Jean Paul Guastalla

A phase Ib trial of Docetaxel, Carboplatin and Erlotinib in ovarian, fallopian tube and primary peritoneal cancers.

The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m−2) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day−1 (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day−1 (cohort 2b; the erlotinib dose was escalated to 100 mg day−1 in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100–150 mg day−1, with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.

HER2 Overexpression/Amplification and Trastuzumab Treatment in Advanced Ovarian Cancer: A GINECO Phase II Study

Background Variable rates of HER2 protein overexpression and gene amplification have been reported in advanced ovarian cancers (AOC). Trastuzumab, tested only as a single agent, has been shown to achieve 7% response in heavily pretreated patients with AOC with 3+ and 2+ HER2 immunostaining by immunohistochemistry (IHC). The GINECO trial explored the combination of trastuzumab with paclitaxel and carboplatin in patients with resistant AOC (< 6 months) and HER2 gene amplification.

Phase I study of RP 49532A, a new protein-synthesis inhibitor, in patients with advanced refractory solid tumors

Giroline (RP 49532A) is a new protein-synthesis inhibitor with broad antitumor activity in experimental models. In the present phase I study, Giroline was given by 24-h i.v. infusion every 3 weeks at doses ranging from 3 to 15 mg/m2 to 12 patients with advanced refractory solid tumors. The dose-limiting toxic effects were delayed hypotension and severe asthenia. The maximum tolerated dose (MTD) was 15 mg/m2. Transient nausea and vomiting during infusion were reported at all dose levels. Mild reversible prolongation of prothrombin time and activated partial thromboplastin time was observed in most patients at dose levels above 3 mg/m2. No antitumor activity was observed. The toxicity profile of Giroline precludes further evaluation in cancer patients.

Phase I study of pegylated liposomal doxorubicin in combination with ifosfamide in pretreated ovarian cancer patients.

Objectives:To determine the dose limiting toxicity, the maximum tolerated dose and the recommended dose of pegylated liposomal doxorubicin (PLD) in association with a fixed dose of ifosfamide (IFO) to patients with recurrent, advanced ovarian cancer (AOC). Methods:Patients with progressing platinum-sensitive or resistant disease were included in 5 dose levels consisting of PLD (25 mg/m2 to 45 mg/m2, day 1) combined with a fixed IFO dose administered as a continuous infusion (1700 mg/m2/d, day 1 to 3) to define the MTD on the basis of acute toxicity during the first 2 cycles, then confirm the MTD, by the evaluation of delayed toxicity (hand-foot syndrome). Results:Forty-eight patients were treated. The MTD was determined in the first 29 patients to be dose level V (45 mg/m2), with 2 cases of febrile neutropenia. The recommended dose (level IV) combines 40 mg/m2 PLD on day 1 and 1700 mg/m2/d IFO day 1 to day 3. The principal toxicity was hematotoxicity (grade 3–4 neutropenia 61.8% of patients, grade 3/4 thrombcytopenia 7.2%, and grade 3/4 anemia 21.8%). Nonhematological toxicity essentially consisted of grade 3/4 nausea and vomiting (14%). Nineteen additional patients were included in levels III (11 patients) and IV (8 patients), to evaluate late-onset toxicity. No hand-foot syndrome was observed in the 48 treated patients, confirming the identification of dose level IV as recommended dose. Conclusion:This study regimen presents an acceptable tolerance. The preliminary assessment of efficacy merits confirmation in a phase II study.

A phase I/II study of 4 monthly courses of high-dose cyclophosphamide and thiotepa for metastatic breast cancer patients.

