European Network of Gynaecological Oncological Trial Groups' Requirements for Trials Between Academic Groups and Industry Partners--First Update 2015.

The first version of ENGOT's Requirements for Trials Between Academic Groups and Industry Partners in Europe was published 2010. This first update integrates the experiences made by the ENGOT network and the cooperative group studies while performing, analyzing, and publishing -among others - three large phase III trials. Furthermore, progress in European legislation and its impact on clinical studies in Europe have been considered in this update process.

Paclitaxel, epirubicin, and carboplatin in advanced or recurrent endometrial carcinoma: a Hellenic Co-operative Oncology Group (HeCOG) study.

OBJECTIVE: Taxanes, anthracyclines, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, epirubicin and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. METHODS: Sixty-three consecutive patients were treated on an outpatient basis with epirubicin 50 mg/m(2), followed by paclitaxel 150 mg/m(2), administered intravenously over a 3-h period. Subsequently, the patients received carboplatin at AUC of 5. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. RESULTS: Response was assessed among 56 eligible patients. Thirty-six (63.2%) patients achieved objective clinical response (95% CI, 50.6-75.7%) including 14 (24.6%) complete and 22 (38.6%) partial responses. The median duration of response was 7.9 months, and the median times to progression and survival for all patients were 7.8 and 13.8 months, respectively. Grade 3 or 4 neutropenia occurred in 9 (15.5%) patients but only 3 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 19% of patients. Two patients died of sudden cardiac death 10 and 14 days after the administration of the first chemotherapy cycle, respectively, but these deaths were not clearly treatment related. CONCLUSIONS: The combination of paclitaxel, epirubicin and carboplatin with G-CSF support appears active in patients with metastatic or recurrent carcinoma of the endometrium.

Paclitaxel, topotecan, and carboplatin in metastatic endometrial cancinoma: a Hellenic Co-operative Oncology Group (HeCOG) study.

OBJECTIVE: Taxanes, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, topotecan and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. METHODS: Thirty-nine consecutive patients were treated on an outpatient basis with paclitaxel 150 mg/m(2), administered intravenously over a 3-h period and followed by carboplatin at AUC of 5 on day 3, with both agents proceding topotecan that was given at 0.75 mg/m(2)/day on days 1 through 3. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. RESULTS: Twenty-one (60%) patients achieved objective clinical response (95% CI, 42.2-75.7%) including 4 (11.4%) complete and 17 (48.6%) partial responses. The median times to progression and survival for all patients were 8.9 and 17.7 months, respectively. Grade 3 or 4 thombocytopenia and neutropenia occurred in 5 (13%) and 4 (10%) patients, respectively, but only 2 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 23% of patients. CONCLUSIONS: The combination of paclitaxel, topotecan and carboplatin with G-CSF support appears active with acceptable toxicity in patients with metastatic or recurrent carcinoma of the endometrium.

Prognostic significance of HER-2, p53 and Bcl-2 in patients with epithelial ovarian cancer.

BACKGROUND: Several oncogenes and onco-suppressor genes have been implicated in epithelial ovarian carcinogenesis, but their clinical significance is not clear and conflicting data have been found in various studies. PATIENTS AND METHODS: The immunohistochemical expression of HER-2, p53 and Bcl-2 proteins was investigated in a cohort of 95 patients with advanced epithelial ovarian cancer (stages IIc-IV). These patients participated in a phase III randomized clinical trial and were treated either with paclitaxel/carboplatin, orpaclitaxel/carboplatin alternating with paclitaxel/cisplatin. RESULTS: Positive immunostaining for HER-2, p53 and Bcl-2 proteins was found in 18%, 70.5% and 69.5% of the cases, respectively. In multivariate analysis, older patients (< 63 vs. > or = 63 years, p < 0.001), worse grade (I-II vs. III, p = 0.04) and p53 expression (negative vs. positive, p = 0.002) were significant prognostic factors independently associated with survival. CONCLUSION: p53 status along with age and grade appear to be independent prognostic factors for survival in patients with epithelial ovarian cancer.

