1 arterial hypertension 2 diabetes 3 obesity 4 coronary heart disease 5 other________________ MH27 PREVIOUS OR CURRENT CANCER DISEASES 0 none 1 other breast 2 ovary 3 GIT _______________ 4 other__________________ MH28 SIGNS AND SYMPTOMS 0 none 1 palpable tumor 2 painful breast 3 skin changes 4 nipple discharge 5 palpable lymph nodes 6 pain in bones 7 abdominal pain 8 dyspnea 9 coughing 10 neurological symptoms 11 losing weight 12 other __________________ MH29 DURATION OF SIGNS AND SYMPTOMS (in months) _______________ MH2 FAMILY HISTORY OF CANCER 0 none (go to A5) 1 breast 2 ovary 3 uterus 4 GIT 5 other (__________________) MH3 FAMILY RELATIONSHIP 1 mother 2 sister 3 other (__________________) MH4 AGE AT DISEASE ONSET (in years) (see A3) 1 _______________ 2 _______________ 3 _______________ MH5 FIRST PERIOD (age in years) _______________ MH6 NUMBER OF PREGNANCIES _______________ MH7 NUMBER OF MISCARRIAGES _______________ MH8 NUMBER OF INDUCED ABORTIONS _______________ MH9 NUMBER OF DELIVERIES/BIRTHS _______________ MH13 AGE AT FIRST BIRTH (years) _______________ MH11 BREASTFEEDING 0 no (go to A13) 1 yes MH12 TOTAL DURATION OF BREASTFEEDING _______________ MH13 HORMONAL CONTRACEPTION 0 never (go to A15) 1 before 2 now MH14 NUMBER OF YEARS of OCP USE _______________ MH15 FERTILITY TREATMENT 0 no (go to A18) 1 yes MH16 DURATION OF FERTILITY TREATMENT (months) _______________ MH17 NUMBER OF STIMULATED CYCLES _______________ FIGURE 2. Medical history. Radiol Oncol 2019; 53(3): 348-356. Arko D and Takac I / Clinical registry for breast cancer350 ment. Until now, data about 3,600 patients have been included in this computer program. Twenty-nine anamnestic data focus on known risk factors for breast cancer as well as current symptoms and signs. Among the risk factors, de- tailed data on family history of breast cancer and other malignancies, reproductive data, use of hor- monal therapy, smoking, and use of alcohol were recorded. Detailed data are listed in Figure 2. The anamnestic data ended with signs and symptoms in the breast, such as breast lump, pain, skin changes, nipple discharge, enlarged axillary lymph nodes as well as their duration and general symptoms, such as bone pain, abdominal pain, dyspnoea, cough, neurological symptoms, and loss of weight. Next section covered a clinical examination with 17 parameters, including inspection and palpation of the breasts and regional lymph nodes, including axillary and supraclavicular lymph nodes. Body mass index data were recorded and data on breast imaging, mammography and ultrasonography of the breast and axillary lymph nodes were collected (Figure 3). The following section contained data about dif- ferent extended investigations before treatment: gynaecological examinations (colposcopy, gy- naecological ultrasound), imaging examinations of liver, lung and bones and certain laboratory testing with the focus on the most common sites of metastases. At the end of this section, WHO and Karnofsky performance status was recorded (Figure 4). The section containing data about the surgical procedure and postoperative care included 16 pa- rameters. Date of procedure, type of surgery, use of frozen section, complications during procedure, and placement of drains were recorded immediate- ly after the surgery. Later, the removal of drains, antibiotic therapy and possible complications were added before the patient leaves hospital (Figure 5). For an easy and fast completion of the inquiry, six types of surgical procedures were listed with sepa- rate marks for the right and left breast. The most common complications during and after surgery were also listed, including the complications in the breasts, such as bleeding or hematoma, seroma, Figure 3: Clinical examination and breast imaging. CLINICAL EXAMINATION CE1 REASON FOR VISIT 0 screening 1 palpable tumor 2 