Gastroesophageal junction and gastroesophageal junction carcinoma : a short update.

Cancer of the gastroesophageal junction (GEJ), although rare, is now considered a separate entity with a distinct pathophysiological and molecular profile. Although much progress has been made over the past decades in delineating the multiple environmental and genetic pathways involved GEJ carcinoma, the exact molecular mechanisms underlying disease initiation and progression are still poorly understood. This is of paramount importance for the treating physician as the disease bears a poor therapeutic response. This review defines the GEJ and types of GEJ carcinoma, and provides useful insight in its pathophysiology. Future aspects include better understanding of GEJ oncogenesis, early detection of precursor lesions, the use of biomarkers and targeted therapy (through molecular profiling) so as to increase overall survival. (Acta gastroenterol. belg., 2016, 79, 471-479).

Genomic instability in ulcerative colitis: a prerequisite for cancer in the inflammatory colon?

Ulcerative colitis (UC), a chronic and relapsing idiopathic inflammatory disease of the colon, although not associated with an increased mortality compared to the general population, has a substantial morbidity leading to sizable health care costs, as it carries an increased risk for development of colorectal cancer (CRC). The pathophysiology behind this carcinogenic pathway is multifactorial. This review summarizes the major pathogenetic steps from which the inflamed colonic epithelium is transformed to a dysplastic and/or cancerous one. The role of the inflammatory and immune system, the oxidative stress generated as well as the genomic stability observed in UC-associated CRC is presented so as to provide a more spherical view of the tumorigenic process and, if possible, offer new diagnostic approaches for the early detection of CRC.

Survival benefit during zoledronic acid and docetaxel-based chemotherapy in metastatic hormone-refractory prostate cancer patients: an institutional report.

PURPOSE: To assess the overall survival (OS) of metastatic hormone-refractory prostate cancer (mHRPC) patients when treated with zoledronic acid (ZOL) in combination with docetaxel-based chemotherapy (docetaxel combined with estramustine or oxaliplatin or gemcitabine). METHODS: A retrospective chart review of mHRPC patients in our clinic was performed. At the time of data collection, 23 patients with mHRPC were identified, of which 15 were still alive at data analysis. Survival data was analyzed through Kaplan-Meier methodology. OS stratification by prostatic specific antigen (PSA) response (50% and 80% decline) and multivariate analysis of prognostic variables were also conducted. RESULTS: 182 cycles of chemotherapy (mean 8.27 cycles, range 1-23) were recorded. Median OS was 26 months (range 5-56; 95% CI: 4.0-48.0). No patient achieved complete response (CR), 5 (21.7%) showed partial response (PR), 2 (8.7%) minor response (MR), 7 (30.4%) stable disease (SD) and 9 (39.1%) progressive disease (PD). Twelve (52.2%) patients exhibited a decrease in PSA levels >50% (9 of 12 >80%). No association of age, PSA response, or tumor response with OS could be demonstrated. The most frequent toxicities were anaemia (52.1%) and neutropenia (26%). CONCLUSION: In our clinical setting, ZOL and docetaxel- containing chemotherapy was a beneficial therapeutic scheme for the patients in terms of safety and survival.

Metastatic melanoma: case report of a patient with seventeen months of complete remission, five years survival and review of the literature.

Melanoma, an aggressive, therapy-resistant malignancy of melanocytes, is the most serious type of skin cancer affecting young and middle-aged people. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. The authors present the case of a patient with advanced-stage melanoma who underwent surgery for metastatic disease. He then received cisplatin-based combination chemotherapy, with disease stabilization. However, after different regimen modifications complete remission (CR) was finally achieved, until the disease progressed once more. Five years after surgery, the patient is still alive and continuing chemotherapy.

Gastrointestinal stromal tumours: clinical overview, surgery and recent advances in imatinib mesylate therapy.