Four cycles of paclitaxel and carboplatin as adjuvant treatment in early-stage ovarian cancer: a six-year experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: Surgery can cure a significant percentage of ovarian carcinoma confined to the pelvis. Nevertheless, there is still a 10-50% recurrence rate. We administered paclitaxel/carboplatin as adjuvant treatment in early-stage ovarian carcinoma. METHODS: Patients with stages Ia or Ib, Grade 2 or 3 and Ic to IIb (any grade) were included. Patients were treated with 4 cycles of Paclitaxel 175 mg/m2 and Carboplatin [area under the curve (AUC) 6 (Calvert Formula)] every 3 weeks. RESULTS: Sixty-nine patients with no residual disease following cytoreductive surgery and minimal or modified surgical staging were included in this analysis. Grade 3 or 4 neutropenia occurred in 29.9% of patients, while neutropenic fever was reported in 4.5%. Neurotoxicity (all Grade 1 or 2) was reported in 50% of cases. Median follow-up was 62 months. 5-year overall survival (OS) and relapse-free survival (RFS) were: 87% (95% confidence intervals [CI]: 78-96) and 79% (95% CI: 69-89), respectively. Significantly fewer patients with stages Ic-IIb and tumor grade 2 or 3 achieved a 5-year RFS than patients with only one of these two factors (73% vs 92%, p = 0.03). CONCLUSION: Paclitaxel/Carboplatin chemotherapy is a safe and effective adjuvant treatment in early-stage ovarian carcinoma. Patients with stages Ic-IIb and tumor grade 2 or 3 may benefit from more extensive treatment.

Correlation of MDR-1, nm23-H1 and H Sema E gene expression with histopathological findings and clinical outcome in ovarian and breast cancer patients.

The development of a molecular screening method for cancer patients is of great importance, since it would contribute to the selection of the most effective chemotherapy regimen for each patient. In the present study we applied such a method, semi-quantative RT-PCR analysis, and we examined the expression of the multidrug resistance gene MDR-1, the metastasis suppressor gene nm23-H1 and the non-MDR drug resistant gene H Sema E in 53 ovarian and breast cancer specimens. Moreover, we have correlated the expression profile of these genes with the histopathological findings and clinical outcome of the examined patients. The majority of specimens were found to be positive for MDR-1 and H Sema E gene expression, while nm23-H1 was detected in less than 50% of the patients. Correlation and statistical analysis of the molecular data with clinicopathological features showed that nm23-H1 could serve as a good prognostic factor for ovarian cancer patients. In breast cancer patients, nm23-H1 expression was associated with a 6.1 higher death risk. Ovarian cancer patients who express nm23-H1, but not MDR-1 and H Sema E, tend to have longer survival than patients with any other gene combination. Finally, breast cancer patients with advanced disease showed a better response when they were negative for all the three genes studied. In conclusion this work proposes that the combined study of the expression of different genes may be a useful approach for evaluating patients' response to therapy.

Tolerability of adjuvant high-dose interferon alfa-2b: 1 month versus 1 year--a Hellenic Cooperative Oncology Group study.

BACKGROUND: High-dose interferon alfa-2b (IFN-alpha2b) as adjuvant therapy for melanoma is associated with substantial dose-limiting toxicity. It has been suggested that the 1-month intravenous (i.v.) induction regimen may be sufficient to reduce the risk of relapse and death. PATIENTS AND METHODS: The Hellenic Cooperative Oncology Group is conducting a multicenter, randomized trial of 1-month i.v. induction versus 1 year of adjuvant IFN-alpha2b therapy in patients with stage IIB/III melanoma. Adverse events reported by the first 200 patients to complete therapy are described. RESULTS: Both induction and maintenance regimens were well tolerated. The most common toxicities were flu-like and gastrointestinal symptoms, neutropenia, liver toxicity, and neurologic toxicity. The incidence of grade 3/4 toxicity was low and occurred mainly during the induction phase in both arms. Dose was reduced in 31% of patients during induction. Only 2% of patients discontinued. Dose was reduced in 8% of patients during maintenance and only 5% of patients discontinued. CONCLUSION: Intravenous induction with 15 MIU/m2/day IFN-alpha2b is well tolerated. Efficacy results from this trial are eagerly anticipated.

Development of a quantum-dot-labelled magnetic immunoassay method for circulating colorectal cancer cell detection.

