This issue (3/99) of our journal is tumor oriented, dealing with non small cell lung cancer. The slight improvement in patients’ survival (1996 versus 1966: 13% vs 8%, all stages together, USA) represents a modest reward for the huge fundamental and clinical research effort done allover the world. An aim of this issue is to present „the state of the art” in the diagnosis and treatment of non small cell lung cancer. Another purpose is to reflect, by the prism of some original clinical trials from Cluj, Bucharest and Sibiu, the tendencies of the clinical research in Romania, willing to offer modem treatment options for these patient population.
Starting with the treatment guidelines published in the nr. 1/99 issue of this journal, TE Ciuleanu (Cancer Institute Cluj) presents, for each therapeutic category (localised, loco regionally advanced and metastatic disease), the consensus data for the standard treatments, as well as the numerous controversies existing in the chemotherapy of non-small cell lung carcinomas. New research modalities are also discussed.
Petronela Rusu (Cancer Institute Cluj) is synthesising the multimodality treatments in stage III non-small cell lung carcinomas, defining the actual role of radiation therapy in this setting.
Two papers are discussing diagnosis in lung cancer. Adriana Ioan (Cancer Institute Cluj) describes the indications, technique and diagnostic role of fiberoptic bronchoscopy. Svetlana Encica (Cardiovascular Surgery Clinics Cluj) is pre- senting the histopathological criteria to be used to make a lung cancer diagnosis.
Seven original papers, are covering all the therapeutic categories in non-small cell lung cancer.. Localised disease (resectable). The paper by Adriana loan, M. Barsan et al., represents a first consistent analysis in the Romanian literature of a large series of patients who benefited by radical surgery (160 stage I-iliA patients). The treatment strategy was discussed at the lung committee at the cancer Institute of Cluj (surgery alone, up front surgery followed by adjuvant chemotherapy and! or radiotherapy, neoadjuvant chemotherapy followed by surgery). The vast ma- jority of the resections were performed at the Cardiovascular Surgery Clinics Cluj. The results achieved (median survival 21 months) are comparable with those published by other prestigious centres and are demonstrating the efficiency of the therapeutic multidisciplinary committees, to adapt the treatment protocols at the therapeutic category and to the individual prognostic factors.
Advanced disease. The papers are reflecting the interest of the Romanian investigators to evaluate the multimodality strategy treatments (neoadjuvant chemotherapy and surgery, sequential or concomitant radiochemotherapy) and to intro- duce some chemotherapy regimens which associate optimal dose Cisplatin to new generation agents (Gemcitabine, Taxol, Navelbine).
In a co-operative study with the French group ATTIT („Association pour Ie traitement des tumeurs intrathoraciques”: H. De Cremoux (CHI Creteil), E. Cvitkovic (Hopital Paul Brousse), Villejuif, J.C. Saltiel (CHU Corbeil), P.Ruffie (Institut Gustave Roussy, Villejuif), TE Ciuleanu and N. Todor (Cancer Institute Cluj) accomplished a multivariate analy- sis of the results of several original neoadjuvant chemotherapy regimens Cisplatin + Vindesine or Vinorelbine based, in stage III non-small cell lung cancers. With a 46% objective response rate, and a median survival of 17 months” ATTIT regimens belong to the most active chemotherapy regimens for this patients population. Main prognostic factors in multivariate analysis were performance status and the achievement of an objective response to the neoadjuvant chemotherapy.
In a randomised phase II trial, T.E. Ciuleanu et al. found the standard Cisplatin + Etoposid regimen equivalent with the investigational Taxol + Cisplatin arm in patients with a stage IIIB or IV non-small cell lung cancer, in terms of objective response (36%, respective 38%) and survival (median 7 vs 9 months).
Petronela Rusu (Cancer Institute Cluj) correlates post therapeutic CYFRA 21.1 levels with prognosis in non-small cell lung cancer.
A short revue of the oral presentations at the 35-th ASCO Congress (Atlanta, May 1999) in the field of head and neck, non-small cell lung cancers and colorectal carcinomas is ending this issue.