AIMS: To review the clinical features of gastrointestinal stromal tumours (GISTs), the role of surgery and its principles and molecular targeted therapies. METHODS: A Medline-based literature search on relevant topics was performed in PubMed for key articles concerning the clinical features, biology and the novel strategies in the management, whether surgical and/or pharmaceutical, of gastrointestinal stromal tumours. Some information was obtained from Proceedings of the American Society for Clinical Oncology published recently. RESULTS: Surgical resection, the first-line intervention for operable GISTs, was historically the only effective treatment. For residual, metastatic and/or inoperable disease, treatment options remain under intense and continuous scrutiny. However, their molecular genetics, i.e. the mutations of the genes coding for KIT or platelet-derived growth factor receptor alpha, two receptor tyrosine kinases, have been targeted for therapeutic intervention by imatinib mesylate -- a tyrosine kinase inhibitor. CONCLUSION: Treatment of GISTs with imatinib has led to dramatic improvements in progression-free and overall survival, thereby rendering its use in the preoperative and postoperative treatment under intense investigation. New investigational agents are being developed and participation in promising clinical trials remains a standard of care.

Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group.

BACKGROUND: In the present phase II multicenter study, we assessed the efficacy and tolerability of the combination of gemcitabine and carboplatin in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated, locally advanced or metastatic pancreatic cancer were treated with gemcitabine 800 mg/m(2) on days 1 and 8 and carboplatin at an AUC of 4 on day 8 of a 3-week cycle, for a total of six cycles. Primary end points were response rate and clinical benefit; secondary end points were, survival, time to progression (TTP) and toxicity. RESULTS: A total of 50 patients were enrolled in the study, 47 of whom were eligible for treatment. The median age was 63 years (range 34-76) and the median Karnofsky performance status (PS) was 80%. Patients received a median of six cycles (range 1-11). Among 35 patients evaluable for response, eight (17%) achieved partial response; 15 (32%) and 12 (25%) patients had stable and progressive disease, respectively. The median overall survival was 7.4 months; the median TTP was 4.4 months and the 1-year survival was 28%. The observed clinical benefit response was remarkable. After the second cycle of chemotherapy, 21 of 31 (68%) patients experienced pain improvement and reduced analgesic consumption. At the same time, 35% and 56% of our patients significantly improved their Karnofsky PS and weight, respectively. Overall, the treatment was well tolerated. The most common grade 3-4 toxicities were hematological, including 8% anemia, 6% neutropenia and 13% thrombocytopenia. CONCLUSIONS: The combination of gemcitabine plus carboplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer. This regimen has an acceptable toxicity profile and provides a significant clinical benefit, and hence warrants further investigation.

Irinotecan or oxaliplatin combined with leucovorin and 5-fluorouracil as first-line treatment in advanced colorectal cancer: a multicenter, randomized, phase II study.

BACKGROUND: Irinotecan (IRI) and oxaliplatin (OXA) are effective in the treatment of colorectal cancer. Previously untreated patients with advanced colorectal carcinoma (CRC) were randomly assigned to receive IRI plus leucovorin (LV)/5-fluorouracil (5-FU), or OXA plus LV/5-FU in order to compare the response rates, time-to-tumor progression, overall survival rates, and toxicity profiles of these two agents. MATERIALS AND METHODS: From January 1999 to February 2002, 295 patients were randomized to receive either IRI/LV/5-FU or OXA/LV/5-FU. The treatment schedules consisted of weekly IRI 70 mg/m(2) or OXA 45 mg/m(2) plus LV 200 mg/m(2) followed immediately by intravenous bolus 5-FU 450 mg/m(2) for 6 weeks, followed by a 2-week rest period. Treatment was continued for up to four cycles or until disease progression, unacceptable toxicity or patient refusal. RESULTS: There were no significant differences between the study arms in the overall response rate (33% with IRI/LV/5-FU versus 32% with OXA/LV/5-FU based on responses demonstrated on a single evaluation; 23% with IRI/LV/5-FU versus 22.3% with OXA/LV/5-FU based on responses confirmed according to WHO criteria) median time to progression (8.9 versus 7.6 months), and median overall survival (17.6 versus 17.4 months). Toxicity profiles (grades 3 and 4) were similar in the IRI and OXA arms (diarrhea 12.3% and 9.8%, neutropenia 8.2% and 4.9%, and febrile neutropenia 1.4% and 1.4%, respectively), with the exception of grade 3 sensory neuropathy, which almost exclusively occurred in the OXA arm (0% versus 5.6%; P=0.003, Fisher's exact test). CONCLUSION: The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA-LV/5-FU.