AIM: To detect of colorectal cancer (CRC) circulating tumour cells (CTCs) surface antigens, we present an assay incorporating cadmium selenide quantum dots (QDs) in these paper. METHODS: The principle of the assay is the immunomagnetic separation of CTCs from body fluids in conjunction with QDs, using specific antibody biomarkers: epithelial cell adhesion molecule antibody, and monoclonal cytokeratin 19 antibody. The detection signal was acquired from the fluorescence signal of QDs. For the evaluation of the performance, the method under study was used to isolate the human colon adenocarcinoma cell line (DLD-1) and CTCs from CRC patients' peripheral blood. RESULTS: The minimum detection limit of the assay was defined to 10 DLD-1 CRC cells/mL as fluorescence was measured with a spectrofluorometer. Fluorescence-activated cell sorting analysis and Real Time RT-PCR, they both have also been used to evaluate the performance of the described method. In conclusion, we developed a simple, sensitive, efficient and of lower cost (than the existing ones) method for the detection of CRC CTCs in human samples. We have accomplished these results by using magnetic bead isolation and subsequent QD fluorescence detection. CONCLUSION: The method described here can be easily adjusted for any other protein target of either the CTC or the host.

Report of the long-term efficacy of two cycles of adjuvant bleomycin/etoposide/cisplatin in patients with stage I testicular nonseminomatous germ-cell tumors (NSGCT): a risk adapted protocol of the Hellenic Cooperative Oncology Group.

OBJECTIVES: Stage I testicular nonseminomatous germ-cell tumors (NSGCT) are highly curable. Following orchidectomy surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection can be applied. Certain factors are used to select patients in high-risk for relapse. We report the outcome and safety of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. METHODS: Between 1994 and 2004, 142 patients with stage I NSGCT and 1 of the following risk factors: lymphovascular invasion (LVI), invasion of tunica vaginalis, spermatic cord, rete testis or scrotal wall, embryonal component >50% of the total tumor, were prospectively included in a protocol of adjuvant chemotherapy consisting of two 3-week courses of bleomycin 15 IU, etoposide 120 mg/m(2), and cisplatin 40 mg/m(2) for 3 consecutive days with G-CSF support. RESULTS: Median follow-up was 79 months and 138 patients have been followed for at least 2 years. Seventy-seven patients (54%) had LVI and 74 (52%) had >50% embryonal component. There was 1 relapse, which was cured with chemotherapy and surgery. Another patient died due to disease-unrelated causes and 1 patient developed a new primary of the remaining testicle, which was cured with surgery. CONCLUSION: Two cycles of bleomycin/etoposide/cisplatin is an effective and safe form of adjuvant therapy in high-risk stage I NSGCT.

Paclitaxel and bevacizumab as first line combined treatment in patients with metastatic breast cancer: the Hellenic Cooperative Oncology Group experience with biological marker evaluation.

BACKGROUND: Randomized studies have shown that bevacizumab combined with taxane-based regimens increases response rates and prolongs progression-free survival (PFS) of patients with metastatic breast cancer (MBC). However predictive or prognostic biological markers that identify the appropriate target population, thus improving the cost-effectiveness ratio of this treatment, are still needed. PATIENTS AND METHODS: Retrospectively, 124 patients with MBC treated either with paclitaxel 90 mg/m² weekly x12 plus bevacizumab 10 µg/kg every 2 weeks or 15 µg/kg every 3 weeks (85 patients) or paclitaxel 175 mg/m² plus bevacizumab 15 µg/kg every 3 weeks for 6 cycles (36 patients) were identified. Additionally, the prognostic significance of a panel of key biological markers was evaluated centrally by immunohistochemistry (IHC) in 88 evaluable patients. RESULTS: More than two thirds of the patients completed chemotherapy, as planned. The response rate was almost identical (55.3% vs. 55.6%) in the patients treated with weekly or 3-weekly paclitaxel, respectively. After a median follow-up time of 23 months, the median PFS of the study population was 13 months, while median survival had not yet been reached. Common severe adverse events were neutropenia (33%), neuropathy (18.6%) and metabolic disturbances (17.6%). The incidence of hypertension of all grades was 28.1%. High expression of vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3) was associated with clinical response, while high expression of VEGFR1 was associated with poor survival. CONCLUSION: The safety and activity of the combination of bevacizumab with paclitaxel given either weekly or 3-weekly in patients with MBC is confirmed.

