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Volum 07 Numarul 1, 2001

4 Editorial

An important event in the Romanian oncology life was the 3rd Balkan Congress of Oncology, held in September 2001, at Poiana Bra~ov. In this issue of our Journal (1/2001) are published in extenso some of the oral presentations from this international meeting, starting with the ones related to the major problem of the cervical cancer and continuing with the chemotherapy of the digestive system turnours, in addition with some other contributions.

This issue includes an overview of the hormone therapy of breast cancer – presented by N. Ghilezan – from

ovarian ablation and tamoxifen, to the main directions for research with analogues LHRH, antiaromatase agents and antiestrogens, with practical recommandations for their integration in the multidisciplinary treatment of breast cancer. Another teaching lecture presents the most important data referring to cervical cancer (Viorica Nagy), starting with epidemiology and etiology to prognostic factors and treatment modalities, ending with future possibilities. Claudia Ordeanu overviews the main brachytherapy methods in cervix carcinoma and analyses the

radiobiological aspects, the advantages and clinical experiences in the use of MDR BT; which represents a good

therapeutical option for cervical cancer.

The cervical cancer epidemiology in Roumania 1959-1999, is discussed with high authority by Ofelia Şuteu. The gravity of this public health problem, demonstrated in the ascending evolution of the incidence and mortality rates, in the la~t 40 years, justifies the need of an organised screening program at a national level.

The majority of advanced stages in cervical carcinoma leads to the search of some new prognostic factors which might be able to find the good therapeutical decision. With this purpose, R. Buigă discusses the predictive value of apoptosis for the response to radiotherapy in advanced cancer of the uterine cervix. The importance of the clinical prognostic factors is revealed in the retrospective study (O.Coza), which analyses the external beam radiotherapy and brachytherapy results, confirmed through histopathological examination of the surgical specimen in locally advanced cervical. carcinoma.

Another important study justifies the necessity of the quality control of all therapeutical modalities in cervical carcinoma. A. Rancea evaluates the influence of the first attempt in Institute of Oncology Cluj of the quality control on the surgical technique in cervical cancel; reffering to the number of the removed lymph nodes, during the Wertheim operation, comparing to the international standards.

The chemotherapy in digestive system turnours is discussed referring to the possible combinations with some new molecules, in more phase II trials: Docetaxel, 5-Fluorouracil and Leucovorin in advanced/metastatic gastric cancer (Al. Eniu); Gemcitabine in combination with „De Gramont” protocol for unresectable or metastatic’ pancreatic carcinoma (Cristina Cebotaru); lrinotecan with high dose infusional folinic acid and 5-Fluorouracil for advanced inoperable, metastatic or relapsed colorectal carcinoma (E. Banu), with promissing results.

In her study, Anca Bojan follows the efficacy of the adjuvant treatment with bisphosphonates, concerning the decrease of the scheletal morbidity in multiple myeloma, through the bone pain intensity and the bone fractures.

Presenting a locally advanced breast cancer case, Dana Grecea discusses the primary treatment and analysis the treatment of metastatic disease which represents an important practical problem.

In the Oncological News section, AI. Eniu overview the most imortant orally presented studies, in the field of breast cancer treatment, during the ESMO Congress held in October 2000, at Hamburg.

The 1/2001 issue is ending with Revue of Literature referring to preoperative chemoradiation in fixed distal rectal cancer (Joana Brie), the „Book Reviews” of the monography „Cancerul Bronhopulmonar” by T. Horvat, M. Dediu, A. Tarlea (T.E. Ciuleanu, N. Ghilezan), the questionnaire of the CME, the calendar of events and the guidelines for the authors.

