A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study.

BACKGROUND: Maintenance strategies beyond response or tumor stabilization with first-line chemotherapy in metastatic breast cancer (MBC) have not been extensively studied. Endocrine therapy combined with continued bevacizumab may be a helpful option for estrogen receptor (ER)-positive MBC. PATIENTS AND METHODS: In this prospective, open-label, phase III study, patients with histologically confirmed ER-positive, HER2-negative MBC and non-progressive disease after 16-24 weeks of taxane plus bevacizumab (T + BEV) were randomized to continuation of T + BEV or maintenance bevacizumab plus exemestane (E + BEV). The primary end point was progression-free survival (PFS) from randomization. To have 80% power to detect an improvement in the 6-month PFS rate (PFS6m) from 50% to 65%, 186 assessable patients were needed for a total of 141 PFS events. An interim analysis was planned after 40% of the required events. RESULTS: The interim analysis with 98 patients showed that the probability of reaching a statistically significant improvement in PFS by the end of the study was only 7%. This led the Independent Data and Monitoring Committee to recommend termination of patient enrollment. After a median of 21-month follow-up of all randomized patients (117 in total), PFS6m from randomization was 67.2% [95% confidence interval (CI) 53.6-77.7] with T + BEV and 55.2% (95% CI 41.5-66.9) with E + BEV [hazard ratio (HR): 1.0, 95% CI 0.7-1.5, P = 0.998]. Median PFS from BEV initiation was 12.5 and 12.3 months in the T + BEV and E + BEV arms, respectively. In the T + BEV arm, taxane was prematurely stopped for the majority of patients (94.9%), mainly due to toxicity (49.2%). Updated data after 35 months' median follow-up showed death rates of 44% and 55% in T + BEV and E + BEV arms, respectively. CONCLUSION: In this trial, maintenance therapy with E + BEV in ER-positive, HER2-negative MBC patients with no evidence of progression after first-line T + BEV did not achieve longer PFS compared with continuation of T + BEV. CLINICALTRIALSGOV: NCT01303679.

Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group.

Advanced ovarian carcinoma in early progression (<6 months) (AOCEP) is considered resistant to most cytotoxic drugs. Gemcitabine (GE) and oxaliplatin (OXA) have shown single-agent activity in relapsed ovarian cancer. Their combination was tested in patients with AOCEP in phase II study. Fifty patients pre-treated with platinum-taxane received q3w administration of OXA (100 mg m(-2), d1) and GE (1000 mg m(-2), d1, d8, 100-min infusion). Patient characteristics were a : median age 64 years (range 46-79),and 1 (84%) or 2 (16%) earlier lines of treatment. Haematological toxicity included grade 3-4 neutropaenia (33%), anaemia (8%), and thrombocytopaenia (19%). Febrile neutropaenia occurred in 3%. Non-haematological toxicity included grade 2-3 nausea or vomiting (34%), grade 3 fatigue (25%),and grade 2 alopecia (24%). Eighteen (37%) patients experienced response. Median progression-free (PF) and overall survivals (OS) were 4.6 and 11.4 months, respectively. The OXA-GE combination has high activity and acceptable toxicity in AOCEP patients. A comparison of the doublet OXA-GE with single-agent treatment is warranted.

Docetaxel and pegylated liposomal doxorubicin combination as first-line therapy for metastatic breast cancer patients: results of the phase II GINECO trial CAPYTTOLE.

