Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma: a randomized phase II study of the Hellenic Cooperative Oncology Group.

PURPOSE: Temozolomide (TMZ) is an oral alkylating agent that produces methyl adducts at the 0.6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (CDDP) is able to down-regulate the AGAT activity, suggesting that CDDP could enhance the antitumor activity of TMZ. We designed a randomized phase II study to evaluate and compare the activity and safety profile of the combination versus single-agent TMZ in patients with advanced melanoma. PATIENTS AND METHODS: From January 2000 to April 2002, 132 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the two arms. Patients with cerebral metastases were included. Patients received TMZ 200 mg/m(2)/day orally for five consecutive days every 4 weeks or TMZ + CDDP 200 mg/m(2) daily on days 1-5 and 75 mg/m(2) of CDDP on day 1. RESULTS: Tumor responses (complete and partial responses) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.8 months in arm A and 5.8 months in arm B. The median overall survival (OS) was 11.5 months in arm A and 12 months in arm B. The difference between treatment arms regarding objective response rates, TTP and OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralgias/myalgias. There was significantly more grade 3 and 4 emesis in the combination arm. CONCLUSIONS: No clear benefit in terms of response rates, median TTP or OS was shown with the combination of TMZ + CDDP. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis.     

Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group.

PURPOSE: Temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma. PATIENTS AND METHODS: Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m(2)) on day 1 and oral temozolomide (150 mg/m(2)) on days 1 to 5, every 4 weeks, for a maximum of six cycles. RESULTS: Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity. CONCLUSION: The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases.     

Brain metastases from epithelial ovarian cancer. The Hellenic Cooperative Oncology Group (HeCOG) experience and review of the literature

BACKGROUND: Brain metastases from epithelial ovarian cancer (EOC) are rare. A retrospective study of all patients diagnosed with brain metastases from EOC over the last 20 years, according to the Hellenic Cooperative Oncology Group (HeCOG) tumor registry, was conducted. PATIENTS AND METHODS: A total of 1450 patients with EOC were treated within various HeCOG protocols from 1983 to 2004. Seventeen (1.17%) of them developed brain metastases. RESULTS: The median age at diagnosis of brain metastases was 58 years (range, 24 to 77). At initial diagnosis, 2 patients had stage II, 12 had stage III and 3 had stage IV disease. Serous papillary adenocarcinoma was the most common histological subtype [12 patients (71%)]. All patients had received initial cisplatin-based chemotherapy. The median time from initial diagnosis to central nervous system (CNS) relapse was 15.9 months (range, 1.4 to 70.8). The CNS was the only site of disease in 13 (76.5%) patients, whereas 4 (23.5%) patients had additional extracranial disease. Two (12%) patients with isolated single brain lesions underwent surgical excision of the metastases, followed by whole brain radiation therapy (WBRT) and chemotherapy. Four (24%) patients were treated with WBRT alone, 6 (35%) patients with WBRT plus chemotherapy and 2 (12%) had only supportive care, while 3 (18%) patients decided not to have any further treatment after the diagnosis of brain metastases. The median survival time from diagnosis of CNS relapse was 5.7 months (range, 0.2 to 22.6) and the median survival time from diagnosis of EOC was 27.4 months (range, 3.0 to 71.4). In patients with CNS recurrence as the only site of disease, the median survival time from diagnosis of CNS relapse was 5.3 months (range, 0.6 to 22.6) and in those with both CNS and extracranial disease, the median survival time was 3.9 months (range, 0.2 to 11.9) (p=0.5597). There was a statistically significant difference in survival for those treated with WBRT plus chemotherapy (10.0 months) versus those treated with WBRT alone (1.5 months) and those who had only supportive care (0.2 months) (p=0.0003). CONCLUSION: The incidence of cerebral metastases in our patients with EOC was 1.17%, which is consistent with the mean value of all series reported in the literature. The prognosis of patients with brain metastases from EOC is poor. Patients who had WBRT and chemotherapy fared better than those who received WBRT alone.     