Oncological Institute „Prof I. Chiricuţă” Cluj-Napoca
For lung cancer, the last decade meant: a) a 1 % fall in the incidence (only) in the develloped countries as a consequence of a long term application of prophylactic measures. b) an impressive progress in the characterization of the molecular markers. c) an improved UICC staging d) confirmation (meta-analysis, multicenter randomized trials) of the benefit of using Platinum based chemotherapy to all the therapeutic categories of lung cancer patients (localised, locoregionally advanced, metastatic) e) new Platinum combinations with new generation active agents which lead, sometimes, to a (yet modest) improvement in survival as compared with the previous combinations. f) progress in the combined multimodality treatments. g) translation in the clinical research of an array of new therapeutic modalities (modifiers of the signal transduction pathway, MMPIs and antiangiogenic agents, gene replacement therapy), which open new perspectives of further improving results.
Keywords: non-small cell lung cancer, chemotherapy, new citostatic agents
Radioterapie & Oncologie Medicală, 1999, 3: 157-169
Oncological Institute „Prof I. Chiricuţă” Cluj-Napoca
Lung cancer is a leading cancer site in men and women with a high incidence and mortality rate. Most patients are diagnosed when the disease has already spread. An early detection and immediate and accurate histological or cytologi- cal diagnosis are essential for a hopeful outcome. In most patients, bronchoscopy is the method of choise in establishing a suspencted lung neoplasm. With the rigid and flexible method, two complementary techniques are available. Rigid bronchoscopy offers the possibility of obtaining large biopsy specimens from the tumors tissue and provides an effective tool in the control of major haemorrage. However, it cannot be used for the inspection of further peripherally located parts of the bronchial system and needs general anesthesia. In contrast, the flexible method can be quickly and readily performed at practically any localisation using portable equipment. Bronchi can be inspected up to the 8th order and with bronchial washing, forceps biopsy, brush and flourescence bronchoscopy tehniques with a high diagnostic yield are available. This hold true, especially if sampling techniques are used as complementary methods.
Keywords: bronchoscopy, lung cancer, sampling techniques.
Radioterapie & Oncologie Medicală. 1999, 3: 170-178
Dept. of Pathology, Hearth Institute „N. Stăncioiu „, Cluj-Napoca
This paper summarize some suggestions for the reporting of the resected primary lung cancer and characterizes the
major histological types (epidermoid carcinoma, adenocarcinoma, large cell and small cell carcinoma). Keywords: lung carcinoma, hystological type.
Radioterapie & Oncologie Medicala, 1999, 3: 179-184
Oncological Institute „Prof I. Chiricuţă” Cluj-Napoca
Stage III non-small cell lung cancer (NSCLC) represents’ the vast majority of patients with lung cancer, and is still a heterogeneous group in spite of the subsequent refinements of the Staging System. An accurate staging including medi- astinoscopy and metastatic work-up is required in order to decide treatment strategy. For patients staged as IlIA, induc- tion therapy of chemotherapy or chemoradiotherapy before surgery is a reasonable approach. For patients with stage IIIB and inoperable stage IlIA, combination chemotherapy and radiation should be the standard of care. The issue of induc- tion therapy, the role of surgery, the timing of treatment modalities ,the choice of best radiotherapy delivery technique, the selection of the best newer drugs combination in order to improve the outcome and to have a more favourable toxicity profile are still subjects of debate. Real steps of progress have been made in the last decade, in the treatment ofNSCLC, in order to improve the modest prognosis of the disease. The better understanding of molecular biology opens promising perspectives in the management ofNSCLC.
Key words: advanced stage III NSCLC, combined modality therapy, prognosis, results, perspectives.
Radioterapie & Oncologie Medicală, 1999.3:185-194
Adriana Ioan1,T.E. Ciuleanu1, M. Bârsan2, N. Todor1, N. Ghilezan1, Claudia Burz1
1Oncological Institute „Prof I. Chiricuţă” Cluj-Napoca
2Cardiovascular Surgery Hospital Cluj-Napoca
Purpose: to assess the results obtained in stage 1 to III NSCLC patients, treated with surgery alone or integrated in a pluridisciplinary approach, following the decision taken at the Lung Committee of the Oncological Institute Cluj (OIC). Endpoints: correspondence between clinical and pathological staging, complications of surgery, survival, prognostic factors.
