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Volum 09 Numarul 4, 2003

148 Editorial

In the fall the baby ducks could be counted is an old Romanian saying that is very appropriate or this issue of our journal. But who are these baby ducks we are proud of?

With joy and satisfaction I am greeting a premiere in the Romanian radiotherapy realized at the Center for Medico-Military Scientific Research from Bucharest by L. Bujor, R. Perin and V; Ciubotaru (the Bagdsar-Arseni Hospital for Neurosurgery and the Clinical Institute Fundeni). It is a privilege for our journal to publish the first stereotactic irradiation of an acoustic neurinoma realized in Romania, event that demonstrates that Romanian radiotherapy also could rise to the highest international standards if the technology is provided because enthusiasm and skill exist! Congratulations for the authors of this fine exploit and best luck for further successful practice! We recommend to our readers this paper, as it is very interesting and enticing to continue this trend.

The journal is trying also in this issue to offer an interesting and varied content with general articles and original experiences. With the same satisfaction we are signaling two reviews in molecular biology field, domain more and more pregnant in our specialty, trend that begins to be present also in our journal. Carmen Stugren presents the implication of TGF-β in so many biological processes as cancerogenesis, tumor progression, immunity and especially for us, due to the role in the pathogenesis of the late effects of irradiation i.e. fibrosis and possible therapeutic interventions. Luminiţa Leluţiu and C.D. Olinici present a synthesis of the role of tumor suppressor genes in ovarian cancer and the LOH techniques for their identification. Both reviews present also experimental data of the authors and even they are at the beginning is very encouraging for us because they point to the activity of the Radiation Oncology Research Center, the loved pet of our society. The last overview on the radiochemotherapy for esophageal cancer comments on the present trends in the field with practical recommendations for daily practice (N. Ghilezan).

The original studies offer the opportunity to know the results of our colleagues concerning treatments and problems of general interest. The group of T.E. Ciuleanu reports on the efficacy of 3 different Platinum based combinations in advanced non-small lung cancer. The doublet combination with Gemcitabine, Paclitaxel and Etoposide is analyzed on more than 100 patients and the results show a significant increase of the median survival for the Gemcitbine-Platinum doublet even if the response rate was similar. Al. Eniu et. al. investigates the efficacy of weekly administration of the combination Navelbine, 5FU and Folinic Acid (FuFoINav) in metastatic or recurrent breast cancer. In the authors’ experience, this regimen was well tolerated and efficient for these advanced cases previously treated with anthracyclines, and has improved the quality of life so they suggest that it could be used as a first choice for the metastatic disease.

A special mention deserves the article presented by Viorica Nagy, Adriana Tudosescu, N. Todor and R. Babici: in the same methodical style which is familiar to V. Nagy, an analysis of the significance of the para aortic lymph node metastases in cancer of the cervix is presented based on a group of 461 stage IIb-IIIb patients treated in the Cancer Institute Cluj during 1995-2000 period. The status of the lomboaortic lymph nodes significantly influences the prognosis even from 1 cm diameter. The 5 year survival (overall & disease-free was with 16 and respectively 11 % higher in less than 1 cm lymph nodes vs. larger dimensions and this finding underlines the importance of a CT evaluation of these patients and suggest the reconsideration of the extension of the target volume for the cases at risk.

Other field but also interesting, is approached by Ofelia Şuteu who makes a cost-efficiency study for the screening of cervical cancer, based on the ongoing experience in the Cluj county. This is a true methodological letter for selecting the best strategy and we hope that the arguments would be convincing also for our Health Department who ultimately has the responsibility for the implementation of these programs.

This number of the journal contains also comments from ASCO 2003 on the lung cancer treatment (T.E. Ciuleanu) and from ESMO Educational Conference from June 2003 (Marişca Marian), literature reviews an a timid and very short CME in concordance with the interest not at all enthusiastic of our readers. However, we acknowledge the efforts of our colleague Ovidiu Bogdan, the only one who is sending his answers but we still hope that this column also will reach the fall when its baby ducks will be counted…

We are closing our comments wishing you a pleasant and useful reading!