Two cycles of etoposide/cisplatin cured all patients with stage I testicular seminoma: risk-adapted protocol of the Hellenic Cooperative Oncology Group.

OBJECTIVES: Adjuvant carboplatin is used as adjuvant therapy in Stage I testicular seminoma. Although cure is the rule, relapses still occur, especially in high-risk populations. We report the results of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. METHODS: From 1996 to 2003, 64 patients with Stage I seminoma and one of two risk factors (maximal tumor diameter greater than 4 cm and/or age younger than 34 years) were prospectively included in a protocol of adjuvant chemotherapy. Treatment consisted of two 3-week courses of etoposide 120 mg/m2 and cisplatin 40 mg/m2 for three consecutive days with granulocyte colony-stimulating factor support. RESULTS: Of the 64 patients, 43 (67%) were younger than 34 years and 55 (86%) had a tumor diameter greater than 4 cm. Neutropenia and nausea and vomiting were the most frequent grade 3 or 4 toxicities (16.5% and 9.5%, respectively), apart from alopecia. After a median follow-up of 60 months (range 7 to 118), no disease relapses have occurred. A metachronous testicular carcinoma has been reported. One patient died of causes unrelated to his disease. CONCLUSIONS: The results of our study have shown that two cycles of etoposide and cisplatin is an effective and safe form of adjuvant therapy for Stage I testicular seminoma. Risk factors can be used to identify patients who could benefit from etoposide and cisplatin treatment.

The combination of gemcitabine and carboplatin as first-line treatment in patients with advanced urothelial carcinoma. A Phase II study of the Hellenic Cooperative Oncology Group.

BACKGROUND: The toxicity of platinum-based combinations represents a common problem for patients with advanced urothelial carcinoma. The authors previously reported encouraging efficacy for the combination of carboplatin and gemcitabine in patients considered to be unfit for cisplatin-based treatment. The objective of the current multicenter Phase II study was to evaluate the safety and efficacy of the combination of gemcitabine and carboplatin as first-line treatment in unselected patients with advanced urothelial carcinoma. METHODS: Patients with previously untreated, bidimensionally measurable, inoperable or metastatic urothelial carcinoma were treated with carboplatin, area under the concentration curve of 5 (Day 1) and gemcitabine at a dose of 1000 mg/m(2) (Days 1 and 8), every 21 days for a total of 6 cycles. RESULTS: Sixty patients (49 men and 11 women, with a median age of 69 yrs) were enrolled in the current study. Intent-to-treat analysis demonstrated an objective response rate (ORR) of 38.4% (95% confidence interval [95% CI], 26-51.8%) (11.7% complete responses and 26.7% partial responses). The median time to disease progression was 7.6 months (95% CI, 4.5-10.7 mos) and the median overall survival was 16.3 months (95% CI, 12-20.6 mos). The median survival was comparable to that reported for the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) according to the Memorial Sloan-Kettering Cancer Center prognostic model for patients with similar baseline prognostic features. Grade 3 or 4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) included anemia (18%), thrombocytopenia (23%), and neutropenia (52%), with 7 episodes of febrile neutropenia (11%) reported. Nonhematologic toxicity was rare. One toxic death occurred during the study. CONCLUSIONS: The combination of gemcitabine and carboplatin appears to have considerable activity as the first-line treatment of unselected patients with advanced urothelial carcinoma with manageable toxicity, and deserves further evaluation in this setting.

Advanced stage clear-cell epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience.