Patients and methods: during Jannuary 1994 through December 1998 a prospective nonrandomized study was carried on at OIC, on 161 operated NSCLC patients. The TNM system advocated by the AJCC was used and was determined on CT findings. Although more than half (57%) patients had clinicallocoregional advanced disease (clinical stage III-A), surgery was initially performed at 125 pts. and 36 pts. received neoadjuvant chemotherapy (platinum containing regi- men) followed by surgical resection. 109 pts. underwent complete surgical resection (RO) and depending on pTN (pT3- T4 or/and pN1-N2) they received adjuvant therapy.
Results: correspondence between clinical and pathological staging is 70%, with regard to the T category, the agreement between cT vs. pT reached in 78% and to the N category, in 80%. Lethal complications of surgery was related only after major surgical interventions (pneumonectomy) and is in the range of an accepted international standard (6,8%) and frecvency of postoperative complications was significantly corelated with exploratory thoracotomy and pneumonec- tomy as compared with lobectomy. Survival: with a median follow-up of 15 months [2-60], overall survival was 40% at 23 months. Prognostic factors for survival (univariate analysis) were: weight loss « 5% vs. > 5%: 60% vs. 12%), performance status (0-1 vs. 2: 62% vs. 22%), clinical stage (I vs.1I vs.lII: 60% vs. 56% vs. 32%), pathological stage (I vs.1I vs.IIIA vs.IIIB: 93% Ys.56% vs.16% vs.10%), histology (carcinoid vs. scuamos vs. large cell vs. adenocarcinoma: 71 % vs.48% vs.32 % vs.20%), residual disease (RO vs.R1 vs.R2: 55% vs.21 % vs.O%) and treatment strategy for stage III patients (neoadjuvant chemotherapy+ surgery vs. initial surgery: 51 % vs. 17%).
Conclusion: our results confirm the improvement of prognosis in NSCLC in the last 5 years in Cluj (median survival 21 months, in 161 resected patients), mainly due to a better quality of the surgical act and a more effective pluridisciplinary approach.
Keywords: operated non small cell lung cancer, multimodality therapy.
Radioterapie & Oncologie Medicală, 1999, 3: 195-207
Al. Eniu1,2, T.E. Ciuleanu1,2, Cristina Cebotaru1, N. Ghilezan1,2
1Institute of Oncology „Prof I. Chiricuţă” Cluj-Napoca
2 U.M. Ph. „Iuliu Haţieganu” Cluj-Napoca
Gemcitabine is an active nucleoside analogue in non-small cell lung cancer (NSCLC), with a 25 % response rate as single agent, and with synergism with Cisplatin in advanced NSCLC. The role of this study is to investigate the activity (objective responses and radical resection rate) of the combination in marginally resectable (stage iliA) NSCLC.
Eligibility required patients (pts) with histologically confirmed and measurable stage IIIA (N2) NSCLC, WHO perform- ance status 0-2, adequate haematological, renal and hepatic functions and no prior antineoplastic therapy (radio or chemotherapy). Gemcitabine(1000 mgimp) was given on day 1 and 8 as a 30-min IV infusion, and Cisplatin (100 mg/ mp) on day 1 as an 1 hour infusion. Treatment was repeated every 21 day, for 3 cycles, followed by surgery, or radio- therapy for inoperable patients.
Over a period of one year, 17 patients were enrolled. Demographics: M/F 15/2, mean age 56(44-63)years, PS 1/2 10/7, Nl/N2 7/10. Of the 17 evaluable patients, 14 have completed more than 1 cycle of chemotherapy, in 2 treatment was discontinued after 1 cycle (toxicity, refusal). Toxicity consisted of grade 4 leucopenia in 1 pt, grade 3 trombopenia in 2 patients and grade 3 and 4 nausea and vomiting in 3 patients. Evaluation for response revealed 2 CR, 7 PR, 4 NC and 2 PD. From the 7 patients who were proposed for resection, only 2 accepted surgery and had a complete resection.