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.     

Carboplatin and paclitaxel versus cisplatin, paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer: a Hellenic Cooperative Oncology Group (HeCOG) study

IntroductionThe combination of Carboplatin and Paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of Cisplatin, Paclitaxel and Doxorubicin.Patients and methodsPatients with AOC were randomised to either six courses of Paclitaxel 175 mg/m² plus Carboplatin 7AUC or Paclitaxel at the same dose plus Cisplatin 75 mg/m² plus Doxorubicin 40 mg/m².ResultsAnalysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm.ConclusionThe combination of Cisplatin, Paclitaxel and Doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard Carboplatin/Paclitaxel regimen.     

Expression of angiogenic markers in the peripheral blood of docetaxel-treated advanced breast cancer patients: a Hellenic Cooperative Oncology Group (HeCOG) study

It is well known that low-dose metronomic chemotherapy has antiangiogenic activity. The aim of the present trial was to investigate the antiangiogenic properties of weekly docetaxel in patients with metastatic breast cancer. In total, 157 metastatic breast cancer patients received 35?mg/m2 docetaxel weekly as a recommended treatment. Blood samples were collected before the start of chemotherapy (baseline) and during treatment. Nitric oxide (NO) and vascular endothelial growth factor A (VEGF-A) plasma levels were measured at baseline and during treatment, while VEGF-A, endothelial nitric oxide synthase (eNOS) and thrombospondin-1 (THBS-1) peripheral blood mRNA levels were measured at baseline, in 127 patients and 39 female healthy controls. In general, the treatment was well-tolerated. Sixty-one patients (38%) achieved an objective response (4% complete and 34% partial response), while 52 (33%) had stable disease and 27 (17%) progressed. At a median follow-up of 33.5 months (range 2.8-45.0), 118?patients (74%) demonstrated disease progression and 94 (59%) had died. Median progression-free survival (PFS) was 8.8?months and median overall survival (OS) was 27.7?months. Median baseline level of plasma NO was significantly lower in patients than in healthy controls (p=0.010), while none of the plasma markers significantly changed upon docetaxel treatment. In addition, the median relative quantification value for THBS-1 mRNA was significantly higher (p<0.001) in patients as compared to healthy controls. NO plasma levels were positively associated with the number of organs involved (p=0.008). In multivariate analysis, low eNOS mRNA levels showed adverse prognostic significance for OS and high THBS-1 mRNA levels were found to be associated with shorter OS and PFS, independently from established clinical prognostic factors. Although an antiangiogenic activity of weekly docetaxel was not demonstrated in the present study, some interesting observations regarding the prognostic role of a number of blood angiogenic markers could be made.     

Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study

BackgroundWe undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix.Patients and methodsOne hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m², daily, on days 1–3 and cisplatin 70 mg/m² on day 2) or the same combination with the addition of paclitaxel 175 mg/m² on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis.ResultsA modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P = 0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P = 0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P = 0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P = 0.046) and 0.75 for death (P = 0.124) compared with the doublet.ConclusionThe ITP combination merits further investigation in randomized phase III studies.     

Primary gastrointestinal non-Hodgkin's lymphoma: a clinicopathologic study of 128 cases in Greece. A Hellenic Cooperative Oncology Group study (HeCOG)