The combination of estramustine and mitoxantrone in hormone-refractory prostate cancer: a phase II feasibility study conducted by the Hellenic Cooperative Oncology Group.

OBJECTIVES: To consider the safety profile and therapeutic value of the combination of estramustine and mitoxantrone in a bimonthly schedule to treat hormone-refractory prostate cancer. The survival of patients with prostate cancer who relapse after androgen ablation is limited and the therapeutic options are restricted. METHODS: Twenty-nine patients with relapse after previous treatment were included in the study; however, 3 patients who refused to start treatment were not included in the analysis, leaving 26 eligible patients. The median age was 64 years (range 44 to 82), the World Health Organization performance status ranged from 1 to 3, and the mean prostate-specific antigen level was 103 ng/mL (range 1 to 620). The Gleason score ranged from 2 to 9. The patients received a total of 208 therapeutic cycles (mean 8, range 3 to 24). Every cycle consisted of oral estramustine 140 mg, 3 times a day continuously, and intravenous mitoxantrone 20 mg (total dose). The regimen was repeated every 2 weeks. RESULTS: Twenty-seven percent of patients with measurable soft-tissue disease demonstrated an objective response, which included one complete and six partial responses. Thirteen patients (50%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 9.2 months, and the median survival for all patients was 15 months. The most common side effects were neutropenia and thrombocytopenia. CONCLUSIONS: The combination of estramustine and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer. More patients are needed to partake in Phase III studies to establish the survival benefit that this combination may offer.

Vinblastine and interferon-gamma combination with and without 13-cis retinoic acid for patients with advanced renal cell carcinoma. Results of two phase II clinical trials.

BACKGROUND: The aim of this study is firstly to determine the response rates and toxicity of two regimens containing vinblastine (VBL) in combination with interferon-gamma (IFN-gamma) in the treatment of patients with advanced renal cell carcinoma (RCC), and secondly to evaluate the additional efficacy of 13-cis retinoic acid (13-CRA) in RCC. METHODS: Twenty-nine patients were included in the first trial (Trial 1) and 40 in the second one (Trial 2). The therapy given in Trial 1 consisted of VBL 0.15 mg/kg i.v. every 2 weeks and IFN-gamma 100 microg s.c. 3 times weekly. In Trial 2, the therapy consisted of the same two drugs, in the same doses, plus oral 13-CRA 40 mg/day. RESULTS: In Trial 1 there were 3 (10.3%) patients with complete response, 3 (10.3%) patients with partial response, 8 (27.6%) patients with stable disease and 15 (51.7%) patients with progressive disease. In Trial 2, there was no complete response, however, 3 (7.5%) patients had partial response. Additionally, 15 (37.5%) patients maintained stable disease and 14 (35%) patients had progressive disease. In Trial 1, the median survival was 12.56 months (95% CI, 6.8-18.3, range 0.59-42.49) and the median time to progression was 3.21 months (95% CI, 1.7-4.7, range 0.03-42.49). In Trial 2, the median survival was 9.54 months (95% CI, 5.9-13.1, range 0.43-24.1) and the median time to progression was 3.9 months (95% CI, 0.8-7, range 0.26-24.1). In Trial 1, granulocytopenia grade 3 and 4 appeared in 5 (17.2%) patients and anaemia grade 3 in 1 (3.4%) patient. In Trial 2, there were grade 3 toxicities, as granulocytopenia in 5 (12.5%) patients, anemia in 4 (10.0%) patients, stomatitis in 3 (7.5%) patients, fatigue/malaise in 3 (7.5%) patients and 1 (2.5%) had diarrhea. No toxic deaths occurred in both studies. CONCLUSION: The use of IFN-gamma does not enhance the low response of VBL-based chemotherapy. The additional administration of 13-CRA with the combination of VBL and IFN-gamma does not add to the efficacy of this combination in patients with advanced renal cell carcinoma. New active agents are needed to treat patients with this disease.