physician’s recommendation 3 diagnostics 4 other__________________ CE2 INSPECTION 0 NAD (nothing abnormal detected) 1 asymmetric 2 skin retraction 3 skin redness 4 skin edema 5 nipple retraction 6 nipple eczema 7 ulcer 8 scar 9 other__________________ CE3 LUMPS 0 not present 1 less obvious 2 obvious CE4 THICKENED TISSUE IN BREAST 0 not present 1 single palpable induration/nodule 2 several palpable indurations/nodules 3 diffuse nodules CE5 SITE OF CHANGE 1 upper outer quadrant 2 lower outer quadrant 3 upper inner quadrant 4 lower inner quadrant 5 central CE6 CONSISTENCY 1 hard 2 soft 3 elastic CE7 FIXITY 1 mobile 2 fixed to skin 3 fixed to underlying structures (fascia) CE8 SURFACE 1 smooth 2 tethering (knotty) 3 infiltrating CE9 MAX. DIAMETER (mm) _________________ CE10 NIPPLE DISCHARGE 0 none 1 spontaneous 2 triggered CE11 COLOUR OF NIPPLE DISCHARGE 1 clear 2 milky 3 purulent 4 dark 5 bloodstain R L R L R L R L R L R L R L R L R L R L CE12)NO. OF EXCRETORY DUCTS ______________ CE13 REGIONAL LYMPH NODES 0 not palpable 1 mobile non-suspicious axillary lymph nodes 2 mobile suspicious axillary lymph nodes 3 fixed axillary lymph nodes 4 supraclavicular lymph nodes CE14 CLINICAL IMPRESSION 0 normal breast 1 inflammation 2 lump (probably benign) 3 lump (probably malignant) 4 carcinoma CE15 BODY WEIGHT(kg) _____________ CE16 HEIGHT (cm) _____________ R L R L R L CE17 BODY MASS INDEX (BMI) (kg/m2) _____________ MAMMOGRAPHY M1 MAMMOGRAM RESULTS (BIRADS) 1 normal 2 clearly benign 3 probably benign - follow-up at 6 to 12 months 4 suspicious - X-ray or ultrasound-guided core-needle biopsy recommended 4A low suspicion of malignancy 4B moderate suspicion of malignancy 5 high probability of malignancy - core-needle biopsy recommended 6 known cancer proven by biopsy US1 ULTRASOUND RESULTS (BIRADS) 1 normal 2 clearly benign 3 probably benign - follow-up at 6 to 12 months 4 suspicious - X-ray or ultrasound-guided core-needle biopsy recommended 4A low suspicion of malignancy 4B moderately low suspicion of malignancy 4C high suspicion of malignancy 5 highly suggestive of malignancy - core-needle biopsy recommended 6 known cancer proven by biopsy US2 TUMOUR SIZE (mm) _______________ US3 TUMOUR BLOOD SUPPLY 1 decreased 2 increased US4 AXILLARY LYMPH NODES 0 not suspicious (go to US5 and US6) 1 suspicious US5 SIZE OF LARGEST LYMPH NODE (mm) ________________ _____________________ US6 NO. OF SUSPICIOUS LIMPH NODES _____________________ ULTRASOUND FIGURE 3. Clinical examination and breast imaging. Figure 4: Investigations before treatment. PREOPERATIVE INVESTIGATION PI1 COLPOSCOPY: 0 not performed 1 O,E,CP 2 L,D,M,aCP 3 carcinoma 4 other (please, specify) PI2 CERVICAL CYTOLOGY SCREENING (SMEAR) : 0 not performed 1 A 2 B 3 C APC-N 4 C APC-VS 5 C PIL-NS 6 C PIL-VS 7 C P-CA 8 C AGC-N 9 C AGC-FN 10 C AIS 11 C A-CA 12 C SUSP-N 13 C MLG-N PI3 GYN ULTRASOUND: 0 not performed 1 normal findings 2 fibroids 3 ovarian cyst - right 4 ovarian cyst - left 5 no uterus or adnexa 6 other (please, specify) PI4 ENDOMETRIAL THICKNESS: Date of measurement: Thickness (mm): PI5 LIVER ULTRASOUND SCAN: 0 not performed 1 normal findings 2 cholelithiasis 3 steatosis 4 cirrhosis 5 metastases 6 other (please, specify) PI6 LIVER CT SCAN: 0 not performed 1 normal findings 2 one tumor 3 several tumors 4 steatosis 5 cirrhosis 6 other (please, specify) PI7 CHEST RADIOGRAPH: 0 not performed 1 normal findings 2 atelectasis 3 metastases 4 effusion R 5 effusion L 6 other (please, specify) PI8 SPINAL RADIOGRAPH: 0 not performed 1 degenerative changes 2 osteomalacia 3 metastases 4 other (please, specify) PI9 BONE SCINTIGRAPHY: 0 not performed 1 normal findings 3 limited accumulation 3 other (please, specify) PI10 MINERAL BONE DENSITY: Date of measurement: spine (T): hip (T): radius (T): PI11 SR: PI12 L: PI13 Hb: PI14 T: PI15 AST: PI16 ALT: PI17 γGT: PI18 AP: PI19 CEA: PI19 CA 15-3 PI20 WHO Karnofsky PERFORMANCE STATUS 0 100 Active, no evidence of disease 1 90 Active, minor signs or symptoms of disease 1 80 Reduced activity, some signs of symptoms of disease 2 70 Cares for self, unable to carry on normal activity or do active work 2 60 Requires occasional assistance 3 50 Requires considerable assistance and frequent medical care 3 40 Disabled; requires special care and assistance 4 30 Severely disabled; hospitalization is indicated 4 20 Very sick; hospitalization necessary, active supportive treatment necessary 4 10 Moribund 5 0 Exitus FIGURE 4. Investigations before treatment. Radiol Oncol 2019; 53(3): 348-356. Arko D and Takac I / Clinical registry for breast cancer 351 wound infection, wound dehiscence and systemic complications, such as fever, deep vein thrombosis and pulmonary embolism. For radiation therapy, eight boxes were de- signed: type, dates of starting and ending radio- therapy and possible complications (Figure 5). As in the case of surgery, the most common type and complications of radiotherapy were provided in the inquiry. Because radiotherapy was performed at the Department of Oncology, data about this part of treatment were filled after complete treat- ment, at the first follow-up visit at the latest. In the next section, data on cytological and his- topathological examination of tumour and lymph nodes were collected. The first part of this section included data on preoperative diagnostics, which could be collected prior to the primary treatment. The inquiry included data on the tumour histology before and after surgery, cytology and histology of sentinel node biopsy (SNB) and/or axillary node dissection and the main predictive and prognos- tic biomarkers, oestrogen receptors (ER), proges- terone receptors (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67 (Ki67) (Figure 6). Full data on histopathology were usually available after the patient leaves the hospital; hence, this part of the inquiry was com- pleted later on. Since the systemic therapy represented an im- portant part of breast cancer treatment in the con- trol and cure of breast cancer, a relatively large part of the inquiry was dedicated to this issue. Detailed information about adjuvant or neo- adjuvant chemotherapy was collected in the spe- cial section of the inquiry boxes during treatment (Figure 7). Among others, this data included the date of each chemotherapy cycle and chemo- therapy regimen. The presence of the adverse events during chemotherapy was collected in the Chemotherapy section. Detailed data regarding the type and severity of adverse events were col- lected in the section Adverse events. A separate sheet contained data on systemic anti-cancer treatment, including chemotherapy, Figure 5: Surgery and radiotherapy SURGERY RADIATION THERAPY S1 DATE OF PRIMARY SURGERY: S2 DATE OF SECONDARY SURGERY: S3 INTERVENTION done in primary surgery: RT1 RADIATION THERAPY : 0 no (go to H1) 1 yes 2 declined by patient 1 tumorectomy 2 quadrantectomy 3 mastectomy 4 SNB 5 axillary clearance 6 tumor bed re-excision 7 other (please, specify) 8 declined by patient R R R R R R R  L  L  L  L  L  L  L RT2 TYPE OF RADIATION THERAPY: 1 preoperative 2 postoperative 3 radical 4 palliative 5 other (please, specify) S4 INTERVENTION done in secondary surgery: 1 tumorectomy 2 quadrantectomy 3 mastectomy 4 SNB 5 axillary clearance 6 tumor bed re-excision 7 other (please, specify) R R R R R R R  L  L  L  L  L  L  L RT3 KIND OF RADIATION THERAPY: 1 beam radiation 2 interstitial brachytherapy 3 other (please, specify) RT4 DURATION OF RADIATION THERAPY: From (dd-mm-yyyy): Until (dd-mm-yyyy): S5 FROZEN SECTION: 0 no (go to O7) 1 yes S6 FROZEN SECTION RESULTS: 0 benign tumor 1 probably malignant tumor 2 malignant tumor RT5 SOURCE OF RADIATION: 1 linear accelerator 2 iodine-125 3 