The aim of this retrospective study was to illustrate the clinicopathologic data and the treatment results in patients with primary gastrointestinal tract non-Hodgkin's lymphoma (GI NHL). Among 810 patients with NHL, 128 cases (15.8%) were diagnosed as primary GI tract NHL. There were 79 males and 49 females with median age of 62 years. The most common primary site was the stomach (68%). Overall, 67.2% of the patients were in stages I - II, and 32.8% in stages III - IV. Simultaneous involvement of the GI tract and other extranodal sites was observed in 26 patients (20%). Extranodal marginal zone B-cell lymphoma (MZBL) (i.e., low-grade lymphoma of mucosa-associated lymphoid tissue type) accounted for 48.4% of lymphomas. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBL]) accounted for 44.5%. Eighty-three patients (67.5%) achieved complete response (CR), either by surgery (43/43 patients, 17 with DLBL and 25 with MZBL) or by primary chemotherapy (40/64 patients, 22 with DLBL and 17 with MZBL). Sixty-two patients remain in CR; 33/43 after surgical resection (13/17 with DLBL and 20/25 patients with MZBL), and 29/40 after only chemotherapy (18/22 with DLBL and 10/17 with MZBL). The major prognostic factor for outcome in the present study was the stage of the disease. Patients with localized lymphoma (stage I and II) had significantly longer DFS and OS (DFS and OS at 3-year: 83% and 87%, respectively) than patients with extended disease (stage III and IV) (DFS and OS at 3-year: 46% and 60%, respectively) (P < 0.0001). The International Prognostic Index (IPI) for patients with aggressive lymphomas was prognostic only for DFS (79% for low-risk patients [IPI score 0 - 1] vs 49% for higher risk groups [IPI score >1] at 3-year, P = 0.0131).     

Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group.

BACKGROUND: There is now increasing evidence that a constitutive expression of cyclooxygenase (COX)-2 plays a role in the development and progression of malignant epithelial tumors. Expression of COX-2 is seen in 93% of melanomas, as determined by immunohistochemistry. Temozolomide (TMZ) has demonstrated activity against melanoma and has been investigated as single agent or in combination. We designed a phase II study to assess the efficacy and toxicity of the combination of TMZ and celecoxib (a COX-2 inhibitor) in patients with advanced melanoma. PATIENTS AND METHODS: From January 2003 to July 2004, 52 patients were enrolled in the study. Nineteen patients were M1a, six M1b and 27 M1c. Patients received TMZ 200 mg/m(2) per day p.o. for 5 consecutive days every 4 weeks and celecoxib 400 mg b.i.d. p.o. for a maximum of six cycles. Celecoxib was continued until progression. RESULTS: The median age was 63 years. There were 29 males and 23 females. Among 50 assessable patients, there were 11 (21.5%) objective responses including five complete responses and six partial responses. Twenty patients (38.5%) had stabilization of their disease, and 19 (36.5%) progressed. The median time to progression was 4.6 months and the median survival 9.5 months. Twenty-two patients (41.5%) completed all cycles of treatment. Median relative dose intensity of TMZ was 0.99 (range 0.6-1.2). Most commonly seen toxic effects included anemia (27.5%), neutropenia (17.5%), thrombocytopenia (33%), nausea/vomiting (75%), gastrointestinal (52%) and fatigue (46.5%). One patient discontinued due to severe toxicity. COX-2 was determined by immunohistochemistry and was expressed in all cases. CONCLUSION: The combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma. Randomized studies are needed to explore the role of celecoxib in combination with chemotherapy or as maintenance treatment in these patients.     

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 I (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.     

Adjuvant dose-dense sequential chemotherapy with epirubicin, CMF and weekly paclitaxel in patients with resected high-risk breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study

Randomized phase III trials have demonstrated that the addition of paclitaxel is effective in the adjuvant treatment of breast cancer. Forty-five patients with high-risk resected breast cancer entered this study. They were treated with three cycles of epirubicin every 2 weeks, followed by three cycles of intensified CMF, every 2 weeks, followed 3 weeks later by nine weekly cycles of paclitaxel (E-CMF-T). Forty patients (89%) received all cycles of chemotherapy and dose intensity was sufficiently maintained for all drugs. Toxicity was generally mild to moderate. Two cases of febrile neutropenia were reported. The E-CMF-T regimen is feasible and well tolerated.     

