Non small cell lung cancer in the elderly: clinico-pathologic, management and outcome characteristics in comparison to younger patients.

It is controversial whether non-small cell lung cancer (NSCLC) in the elderly constitutes a distinct clinico-biological entity compared to younger counterparts. As reported data are scant and discordant, we sought to analyze retrospectively the medical records of Hellenic NSCLC patients aged >70 years and compare them with those of age (70-45 years) and younger (<45 years) patients. Records were abstracted from the Hellenic Cooperative Oncology Group (HeCOG) cancer registry database. Presentation, management and outcome data of 417 elderly patients aged > or =70, 1374 age 70-45 years old and 115 patients aged < or =45 years old with histologically confirmed NSCLC managed from 1989 until 2004 were retrieved and compared. Elderly patients differed significantly in terms of presence of symptoms (p<0.001), including thoracic pain (p=0.003), dyspnea (p<0.001), cough (p<0.001) and fatigue (p<0.001), eastern Cooperative Oncology Group performance status (PS) 2-3 (p<0.001), and histological type (more commonly diagnosed with squamous cell carcinoma (p<0.002) and less frequently with adenocarcinoma). Although elderly patients had significantly higher rates of PS 2-3, they had significantly better median time to disease progression (TTP) compared to the younger counterpart (6.4 versus 4.3 months p=0.047). Overall survival (OS) was not significantly different between elderly and young patients (median OS 11.8 versus 11.5 months; p=0.6), but platinum-based chemotherapy and radiotherapy were variables associated favorably with TTP and survival in the elderly. This large retrospective series presents strong evidence that NSCLC constitutes a similar clinicopathologic entity in elderly and young individuals with discretely differing biological behavior and that elderly symptomatic patients should be considered for effective anticancer treatment whenever possible.

Combination of pegylated liposomal doxorubicin (PLD) and paclitaxel in patients with advanced soft tissue sarcoma: a phase II study of the Hellenic Cooperative Oncology Group.

Patients with soft tissue sarcoma (STS), even after complete local disease control, often relapse locally or with distant metastases. This multicenter phase II study was conducted to evaluate the safety and efficacy of the combination of pegylated liposomal doxorubicin (PLD) and paclitaxel, as first-line treatment in patients with advanced STS. In all, 42 patients with locally advanced or metastatic STS, median age 54 years and median Eastern Cooperative Oncology Group performance status (PS) 1 were treated with PLD 45 mg m(-2) and paclitaxel 150 mg m(-2), every 28 days for a total of six cycles. Histological types included mainly leiomyosarcomas (43%), malignant fibrous histiocytomas (14%) and liposarcomas (12%). At study entry, 69% of patients had distant metastases. Overall response rate was 16%, including one complete (CR 2%) and six partial responses (PRs 14%), while an additional 14 patients had disease stabilization (SD 33%). At median follow-up 41.5 months, median time to progression (TTP) was 5.7 months with median overall survival (OS) 13.2 months. Grade 3-4 toxicities included neutropenia (17%), anaemia (15%), neurotoxicity (5%) and palmar-plantar erythrodysesthesia (9%). There were no treatment-related deaths. The combination of PLD and paclitaxel is a safe and well-tolerated regimen demonstrating modest efficacy as first-line treatment in patients with advanced STS.

Cavitating squamous cell lung carcinoma-distinct entity or not? Analysis of radiologic, histologic, and clinical features.