iridium-192 S7 COMPLICATIONS DURING SURGERY: 0 no 1 bleeding 2 nerve damage 3 vascular damage 4 anesthetic 5 other (please, specify) RT6 NUMBER OF FRACTIONS: RT7 TOTAL RADIATION DOSE (Gy): RT8 COMPLICATIONS FOLLOWING RADIATION THERAPY: 0 no 1 anemia 2 leukopenia 3 thrombocytopenia 4 dermatitis 5 exitus 6 other (please, specify) S8 BREAST DRAINAGE: 0 no (go to O11) 1 yes S9 DRAINAGE OUTPUT (mL): S10 NO. OF DAYS WITH DRAINAGE: S11 AXILLARY DRAINAGE: 0 no (go to 50) 1 yes S12 AXILLARY DRAINAGE OUTPUT (ml): S13 NO. OF DAYS WITH AXILLARY DRAINAGE: S14 PERIOPERATIVE ANTIBIOTICS: 0 no 1 yes S15 INTRAOPERATIVE ANTIBIOTICS: 0 no 1 yes S16 POST-OPERATIVE COMPLICATIONS: 0 no 1 bleeding 2 seroma 3 hematoma 4 wound infection 5 wound dehiscence 6 febrile condition 7 sepsis 8 deep vein thrombosis 9 pulmonary embolism 10 exitus 11 other (please, specify) S17 DATE OF DISCHARGE FOLLOWING PRIMARY SURGERY: FIGURE 5. Surgery and radiotherapy. Figure 6: Histopathology HISTOLOGY H1 DIAGNOSTIC METHODS: 1 clinical 2 mammogram 3 cytology 4 histology (wide core needle biopsy) 5 histology (biopsy) 6 histology (frozen section) 7 other (please, specify) H12 NO. OF AXILLARY LIMPH NODES: R L H13 NO. OF POSITIVE LIMPH NODES: R L H2 FINE-NEEDLE ASPIRATION (FNA): 0 not performed 1 insufficient material 2 repetition due to 1 (1x, 2x, 3x) 3 sufficient material obtained H14 AXILLARY METASTASES’ DIAMETER: R L H3 FINE NEEDLE ASPIRATION (FNA) RESULTS: 1 C1 – sample inadequate for testing 2 C2 – normal breast cells 3 C3 – cells abnormal 4 C4 – highly suspicious of cancer 5 C5 – carcinoma H15 ESTROGEN RECEPTORS: R L 0 not tested 1 not found 2 present _____________% 3 no data available in % 0 1 2 3 0 1 2 3 H4 TUMOUR SIZE (mm): 1. _______________ 2. _______________ 3. _______________ H16 PROGESTERONE RECEPTORS: R L 0 not tested 1 not found 2 present _____________% 3 no data available in % 0 1 2 3 0 1 2 3 H5 TUMOR HISTOLOGY 0 not assessed 1 DCIS 2 ductal carcinoma 3 LCIS 4 lobular carcinoma 5 medullary carcinoma 6 mucinous carcinoma 7 tubular carcinoma 8 ductal + lobular carcinoma 9 other (please, specify) 1. 2. 3. H17 HER-2 (HISTOCHEMICAL/IMMUNOHISTOCHEMICAL): 0 not assessed 1 negative (0) 2 weakly positive (1+) 3 moderately/borderline positive (2+) 4 strongly positive (3+) H18 HER-2 (FISH): 0 negative 1 positive H19 uPA: 0 not assessed 1 assessed ____________ ng/mg prot. H20 PAI-1: 0 not assessed 1 assessed ____________ ng/mg prot. H21 Ki-67: 0 not assessed 1 assessed _____________ H6 CLEAR MARGINS 0 no 1 yes distance to margin in mm: 1. 2. 3. H7 SENTINEL NODE BIOPSY (SNB) R L 0 no 1 yes 0 no 1 yes H8 NO. OF REMOVED SN: R L H9 CYTOLOGY OF SNB: 0 negative 1 positive H10 HISTOLOGY OF SNB: 0 negative 1 positive 2 micrometastases H11 AXILLARY CLEARANCE: 0 none 1 yes FIGURE 6. Histopathology. Radiol Oncol 2019; 53(3): 348-356. Arko D and Takac I / Clinical registry for breast cancer352 hormonal and targeted therapy, applied as neo- adjuvant or adjuvant treatment. The same page contained boxes for systemic treatment in case of recurrent disease. The most frequently used agents were already listed and categorized for chemo- therapy, hormonal therapy, and targeted therapy. Over the past decades, adjunctive and supportive therapy of breast cancer have evolved substan- tially. In the inquiry, the data on bisphosphonates, erythropoietin and granulocyte colony-stimulating factor (G-CSF) were collected during the systemic treatment (Figure 8). The last section of the inquiry was follow-up sheet (Figure 9). All nine boxes were completed at every follow-up visit. Data collected at follow-up were limited to performance status, pain, clinical examination, mammography, laboratory tests, and the clinical state of the patient. All data collected with the paper inquiry were recorded using the computer program Onko- Online for processing data and statistical