BACKGROUND: This phase II study evaluated the clinical benefit of pegylated liposomal doxorubicin (PLD) and docetaxel (Taxotere) as first-line therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: MBC patients were enrolled to receive six cycles of PLD 35 mg/m2 (day 1) and docetaxel 40 mg/m2 (days 1 and 15), every 28 days (group A). Because of unacceptable toxic effects, doses were modified to PLD 30 mg/m2 (day 1) and docetaxel 75 mg/m2 (day 2), every 3 weeks (group B). The primary end point was clinical benefit. RESULTS: Sixty-seven patients were included (group A, 53; group B, 14). In both groups, the median number of cycles delivered was 4 and the overall dose intensity was 82% for docetaxel and 71% for PLD. In group A, main toxic effects were hematologic, palmar-plantar erythrodysesthesia (PPE), and stomatitis. In group B, higher rates of grade 3-4 PPE, febrile neutropenia, and hematologic toxic effects were reported. The rate of clinical benefit was 47%. Among patients with a measurable disease, 49% achieved a partial response, 27% had a stable disease, and 13% progressed, according to RECIST criteria. CONCLUSION: The combination of PLD and docetaxel delivered at planned doses in this study yields unacceptable toxicity and should not be used routinely in patients with MBC.

[A severe G6PD deficiency revealed during a chemotherapy protocol including rasburicase]. / Un déficit sévère en G6PD découvert au décours d'une chimiothérapie avec utilisation de rasburicase.

We present here the case-report of a man with a severe G6PD deficiency revealed after the use of rasburicase (uricolytic drug) during a chemotherapy protocol. The genotypic analysis done to confirm the biochemical measurement revealed the 'Mediterranean mutation' at the hemizygous state (G6PD gene is located on chromosome X). Consequently to this diagnose, a search for G6PD deficiency has been performed (at the biochemical and genotypic levels) for the 9 children (7 daughters and 2 sons) of the proband. Surprisingly, one of his son was found to be hemizygous for the mediterranean mutation and one of his daughter appeared homozygous for this same mutation. This implies that the proband's wife (not studied) is certainly heterozygous for the mediterranean mutation, as it is very unlikely that this mutation had appeared de novo for two children of this couple.

A recent increase in the incidence of prostatic carcinoma in a French population: role of ultrasonography and prostatic specific antigen.

Between 1979 and 1990, the incidence rate (World Standard) for cancer of the prostate in the region of Isère (France) increased from 22.1 to 45.0 cases per 100,000 men, although there was no concurrent increase in mortality (16.0 to 17.6 cases per 100,000 men). This represents a mean increase per year of 6.3% for incidence, compared with 1.3% (NS) for mortality. Incidence of cases with metastases at diagnosis also remained stable with time. In this area, Prostatic Specific Antigen assays began in 1987, and rectal ultrasonography was implemented in 1984, but activity peaked only in 1988. Thus, during 1986-1988, there was both an implementation of new diagnostic procedures and an increase in the incidence of prostatic carcinoma, which suggests that the latter was the result of increased detection of small latent carcinomas. This has implications for public health since apart from increasing costs, it might unduly disturb the life of otherwise healthy people.

Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m(2) twice daily, days 1-14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0-6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20-36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5-19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatment-related grade 3/4 adverse events. The most common adverse events were hand-foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting.

Efficacy and safety of the combination paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens phase II study.

The French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) conducted a multicenter phase II study of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to evaluate the efficacy and side effects of this combination in pretreated advanced ovarian cancer. Patients with progressive ovarian carcinoma during or after platinum-based chemotherapy received paclitaxel 175 mg/m2 intravenously over 3 hours followed by intravenous carboplatin over 30 minutes every 4 weeks. The dose of carboplatin was calculated using a projected area under the concentration-time curve of 5 mg/mL x min. Of the 50 patients entered, 50 were evaluable for toxicity and 42 for response. There were eight complete and 10 partial responses, for an overall response rate of 43% (95% confidence interval, 28% to 56%). Overall response rates in platinum refractory patients and in those with early (> or = 3 and < 12 months) and late (> or = 12 months) relapse was 28%, 33%, and 71%, respectively. Median response duration, progression-free survival, and overall survivals were 8, 6, and 14 months, respectively. The most frequent and severe toxicity was myelosuppression. Grades 3 and 4 neutropenia occurred in 30% and 23% of cycles, and granulocyte colony-stimulating factor was administered in 6%. Only one case of neutropenic fever was observed. Grades 3 and 4 thrombocytopenia occurred in 3% and 1% of cycles, respectively. Alopecia and moderate nausea or vomiting were frequent. Transitory peripheral neuropathy was present in 45% of patients but was severe in only one patient. One early death was observed due to progressive disease and possibly to therapy. The combination of paclitaxel 175 mg/m2 as a 3-hour infusion and carboplatin dosed to an area under the concentration-time curve of 5 is an effective therapy in patients previously treated with platinum-based chemotherapy and may be administered safely to outpatients who relapse after one or two lines of chemotherapy.