INTRODUCTION: Patients with cavitating squamous lung carcinoma (cSLC) are believed to harbor aggressive, chemoresistant disease with distinct features and fare poorly. We retrospectively analyzed radiologic, histologic, and clinical features of patients with cSLC and solid SLC (sSLC) from the patient registry of four Hellenic Cooperative Oncology Group (HeCOG) cancer centres in an effort to detect distinct characteristics of cSLC. PATIENTS AND METHODS: 37 cSLC and 212 sSLC patients, most of them male smokers, aged more than 60, treated with resection and/or chemotherapy/radiotherapy were included in the analysis. Disease stage, histologic differentiation and lymphatic/vascular invasion, pre-diagnosis symptoms and their duration, tumor size, site and associated features, metastatic sites, chemotherapy administered, responses and duration as well as time to treatment failure, and overall survival were analyzed for significant differences between the two patient groups. RESULTS: Statistically significant differences (two-sided P < 0.05) in patients with cSLC were found for: locally advanced (IIIB) or metastatic (IV) disease (76.5%) at presentation, longer duration of pre-diagnosis symptoms (mean 10 months), more frequent manifestation of fever, cough, weight loss, poor tumor differentiation, lower lobe primary, absence of atelectasis and satellite lesions. Objective response rates (33% for cSLC versus 32% for sSLC) and response duration (median 6 versus 5 months) were no different in the two patient groups. Median time to treatment failure (TTF) and overall survival (OS) were 10 and 13 months for cSLC patients, whereas 12 and 18 months for sSLC patients. Two-year TTF and OS rates were 18.5% and 33.5% for cSLC, while they were 19.3% and 40% for sSLC. No statistically significant differences were observed in any survival curves. CONCLUSION: Patients with cSLC present with high grade tumors that may initially simulate infectious processes, leading to late diagnosis despite long standing symptoms and presentation with advanced disease. In view of lack of evidence for differential disease course, increased chemoresistance and inferior outcome in comparison to sSLC patients, the definition of cavitating pulmonary carcinoma as a distinct clinical subentity cannot be supported.

Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.

PURPOSE: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. PATIENTS AND METHODS: Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status < or = 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. RESULT: Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P =.017), median time to progression (TTP; 9.4 v 6.1 months; P =.003) and median survival (14.2 v 9.3 months; P =.026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P =.005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P =.089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P =.006), thrombocytopenia (5.7% v 0.9%; P =.046), and neutropenic sepsis (11.6% v 3.8%; P =.001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. CONCLUSION: MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.

Prevention of anemia in patients with solid tumors receiving platinum-based chemotherapy by recombinant human Erythropoietin (rHuEpo): a prospective, open label, randomized trial by the Hellenic Cooperative Oncology Group.

OBJECTIVES: Platinum compounds are commonly associated with significant anemia. Erythropoietin administration has been found effective in correcting anemia in patients with solid tumors receiving chemotherapy. We conducted a randomized, open label study to assess the efficacy of erythropoietin in preventing transfusions and significant anemia (hemoglobin <10 g/dl) in patients with solid tumors receiving platinum-based chemotherapy. METHODS: One hundred forty-four patients with hemoglobin <13 g/dl were included in this study (72 in each arm). Patients in the treatment arm received 10,000 U of recombinant human erythropoietin (rHuEPO) thrice weekly s.c. during platinum-based chemotherapy, while patients in the control arm received no treatment. RESULTS: All patients were evaluable for efficacy. Transfusions were reduced by the administration of rHuEPO (15.3 vs. 33.3%, p = 0.019), and fewer patients developed significant anemia (16.6 vs. 45.8%, p < 0.0001). Subgroup analysis showed that patients with observed to predicted (O/P) serum erythropoietin levels 0.9 or non-responders. CONCLUSIONS: rHuEPO at a dose of 10,000 U thrice weekly prevents transfusions and development of significant anemia in patients with solid tumors receiving platinum-based chemotherapy.

Docetaxel in combination with gemcitabine plus rhG-CSF support as second-line treatment in non-small cell lung cancer. A multicenter phase II study.