analysis. The program enables to find, list and sort data in a quick and easy manner. The existing data could be modified or new data could be added, if necessary. Discussion The breast cancer inquiry collected extended infor- mation on altogether 167 questions about breast cancer patient medical history, clinical status, treat- ment, and its outcome. Among the risk factors, we recorded data known to be associated with high risk for breast cancer. It is well known that there is a two-fold increase in the risk of developing breast cancer for women with breast cancer in their first-degree family, es- pecially among women with a first-degree relative diagnosed before the age of 50.6,7 Among the repro- ductive data, young age at menarche, late meno- pause, late age at first pregnancy, low number of deliveries, spontaneous or induced abortions, and lack of breastfeeding are known to increase the risk of breast cancer.8,9 Known risk factors also include hormonal contraception and hormonal replace- ment therapy, although the absolute increase in risk, especially for contraception, is small.10,11 Some studies reported a link between infertility and in- creased breast cancer risk, while others were not able to find a connection.12, 13 The results of recently published data in literature strongly support the role of cigarette smoking in breast cancer etiol- ogy.14 The risk of breast cancer is significantly in- creased by alcohol consumption as well.15 Data on body mass index were included, since it is known that obesity is associated with an increased relative risk, especially for postmenopausal receptor-posi- tive breast cancer.16 Known risk factors for breast cancer were included to determine the frequency of these risk factors in our population. Moreover, the knowledge of these risk factors in a subset of patients could lead to a better understanding of different factors involved in the breast cancer de- velopment. Typical local signs and symptoms for breast cancer are: a breast lump, usually painless; skin retraction, nipple retraction, nipple discharge, and swelling in the armpit.17 All these signs were listed in the inquiry as well as palpable lymph nodes in the axilla. We also added some typical signs of a metastatic disease (bone pain, dyspnoea, persistent cough, abdominal pain, weigh loss), although primary metastatic cancer is relatively rare. According to our registry, in Slovenia 7.1% of patients were pre- sented with primary metastatic disease in 2015.1 The data in the literature for developed countries Figure 7: Adjuvant or neoadjuvant chemotherapy ST1 CHEMOTHERAPY CYCLE / TREATMENT LEVEL: 1 2 3 4 5 6 ST2 DATE: ST3 BODY WEIGHT (kg): ST4 HEIGHT (cm): ST5 SURFACE (m2): ST6 PERFORMANCE STATUS: (See P21) 0 3 1 4 2 5 ST7 EXAMINATION: 0 NAD 3 lymphedema 1 tumor 4 metastasis 2 hydrothorax 5 other (specify) ST8 CHEST RADIOGRAPH: 0 NAD 2 hydrothorax 1 metastases3 other (specify) ST9 LIVER ULTRASOUND SCAN: 0 NAD 2ascites 1metastases3 other (specify) ST10 BONE SCINTIGRAPHY: 0 NAD (nothing abnormal detected) 1 metastases (site) 2 diffuse accumulation (site) ST11 BONE RADIOGRAPHY: 0 NAD (nothing abnormal detected) 1 metastases (site) 2 diffuse changes (please, specify) ST12 Ca 15-3 ST13 DOSE REDUCTION (%) ST14 REASON FOR REDUCTION a ↓ L c liver dysfunction b ↓ T d renal dysfunction ST15 CYTOTOXIC 1: (mg) ST16 CYTOTOXIC 2: (mg) ST17 CYTOTOXIC 3: (mg) ST18 G-CSF (dose) ST19 ANTIEMETIC (mg) ST20 PATHOLOGY LAB. RESULTS biochemistry (AP, GT…) marker (CEA) other (please, specify) ST21 VOMITING: 0 no 2 6x–10x 1 1x–5x 3 > 10x ST22 ADVERSE EVENT: (See page 6) 0 no 1 yes FIGURE 7. Adjuvant or neoadjuvant chemotherapy. Radiol Oncol 2019; 53(3): 348-356. Arko D and Takac I / Clinical registry for breast cancer 353 TREATMENT SCHEME (TS1) LEVEL OF TREATMENT (ST2 – ST7) CHEMOTHERAPY (ST8 – ST12) HORMONAL THERAPY (ST13 – ST19) TARGETED (BIOLOGICAL) TREATMENT (ST20 – ST22) ADJUVANT THERAPY ST23 OUTCOMES, RESPONSE 0 no 1 yes 1 cyclophosphamide 2 methotrexate 3 5-fluorouracil 4 capecitabine 5 doxorubicin 6 epirubicin 7 paclitaxel 8 docetaxel 9 cisplatin 10 carboplatin 11 vinorelbine 12 other (specify) No. of cycles Date - since 0 no 1 yes 1 tamoxifen (Nolvadex) 2 anastrazole (Arimidex) 3 exemestane (Aromasin) 4 letrozole (Femara) 5 fulvestrant (Faslodex) 6 GnRH (Zoladex) 7 other (specify) Dose Date - since 0 no 1 trastuzumab 2 lapatinib 3 bevacizumab 4 other (specify) Dose No. of cycles Date - since 1 Bisphosphonates 2 Erythropoietins 3 GCSF 4 other (specify) Date - since Frequency of cycles Date - since Date - until cumulative dose Frequency of cycles Date - until Date - until NON-ADJUJVANT 0 disease-free 1 progress during chemotherapy and/or targeted (biological) treatment 2 progress following chemotherapy and/or targeted (biological) treatment 3 condition unknown ADJUVANT 0 disease-free 1 progress during chemotherapy and/or targeted (biological) treatment 2 progress following chemotherapy and/or targeted (biological) treatment 3 condition unknown PRIMARY METASTATIC DISEASE 1. RELAPSE (LINE) 0 no 1 yes, clinical 2 yes, biochemical 3 yes, x-ray, ultrasound, scintigraphy 4 yes, confirmed by biopsy DATE 1. RELAPSE 0 complete remission (CR) 1 partial remission (PR) 2 stable disease (SD) 3 progressive disease (PD) 4 condition unknown 2. RELAPSE (LINE) 0 no 1 yes, clinical 2 yes, biochemical 3 yes, x-ray, ultrasound, scintigraphy 4 yes, confirmed by biopsy DATE 2. RELAPSE 0 complete remission (CR) 1 partial remission (PR) 2 stable disease (SD) 3 progressive disease (PD) 4 condition unknown 3. RELAPSE (LINE) 0 no 1 yes, clinical 2 yes, biochemical 3 yes, x-ray, ultrasound, scintigraphy 4 yes, confirmed by biopsy DATE 3. RELAPSE 0 complete remission (CR) 1 partial remission (PR) 2 stable disease (SD) 3 progressive disease (PD) 4 condition unknown 4. RELAPSE (LINE) 0 no 1 yes, clinical 2 yes, biochemical 3 yes, x-ray, ultrasound, scintigraphy 4 yes, confirmed by biopsy DATE 4. RELAPSE 0 complete remission (CR) 1 partial remission (PR) 2 stable disease (SD) 3 progressive disease (PD) 4 condition unknown CR = complete response (disappearance of all target lesions); PD = progressive disease (20% increase of sum of the longest target lesions dimension); PR = partial response (30% decrease of sum of all target lesions dimension); SD = stable disease (minor lesions not qualifying for CR/PR/PD) FIGURE 8. Treatment scheme. FIGURE 8. Treatment scheme. are similar, approximately 5-10% of all breast can- cer patients were presented with distant metasta- ses at initial diagnosis.18 Clinical breast examination is not a reliable di- agnostic tool19, but it has to be performed in all known breast cancer patients when planning pri- mary treatment - surgical or neoadjuvant systemic therapy. Ultrasound preoperative examination of axilla was routinely performed to avoid two- stage axillary surgery in selected patients.20, 21 At the moment, MRI was not included in the inquiry. Since both MRI and digital breast tomosynthesis are nowadays common diagnostic procedures in breast diagnostics, we intended to add both proce- dures to the pre-treatment diagnostics. According to Slovenian recommendations for stage I and II breast cancer, laboratory tests, in- cluding blood count, liver function tests, alkaline phosphatase, calcium levels, and chest X-ray were routinely performed.22 In case of clinical symp- toms and/or pathological laboratory results as well as in all stage III and IV patients, thoracic and abdominal CT scan and bone scintigraphy were performed.22 In the inquiry section covering a surgical pro- cedure, breast reconstruction was not included, since this type of procedure was performed at the Department of Plastic and Reconstructive