Viorica Nagy

5 Hormonal Therapy in Breast Cancer

Teaching Lecture

  1. Ghilezan1,2

1Institute of Oncology „Prof I. Chiricuţă”, 2UMPh „I. Haţieganu” Cluj-Napoca

An overview of the hormone therapy of breast cancer is presented. The most extensive experience to date is with ovarian ablation and tamoxifen as it was analyzed and presented by the EBCTCG. OA has increased l5-year survival vs. no OA (52.4% vs. 46.1 %) and DFS = 45.0% vs. 39.0% and 5 years of adjuvant tamoxifen produced an impressive benefit of47% reduction the risk for recurrence and 26% for death for patients ER + tumors, irrespective of age, menopausal status and additional chemotherapy. Despite these excellent results, efforts are made for development of new compounds more efficacious and less toxic. The main directions for research are the analogues LHRH, antiaromatase agents and antiestrogens. The most promising new approaches are the maximal estrogen blockade by using a LHRHa in combination with tamoxifen and the antiaromatase agents. The main studies are presented and the future trends are outlined as well the practical recommendations for the integration of the new compounds in the multidisciplinary treatment of breast cancer.

Key words: hormone therapy, LHRHa, antiaromatase agents, antiestrogens.

Radioterapie & Oncologie Medicală, 2001, 1:5-19

20 Cervical Cancer

Teaching Lecture

Viorica Nagy1,2

1Institute of Oncology „Prof I. Chiricuţă”, 2UMPh „I. Haţieganu” Cluj-Napoca

The actual study of the vast problem of the cervical cancer is presented: there are overviewd the knoledges about the” epidemiology and etiology, natural history, molecular biology, diagnostic workup and the different staging systems. There are presented the most important literature data concerning the prognostic factors, and the therapeutical methods, 1 emphasizing the multi modality treatment in locally advanced stages. The lecture is ending with the results and future possibilities.

Radioterapie & Oncologie Medicală 2001, 1:20-32

33 Medium Dose Rate Brachytherapy: Therapeutical Option for Cervical Cancer*

Claudia Ordeanu, Ioana Todor, Olga Burghelea, S. Gavriş, O. Coza

Institute of Oncology „Prof I.Chiricuţă”, Cluj-Napoca

Modem intracavitary brachytherapy carefully combined with external beam radiotherapy is responsable for the high cure rates achieved with radiation treatment of invasive cervical cancers.

For the brachytherapy component of the radioation treatment of cervical carcinoma, medium dose rate (MDR) is slowly replacing conventional low dose rate (LDR) due primarily to radiation safety and other physical benefits attributed to the MDR modality. Many radiation oncologists are reluctand to make this change because of perceived radiobiological disavantages of MDR. However, in clinical practice MDR appears to be as effective as LDR.

Key words: cervical cancer, MDR, brachytherapy.

Radioterapie & Oncologie Medicală, 2001, 1:33-39

40 Cervical Cancer Epidemiology in Romania, 1959-1999

Ofelia Şuteu1, N. Ghilezan1,2 N. Todor2, Ecaterina Scoţan3

1UMPh „Iuliu Haţieganu” Cluj-Napoca

2Institute of Oncology „Prof I. Chiricuţă” Cluj-Napoca

3Computer, Sanitary Statistics and Medical Evidence Centre, Bucharest.

Cervical cancer represents an important problem of public health, being situated on the second place of the neoplasm diseases, after the breast cancer, regarding both its incidence and mortality. In 1998, Romania registered the highest rates of the incidence and mortality by cervical cancer in Europe; regarding mortality, the situation maintained constantly in the last two decades, in the context in which there is a marked tendency of diminution of mortality by cervical cancer throughout the world, in the countries that have adopted national screening programmes. The standardized mortality rates, with an ascending evolution in the last 40 years, from 6.9%000 in 1959, to 11 %000 in 1999, reflect both the continuous growing incidence and the advanced stage of the disease at the diagnose moment, in the context of the absence of an organised screening programme in our country. More than 1700 death cases are registered every year (representing 11 % of all cancer deaths among female population) and 2600 new cases, corresponding to a crude rate of the incidence 22.78%000. Correlated with the diagnose of two thirds of the cases in belated stages (liB, III or IV) the relative survival to 5 years do not overpass 40%, being among the lowest in Europe. The continuous ascendent course of mortality rates by cervical cancer in our country fully justifies the efforts for primary and secondary prevention of the disease and underlines the necessity of a pressing intervention at the population level, in order to investigate the risk factors and establish which of them could be influenced as well as the implementation of an organised screening program at national level that is essential to reduce the impact of this malignant neoplasm.