Our interim results indicate that in the group of favourable prognostic IIIA patients, gemcitabine and cisplatin have a tolerable toxicity profile and can induce an objective response in more than half of the patients, increasing the rate of radical resection.
Key words: lung cancer, neoadjuvant chemotherapy, gemcitabine, cisplatin
Radioterapie & OncologieMedicală, 1999, 3:208-212
Institute of Oncology Bucharest
Purpose: to evaluate the efficiency and toxicity of High doseCisplatin with concurrent radiation therapy in stage III A NSCLC(non small cell lung cancer) at the Institute of Oncology Bucharest
Methods: during March 1992- April 1995, 53 patients with stage 111 A, NSCLC were treated in lOB with concurrent chemo radiation therapy. Eligibility criteria were ECOG performance status 0-2, adequate renal and liver function, age < 65 years, and histological proven NSCLC. Chemotherapy consisted of 6 cycles Cisplatin 60 mg/m2 and Vinblastine 6 mg/m2 on day 1 +8, repeated at 21 days for the first 3 cycles and at 28 days for the last 3 ,which were administrated concurrent with the radiation therapy. Irradiation began on day 70, and was planned to achieve 60 Gy ,by 2 Gy/day 5 days/week
Results: of the 53 patients 9 (17%) were T3,NO, I and 44 patients (83%) were T3, N2. At the end of the treatment 25 patients (48%)were classified as complete or partial responders (95% confidence interval -CI- of 33.3%-61.4%), 15 patients (28%) had stable disease (CI : 16.8%-42.3%) and 13 patients (24%) had progression disease (CI: 13.8%-38.3%). Progression free survival for the entire group was II months (CI: 8.99-13.01), with a median survival interval of 14 months (CI: 10.87-17.03), 1 year survivors rate was 52% (28 patients) and 2 years survivors rate was 14% (7 of which 3 were T3NO,I). For the T3 NO,1 group the median survival was 18 months. Site of first relapse was local only for 10 patients (18%, CI : 9.4%-32%) and distant only for 34 (64%, CI :49.8%-76.9%) Important toxicities of the regimen were anemia (22% grade III-IV) and esophagitis (32% grade III-IV). No important renal or neurologic toxicity was recorded.
Conclusions: day 1 +8 high dose Cisplatin is a safe regimen for NSCLC chemotherapy, with important grade anemia as main toxicity. Improving of irradiation planning is mandatory for avoiding the high rate of severe esophagitis. For T3 NO,1 patient chemo radiation therapy without surgery is no longer an adequate therapeutical option.
Keywords: high dose cisplatin, day 1 +8 shedule, concurrent CT-RT, stage III A, NSCLC
Radioterapie & On cologie Medicală, 1999, 3:213-220
1OncologicalInstitute „Prof I. Chiricuţă”, Cluj-Napoca
3Institut Gustave Roussy, Villejuif
4Laboratoires Rhone Poulenc Rorer, Antony
5Centre Hospitalier Intercommunal, Creteil
6Centre Hospitalier Urbain, Corbeil, France
Purpose: To assess the results obtained with neoadjuvant Cisplatin/ Vindesine or Vinorelbine based CT in unresectable st III NSCLC. Methods: From 4/87 to 2/96, 158 previously untreated patients (pts) received median 3 courses of 5 Cisplatin/ Vinca combinations (ATTIT 1-2-3-5-6). Results: Pts characteristic: age 57 [37-72]; 91 % males; Karnofsky (KI) 60-70% 29, >70% 129 pts; histology (H): squamous 91, adeno 37, large cell 25, adenosquamous 5 pts; AJCC stages: IIIA 74, IIIB 84 pts. Activity: 73 pts achieved an objective response (OR) (46%, CI [38%-54%] 7 CR, 66 PR); st IlIA vs IIIB: 54% vs 39% OR (p=.06). Further trt: 35 pts (22%), 24 