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PURPOSE Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm ( P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months ( P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm ( P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Resume Les auteurs rapportent l’observation d’une jeune femme âgee de 24 ans en remission complete quatre ans apres la fin d’un traitement pour un pneumoblastome biphasique. Apres une lobectomie inferieure gauche, la patiente a presente une recidive locale traitee par chimiotherapie. Cette observation est l’occasion de refaire le point sur les aspects cliniques, radiologiques et therapeutiques de ce type tres rare de tumeur maligne du poumon.

Resume Rationnel La chimiotherapie de seconde ligne (CSL) n’est pas validee dans le mesotheliome pleural malin (MPM). Dans notre experience, de nombreux patients en bon etat general au moment de la rechute sont pourtant candidats a un traitement de rattrapage. Methode Nous avons retrospectivement analyse notre experience en matiere de CSL dans le MPM dans deux centres parisiens de cancerologie thoracique (l’institut Gustave-Roussy, a Villejuif et l’hopital d’Instruction des Armees Percy, a Clamart). Resultats Pendant la periode du 1er janvier 2005 au 31 decembre 2006, nous avons collige 84 patients consecutifs, porteurs d’un MPM en progression apres une chimiotherapie de premiere ligne a base de pemetrexed. Un traitement de seconde ligne est administre a 44 patients (30 hommes et 14 femmes) qui presentent un âge moyen de 58 ans (extremes : 34 a 70 ans), un performance status (PS) inferieur ou egal a 1 dans 82 % des cas et une histologie epithelioide dans 91 % des cas. Le temps jusqu’a progression est egal a 6,1 mois. La mediane de survie est egale a 12,2 mois (extremes : deux a 72 mois). Secondairement, une troisieme et une quatrieme ligne de traitement ont ete realisees respectivement chez quatre et deux patients. Conclusions Dans notre experience, chez les patients ayant un MPM en rechute apres une premiere ligne standard a base de pemetrexed et en bon etat general, il est possible d’administrer un traitement de rattrapage. La CSL optimale n’est pas encore definie actuellement et des etudes prospectives sont necessaires dans ce cadre.

The respiratory infections are very frequent during lung cancer. Their diagnosis is often difficult because of the various etiologies (cancer, chemotherapy, radiotherapy) and this complexity can make discuss a preliminary bronchial exploration before any therapeutics. When it is about a located infection, germs in cause are often the same that in the community respiratory infections, in particular bacilli Gram negative, and it is thus logical to treat by the penicillin A. In front of an interstitial syndrome, it is necessary to evoke the opportunist infections, which are increasing in patients with cancer because of the multimodality therapeutic and the elongation of the survival. The neutropenic patient must be distinguished because of its specificities. The pulmonary infections lead to an important mortality. According to the patient (advanced age, underlying chronic obstructive pulmonary disease [COPD]) and to the treatment (chemotherapy, pneumonectomy), prevention must be discussed as the pneumococcal and Haemophilus influenzae vaccination.

Resume Le mesotheliome pleural malin (MPM) est une tumeur rare et incurable. Longtemps neglige, le MPM connait recemment un regain d’interet explique par l’augmentation reguliere de son incidence, temoignant d’une utilisation intensive de l’amiante, sa principale etiologie, mais aussi par une sensibilisation des milieux politiques et scientifiques confrontes a un veritable enjeu de sante publique. Le niveau des connaissances s’ameliore regulierement dans les domaines du diagnostic anatomo-pathologique et des mecanismes de la carcinogenese mesotheliale ; le MPM profite aussi d’innovations technologiques comme l’illustrent l’identification de marqueurs biologiques modernes, l’acces a l’imagerie metabolique et la recherche clinique sur les traitements cibles. La prise en charge du malade implique desormais la societe francaise toute entiere, depuis la mise en place de procedures d’indemnisation sociales. Surtout, une approche therapeutique plus volontaire se dessine en 2007 depuis la decouverte de chimiotherapies efficaces, l’optimisation des techniques de radiotherapie et l’emergence du concept de traitement multimodal centre sur la pleuropneumonectomie elargie. Ces avancees suscitent de reels espoirs, mais aussi beaucoup d’incertitudes, car aucun standard n’est encore clairement identifie.