First-line chemotherapy with docetaxel for unresectable or metastatic carcinoma of the biliary tract. A multicentre phase II study.

The purpose was to evaluate the efficacy and safety profile of docetaxel as first-line chemotherapy for patients with locally advanced or metastatic biliary tract carcinoma. 25 chemotherapy-naïve patients with unresectable or metastatic biliary tract carcinoma were entered into this phase II trial. Docetaxel was given at the dose of 100 mg/m2 as a 1-h infusion on day 1, after appropriate premedication with dexamethasone; treatment was repeated every 21 days. Patients were assessed for response every three chemotherapy cycles. 24 patients were evaluable for response and 25 for toxicity. A total of 98 cycles were administered with a median of three cycles/patient. Two complete (CR=8%) and three partial (PR=12%) responses were observed (overall response rate: 20%; 95% confidence interval (C.I.) 4-36%); in addition, 6 (24%) patients had stable disease and 14 (58%) progressive disease. With a median follow-up of 8 months, the median duration of response was 4 months, the median time to tumour progression (TTP) was 6 months and the overall median survival was 8 months. The 1-year survival rate was 26%. Grade 3 and 4 granulocytopenia occurred in 36 and 20% of the patients, respectively, and febrile neutropenia was observed in 16% of them; there were no treatment-related deaths. Grade 2-3 fatigue was reported in 24% of patients. These results indicate that docetaxel is an active drug against adenocarcinomas of the biliary tract.

Docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer: a Hellenic Cooperative Oncology Group Phase II study.

A phase II study was conducted to evaluate the activity and toxicity profile of the combination of docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer (ABC). Thirty-nine eligible patients with a median performance status of 1 (range, 0-2) were enrolled in the study. Treatment consisted of docetaxel 75 mg/m2 in a 1-hr infusion on day 1 preceded by gemcitabine 1000 mg/m2 over 30 min on days 1 and 8. One hundred eighty-one treatment cycles were administered, 113 (62.4%) of them at full dose. Relative dose intensity of gemcitabine and of docetaxel was 0.73 and 0.85, respectively. More common grade 3-4 toxicities included neutropenia (49%), anemia (10%), fatigue (10%), nausea/vomiting (8%), and alopecia (77%). Seven patients were hospitalized for febrile neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was required in 90% of patients. Overall, 14 patients (36%) responded, 3 (7.5%) of them completely. Median duration of response was 10.3 months (range, 4.6-17.5+). Median time to progression was 7 months (range, 0.2-17.5+) and median survival 12.7 months (range, 2-20.5+). In conclusion, the combination of docetaxel and gemcitabine, as used in the present study, has moderate activity in anthracycline-resistant ABC. Future studies should incorporate prophylactic administration of G-CSF to reduce the incidence of febrile neutropenia and maintain dose intensity.

Second-line chemotherapy with weekly oxaliplatin and high-dose 5-fluorouracil with folinic acid in metastatic colorectal carcinoma: a Hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study.