Low-grade mucosa-associated lymphoid tissue lymphoma: a retrospective analysis of 97 patients by the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: The aim was to examine characteristics and treatment results of patients with mucosa-associated lymphoid tissue (MALT) non-Hodgkin's lymphomas. PATIENTS AND METHODS: Epidemiological and clinical features of 97 patients with MALT lymphoma from the Hellenic Cooperative Oncology Group registry were analysed retrospectively for their prognostic significance in progression-free survival (PFS) and overall survival (OS). Comparisons were made between patients with gastric and nongastric sites of primary lymphoma and between different therapeutic modalities. RESULTS: Sixty-five patients presented with gastric and 32 with nongastric lymphomas. The most frequent locations of nongastric lymphomas were the bowel, lung and parotid. Gastric lymphomas occurred more frequently in males and younger patients compared with nongastric lymphomas. Seventy-four per cent of patients had early (Ann Arbor stages I-II) and 26% had advanced (stages III-IV) disease. The median PFS for the entire population was 44 months. At 5 years, 47% of patients were progression free and the OS rate was 80%. The most reliable prognostic factor for PFS and OS was the Ann Arbor stage; 5-year PFS was 67% versus 13% and 5-year OS 91% versus 51% for patients with early versus advanced disease, respectively (P < 0.001). Of the patients treated with chemotherapy only, 87% achieved an objective response and 71% complete response. Surgery did not offer survival benefit compared with chemotherapy in localised gastric lymphoma. CONCLUSION: MALT lymphomas represent a distinct disease entity with widespread extranodal origin, indolent clinical course and high chemosensitivity. Ann Arbor stage was the most reliable prognostic and predictive factor.     

Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation

BackgroundConcomitant administration of radiation therapy (RT) and chemotherapy with cisplatin (CCRT) is considered standard treatment in patients with locally advanced nasopharyngeal cancer (LA-NPC). The role of induction chemotherapy (IC) when followed by CCRT in improving locoregional control remains controversial.Patients and methodsTotally, 141 eligible patients with LA-NPC were randomized to either three cycles of IC with cisplatin 75 mg/m², epirubicin 75 mg/m² and paclitaxel (Taxol) 175 mg/m² (CEP) every 3 weeks followed by definitive RT (70 Gy) and concomitant weekly infusion of cisplatin 40 mg/m² (investigational arm, 72 patients) or to the same CCRT regimen alone (control arm, 69 patients).ResultsSixty-two patients (86%) received three cycles of IC. No difference between the arms was observed in the number of patients who completed RT (61 versus 64, P = 018). Overall and complete response rates were very similar in the two arms and so were 3-year progression-free and overall survival rates. Grade III or IV toxic effects from IC were infrequent, apart of alopecia. Mucositis, weight loss and leukopenia were the most prominent side-effects from CCRT.ConclusionIC with three cycles of CEP when followed by CCRT did not significantly improve response rates and/or survival compared with that of CCRT alone.     

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

Backround:Oxaliplatin is a novel platinum derivative, which,combined with 5-fluorouracil (5-FU), and folinic acid (FA), demonstratessynergistic activity in metastatic colorectal cancer (MCC). The HeCOGperformed a multicenter phase II study of a weekly oxaliplatin administrationschedule in patients with previously treated MCC to evaluate the antitumorefficacy and toxicity of this combination. Patients and methods:Eligible patients included those whorelapsed after or during chemotherapy with 5-FU and FA and/or irinotecan.Prior radiotherapy was accepted provided that measurable disease was outsidethe radiation fields. Other eligibility criteria included written informedconsent, a WHO performance status 2 and adequate bone marrow, liver andrenal function. Treatment consisted of Oxaliplatin 50 mg/m² bytwo-hour intravenous (i.v.) infusion followed by FA 500 mg/m²(two-hour i.v. infusion) and 5-FU 2500 mg/m² (24-hour continuousi.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every50 days. Results:Thirty-two patients (Median age 61 years, range25–76) entered the trial. The majority (75%) had progressed afterreceiving first-line chemotherapy.Diarrhea was the main non-hematologic toxicity. More than half of thepatients (53%) developed grades 3 or 4 diarrhea. Due to this sideeffect only 29% of cycles were given with at least 90% of theplanned dose of 5-FU. Hematologic toxicity included grade 3 neutropenia andthrombocytopenia (10% for each), and grade 4 thrombocytopenia(3%). Two patients (6%) died of sepsis, one related toneutropenia 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%) progressivedisease. The median time to progression was three months and the mediansurvival was nine months from the start of therapy. The Kaplan–Meierestimated probability of one-year survival for the group as a whole was32%. Conclusions:The weekly administration of oxaliplatin with 5-FUand FA was associated with considerably less neurotoxicity than otherschedules. However, the high percentage of diarrhea suggests that a dosereduction of 5-FU in this regimen may result in better therapeutic synergy.     