Key words: incidence and mortality rates, cervical cancer.

Radioterapie & Oncologie Medicală, 2001,1:40-51

52 Apoptosis in Advanced Cancer of Uterine Cervix: Predictive Value for the Response to Radiotherapy

R.P. Buiga1, C.D. Olinicil,2, G. Jacob2, Viorica Nagyl, N. Ghilezan1

lInstitute of Oncology „Prof. I. Chiricuţă”, Cluj-Napoca

2Dept. of Pathology, UMPh „Iuliu Haţieganu” Cluj-Napoca

The authors have studied the apoptotic index in 20 cases of advanced squamous cell carcinoma of the uterine cervix before radiotherapy. The results 3uggest that the pretreatment levels of apoptosis are not correlated with the radiosensitivity.

Key words: uterine cervix, cancer, apoptosis, radiotherapy.

Radioterapie & Oncologie Medicală. 2001, 1:52-56

57 Endocavitary MDR-Brachytherapy and External Beam Radiotherapy in the Multidisciplinary Treatment of Loco- Regional Advanced Cervical Carcinoma

  1. Coza1,2, S. Gavriş2, Claudia Ordeanu2, Ioana Todor2

1U.MPh. ,,I. Haţieganu”

2Institute of Oncology „Prof I. Chiricuţă”,Cluj-Napoca

In advanced cervical carcinoma the associate treatment of External Beam Radiotherapy (EBRT) and Brachytherapy (BT) is widely accepted as the „golden standard”. This study deals with 122 patients treated for loco-regional advanced cervical carcinoma from 1996 to 1998 with associate EBRT+BT followed by surgery. We used a particular type of vaginal applicator – the ring-type one – and another characteristic of this study was the median MDR-BT(medium dose rate BT) dose rate of 3.3 Gy/h. End-points were histological sterilization of the surgical specimens and local control. We found that the only predictive factor for local control was the histological sterilization (univariate analysis). Histological findings were predicted only by the tumor volum, neither geometry ofMDR-BT or the dose/ fraction had no influence.

Key words: MDR-BT, ring-type applicator, histological sterilization.

Radioterapie & Oncologie Medicală, 2001. 1:57-62

63 The Influence of Quality Control (QC) on the Surgical’ Technique in Cervical Cancer

A.C. Rancea1,2, Viorica Nagyl,2, N. Todor2, N.Ghilezan1,2

1U.M.Ph.”I. Haţieganu” Cluj-Napoca

2Institute of Oncology „Prof I. Chiricuţă” Cluj-Napoca

Introduction: the aim of this study is to measure the influence of the first attempt ofQC in surgery did in our institute at the beginning of 1999 and to improve the way of doing QC in our surgical departments.

Material and methods: we reviewed the medical records of a first group of 141 patients who underwent a Wertheim operation in 1998. From the pathology reports we identified the number of lymph nodes (LNs) removed for each patient by each surgeon. The specimens with fewer than 10 LNs were considered unsatisfactory. We did the same study for a second group of 181 patients operated on between June’99 and July’OO, and we compared the results of the two groups with regard to unsatisfactory specimens.

Results: in 1998 a total number of 33 cases (26%) out of 127 had an unsatisfactory specimen. In the second period (June’99 – July 2000), 29 cases (18%) out of 160 had an unsatisfactory specimen.

The improvement was statistically nonsignificant (p=0.1 0). Conclusions: the actual number of unsatisfactory specimens (29 cases-18%) is still high and a lowering of this figure to less than 10% is acceptable and desirable as it is shown in the literature. The observed improvement shows that QC is necessary and benefic and must be continuous. This study demonstrates that QC is a team problem and should involve the pathologists too.

Key words: cervical cancer, quality control, number of lymph nodes, surgical technique.