BACKGROUND: Docetaxel in combination with gemcitabine is an active front-line chemotherapy regimen against non-small cell lung cancer (NSCLC) with acceptable toxicity. A multicenter phase II study was conducted in order to determine the toxicity and efficacy of this combination, as salvage treatment in patients progressing after a cisplatin-based front line regimens. PATIENTS AND METHODS: Thirty-two patients with histologically confirmed, bidimensionally measurable NSCLC, who failed prior cisplatin-based chemotherapy were enrolled. The patients' median age was 62.5 years, 29 (91%) were male, 23 (72%) had disease stage IV, and 22 (69%) had a performance status (WHO) 0-1. Gemcitabine (900 mg/m(2)) was administered on days 1 and 8 and docetaxel (100 mg/m(2)) on day 8, after appropriate premedication. rhG-CSF (150 microg/m(2)) was given prophylactically from day 9 to 15. Treatment was repeated on an outpatient basis every three weeks. RESULTS: A total of 127 chemotherapy cycles were administered. In an intention-to-treat analysis five patients (15.6%; 95% CI: 3.04-28.21%) achieved a partial response, 11 (34.4%) stable disease, and 16 (50%) progressive disease. The median duration of response was 9 months, the median TTP 7 months, and the overall median survival 6.5 months; the overall 1-year survival probability was 27.6%. Grade 3/4 neutropenia was observed in five (15.6%) patients and in two of them associated with fever. Grade 3 anemia and thrombocytopenia occurred in three (9%) and two (6.5%) patients, respectively. Non-hematologic toxicity was very mild with only one episode of grade 4 diarrhea and mucositis, respectively; two (6%) patients complained for grade 3 asthenia. CONCLUSION: The combination of gemcitabine and docetaxel with prophylactic use of rhG-CSF is a safe and well-tolerated regimen for the treatment of patients with advanced NSCLC, who failed front-line treatment with cisplatin-based regimens.

Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer. A Hellenic Cooperative Oncology Group phase II study.

AIM: To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC). BACKGROUND: Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC. PATIENTS AND METHODS: From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells. RESULTS: Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached CONCLUSIONS: The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.

Gemcitabine and vinorelbine as second-line treatment in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy: a phase II study conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: Gemcitabine and vinorelbine have shown activity in breast cancer. A phase II trial was initiated in order to evaluate the response rate (RR) and time to progression (TTP) of the combination of the two drugs in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy. PATIENTS AND METHODS: Thirty-one patients were treated with the combination of gemcitabine 1000 mg/m2 days 1 + 8 and vinorelbine 30 mg/m2 days 1 + 8. The cycles were repeated every three weeks. RESULTS: Of 27 evaluable patients 1 (4%, 95% confidence interval (95% CI): 0.1%-19%) achieved complete remission (CR), five (18%; 95% CI: 6%-38%) partial remission (PR), eleven (40%; 95% CI: 22%-61%) stable disease and ten patients progressed. The median duration of response was six months (range 4-10+) and the median duration of disease stabilization was five months (range 2-22+). With a median follow-up of 16 months (range 0.4-22+) the median TTP was 3.5 months (range 0.4-22+) and the median survival was 9.5 months (range 0.4-22+). Grade 3-4 toxicities were granulocytopenia 15 patients (48%), rash 3 patients (10%), neuropathy 1 patient (3%) and thrombocytopenia 1 patient (3%). In conclusion the combination of gemcitabine/vinorelbine in the doses administered in this group of patients had a response rate of 22% and needs to be further evaluated in metastatic breast cancer.

Platinum-based chemotherapy of primary extragonadal germ cell tumours: the Hellenic Cooperative Oncology Group experience.

Extragonadal germ cell tumours (EGCT) are uncommon, most frequently arise in the mediastinum and retroperitoneum and have variable responses to platinum-based chemotherapy. A retrospective analysis was performed on 38 patients with EGCT treated with cisplatin-based (CDDP) or carboplatin-based (CBDCA) chemotherapy between 1984 and 1998. Twenty-four patients had nonseminomatous germ cell tumours (NSGCT) and 14 seminoma. Twenty-two tumours arose in the mediastinum (13 nonseminomas, 9 seminomas) and 16 in the retroperitoneum (11 NSGCT, 5 seminomas). Initial surgery included complete resection in 1 patient, biopsy in 27 patients and debulking surgery in 10 patients. Complete response rates with chemotherapy +/- surgery were as follows: mediastinum 14 of 21 (66.66%) patients (8 of 12-75% NSGCT, 6 of 9-66.66% seminomas) and retroperitoneum 14 of 16 (87.5%) patients (9 of 11-81.81% NSGCT, 5 of 5-100% seminomas). One patient who underwent complete resection of a mediastinal malignant teratoma combined, received PVB chemotherapy on an adjuvant basis and remains alive and disease-free. Three additional seminoma patients who achieved partial response after chemotherapy remain alive and disease-free following mediastinal radiotherapy. All 14 patients with extragonadal seminomas remain alive with no evidence of disease at a median follow-up of 49 months (range 7-164), giving an overall survival of 100%. Nine of 13 (69.23%) patients with mediastinal NSGCT are long-term disease-free at a median follow-up of 43.5 months (range 7-152). Nine of 11 (81.81%) patients with retroperitoneal NSGCT remain alive and disease-free at a median follow-up of 56 months (range 14-110). Complete surgical resection of residual mass was undertaken in 10 patients (3 seminomas, 7 nonseminomas). The histology revealed necrosis/fibrosis in 6 patients (3 seminomas, 3 NSGCT) and viable cancer in 4 patients. Patients who had viable malignant cells in the resected specimens received two more courses of VelP chemotherapy. None of our patients had relapsed at the time of this analysis. None of our 6 patients who underwent testicular biopsy (1 patient) or orchiectomy (5 patients) due to suspicious ultrasound of the testis were found to have testicular tumour or fibrotic scar. In conclusion, this retrospective analysis showed significant responses in patients with either mediastinal or retroperitoneal NSGCT treated with CDDP- or CBDCA-based chemotherapy +/- surgery. All patients with extragonadal seminomas remain alive with no evidence of disease, regardless of the site at presentation.