Phase II study of temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases from solid tumors

BACKGROUND: The aim of this study was to evaluate the effectiveness and possible toxicity of the combination of temozolomide (TMZ) with whole-brain irradiation (WBI) in the treatment of brain metastases from solid tumors. PATIENTS AND METHODS: 33 patients with brain metastases were included in the study and treated with TMZ 60 mg/m2/day (days 1-16) concomitantly with WBI (36 Gy/12 fractions given in 16 days). One month after the end of radiotherapy, 6 cycles of TMZ were administered as adjuvant treatment (200 mg/m2/day for 5 consecutive days every 28 days). RESULTS: Responses were assessed using computed tomography at the end of the 3rd and 6th cycle of chemotherapy. The objective response rate was 54.5% and 57.6% after the 3rd and the 6th cycle, respectively. The median overall survival was 12 months. In patients with metastases from lung cancer the objective response rate was 11/14 (78.6%) after both the 3rd and the 6th cycle of treatment. The most common side effects were anemia (24.2%), thrombocytopenia (18.2%), as well as nausea and vomiting (18.2%). The high incidence of hepatotoxicity (45.5%) might be related to concomitantly administered antiepileptic drugs and not to TMZ. CONCLUSION: WBI combined with TMZ as concomitant and adjuvant treatment is effective in treating brain metastases, with acceptable mild side effects.     

Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study

BACKGROUND: Temozolomide plus thalidomide is a promising oral combination regimen for the treatment of metastatic melanoma. The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases. METHODS: Patients with histologically confirmed metastatic melanoma and measurable brain metastases received temozolomide (75 mg/m2 per day for 6 weeks with a 2-week break between cycles) plus concomitant thalidomide (200 mg/day escalating to 400 mg/day for patients < 70 years or 100 mg/day escalating to 250 mg/day for patients > or = 70 years). The primary end point was tumor response in the brain assessed every 8 weeks. RESULTS: Twenty-six patients with a median age of 60 years were treated. All patients had progressive brain metastases: 16 were symptomatic and 25 had extensive extracranial metastases. Eight patients had received whole-brain radiotherapy, 4 had received stereotactic radiotherapy, and 8 had received craniotomy with resection of hemorrhagic lesions. Fifteen patients completed > or = 1 cycle (median, 1 cycle; range, 0-4 cycles), and 11 discontinued treatment before completing 1 cycle (7 for intracranial hemorrhage, 2 for pulmonary embolism, 1 for deep vein thrombosis, and 1 for Grade 3 rash). Of 15 patients assessable for response, 3 had a complete or partial response (12% intent to treat) and 7 had minor response or stable disease in the brain. However, 5 of these 10 patients had disease progression at extracranial sites. The median survival period was 5 months for all 26 patients and 6 months for the 15 assessable patients. CONCLUSIONS: Temozolomide plus thalidomide was an active oral regimen for patients with brain metastases from malignant melanoma.     

Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group (HeCOG)

BackgroundPaclitaxel (Taxol) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer.Patients and methodsChemotherapy-naive patients, stage IIIbwet and IV with performance status (0–1), were randomized to receive paclitaxel 200 mg/m² on day 1 plus gemcitabine 1 gm/m² (group A) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m² plus vinorelbine 22.5 mg/m² (group B) on days 1, 8 and 15 every 4 weeks.ResultsA total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0 months [95% confidence interval (CI) 4.3–5.6] and 4.4 months (95% CI 3.7–5.2) for groups A and B respectively (P = 0.365). Median survival was 11.1 months (95% CI 9.2–13.0) and 8.6 months (95% CI 7.0–10.2) for groups A and B respectively (P = 0.147). Grade 3/4 neutropenia and leukopenia were worse in group B (P < 0.001, in both cases). Febrile neutropenia and severe infections were more prominent (P < 0.001, P = 0.029 respectively) in group B.ConclusionAlthough response rate, PFS and survival were non-different in both groups, toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value.     

Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study.

BACKGROUND: We compared the combination plus Carboplatin plus paclitaxel, which is considered the treatment of choice for initial chemotherapy of advanced ovarian cancer (AOC) with a regimen combining alternating carboplatin and cisplatin plus paclitaxel. The two platinum derivatives have been previously combined as they are not totally cross-resistant and as they share no overlapping toxicities. PATIENTS AND METHODS: Patients with AOC, after the initial cytoreductive surgery were randomized to either 6 courses of paclitaxel at 175 mg/m2 as 3 h infusion plus Carboplatin at 7 AUC (Arm A) or Paclitaxel at the same dose plus Carboplatin again at 7 AUC for cycles 1,3,5, while for cycles 2,4,6 Cisplatin at 75 mg/m2 substituted for Carboplatin (Arm B). RESULTS: 247 patients are analyzed. Significant differences were not found, both in terms of PFS (38 vs 39 months, p=0.95) and overall survival (40.6 vs 38.6 months, p=0.79). There was not also difference in 5-year survival rate (35% vs 39%) or 5-year PFS rate (23% vs 28%). Age >60, PS 2, stage IV disease and presence of residual disease were adversely related to the overall survival. CONCLUSION: Both regimens are well tolerated and effective. Alternating cisplatin with carboplatin does not improve the results compared with the standard combination.     

Phase II investigation of docetaxel in pediatric patients with recurrent solid tumors: a report from the Children's Oncology Group

BACKGROUND: Docetaxel, which is an antitubulin agent, has demonstrable activity against murine and human tumors. The current study was designed to determine response rates to docetaxel in various strata of recurrent solid tumors of childhood and to assess toxicity in a group of patients who were assigned to receive it. METHODS: Docetaxel was given at a dose of 125 mg/m2 once every 21 days as a 1-hour intravenous infusion for a maximum of 12 courses. From January 1997 to November 2001, 109 male patients and 68 female patients (total, 177 patients) were enrolled, and 173 patients were eligible. The median patient age at entry was 13 years (range, 1-27 yrs). One hundred sixty patients were evaluable for response. RESULTS: There were no deaths attributable to study drug. Hematologic toxicity was common during therapy. Dermatologic, neurologic, pulmonary, and infectious side effects as well as edema were significant. One patient each had acute myeloid leukemia, acute lymphoid leukemia, and high-grade glioma reported as secondary malignancies. One patient with osteosarcoma and 1 patient with rhabdomyosarcoma achieved a complete response. Partial responses were observed in patients with Ewing sarcoma (3 patients), osteosarcoma (1 patient), squamous cell carcinoma (1 patient), and medulloblastoma (1 patient). Seventeen patients had stable disease. The 1-year and 5-year overall survival rates for the 160 evaluable patients were 24% (standard error = 4%) and 6% (standard error = 2%), respectively. CONCLUSIONS: Docetaxel demonstrated activity in patients with recurrent Ewing sarcoma but was found to be ineffective for treating the other types of recurrent solid tumors that were studied.