Radioterapie & Oncologie Medicală, 2001,1:63-70

71 DFL (Docetaxel, 5-Fluorouracil And Leucovorin) An Effective Outpatient First Line Chemotherapy For Advanced/ Metastatic Gastric Cancer Patients. A Phase II Study

  1. Eniul, T. E. Ciuleanul,2, N. Todorl, Helene Homokosl, Cristina Neacşul, Anca Mihailovl, C. Căinapl, Dana Iancul, N. Ghilezanl,2

1Institute ofOncology „Prof I. Chiricuţă” Cluj-Napoca

2U.MPh. „I. Haţieganu” Cluj-Napoca

For gastric cancer, Docetaxel has shown promising antitumor activity as first line chemotherapy (CT). The purpose of this study was to assess the activity and tolerability of Docetaxel+5-FU+Leucovorin (DFL) as fIrst line outpatient CT for advanced/metastatic gastric cancer. Methods: From 3/1998 to 1/2000,26 chemonai:ve patients with measurable advanced (6 patients) and/or metastatic (20 patients) gastric cancer were enrolled in this phase II trial. Treatment consisted of up to six cycles of DFL regimen: 5-FU 600mg/m2 in 2 hrs days 1 to 4, preceded by Leucovorin 30mg/m2, and Docetaxel80mg/ m2 in 1 h on d 2, every 21 days. Patients: Median age was 52 [30-69], MIF 19/7 with performance status (WHO) 1- 8 patients and 2 -18 patients. Metastatic sites: liver 7, multiple 5, peritoneal 3, skin 3, ovarian 1 and lung 1. Histology revealed diffuse type adenocarcinoma in 11 and intestinal type in 15 patients. Initial weight loss was <5% in 12 and >5% in 14 patients. Results: We observed 8 PRs and no CRs, for an overall response rate of 31 % (0.05 CI: 12%-49%). In addition 9 (34%) patients had stable disease. Nine patients (34%) progressed under CT. Overall, 17 patients (=65%, CI: 46%-85%) had clinical benefit (increase of body weight, palliation of symptoms and improvement of performance status).. With a median follow up of 12 months, the median duration of response was 8 months (range 3-9), the median time to progression 7 months (range 3-9). Median survival was 6 months and 1 year actuarial survival 7%. A total of 100 cycles were administered, with a median 3.8 cycles per patient (range 1-6). Toxicity was mild and there were no toxic deaths. Grade 3-4 toxicities included anemia in 5%; neutropenia in 3%; and vomiting in 5% of the cycles. Conclusion: The DFL regimen proved to be active in the first line palliative treatment of advanced/metastatic gastric cancer. This combination can be safely administered in the outpatient setting with only mild toxicity.

Key words: gastric cancer, chemotherapy, docetaxel, phase II trial

Radioterapie & Oncologie Medicală, 2001, 1:71-76

77 Gemcitabine in Combination with «De Gramont» Protocol as First-Line Chemotherapy for Unresectable or Metastatic Pancreatic Carcinoma. A phase II study

Cristina Cebotarul, N. Ghilezanl,2, N. Todor1, Luminita Popal, Dana Iancul, C. Căinapl, E. Banul, AI. Eniul, Anca Mihailovl, Helene Homokosl, T.E. Ciuleanul,2