PURPOSE: Ovarian clear-cell carcinomas (OCCC) are known to be possibly resistant to platinum-based chemotherapy and to have a poorer prognosis with respect to other subtypes of epithelial ovarian cancer (EOC). This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stage III and IV OCCC and serous EOC (sEOC). PATIENTS AND METHODS: A retrospective analysis was performed in patients with advanced stage of OCCC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 1/2/1987 and 31/10/2003. The outcome was compared to that of patients with sEOC treated according to the same protocols during the same study period. RESULTS: One hundred and five patients (35 stage III and IV OCCC, 70 stage III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for OCCC was 45% (complete response 25%) (95% CI, 23.1% to 68.5%) and 81% (complete response 46%) (95% CI, 67.4% to 91.1%) for sEOC. The overall response rate was significantly higher for sEOC (P = 0.008). In the subgroup of stage III patients, the rate of complete responders was higher among sEOC patients (P = 0.023). After a median follow-up of 61.1 months, median survival and time to tumor progression were not significantly different between the two groups (25.1 months [95% CI 11.7 to 38.5 months] versus 49.1 months [95% CI 36.5 to 61.6 months], P = 0.141, 12.0 months [95% CI 6.5 to 17.3 months] versus 18.0 months [95% CI 14.7 to 21.6 months], P = 0.384, respectively). CONCLUSION: Patients with OCCC have significantly lower response to platinum-based first-line chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in significantly shorter survival. The current study outcomes are provocative and suggest that a new strategy for chemotherapy in OCCC should be adopted, possibly one that focuses on new agents without cross-resistance to platinum agents.

Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study.

PURPOSE: To evaluate the efficacy of temozolomide (TMZ) combined with cisplatin (CDDP) in terms of response rate, time to progression (TTP) and overall survival (OS), as well as the tolerability of the regimen in patients with brain metastases from solid tumors. PATIENTS AND METHODS: Patients (n=32) with brain metastases were treated with TMZ 150 mg/m2/day (chemotherapy-pretreated) or 200 mg/m2/day (chemotherapy-naive) for 5 days, combined with CDDP 75 mg/m2 on day 1, every 28 days. Primary tumor sites included breast cancer (n=15), lung cancer (n=12) and other (n=5). Twenty-seven patients had received prior chemotherapy for extracranial disease and 17 had prior radiotherapy to the brain. RESULTS: One patient (3.1%) with non-small cell lung cancer (NSCLC) achieved complete response. Nine patients (28.1%; six with breast cancer, two with melanoma and one with NSCLC) achieved a partial response and five patients (16%) had stable disease. Median OS was 5.5 months and median TTP 2.9 months. One patient died from septicemia/neutropenic fever. Grade III-IV toxicities included anemia (9%), leukopenia (6%), thrombocytopenia (3%), renal toxicity (3%), headache (3%), fatigue (3%), nausea (3%), vomiting (3%), and alopecia (6%). CONCLUSIONS: TMZ combined with CDDP is an active and well-tolerated combination in patients with brain metastases from solid tumors.

Second line chemotherapy with 5 fluorouracil and vinorelbine in anthracycline and taxane pretreated patients with metastatic breast cancer.

PURPOSE: 5-Fluorouracil (5-FU) and Vinorelbine (Vin) are active in the second line therapy of metastatic breast cancer (MBC). We conducted a multi-institutional phase II study to assess the activity of the combination of 5-FU and Vin in anthracycline and taxane pretreated patients with MBC. PATIENTS AND METHODS: Patients with MBC previously treated with anthracyclines and taxanes, who had measurable or evaluable disease, were treated with folinic acid 200 mg/m2 IV, 5-FU 400 mg/m2 IV bolus, and 5-FU 600 mg/m2 continuous infusion over 24 hours on days 1, 2, 15, and 16 and Vin 25 mg/m2 on days 1 and 15 of a 28-day cycle, for six cycles. Response rate, time to disease progression, overall survival, and toxicity were evaluated. RESULTS: Thirty-eight patients were enrolled and 35 were evaluable for response. Grade III and IV neutropenia was seen in four and three patients, respectively. At a median follow-up of 19.5 months, 33 patients have progressed, 14 during treatment and 19 during the follow-up period, and 23 have died for an overall survival of 12.3 months. The time to progression was six months. Eight patients had a partial response and 14 had stable disease for a clinical benefit rate of 63%. CONCLUSION: The combination of 5-FU and Vin is well tolerated and is a good option for the palliative care of patients with MBC.

Treatment of ovarian germ cell tumors with a 3-day bleomycin, etoposide, and cisplatin regimen: a prospective multicenter study.