BACKGROUND: Oxaliplatin is a novel platinum derivative, which, combined with 5-fluorouracil (5-FU), and folinic acid (FA), demonstrates synergistic activity in metastatic colorectal cancer (MCC). The HeCOG performed a multicenter phase II study of a weekly oxaliplatin administration schedule in patients with previously treated MCC to evaluate the antitumor efficacy and toxicity of this combination. PATIENTS AND METHODS: Eligible patients included those who relapsed after or during chemotherapy with 5-FU and FA and/or irinotecan. Prior radiotherapy was accepted provided that measurable disease was outside the radiation fields. Other eligibility criteria included written informed consent, a WHO performance status < or = 2 and adequate bone marrow, liver and renal function. Treatment consisted of Oxaliplatin 50 mg/m2 by two-hour intravenous (i.v.) infusion followed by FA 500 mg/m2 (two-hour i.v. infusion) and 5-FU 2,500 mg/m2 (24-hour continuous i.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every 50 days. RESULTS: Thirty-two patients (Median age 61 years, range 25-76) entered the trial. The majority (75%) had progressed after receiving first-line chemotherapy. Diarrhea was the main non-hematologic toxicity. More than half of the patients (53%) developed grades 3 or 4 diarrhea. Due to this side effect only 29% of cycles were given with at least 90% of the planned dose of 5-FU. Hematologic toxicity included grade 3 neutropenia and thrombocytopenia (10% for each), and grade 4 thrombocytopenia (3%). Two patients (6%) died of sepsis, one related to neutropenia and one due to urinary tract sepsis. Sixteen patients (50%) developed grades 1 and 2 neurotoxicity in the form of sensory neuropathy, which was mild and transient. The objective response rate was 13% (95% CI: 3%-29%). All four responses were partial. Twelve patients (38%) had stable disease and 8 (25%) progressive disease. The median time to progression was three months and the median survival was nine months from the start of therapy. The Kaplan-Meier estimated probability of one-year survival for the group as a whole was 32%. CONCLUSIONS: The weekly administration of oxaliplatin with 5-FU and FA was associated with considerably less neurotoxicity than other schedules. However, the high percentage of diarrhea suggests that a dose reduction of 5-FU in this regimen may result in better therapeutic synergy.

Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor: a multicenter phase II study.

PURPOSE: To determine the efficacy and tolerance of single-agent docetaxel and granulocyte colony-stimulating factor in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Thirty-three chemotherapy-naive patients (median age, 65 years) with histologically confirmed pancreatic cancer were treated, after appropriate premedication, with docetaxel (100 mg/m(2)) and granulocyte colony-stimulating factor (150 microg/m(2)/d subcutaneously days 2 through 10) every 3 weeks. World Health Organization performance status was 0 to 1 in 28 patients (85%) and 2 in 5 patients (15%). Twenty-nine patients had stage III and IV disease. RESULTS: One complete response (3%) and one partial response (3%) were observed for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had stable disease and 12 (36%) had progressive disease. The duration of the two objective responses was 10 and 28 weeks, and the median time to tumor progression was 20 weeks. The median overall survival was 36 weeks. The actuarial 1-year survival was 36.4%. The performance status improved in seven of 21 assessable patients (24%) and pain improved in 14 of 21 (67%) assessable patients; five patients (29%) experienced weight gain during treatment. Disease-related asthenia, anorexia, vomiting, and diarrhea improved in 29%, 15%, 67%, and 47% of the assessable patients, respectively. Serum concentrations of CA 19-9 were decreased by more than 50% in seven patients (35%). Grade 3 and 4 neutropenia occurred in four patients (12%) and eight patients (24%), respectively, with two episodes of febrile neutropenia. There were no treatment-related deaths. Grade 3/4 asthenia occurred in three patients. CONCLUSION: Although docetaxel has a marginal objective activity in pancreatic cancer, it seems to have an important effect on tumor growth control, conferring a clinical benefit.

Docetaxel and granulocyte colony-stimulating factor in patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapy: a multicenter phase II trial.

PURPOSE: To investigate the activity of docetaxel and granulocyte colony-stimulating factor support (G-CSF) in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with cisplatin. PATIENTS AND METHODS: A total of 60 patients with locoregional and metastatic NSCLC who had relapsed or progressed after first-line treatment with cisplatin-based regimens were enrolled into the trial. Docetaxel at 100 mg/m2 was given as a 1-h infusion with G-CSF (rhG-CSF given s.c. at 150 microg/m2) support from day 2 to day 8 every 3 weeks; all patients received premedication with corticosteroids. RESULTS: In all, 1 (1.6%) and 14 (23.3%) patients achieved a complete response (CR) and a partial response (PR), respectively, for an overall response rate of 25% (95% CI 14.0-35.9%); stable disease (SD) and progressive disease (PD) were documented in 18 (30%) and 27 (45%) patients, respectively. The median duration of response was 20 weeks and the median time to tumor progression was 28 weeks. The median overall survival was 32 weeks and the 1-year survival rate was 23%. A total of 263 courses were given at a median of 3 cycles/patient. Grade 3 and 4 neutropenia occurred in 11 (18%) and 14 (23%) patients, respectively, with 18 (30%) patients requiring hospitalization for neutropenic fever; 1 patient died of sepsis. Grade 2 peripheral neuropathy occurred in 9 patients (15%) and grade 3 asthenia, in 4 (7%). Other toxicities were mild. CONCLUSIONS: Docetaxel has considerable single-agent activity in patients with NSCLC who have relapsed or progressed after first-line chemotherapy with cisplatin-based regimens.