  1. Ghilezan

149 Transforming Growth Factor -β (TGF –β) and its Role in Biological Processes

Carmen Stugren

Cancer Institute „Prof I. Chiricuta”, Cluj-Napoca

Transfonning growth factor-β is a multifunctional cytokine whose action is dependent on several factors, including target cell type and differentiation as well as interactions with other growth factors. TGF-β controls the proliferation and differentiation of cells, embryonic development, wound healing, synthesis and deposition of extracellular matrix components, angiogenesis and apoptosis. TGF- β has also a regulatory activity on the immune system and inflammatory process. Increase and decrease in the production of TGF- β has been linked to numerous diseases like fibrotic disease of the lung, skin, kidney and liver. Mutations in the genes for TGF- β, in its receptors or in the intracellular signaling specific proteins associated with TGF- β are very important especially in tumorigenesis.

Key words: Transforming growth factor -fi, Receptors, Signal transduction, Fibrotic disease, Tumorigenesis.

Radioterapie & Oncologie Medicala, 2003,3:149-156

157 Molecular Biology of Ovarian Cancer: Tumor Suppressor Genes

Luminiţa Leluţiu1, C.D. Olinicil,2

1 Dept. of Pathology, UMPh „Iu/iu H aţieganu” C/uj-N apoca

2 Cancer Institute „Prof I. Chiricuţă” C/uj-N apoca

It is believed that malignant transfonnation of the ovarian epithelium is the consequence of accumulation of genetic alterations resulting in the inactivation of tumor suppressor genes (TSGs) and/or the over expression / amplification of oncogenes. Identification of TSGs has been facilitated by loss of heterozygosity (LOH) studies that have guide the localization of minimally deleted regions on chromosomes. In ovarian carcinoma, the search for LOH has resulted in the identification of several chromosomal regions which may harbor putative TSGs.

Key words: Ovarian cancer, Tumor suppressor gene (TSG), Loss of heterozygosity (LOR).

Radioterapie & Onc%gie Medica/a, 2003, 3:157-160

161 Radiochemotherapy for Cancer of the Esophagus

  1. Ghilezan

UMPh „Iuliu Hapeganu” Cluj-Napoca Cancer Institute „Prof I. Chiricula” Cluj-Napoca

In the last 10 years, significant progress was realized in the treatment of advanced cancer of the esophagus. After the pivotal RTOG 85-01 study, updated until 1999, the concomitant radiochemotherapy with 64 Gy and 2 cycles of5FU/ DDPbecame the golden standard, with results significant superior to those of each method given alone. In the same time, several predictive factors have been identified as the quality of response and the possibility to have surgery after chemoirradiation. The still high incidence of local failures, around 50%, lead to further research, either through escalation of drug doses or of the radiation but the results remained unsatisfactory due to an unacceptable toxicity. The present therapeutic standard, proven by some recently published trials, favor a dose of 50 Gy for chemotherapy given concurrently with 2 cycles of 5FU-DDP, as exclusive treatment for locally advanced disease or preoperatively for early/localized cancers.

Key words: Cancer of the esophagus, Concurrent radiochemotherapy, Toxicity, Results.

Radioterapie & Oncologie Medicalii, 2003, 3:161-166

167 Comparison of Three Cisplatin (P) Based Doublets (Gemcitabine/P, Paclitaxel/P, Etoposide/P) in Advanced Non-Small Cell Lung Cancer

T.E. Ciuleanul,2, Marişca Marian1, N. Todor1, Cristina Cebotaru1, Dana Iancu1, N. Ghilezan1,2

1Cancer Institute” Prof I. Chiricuta” Cluj-Napoca;