Weekly alternating non-cross-resistant chemotherapy for small cell lung cancer with a good prognosis: a study of the Hellenic Cooperative Oncology Group.

This trial was conducted by the Hellenic Cooperative Oncology Group to improve the responses and survival in small cell lung cancer with a good prognosis, using a weekly intensive chemotherapy with alternated non-cross-resistant myelosuppressive agents. Patients were classified into two groups; group A consisted of those who received the initial designed regimen (29 patients), and group B consisted of those who received the more intensified regimen that increased by 25% the doses of carboplatin, epirubicin, and ifosfamide, and by 33% the doses of etoposide given on days 1, 2, and 3 with prophylactic granulocyte colony-stimulating factor support. Chemotherapy in group A consisted of carboplatin 150 mg/m2 in 250 ml of 5% dextrose in water as an 1-hour infusion on day 1, etoposide 75 mg/m2 in 250 ml normal saline as an 1-hour infusion on days 1 and 2 alternating with epirubicin 30 mg/m2 intravenous push on day 8, and ifosfamide 2 g/m2 in 500 ml 5% dextrose in water as a 2-hour infusion with mesna protection on day 8. Responding patients with limited disease were also treated with thoracic irradiation. Those who achieved complete response received prophylactic cranial radiotherapy. In group A, the overall response rate was 79.3%, with a 27.6% complete response rate, a median time to progression of 5.71 months, and a median survival of 8.3 months. For patients with limited disease, the response rate was 75%, with a 40% complete response rate, a median time to progression of 5.87 months, and a median survival of 10.98 months. The respective numbers for extensive disease were 89% (only partial responses), 4.82 months, and 5.67 months. The toxicity was mild and manageable. There were no dose reductions or treatment delays. In view of the excellent tolerability and the rather low efficacy of the initial regimen, we decided to administer the more intensified one with granulocyte colony-stimulating factor support. In Group B, the overall response rate was 91.8%, with a 45.9% complete response rate, a median time to progression of 7.05 months, and a median survival of 10.16 months. For limited disease, the response rate was 93%, with a 52% complete response rate, a median time to progression of 7.05 months, and a median survival of 10.49 months. The respective numbers for extensive disease were 88% (25% complete response), 6.82 months, and 9.02 months. The toxicity of this more intensified regimen was more severe but acceptable. Myelosuppression was the main toxicity. However, grade 3-4 febrile neutropenia requiring hospitalization occurred only in 6% of patients. The relative dose intensity was 91%, probably the result of the prophylactic use of granulocyte colony-stimulating factor. The differences in response rate, time to progression, and survival were not statistically significant between the two groups. There were statistically significant differences in the response rate (p = 0.019) and survival rate (p = 0.001) between limited disease and extensive disease only in group A. In conclusion, this weekly, alternated regimen, specifically the intensified regimen, appears to be very active and well tolerated in patient who have small cell lung cancer with a good prognosis. However, despite the high efficacy, this study failed to show any survival advantage as compared with that obtained with the standard treatment for small cell lung cancer.