Doxorubicin cardiotoxicity and serum lipid increase is prevented by dextrazoxane (ICRF-187).

This study is related to the serious side effects of Doxorubicin-cardiotoxicity and serum lipid caused by the drug's cumulative effect. Studies were performed on experimental animals treated with intensive administration of Doxorubicin. Seventy five wistar rats were divided in two equal groups A and B. Group A was used for doxorubicin administration and B for doxorubicin and dextrazoxane. The drugs were administered weekly for twelve weeks at doses 0.2 mg/100 g BW for doxorubicin and 1.5 mg/100 g BW for dextrazoxane. Histological examination of the cardiac muscle, large vessels, liver and other organs and biochemical examination for serum lipids and liver enzymes were performed on certain weeks. Comparison of the findings of the two groups showed a) a reduction in doxorubicin cardiotoxicity by dextrazoxane and b) the addition of dextrazoxane to doxorubicin resulted in lowering the increase of serum lipids produced by doxorubicin. c) In vitro tests by chemiluminescence showed that dextrazoxane acts as a scavenger of oxygen free radicals.

Effects of tubulin-inhibiting agents in human lung and breast cancer cell lines with different multidrug resistance phenotypes.

Drug sensitivity was studied for the tubulin inhibitors taxol, taxotere, rhizoxin and for doxorubucin and cisplatin, in human lung and breast cancer cell lines, including drug-selected cell lines, overexpressing the membrane transporter P-glycoprotein (Pgp) or the multidrug resistance protein (MRP). All tubulin-inhibiting agents were more potent than doxorubicin and cisplatin in all cell lines. In the drug resistance-selected cell lines (doxorubicin or mitoxantrone resistant) there was cross-resistance between the tubulin inhibitors and the selecting agent; however, MRP overexpressing cells were relatively less resistant to taxanes than the Pgp overexpressing cells. Polymerization of microtubules after exposure to taxol was observed in drug sensitive cell lines, but not in resistant cell lines, even at high taxol concentrations and after long exposure times. In the Pgp overexpressing cell lines, steady accumulation of 14C-taxol was defective and could be reverted by verapamil. MRP overexpressing cells did not have a significant accumulation defect of taxol, compared to the parental cell lines, and verapamil did not have any effect. These data confirm that the Pgp overexpression is an important mechanism of resistance to taxanes and rhizoxin in human lung and breast tumor cells. However, the presence of mechanisms other than transport defects may play an important role in non-Pgp expressing cells, and these may include an altered function of tubulins.

Chemo-radiotherapy versus chemo-surgery in stage IIIA non-small cell lung cancer.

Forty patients with non-small cell lung cancer stage IIIA, aged 33-72 years were allocated to two groups in order to get therapy of two different combined modalities. All the patients were staged and considered inoperable. Staging was done by bronchoscopy, CT scan, bone scan and in patients with mediastinal lymph nodes less than 2 cm in size by thoracotomy. Group A patients were programmed to have induction chemotherapy and then radiotherapy while patients of group B to have induction chemotherapy, of the same kind as Group A and then surgery. Chemotherapy included cis-platinum 90 mg/m(2) given once every 3 weeks for 4-6 courses. Radiotherapy of Group A patients was 5000 cGy in the primary tumor site and mediastinum. Toxicity was tolerable. The following results were obtained: a) high response rate (over 70%) after chemotherapy, b) 66% of Group B patients were redered operable and c) the survival rate was significantly higher in patients with chemo-surgery versus those with chemo-radiotherapy.