IIIA (32%) and IIIB (13%) (p<.Ol), were rendered operable after CT (19 lobectomies, 16 pneumonectomies). Seven pts (4%) were pCR. Major surgical complications: 5 fatal broncho-pleu- ral fistula. After surgery, 20 N+ pts had aditional RT. 36 non resectable CT responders received RT. Duration ofresponse: 15 months (m) [2+..44+]. OR after all local tIt was 55%. Survival (S): with a median follow-up of 36 m [3-66], median S is 17 m; 19 vs 12 m for KI >70% vs 60-70% (p<.01); 26 vs 13 m for CT responders vs non responders (p<.01); 27 vs 16 vs 13 m for adeno vs epidermoid vs large cell (p=.04). Actuarial S at 36 m is 42% vs 29% for resected vs irradiated CT responders (p=.79). S was not influenced by substage, or CT protocol. Multivariate analysis: A prognostic score (PS) was defined using Cox model: PS= 2*KI + 2*OR + H. Three prognostic groups resulted (good 7-10; intermediate 5-6; poor =4) with median S of27 vs 19 vs 7 m (p<O,Ol). To date, 59 pts are alive (25 in CR) and 99 have died: 93 pts disease progression (62 pts locoregional (LR), 8 pts metastases (M) only, 23 pts LR+M), 5 pts surgical complications, 1 pt other disease. Brain was the main site of metastatic relapse (19 pts). Conclusions: 1) 46% OR rate with Cisplatin-Vinca com- binations confirm single institution experiences. 2) In our study, there is no difference in 3y S between resected and in-adiated CT responders. Controlled trial comparing for CT responders surgery + RT and RT alone is needed. 3) Main prognostic factors for S were performance status and response to neoadjuvant CT.
Key words: non-small cell lung cancer, locoregionally advanced, neoadjuvant chemotherapy, multivariate analysis
Radioterapie & Oncologie Medicală, 1999, 3:221-236
1Cancer Institute „Prof I. Chiricuţă”, Cluj-Napoca
2 University of Medicine and Pharmacy „Iuliu Haţieganu” Cluj-Napoca
Purpose: To assess, in a randomised phase II trial, the results obtained in advanced (st IIIB and IV) NSCLC pts with TP versus the standard EP regimen.
Methods: From 9/96 to 2/99,79 previously untreated patients (pts) received either TP (Taxo1200 mg/m2, Cisplatin 80 mg/m2 dl) or EP (Etoposide 100 mg/m2 d 1-3, Cisplatin 80 mg/m2 on dl) q3wks. St IIIB pts had 3 cycles (cyc) followed by RT at 60 Gy; st. IV up to 6 cyc (less if progressive disease).
Results: 84% males; age 56 [34-68]; WHO PS 0&1 in 45,2 in 34 pts; histology: squamous 52, adeno 15, large cell 8, mixed 4 pts; AJCC st: IIIB 50, IV 29 pts; TP 32, EP 47 pts. Toxicity: 256 cyc were given, with one toxic death in EP arm (renal failure). Gr. 4 haematological tox was rare (neutropenia 7, anaemia 1 cyc, in both arms). Gr. 1 neurological and cardiac tox occurred in 4 and 1 TP pts, respectively. Activity: 29 pts had an objective response (OR) to CT (=37%, CI [26%-47%]),4 CR, 25 FR. Response rate was influenced by the PS (0-1 vs 2: 49% vs 21 %, p<.OI) and weight loss (=5% vs > 5%: 45% vs 17%, p<.02). Similar OR resulted with both protocols. Survival (S): at a median follow-up of 8 months (m) [1-23], median S is 7.5 m; 9 vs 7 m for st IIIB vs st IV pts (p<.03); 10 vs 6.5 m for CT responders vs refractory pts (p <.01). A trend existed in favour ofTP (median S with TP vs EP: 9 vs 7 m, I-year S 34% vs 14%).
Conclusions: 1) TP and EP were equally active in advanced NSCLC pts (OR 38% vs 36%).2) There was a trend towards
improved survival with TP. 3) Prognostic factors found: for response – PS and weight loss; for survival – stage and
response to CT.