This pilot phase I/II study intended to determine the maximum tolerated dose of cyclophosphamide and thiotepa administered on four consecutive courses with peripheral blood progenitor cell and granulocyte-colony stimulating factor support, as first-line therapy for hormone-refractory metastatic breast cancer patients. Twenty-eight patients were entered in the study. After two courses of epirubicin (120 mg m−2) and cyclophosphamide (2 g m−2) followed by granulocyte-colony stimulating factor injection and leukaphereses, patients received four cycles of cyclophosphamide and thiotepa. Each cycle was followed by peripheral blood progenitor cell and granulocyte-colony stimulating factor supports, then repeated every 28 to 35 days. Six escalating dose levels of cyclophosphamide and thiotepa were planned, beginning at cyclophosphamide 1.5 g m−2 and thiotepa 200 mg m−2. At least three patients were enrolled for each dose level. Eighteen patients completed the study. The maximum tolerated dose was 3000 mg m−2 cyclophosphamide and 400 mg m−2 thiotepa per course. Haematological toxicity was manageable on an outpatient basis and did not increase significantly with dose escalation. Dose-limiting toxicity was chemotherapy-induced immuno-suppression, which resulted in one toxic death and two life-threatening infections. Median times to treatment failure and survival were 11 and 26 months, respectively. Three patients were alive, free of disease 30 months after completion of the study. Such therapy allows for high-dose intensity and high cumulative doses on a short period of time with manageable toxicity.

Tumeurs rares malignes de l’ovaire

Résumé:Les tumeurs rares de la sphère ovarienne adulte représentent moins de 10 % des tumeurs ovariennes de l’adulte. Le traitement des tumeurs rares de l’ovaire est actuellement établi comme suit:—la chirurgie est calquée sur la chirurgie des adénocarcinomes ovariens, avec une différence majeure: l’objectif d’être conservateur de la fonction génitale chez les femmes en âge de procréer (cas habituel dans ce type de tumeur);—la chimiothérapie basée sur les données de la littérature est calquée sur celle des tumeurs germinales testiculaires;—la chirurgie, la chimiothérapie et une éventuelle chirurgie des lésions résiduelles sont fortement intriquées.Cependant, les tumeurs non épithéliales malignes de l’ovaire sont des cancers rares dont l’histoire naturelle est mal connue et dont les facteurs pronostiques ne sont pas précisés; pour ces raisons tous les malades devraient être adressés à des centres spécialisés ayant un intérêt spécifique pour ce type de tumeur et disposant d’un département d’anatomopathologie adéquat. En effet, les études récentes décrivent comme facteurs pronostiques, outre le stade de la maladie, le nombre de patientes pris en charge tant d’un point de vue chirurgical que médical, témoin de la nécessité d’une expérience importante dans ce domaine. Du fait de l’extrême rareté de ces tumeurs, un site Internet dédié à la prise en charge de ces tumeurs rares a été élaboré puis installé pour mettre à disposition de tous, des avis concernant la prise en charge chirurgicale, oncologique en première, deuxième, etc. ligne de traitement par l’intermédiaire d’un forum de discussion accessible par Internet. D’autre part des programmes de recherche cliniques et de l’information pour le public ont été développé dans le même temps. Ce protocole de prise en charge concerne les tumeurs malignes ovariennes germinales, et les tumeurs malignes stromales des cordons sexuels (tumeurs de la granulosa et cellules de Sertoli Leydig).Abstract:Germ cell tumours and ovarian sex cord tumours are extremely rare malignant diseases of the ovaries. Stromal tumours (Leydig cells) and/or sex cord tumours (Sertoli cells) represent approximately 5% of ovarian tumours and develop from the conjunctive tissue (interstitial and nurse cells respectively) of the ovaries. All together, they represented less than 20% of the malignant ovarian tumours in adults. Treatment of rare ovarian tumours is currently as follows:—surgery is the same as that for ovarian adenocarcinomas, with one major difference: conservation of the reproductive function in women of reproductive age is usual for this type of tumour;—chemotherapy, based on data reported in the literature, is the same as that prescribed for testicular germ-cell tumours;—surgery, chemotherapy and possible surgical intervention for residual lesions are highly complex.Also, these rare non epithelial malignant tumours are not very well understood as regards their prognostic factors. Too rare to be included in randomized studies, treatment of these tumours has benefited from the therapeutic advancements made against testicular germ-cell tumours and must be realized in specialized centres. Effectively, some factors such stage, histology and the number of managed patients seems to be prognostic for survival. Because of the rarity of these tumours, a specialized website (www.ovaire-rare.org) was developed in France in 2002. Objectives were to delineate prognostic factors of these very rare diseases; to favour patient inclusion in a clinical trial available online; to provide access to medical expert forums online (disease-related) for complex cases; and finally, to demonstrate the impact of these tools on improving medical practice. The website provides very interesting data for a better knowledge of these rare tumours and will possibly help improve medical practice.