Surgery at the University Medical Centre Maribor and not within our department. Breast reconstruction is an important part of breast cancer management which has evolved significantly in the past decades because of advances in reconstructive strategy.23 It is oncologically safe and associated with high satis- faction rates.24 In the case of breast reconstruction, data was recorded in the inquiry during the first follow-up visit. Over the last two years, radiation therapy for breast cancer patients has mostly been adminis- tered at our hospital at the Department of Oncology at the University Medical Centre Maribor, but some patients still receive therapy at the Institute of Oncology in Ljubljana. All data concerning radi- otherapy, including complications, were collected at the first follow-up visit. According to the data in literature, fine-needle aspiration cytology (FNAC) and core needle biop- sy (CNB) have similar values of diagnostic accura- Radiol Oncol 2019; 53(3): 348-356. Arko D and Takac I / Clinical registry for breast cancer354 cy.25, 26 We routinely used CNB as the first method in breast cancer diagnostics, because hormonal re- ceptor (HR) status and expression of HER2 can be tested. Sometimes, this information was crucial for planning the treatment, e.g. neoadjuvant systemic therapy. TNM classification of breast cancer was not in- cluded in the computer program and it served as a tool to define the correct stage in the general data (Figure 1 – G14). The data set about the systemic treatment has been designed to provide access to quick and trans- parent information on systemic therapy for pa- tients and enable easier decision-making processes for further treatment in case of disease progression. Every list of chemotherapy, hormonal and target- ed therapy was given the option “others” to name drugs, which were not included. Novel therapeu- tic approaches included immunologic therapies, PARP inhibitors, PI3K inhibitors, and CDK4/6 in- hibitors, and others to be added to the inquiry at any time. In the inquiry, information on date of diagnosis and date of starting (different) treatment were in- cluded. The inquiry collected the date of first and second surgery, date of all neoadjuvant or adju- vant chemotherapy cycles, beginning and ending date of radiotherapy, and beginning and ending date for all types of systemic treatments. There are data in the literature suggesting that time to start of adjuvant treatment might have an influence on survival.27 Delays to adjuvant radiotherapy are also related with decreases in survival of patients with locally advanced tumours.28 The purpose of a follow-up was surveillance for recurrence, management of long-term effects of cancer treatment, and management of medication side effects. At our department, follow-up was per- formed over a time period of 10 years. According to Slovenian recommendations22, follow-up visits for asymptomatic patients were performed every six months for the first 3 years and then annu- ally. At each visit, clinical examination was per- formed. Patients underwent mammography on S1 DATE: S2 TYPE OF EXAMINATION: 1 outpatient clinic 2 hospital S3 WHO PERFORMANCE STATUS: 0 asymptomatic, but completely ambulatory 1 symptomatic, 2 symptomatic, up and about more than 50% of waking hours 3 symptomatic, confined to bed or chair more than 50% of waking hours 4 confined to bed S4 PAIN: 0 no pain 1 mild pain 2 moderate pain 3 severe pain S5 EXAMINATION 1 NAD (nothing abnormal detected) 2 tumor (size) 3 lymph nodes in axilla 4 lymph nodes above collar bone 5 hand edema 6 other (describe) S6 MAMOGRAPHY: S7 LABORATORY: S8 CONDITION ASSESSMENT: S9 NOTES: 0 N/A 1 NAD (nothing abnormal detected) 2 suspicious findings 3 carcinoma 4 other (specify) D 1 2 3 9 1 NAD (nothing abnormal detected) 2 high ESR levels 3 anemia 4 leukopenia 5 