1Institute of Oncology „Prof I.Chiricuţă” Cluj-Napoca

2U.MPh. „I. Haţieganu” Cluj-Napoca

This phase II study was initiated to detennine the efficacy and tolerability of gemcitabine added to «De Gramonb> regimen as first line chemotherapy (CT) for advanced/metastatic pancreatic carcinoma. From 1/1999 to 4/2000,23 chemonalve patients were enrolled. Up to 6 cycles ofFOLFUGEM regimen were given: Folinic acid 200 mg/m2 in 2 ills, 5-FU 400 mg/m2 in bolus, 5-FU 600 mg/m2 in 22 hrs infusion days 1,2 and Gemcitabine 800 mg/m2 in 1 hr on d2, every 14 days. Median age was 52, M/F 19/4, perfonnance status (WHO) 1 (14 patients), 2 (3 patients) and 3 (6 patients). Initial weight loss was <5% in 15 and> 5% in 8 patients. In 17 evaluable patients, 3 CRs and 2 PRs were observed, for an overall response rate of29% (0.05 CI: 6%-53%). Four patients (19%) had stable disease. Eight patients (32%) progressed under CT. Overall, 14 patients among 22 evaluable (=64%, CI: 42%-85%) had clinical benefit. With a median follow-up up 3.5 months, median survival was 6.6 months and 1 year actuarial survival 34% (0.05 CI: 13%-64%). Sixtynine cycles were administered; median 2 cycles (range 1-8). Toxicity was mild and there were no toxic deaths. Grade 4 thrombopenia in 1 patient and gr. 3 cardiac toxicity in 1 patient was reported. The FOLFUGEM regimen can safely be administered with mild toxicity and proved to be active in the first line palliative treatment of advanced/metaf:tatic pancreatic cancer.

Key words: pancreatic carcinoma, combination chemotherapy, gemcitabine, «De Gramont» protocol

Radioterapie & Oncologie Medicală, 2001, 1: 77-84

85 Bi-Monthly Irinotecan with High Dose Infusional Folinic Acid and 5 Fluorouracil for Advanced Inoperable, Metastatic or Relapsed Colorectal Carcinoma Patients

  1. Banu1, N. Ghilezan1,2, N. Todor1, Cristina Cebotaru1, Ioana Radulescu1, AI. Eniu1, Cristina Neacşu1, C. Căinapl, Anca Mihailovl, Dana Iancu1, Helene Homokoşl, T.E. Ciuleanu1,2

1Institute of Oncology „Prof I. Chiricuţă” Cluj-Napoca

2U.MPh. „I. Halieganu” Cluj-Napoca

Recently, it was shown that a) irinotecan adds to the efficacy of fluorouraciV folinic acid combination in the chemotherapy (CT) of advanced/ relapsed colorectal carcinoma (CRC) patients. b) irinotecan as well as high dose infusional fluorouraciV folinic acid regimens are active as rescue treatment in 5FU resistant CRC patients. This paper presents the results of two phase II trials exploring the „CPT II L V5 FU2” regimen (Irinotecan 180 mg/m2 dl, followed by „de Gramont” regimen: Folinic Acid 200 mg/ m2 as 2h infusion followed by 5 FU 400 mg/m2 bolus + 600 mg/m2 in 22 h IV infusion, days 2-3) in first and second line setting. Patients and methods: a) First line: between 6/1999 and 4/2000, 25 patients (12 m, 13 f) with histologically confirmed CRC entered the study. Age: median 55y [30-68]. Performance status (PS): 0&1 vs 2&3: 18 vs 7 patients. Weight loss =5% vs >5%: 19 vs 6 patients. Primary tumour localisation: colon vs rectum: 19 vs 6 patients. Histology: adenocarcinoma not other specified 18, mucinous 2, tubular 5 patients. One hundred fifteen CT cycles were administered. Median number of cycles: 4 [1-11]. b) Second line: between 6/1999 and 4/2000, 17 patients (10 males, 7 females) with histologically confirmed CRC entered the study. Age: median 52y [42-75]. Performance status (PS): 1 – 9 patients, 2 – 7 patients, 3 – 1 pt. Weight loss =5% vs >5%: 9 vs 8 patients. Primary tumour localisation: colon vs rectum: 10 vs 7 patients. Histology: adenocarcinoma in all patients. Forty three cycles were administered. Median number of cycles: 2 [1-4]. Results: a) First line: there were no toxic deaths. Haematological toxicities were mild: leukopenia gr.3 – 1 cycles, gr.2 – 2 cycles; thrombopenia gr. 2 – 3 cycles; anemia gr. 2 – 1 cycles. Non- hematological toxicities: gr. 3 delayed diarrhoea – 2cycles, gr. 2 stomatitis – 1 cycle; gr. 3 vomiting – 1 cycle. Among 21 patients evaluable for response, there were 11 objective responses (=52%, CI [30%-75%]) with 3 CRs (=14%) and 8 PRs (38%), no change 8 patients (38%) and progressive disease 2 patients (10%). As of May 2000, median follow up is 3 months [1-11]. One patient died by progressive disease at 10 months. b) Second line: there were no toxic deaths. Grade 3-4 toxicity included: leukopenia 3 cycles, anemia 2 cycles; delayed diarrhoea 4 cycles, vomiting 1 cycle. Responses: Among 13 patients evaluable for response, there were 2 PRs (=15%, CI [0-37%]), no change 9 patients (69%) and progressive disease 2 patients (15%). As of May 2000, median follow up is 2.7 months [1-11] and all included patients are still alive. Conclusion: a) First line: the first line combination ofirinotecan with high dose infusional5FU/ Folinic acid bi-weekly regimen has a mild toxicity and proved to be very active (52% objective response rate) in the first line palliative chemotherapy for metastatic/ recurrent colorectal carcinoma patients. b) Second line: The second-line combination of irinotecan with high dose in fusional 5FU/ Folinic acid bi-weekly regimen has a mild toxicity and proved to be only marginally active (15% objective response rate) in the second line palliative chemotl1erapy for metastatic/ recurrent colorectal carcinoma patients, resistant to previous FU-FOL Mayo regimen.