[Chemotherapy of small-cell lung cancer by a combination of teniposide, ifosfamide and carboplatin]. / Chimiothérapie du cancer bronchique à petites cellules par une association de téniposide, ifosfamide et carboplatine.

Thirty six SLC patients have been treated with a combination therapy of ifosfamide 2 g/m2, D1 and D2, carboplatin 300 mg/m2 D1 and teniposide 100 mg/m2 D1 to D3. All patients were younger than 70 years, 31 males, five females, ten limited diseases, 26 extended diseases (without brain metastasis) Performance status 0, 1 or 2, mean weight loss 3.7 kg. Thirty six patients were evaluable for response. We have noted three complete response and 28 partial response (objective response rate 86%). The main toxicity of this combination therapy was myelo-suppression (86% of grade 3 and 4). Twenty seven patients have relapsed, the median relapse free survival time is 310 days. The median survival of the 36 patients is 340 days, one patient is alive more than 30 months after the diagnosis. The ifosfamide-carboplatin-teniposide combination is an effective treatment in small cell lung cancer, its toxicity remains tolerable.

[Incidents of brain tumors observed in the Grenoble area (canton of Meylan) 1979-1990]. / Etude des cas incidents de tumeurs intra-crâniennes observés entre 1979 et 1990 dans la région de Grenoble (canton de Meylan).

A high excess of risk (standardized incidence ratio S.I.R.: 320 [190-490]) of intracranial tumors among men living within the county of Meylan, in the suburb area of Grenoble, as compared with the overall population was shown by the Isère Cancer Registry, for the period 1979-1984. There has been no change of this excess of risk between 1979 and 1990 (S.I.R. = 190). The pathological homogeneity of this cluster (neuroglial tumors) among men is noticeable. This county is known as a concentration of high-tech and intellectual professional activities. A descriptive study was conducted on the 24 cases diagnosed between 1979 and 1990, based on retrospective interviews of patient's family. Ethnical origins, blood groups, personal and familial medical history (with special interest in cranial injuries), socio economic status, chemicals, radiations and electro-magnetic exposures, acoustic and visual exposures (such as noises and T.V.), drinking water, tobacco and food consumptions, were investigated. Educational level, occupation, and European ethnic origin are all pointing to the same direction: a higher risk in high level social classes and high level professions. An analytical study is going on, that would give a deeper insight in these phenomenons.

[Clinical data and descriptive epidemiology of primary bronchial cancer. 9 years of activity of the Isère Registry]. / Données cliniques et épidémiologie descriptive du cancer bronchique primitif. Neuf années d'activité du Registre de l'Isère.

Systematical registration of morbidity for lung carcinoma of the primary type was performed since January 1979 for the department of Isere, where a population of 940,000 inhabitants are living. Results for nine years registration (1979-1987) are dealing with 2,590 new cases. Crude incidence for primary lung carcinoma is 55.7 per 100,000 among men, and 5.9 for women (sex ratio: 11.7). Upper lobe is the site more concerned. There is no preference as regard laterality. When lymphatic nodes are explored (32%), there is an extension of the carcinoma for 75.2% of them. At the moment of the diagnostic, there is already a metastasis for 24% of the patients, mainly for bones. Among men and women, proportions for the squamous cell type are respectively 52.6% and 22.3% (60.8% and 28.7% of histologically identified cases), for the small cell type: 18.4% and 16.3% (21.2% and 21.0% of histologically identified cases), and for glandular carcinomas: 13.2% and 32.1% (11.9% and 41.5% of histologically identified cases). Results of the pathological examination are known in 92.8% for primary lung carcinoma cases. As regard first course treatment, surgery is performed in 34.9% of the cases, radiotherapy in 60.4%, and chemotherapy in 32.2%. Fairly high incidence of lung carcinoma in man in Isere, contrasts with rather low incidence in woman, a situation rather different that the one in England and North America, where figures for women are slowly gaining over the one's for men.

Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group.

ICON3 trial results have suggested that CAP and carboplatin-taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m(-2), epirubicin (E) 50 mg m(-2), and cisplatin (P) 75 mg m(-2) or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m(-2) and filgrastim 5 mug kg(-1) per day x 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3-4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3-4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I (P>0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC.

Second-line chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: a GINECO phase II trial.

BACKGROUND: Platinum-based chemotherapy is standard second-line treatment of patients with advanced ovarian cancer (AOC) in late relapse. Pegylated liposomal doxorubicin (PLD) has significant single-agent activity in this setting. Therefore, we evaluated the use of PLD plus carboplatin in this patient population. PATIENTS AND METHODS: PLD 30 mg/m(2) followed by carboplatin at area under the curve (AUC) 5 mg.min/ml, repeated every 28 days for a maximum of nine cycles, was administered to 104 women with AOC relapsing >or=6 months after completion of first- or second-line therapy with platinum-taxane-based regimens. RESULTS: Overall response was 63%, with a 38% complete response, median progression-free survival of 9.4 months, and median overall survival (OS) of 32 months. Grade 3 or 4 neutropenia occurred in 51% of patients, but febrile neutropenia in only 3%. Nonhematologic toxic effects were primarily grades 1 and 2, with low rates of alopecia and neurotoxicity. CONCLUSIONS: PLD plus carboplatin is highly effective, prolongs OS, and is well tolerated in women with AOC in late relapse previously treated with both platinum and taxanes. Evaluation of this regimen in phase III trials is warranted.

Role of autologous lymph node T cells in membrane expression of mu- or gamma-heavy chain isotype by malignant B NHL cells.

We investigated the possibility that T cells observed in lymph nodes involved by B-non-Hodgkin's lymphomas (B-NHL) may have a direct role in the expression of Mu- or Gamma- heavy chain isotype by autologous malignant B cells. T cells were separated from lymph nodes involved by B-NHL cells expressing either surface IgM (19 cases) or surface IgG (4 cases) and compared to peripheral blood T lymphocytes of healthy subjects (19 cases) for their ability to promote both IgG and IgM secretion in Cowan-activated normal B lymphocytes. The mean values of IgG/IgM ratios obtained under the influence of T cells associated with malignant B cells expressing either surface IgM or surface IgG were not statistically different to that obtained with the help of control T cells (0.60 and 0.62 versus 0.47, respectively). These results do not account for the hypothesis that autologous lymph node T cells may directly affect the expression of the heavy chain isotype by malignant B-NHL cells.

Oral vinorelbine: feasibility and safety profile.

BACKGROUND: Patient preference as well as concerns and difficulties with intravenous access and pharmaco-economic issues have driven the development of oral vinorelbine. PATIENTS AND METHODS: Four phase II studies were conducted in chemotherapy-naive non-small-cell lung cancer (NSCLC) and as first-line chemotherapy of advanced breast cancer (ABC). As recommended in the phase I dose-finding study, the first step used a weekly dose of 80 mg/m2. This regimen was associated with an excessive rate of early deaths (10%) due to complicated neutropenia and led to discontinuation of the first two studies. In a second step, the dose of 60 mg/m2/week was given for the first three courses and subsequently increased to 80 mg/m2/week, in the absence of severe neutropenia. RESULTS: One hundred and thirty eight patients (76 with NSCLC and 62 with ABC) received this regimen, of whom only five were unable to undergo dose escalation. The incidence of febrile neutropenia and neutropenic sepsis were low (2.9 and 3.6%, respectively). Although severe events were uncommon, nausea/vomiting and diarrhoea were frequent and primary prophylaxis with antiemetics should be recommended. CONCLUSIONS: Overall, the safety profile of oral vinorelbine at 60 mg/m2/week for the first three courses with escalation to 80 mg/m2 is qualitatively comparable to that of i.v. vinorelbine at standard doses. Similarly to i.v. chemotherapy, close haematological monitoring is necessary.

HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group.

BACKGROUND: Despite numerous studies, no biological marker has been identified that accurately predicts prognosis of advanced ovarian cancer. Tumors from a homogeneous population of 117 patients with a stage III/IV ovarian cancer, enrolled in a multicenter prospective GINECO clinical trial were analyzed retrospectively. PATIENTS AND METHODS: All patients received the same platinum-based combination therapy and were followed-up for a median of 68 months. Tumor expression of Ki67, BCL-2, BAX, P53 or c-erbB-2 proteins was evaluated immunohistochemically on paraffin-embedded tissues and their prognostic impact analyzed. RESULTS: The median rate of Ki67-positive nuclear area was 30%. BCL-2, BAX and P53 proteins were expressed in 52, 54 and 71% of the tumors, respectively, while HER-2 protein was overexpressed in 16%. Only HER-2 overexpression was significantly associated with shorter progression-free survival and overall survival. According to our multivariate analysis, the HER-2 prognostic impact was independent of classical clinical prognostic factors. CONCLUSION: HER-2 appeared to influence the outcome of advanced ovarian cancer patients included in a clinical trial with prolonged follow-up, thereby suggesting that HER-2 is a potential target for treatment of this cancer.

Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma. A multicenter GINECO (Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens) phase II study.

BACKGROUND: Platinum compounds are the most active drugs in ovarian cancer treatment; cisplatin and carboplatin demonstrated similar efficacies but different toxicity profiles. Paclitaxel combined with cisplatin as first-line treatment improved overall survival when compared to a cisplatin-cyclophosphamide combination, but generated higher rates of neutropenia, febrile neutropenia and neurotoxicity. The paclitaxel-carboplatin combination may be better tolerated than cisplatin-paclitaxel. DESIGN: The objective of the present study was to assess the efficacy and safety of the combination of paclitaxel and carboplatin in previously treated advanced ovarian cancer patients. PATIENTS AND METHODS: During or after platinum-based chemotherapy, 73 patients with progressive advanced epithelial ovarian carcinoma were enrolled to receive every four weeks a three-hour infusion of paclitaxel 175 mg/m2 followed by a 30-minute carboplatin infusion. The carboplatin dose was calculated to obtain the recommended area concentration-versus-time under the curve of 5 mg x ml-1 x min. RESULTS: Toxicity and response could be evaluated for 72 and 62 patients, respectively. Eleven complete and 15 partial responses gave an overall response rate of 42% (95% CI: 30%-54%). Response rates for platinum-refractory patients and those with early (> or = 3 and < 12 months) and late (> 12 months) relapses were 24%, 33% and 70%, respectively. The respective median response duration, the median progression-free survival and median overall survival were 8, 6 and 14 months. Myelosuppression was the most frequent and severe toxicity. Grade 3 and 4 neutropenia occurred, respectively in 30% and 23% of the cycles; 6% of the cycles benefited from medullary growth factors. Only one episode of febrile neutropenia was observed. Grade 3 and 4 thrombocytopenia occurred, respectively during 3% and 1% of the cycles. Alopecia was frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death was attributed to progressive disease and possibly to therapy. CONCLUSION: This combined paclitaxel-carboplatin therapy is effective and can be safely administered to ovarian cancer patients who relapse after one or two regimens of platinum-based chemotherapy.