leukocytosis 6 high AST levels 7 high ALT levels 8 high γGT levels 9 high ALP levels 10 high CEA levels 11 high CA 15-3 12 other (specify) 0 alive, no symptoms (CR or DF) 1 alive, partial remission (PR) 2 alive, stable disease (SD) 3 alive, relapse 4 alive, progressive disease (PD) 5 alive, condition unknown 6 ex due to breast malignancy 7 ex during treatment 8 ex due to other disease, no breast symptoms 9 ex due to other disease, breast symptoms present 10 ex, cause unknown 11 condition unknown Figure 9: Follow-up. FIGURE 9. Follow-up. Radiol Oncol 2019; 53(3): 348-356. Arko D and Takac I / Clinical registry for breast cancer 355 a yearly basis. Laboratory tests were indicated in case of clinical symptoms. Liver ultrasound, chest radiography, bone scan, and other investigations were performed only in case of clinical symptoms or pathological laboratory tests. At the end of the follow-up visit, treatment response rate was esti- mated. Treatment response rates were mostly eval- uated on the basis of WHO criteria29, although new and updated criteria had been published for more precise and objective response.30,31 There is no evidence that the detection of asymp- tomatic distant metastases leads to a longer sur- vival.32 Some data indicated that the detection of isolated loco-regional or contra-lateral breast can- cer recurrences in patients without symptoms has beneficial impact on survival of breast cancer pa- tients when compared to late symptomatic detec- tion33; however, it was shown that only 40 % of the isolated loco-regional recurrences in asymptomatic patients were detected during routine examina- tion.34 But, the vast majority of the patients took ad- vantage of the follow-up and one of the important goals of the follow-up care is to offer psychological support and reassurance by their physician.35, 36 The type of treatment in patients who were metastatic at first presentation was recorded in the same way as for patients with localised or region- al cancer. In case of disease relapse after primary treatment, data about the date of relapse, site of relapse and treatment of relapse were recorded in the section General data. Detailed data about sys- temic treatment of relapse were recorded also in the Treatment scheme section. Conclusions The clinical cancer registry plays an important role in the evaluation of clinical practice with the pur- pose to improve organisation in daily clinical work and treatment of the disease. It allows us to con- tinuously compare treatment results with national and international standards. The data can also be used for research projects and studies on cancer survivorship. The computer program Onko-Online allows quick and reliable processing and analysis of 167 different data obtained from breast cancer patients, i.e. general information, medical history, diagnos- tics, treatment and follow-up. The computer pro- gram allows us to follow the timing of different treatments procedures to assure optimal treatment for all breast cancer patients. A potential limitation of the registry is the in- complete or incorrect data input. With this amount of data collected by different healthcare providers there is a risk that a mistake will occur, but not in the extent to which it could influence the reliability of the data. References 1. Cancer in Slovenia 2015. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2018. 2. Hočevar M. Klinični registri v onkologiji. Onkologija 2011; 15: 14-7. 3. Clinical register of skin melanoma. In: Cancer Registry of Republic of Slovenia, editor. Epidemiology and Cancer Registry. [cited 2019 Jan 15]. Available at: https://www.onko-i.si/eng/ 4. Takač I, Ferletič M, Arko D, Gorišek B. Follow-up computer program for patients with ovarian malignancy In: Bigec M, Lavrenčič D, Kokol P, editors. 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