Môles hydatiformes et tumeurs trophoblastiques gestationnelles

Partial and complete hydatidiform moles can secondarily turn to gestational trophoblastic neoplasia (GTN). Diagnosis of GTN is made when hCG does not return to normal value after a molar pregnancy or when histology findings show a choriocarcinoma. A check-up for metastasis allows calculating the FIGO score that differentiates low risk patients treated with methotrexate from high risk patients treated with polychemotherapy. The French trophoblastic disease reference centre has been implemented as an entity within a network organised between Lyon, Tours, Paris and Marseille; this network aims to register patients and optimize the treatment of GTN patients in France.RésuméLes môles hydatiformes complètes et partielles peuvent se compliquer à distance par une tumeur trophoblastique gestationnelle. Le diagnostic de tumeur repose sur l’évolution anormale des hCG dans les suites d’une môle ou plus rarement sur l’histologie de choriocarcinome. Le bilan d’extension des tumeurs permet de calculer le score FIGO qui définit les tumeurs à bas risque à traiter par méthotrexate et les tumeurs à haut risque à traiter par polychimiothérapie. Le centre français de référence des maladies trophoblastiques fonctionne en réseau entre Lyon, Tours, Paris et Marseille avec pour buts d’enregistrer les patientes et d’optimiser leur prise en charge en France.

Thérapeutiques du cancer de l’ovaire

Le but du traitement chirurgical du cancer epithelial de l’ovaire est de realiser une stadification anatomique precise et une reduction tumorale optimale.

Tumeurs trophoblastiques et gestationnelles

Les maladies trophoblastiques gestationnelles comprennent un large spectre de pathologies (1) allant des lesions precancereuses benignes, mole hydatiforme partielle et complete, aux lesions malignes, le choriocarcinome etant le plus grave, regroupees sous le terme de tumeur trophoblastique gestationnelle (TTG). La survenue habituelle des TTG apres une mole hydatiforme est a l’origine d’une confusion frequente entre ces deux pathologies. Le diagnostic par exces de TTG chez une patiente presentant une simple mole aboutirait a la realisation d’un bilan d’extension inutile, a une chimiotherapie potentiellement toxique et a la genese d’une angoisse infondee. Pour eviter cet ecueil, la FIGO a valide et publie en 2002 les criteres de definition d’une tumeur trophoblastique gestationnelle survenant apres une mole hydatiforme (2). De plus, certaines tumeurs trophoblastiques ne surviennent pas apres une mole mais apres un accouchement.

Tumeurs stromales de l’ovaire

Approximativement 8 % des tumeurs ovariennes derivent du stroma et/ou des cordons sexuels. Ces tumeurs sont generalement fonctionnelles puisque la plupart peuvent synthetiser des hormones (oestrogenes, androgenes, corticoides). Leur pronostic est difficile a etablir, certaines etant de comportement presque toujours benin (tumeurs a cellules de Sertoli, tumeurs a cellules de Leydig), d’autres de comportement malin mais avec des recidives locoregionales plus ou moins tardives. Les criteres histologiques d’agressivite sont mal connus de telle sorte qu’il est difficile de proposer une classification anatomopathologique dichotomique benin/malin et s’il n’y a pas de criteres cliniques de «malignite», ces tumeurs sont classees comme etant de pronostic incertain. Dans ce groupe de tumeurs, celles qui auraient plutot un comportement «malin» sont les suivantes: les tumeurs de la granulosa, les androblastomes (ou tumeurs de Sertoli-Leydig), les tumeurs des cordons sexuels avec tubules anneles, les tumeurs a cellules steroidiennes sans autre precision et les fibrosarcomes (1).