2UMPh „luliu Hatieganu” Cluj-Napoca

Purpose: Randomized phase II trial, of two 3rd generation platinum doublets versus Etoposide/ Cisplatin. Patients and methods: 118 patients (pts) received either GP (Gemcitabine 1250 mg/m2 dl,8, Cisplatin 80 mg/m2 day (d) I), TP (Paclitaxel 175 mg/m2, Cisplatin 80 mg/m2 d 1) or EP (Etoposide 120 mg/m2 d 1-3, Cisplatin 80 mg/m2 d 1 ) q3wks. Results: 82% males; age 57 (34-74); WHO PS (Performance Status) 0& 1 in 70, 2 in 48 pts; Histology: squamous 74, adenocc. 30, large cell 8, mixed 2 pts, non-smal14 pts; AJCC: IIIB 61, IV 57 pts; GP 43, TP 30, EP 45 pts. Toxicity: 405 cycles given, with one toxic death in EP (renal failure). Febrile neutropenia (GP vsTPvs EP) in2 vs7vs 7 cycles. Activity: ORR =31%, CI (23%-39,7%), 4 CR (Complete Responses), 33 PR (Partial Responses). Response rate was influenced by the PS (0-1 vs 2: 40% vs 19%, p=.O2). Survival (S): At a median (med) follow-up of7 months (m) (1-31), overa1lmed S is 8,4 m and lyear S is 27%. Med S was influenced bythePS (0-1 vs2: 9. 7vs6.6m, p=.0038), response (CR+PR vs SD+PD: 10.3 vs 6.9 m, p=.0032). and protocol: GP vs EP (10,3 vs 7.1 m, p=.0353, I-year S 39% vs 14%, p<.05), TP vs EP p=ns. Conclusions: 1) There were no differences in response among the three platinum doublets. 2) Survival was significantly improved with GP over EP.

Key words: Gemcitabine, Paclitaxel, Advanced non-small cell lung cancer (NSCLC).

Radioterapie & Oncologie Medicaid, 2003, 3:167-175

176 Vinorelbine, 5-Fluorouracil and Folinic Acid (FuFolNav) is an Effective Outpatient Regimen for the Treatment of Metastatic or Relapsed Breast Cancer Patients

Al. Eniul, Cristina Vitocl, N. Todorl, N. Ghilezanl.,2

1Cancer Institute „Prof I. Chiricuţă „, Department of Breast Tumors;

2UMPh „I. Hatieganu” Cluj-Napoca

Background: In metastatic or relapsed breast cancer patients (pts) previously treated with anthracyclines (A), the combina- tion ofVinorelbine and 5-Fluorouracil (5-FU)+FolinicAcid (FuFolNav) represents a non cross-resistant regimen. Purpose: The aim of this ongoing study was to assess the activity and the feasibility of the combination as an outpatient treatment. Patients and Methods: From 8/1999, 33 patients (pts) with metastatic or relapsed breast cancer were treated with a maximum of 8 cycles ofFuF olNav: 5- FU 600mg/m2, preceded by Folinic Acid 30 mg/m2, and Vinorelbine 25mg/m2, day 1 and day 8, on an outpatient basis every three weeks. Median age was 49 (34-69). Metastatic sites: liver 8, lung 6, lymph nodes 7, skin 6, multiple 5, and peritoneal 1. All patients received previous treatment with A, 26 in the adjuvant setting and 7 as a first line therapy for metastatic disease. FuFolNav represented first line treatment for metastatic disease in 22 pts, and second line in 11 pts. Results: We observed 19 FRs and no CRs, for an overall response rate of58% (95% CI: 410/0-74%). Nine pts (27%) had stable disease. Five pts (15%) progressed under CT. Overall, 28 pts (85%, CI: 730/0-97%) had clinical benefit quantified as PR+SD. With a median follow up of 11 mths (range 2-33), the median time to progression was 7 mths (range 2-33). Median survival was 12.6 mths so .1 year actuarial survival was 50%. A total of 148 cycles were given, with a median 4 cycles per patient (range 2-6). Toxicity was mild and there were no toxic deaths. Grade 3-4 toxicities included neutropenia (7%), peripheral neurologic toxicity (limbs) (3%), ileus-like syndrome (6%), and mucositis (5%) of cycles. No patient developed complete alopecia. Conclusions: The FuFolNav regimen can be safely administered in the outpatient setting with low toxicity, and proved to be active in the treatment of metastatic or relapsed breast cancer previously treated with anthracyclines. It represents an active regimen with minimal burden for the patients, favoring quality of life for these incurable patients.