BACKGROUND: Ovarian germ cell tumors (OGCT) are highly curable when treated with cytoreductive surgery and platinum-based chemotherapy. We evaluated the safety and activity of a 3-day modified bleomycin, etoposide, and cisplatinum (mBEP) regimen in patients with OGCT. PATIENTS AND METHODS: Patients with FIGO stages I-IV OGCT were treated with three (stages I-III complete resection) or four cycles (incomplete resection or stage IV) of bleomycin 15 mg iv, etoposide 120 mg/m(2) iv, and cisplatin 40 mg/m(2) iv for 3 days every 3 weeks. RESULTS: Forty-eight patients (14 with dysgerminoma and 34 with non-dysgerminomatous tumors) were included in our study. Most patients had stage I disease (65%) and complete resection of their tumor (67%). Twenty percent of patients developed grade 3 or 4 neutropenia with 4 episodes of neutropenic fever. During follow-up (median: 5 years), two patients developed progressive disease including one patient who died. All patients with stage I or II disease and all patients with dysgerminoma remain free of disease. However, 20% of patients with non-dysgerminomatous tumors stage III or IV experienced progressive disease. CONCLUSION: The modified 3-day BEP regimen was safe and effective in patients with OGCT. Further improvements are needed for patients with advanced, suboptimally debulked non-dysgerminomatous tumors.

Paclitaxel and gemcitabine, as first-line chemotherapy, combined with trastuzumab in patients with advanced breast cancer: a phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG).

PURPOSE: Advanced breast cancer (ABC) is an incurable disease. Standard first-line treatment for patients with HER-2/neu overexpressing tumors includes the combination of the humanized monoclonal antibody trastuzumab with chemotherapy, mainly paclitaxel. This combination is the first to demonstrate a survival advantage in this group of patients. To improve on these results, we investigated a triplet, paclitaxel-gemcitabine-trastuzumab (TGH), in a phase II study. PATIENTS AND METHODS: Patients with ABC were accrued to the study. Treatment consisted of paclitaxel 80 mg/m2/week, gemcitabine 1000 mg/m2 every 2 weeks, and trastuzumab 4 mg/kg loading dose and then 2 mg/kg/week. Patients were treated on study for a total of 12 weeks. Response evaluation was performed at the end of the 12 weeks. Continuation of treatment beyond the 12 weeks was left to the discretion of the investigator. Primary study endpoint was response. Toxicity assessment and survival were secondary endpoints. RESULTS: Between November 2000 and May 2002, 40 patients were accrued and 32 patients completed all 12 weeks of therapy. One patient died of septic shock during therapy. Grade III and IV neutropenia was seen in 12.5% of cases each. Grade III anemia was seen in two patients, and grade III and IV thrombocytopenia in three and two patients, respectively. Both paclitaxel and gemcitabine were delivered at 86% of the planned dose intensity. Six patients achieved a complete response (CR) and 15 a partial response for an overall response rate of 52.5%. An additional 25% demonstrated stable disease and 20% progressive disease. Median duration of response was 14 months. All six patients who achieved CR are still in CR for 6 to 19 months. After a median follow up of 12.2 months, 19 patients have progressed and 7 have died. Median time to progression is 13.7 months, whereas median survival has not been reached. CONCLUSION: TGH is a well-tolerated and effective regimen for the first-line treatment of ABC. Randomized comparison between paclitaxel, trastuzumab, and triplets are warranted.

Second-line chemotherapy with gemcitabine and carboplatin in paclitaxel-pretreated, platinum-sensitive ovarian cancer patients. A Hellenic Cooperative Oncology Group Study.

OBJECTIVE: Patients with epithelial ovarian cancer (EOC) who relapse more than 6 months following completion of platinum-based primary chemotherapy are considered platinum-sensitive, and can be effectively retreated with cisplatin or carboplatin. The nucleoside analogue gemcitabine has proven activity in both platinum-sensitive and platinum-resistant disease. We conducted a phase II study using the combination of carboplatin and gemcitabine for the treatment of patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. METHODS: Forty-three patients were treated with gemcitabine 1000 mg/m(2), intravenously, over 30 min on days 1 and 8, and carboplatin at AUC 5 on day 1. Courses were administered every 3 weeks on an outpatient basis. RESULTS: Among 37 patients with measurable or evaluable disease, 15 (40.5%) achieved an objective response including 10 complete and 5 partial responses. The median overall survival was 24.5 months, and the median time to progression for all patients was 9 months. The treatment was well tolerated without toxic deaths; the most common toxicities were Grade 3 or 4 neutropenia, anemia, and thrombocytopenia that occurred in 69%, 26%, and 24% of patients, respectively. CONCLUSIONS: The combination of carboplatin and gemcitabine is a well-tolerated outpatient regimen with activity in patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. However, a randomized prospective study is justified to define whether the addition of gemcitabine to single-agent carboplatin results in improved efficacy in this subset of patients.