Key words: taxol, advanced non-small cell lung cancer
Radioterapie & Oncologie Medicală, 1999, 3: 237-246
A.Moga1, Monica Pătran2, Emilia Popescu2
1Faculty of Medicine „Victor Papilian” Sibiu
2County Clinical Hospital Sibiu
The aim of the paper is to analyze the results of a complex treatment of lung cancer patients in the Oncology Clinic of Sibiu. The study considers 133 patients hospitalized between 1 July 1944 and 30 June 1996. They have under-gone an associated chemo-radiotherapy treatment, or an exclusive chemo- or ra-diotherapy one, with curative or palliative intent. The distribution of the patients of the non-small category according to the ~tage is as follows: 44 patients in stage ilia, 29 patents in stage IIIb and 39 in stage IV.In the small cell catego-ry we had 13 cases of which 3 patients with limited disease and 9 with ex-tended disease. In other 6 cases, operated on in other departments the stage has not been established. In stage ilia patients the median survival was 19 months when chemo- radiotherapy was done curatively compared to only the 4 month median survival in the case of radiotherapy treatment alone with curative aim.
In stage IIIb patients the median survival was 3 months for radiotherapy with palliative aim and 4 months for the ones who have done chemotherapy palea-tively. In stage IV patients the survival rate was not improved significant, but the quality of life was improved through palliative chemo- or radiotherapy.
Key words: lung cancer, radiotherapy, median survival
Radioterapie & Oncologie Medicală, 1999,3:247-251
Petronela Rusu1, N. Ghilezan1,2, Otilia Bojan1, Dana Cernea1, Adriana loan1, T.E.Ciuleanu1,2, N. Todor1
1Oncological Institute „Prof I. Chiricuţă” Cluj-Napoca
2U.M.Ph. „Iuliu Haţieganu” C/uj-Napoca
In order to investigate the clinical relevance, serum levels of Cyfra 21-1 have been measured by enzyme-immuno- assays, for 107 patients: 70 patients with LC, 15 with benign lung diseases, 22 patients with cancers, others than lung cancer (including 3 mesotheliomas).
Measured before treatment, Cyfra 21-1 showed a sensitivity of 58 % for non small cell lung cancer (NSCLC), with the best value of 68%, for squamous cell carcinoma, better than for CEA, 42% and 43% respectively. At diagnosis, the median level was 4.37 ng/ml, with a mean value of 10.35 ng/rnl (standard deviation 13.8 ng/ml). There has been found a correlation with the extent of disease and performance status (PS): sensitivity 50% in stage II+IIIA, 72.5% in stage III+IV, 56% in patients with PS 1-2, 85% in patients with PS 3, considering a threshold value of 3,3 ng/ml, but differ- ences were not statistically significant.
The predictive value of pretreatment Cyfra 21-1 levels on treatment response was assessed. Patients with complete and partial response (CR+PR) had high pretreatment levels in 58%, comparing with patients with ” no change” (NC) or progressive disease (PD), in 66%, but differences were not statistically significant.
Determined after treatment, in 30 patients. Cyfra 21-1 levels, returned to normal in 81 % of patients with CR+PR and 27% of patients with NC+PD (p=0.Q6). Ten patients underwent surgery. Cyfra levels returned to normal in 4/5 patients with complete resection and 3/5 patients with partial resection.
During follow-up period, Cyfra21-1 measured in 10 patients. was elevated in 6/7 relapses, preceeding clinical detection from one to three months. Therefore constant increase of the marker justifies extensive diagnostic procedures in order to confirm recurrence.
In conclusion, Cyfra21-1, presents a good sensitivity in NSCLC, with the highest values in squamous cc, a good corre- lation with disease extent, PS and treatment efficacy. Normal Cyfra 21-1 values seem to predict a better survival curve, but in our study differences haven’t reached statistical significance. We found that returning to normal of the marker after treatment, has an impact on survival (p=patients 0,04).
Key Words: Cyfra 21-1, lung cancer, tumor marker.
Radioterapie & Oncologie Medicală, 1999,3:252-260
T.E. Ciuleanu, Elisabeta Ciuleanu, Ioana Rădulescu, Cristina Cebotaru