Key words: Metastatic breast cancer, Vinorelbine, Outpatient treatment.

Radioterapie & On cologie Medicala, 2003,3:176-181

182 The Incidence and Significance of the Para-Aortic Lymph Node Metastasis in Locally Advanced Cervical Carcinoma

Viorica Nagyl,2, Adriana Tudosescu2, N. Todor2, R. Babicil

1UMPh „Iuliu Hţtieganu” Cluj-Napoca;

2 Cancer Institute „Prof I. Chiricuţă” Cluj-Napoca

Purpose: to evaluate the incidence and prognostic significance of the para-aortic lymph nodes diagnosed through computed tomography (CT) in locally advanced cervical cancer. Methods and Materials: This is a retrospective review of 461 patients with stage IIB-IIIB cervical cancer first treated with radiation therapy or radio-chemotherapy from 1995 to 2000 in Radiotherapy Department II of the „Ion Chiricuta” Oncology Institute from Cluj. Para-aortic lymph nodes (PALN) were assessed by pretreatment contrast-enhanced CT. Lymph nodes <I cm on images were regarded as negative and analyzed together with cases without visible PALN, and those with ≥l cm were considered metastatic. Results: Nineteen percent of the patients included in the study had PALN≥1 cm, the incidence being correlated with clinical stage and tumor size. The overall survival and disease-free survival at 5 years were significantly lower for the patients with PA LN metastases: 60% vs 76 %, 45% vs 66% respectively (p<0.0 I). Treatment failure was identified in 52% of the patients with PA LN≥1 cm, vs 28% of the patients with negative lymph nodes. Conclusion: The PA LN status assessed using CT is a significant prognostic factor in locally advanced cervical carcinoma, the lymph node metastasis being con-elated with poor survival and high rate of treatment failure, which requires an aggressive treatment.

Key words: Cervical carcinoma, Para-aortic lymph node metastases.

Radioterapie & Oncologie Medicaid, 2003, 3:182-187

188 Cost-Effectiveness of Alternative Strategies for Cervical Screening in Cluj County. Health Policy Implications

Ofelia Şuteu

Department of Epidemiology, UMPh „Iuliu Hapeganu”; Cancer Institute „Prof I. Chiricu{a”, Cluj Napoca

The paper presents the economic evaluation with a framework for comparison of 3 strategies of screening programme, by conventional cytology, based on cost effectiveness criteria, wich differ by design parameters, such as the coverage rate of target population and population segments to screen. The costs of the 3 programmes were estimated, in order to assess the budgetary and medical staff resources required to extend the screening programme in Cluj county and also to select the strategy with the

most cost-effective ratio, with the estimated impact evaluation of these programmes on health status of tested population.

Key words: Cost-effectiveness, Cervical screening programme.

Radioterapie & On cologie Medicala, 2003, 3:188-193

194 First Stereotactic Radiosurgery Treatment in Case of Acoustic Neuroma

  1. Bujor1, R. Perin2, V. Ciubotaru3

1 Army:V Center for Medical Scientific Research, Bucharest;

2Bagdasar-Arseni” Neurosurgey Hospital, Bucharest;

3Fundeni Clinical Institute, Bucharest

We describe the first radiosurgery treatment delivered in a case of acoustic neuroma performed by an interdisciplinary team at Anny’s Center for Medical Scientific Research from Bucharest. We are using a dedicated system for stereotactic radiotherapy linac based. The QA tests enable us delivering high precision stereotactic radiotherapy.

Radioterapie & Oncologie Medicaid, 2003, 3:194-196

197 Lung Cancer. Report on ASCO Meeting, 2003, May 31st-June 4th, Chicago, IL- USA (I)

T.E. Ciuleanu

202 ESMO Summer Educational Conference (ESE C), 2003, 19-22 June, Edinburgh, UK

Marişca Marian