Key words: colorectal carcinoma, Irinotecan, high dose infusional 5 Fluorouracil.

Radioterapie & Oncologie Medicală, 2001, 1:85-91

92 Bone Disease in Multiple Myeloma and the Treatment with Bisphosphonates

Anca Bojan, L. Petrov

Institute of Oncology „Prof I. Chiricuţă” Cluj-Napoca

U.MPh. „I. Haţieganu” Cluj-Napoca

Bone lesions are a hallmark of multiple myeloma. They contribute to most of the clinical manifestations and complications of the disease. The bone lesions progress under chemotherapy cures. In the last decade the bisphosphonates have been introduced to reduce the skeletal morbidity. We studied 20 patients with multiple myeloma treated with bisphosphonates (12 patients with Clodronate 1600 mg p.o. daily and 8 with Pamidronate, 90 mg i.v. every 4 weeks. The results were compared with those from the control group (20 patients with multiple myeloma treated with chemotherapy alone). A decrease in bone pain intensity was recorded in 70% of the patients treated with bisphosphonates compared with 40% in the control group. Therefore, the use of narcotics in group with associated treatment was lower than in the control group. No majore differences were found between the two groups concerning the incidence of bone fractures during the treatment.

Key words: multiple myeloma, bisphosphonates, Clodronate, Pamidronate.

Radioterapie & Oncologie Medicală, 2001,1:92-98

99 Therapeutic Strategies in 1st and 2nd Line for Locally Advanced Breast Cancer

Dana Grecea

Institute of Oncology „Prof I. Chiricuţă” Cluj-Napoca

The objective of this paper is to present the indication and the limits ofneoadjuvant chemotherapy for advanced breast cancer and the treatment after relapse. Locally advanced breast cancer (LABC), despite its decreasing frequency, remains an important and challenging problem in practice. In mammographically screened populations, stage III breast cancer seldom amounts to 5 % of those diagnosed, but in many other countries, LABC represents 30% to 50% of newly found malignant breast neoplasms. The management of patients with LABC has evolved substantially over the last three decades. We present a case of a breast cancer, stage III A, who received neoadjuvant chemotherapy, followed by conservative surgery, sequential chemotherapy and radiotherapy. Eighteen months later, she developed pleural metastases and ovaries metastases, followed in 2 months by brain metastases. It is discussed the primary treatment and the treatment ofmetastatic disease in this case.

Key words: locally advanced breast cancer, treatment, relapse and multimodality therapy.

Radioterapie & Oncologie Medicală. 2001. 1:99-104

105 Congress of the European Society for Medical Oncology (ESMO). Breast Cancer Section. October 13-17 2000, Hamburg, Germany