Gemcitabine and carboplatin combination as first-line treatment in elderly patients and those unfit for cisplatin-based chemotherapy with advanced bladder carcinoma: Phase II study of the Hellenic Co-operative Oncology Group.

OBJECTIVES: To evaluate, in a multicenter Phase II study, the safety and efficacy of the combination of gemcitabine and carboplatin, as first-line treatment in elderly and unfit patients with advanced bladder carcinoma. The toxicity of platinum-based chemotherapy combinations represents a common problem for elderly or unfit patients with advanced bladder carcinoma. METHODS: Patients with previously untreated inoperable or metastatic bladder carcinoma and an Eastern Cooperative Oncology Group performance status greater than 2, age older than 75 years, or creatinine clearance of less than 50 mL/min were treated with carboplatin area under the curve 4 on day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8, every 21 days for a total of six cycles. RESULTS: A total of 56 patients (48 men and 8 women, median age 75 years) were enrolled. Of these patients, 46% had a performance status of 2 to 3, 68% had a creatinine clearance of less than 50 mL/min, and 59% had distant metastases. The overall response rate was 36% (95% confidence interval 23.4% to 49.6%), and an additional 14 patients had disease stabilization (25%, 95% confidence interval 14.4% to 38.4%). The median time to progression was 4.8 months, the median overall survival was 7.2 months, and the 1-year survival rate was 26%. Grade 3 or 4 toxicity included anemia (18%); thrombocytopenia (16%); neutropenia (27%), with two episodes of febrile neutropenia requiring hospitalization; diarrhea (2%); and fatigue (5.5%). Two toxic deaths occurred during the study. CONCLUSIONS: The combination of gemcitabine and carboplatin has some activity as first-line treatment of advanced bladder carcinoma in the elderly and those unfit for cisplatin-based chemotherapy, with manageable toxicity, and represents a reasonable choice for the treatment of such patients.

Combination of ifosfamide, paclitaxel, and cisplatin for the treatment of metastatic and recurrent carcinoma of the uterine cervix: a phase II study of the Hellenic Cooperative Oncology Group.

OBJECTIVE: Ifosfamide, paclitaxel, and cisplatin have moderate single-agent activity in patients with metastatic or recurrent cancer of the uterine cervix. We administered a combination of these three agents to a large number of patients with metastatic or recurrent cervical cancer to evaluate its activity. METHODS: Sixty patients were treated on an outpatient basis with Ifosfamide (I) 1500 mg/m(2) intravenously over 1 h on Days 1-3, paclitaxel (T) 175 mg/m(2) as a 3-h intravenous infusion on Day 1, and cisplatin (P) 75 mg/m(2) intravenously over 2 h on Day 2 with granulocyte colony-stimulating factor (G-CSF) support. The chemotherapy was repeated every 4 weeks for a maximum of six courses. RESULTS: Fifty-seven patients received at least two courses of treatment and are evaluable for response. Twenty-six patients (46%) achieved an objective response, including 19% complete and 27% partial responses. The median duration of response was 11.5 months and the median time to progression and survival for all patients were 8.3 and 18.6 months, respectively. Patients with excellent performance status, with disease recurrence outside the radiation field, and with nonsquamous tumors had the highest response rate and best survival. Some degree of neurotoxicity occurred in 44% of patients. Grade 3 or 4 toxicity included granulocytopenia in 26% of patients, anemia in 13%, thrombocytopenia in 7%, and neurotoxicity in 3%. CONCLUSION: The ITP regimen is relatively well tolerated and moderately active in patients with metastatic carcinoma of the uterine cervix. Patients more likely to benefit are those with nonsquamous histology, with excellent performance status, and with disease recurrence outside the radiation field.