Purpose Malignant pleural mesothelioma (MPM) is a disease of increasing incidence for which treatment options are limited. This study reports the clinical efficacy data for vinflunine, a novel microtubule inhibitor, in MPM. Patients and Methods Patients with a histologically confirmed diagnosis of MPM were eligible for enrollment onto this multicenter phase II trial if they had not received prior chemotherapy or radiotherapy and had measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Vinflunine 320 mg/m2 by 10-minute intravenous infusion was administered on day 1 of 21-day cycles. Modifications of dose and schedule were made according to National Cancer Institute Common Toxicity Criteria version 2.0. Efficacy was assessed by an external, independent radiologist. The one-sample multiple testing procedure of Fleming was applied at the predetermined recruitment stages of 20 and 40 assessable patients. Results Sixty-seven patients were enrolled. Five patients were not assessable for tumor response. The response rate was 13.8% (95% CI, 6.5% to 24.7%). The median survival was 10.8 months (95% CI, 7.8 to 12.0 months). The most common adverse events were anemia, neutropenia, fatigue, constipation, and nausea. Of grade 3 and 4 toxicities, neutropenia and constipation were the most common (45% and 9% of patients, respectively). Conclusion Vinflunine can be delivered with high-dose intensity in patients with MPM. The response rate and median survival are encouraging for a single agent. These data suggest that vinflunine should be further evaluated in the management of MPM.

Resume Les tumeurs epitheliales thymiques, regroupant les thymomes et les carcinomes thymiques, sont rares, de croissance le plus souvent lente, se developpant dans le mediastin anterieur. Les thymomes, en particulier, peuvent etre associes a des maladies auto-immunes et plus particulierement a la myasthenie. Leur traitement repose essentiellement sur une chirurgie complete. La radiotherapie postoperatoire y est systematiquement associee dans les thymomes invasifs avec atteinte des organes de voisinage ou dans les formes plus evoluees. Elle est en revanche plus discutee en cas de franchissement de la capsule. Dans les lesions d'emblee inoperables ou metastatiques, la chimiotherapie neoadjuvante a base de cisplatine a sa place, suivie d'une chirurgie maximaliste et d'une radiotherapie postoperatoire.

Resume Les immunonutriments presentent, associe a leur valeur energetique, une action pharmacologique propre. Les acides gras N-3 (AGN-3) grâce a leur action modulatrice de la reponse inflammatoire et a un eventuel effet antitumoral propre ont un role potentiel au cours de la prise en charge de la pathologie cancereuse. Les premieres etudes d'observation etaient prometteuses en montrant une diminution de la perte ponderale au cours de la prise en charge de certains cancers. Les etudes comparatives ulterieures n'ont pas reussi a confirmer cet effet favorable et a mettre en evidence un benefice en faveur de l'utilisation des AGN-3 par rapport a un groupe temoin. Cette discordance apparente, est la consequence des multiples differences qui existent entres les etudes dans : leur conception, les doses d'AGN-3 utilisees, la presentation pharmacologique, et les objectifs etudies. Neanmoins, certaines donnees semblent se degager : 1) il existe une relation dose–effet avec la necessite de prise importante d'AGN-3 ; 2) l'association avec certains acides amines favorise la synthese proteique et diminue la proteolyse ; 3) la compliance des patients avec une mauvaise tolerance digestive souvent responsable des sorties d'etude, est la difficulte majeure qui restreint l'utilisation de ces therapeutiques.

Resume Les cancers bronchiques a petites cellules (CPC) representent 20 % de l’ensemble des cancers bronchiques. Apres le bilan d’extension initial, seul un tiers de ces patients aura finalement une forme limitee. Le traitement des CPC limites repose actuellement sur les associations chimiotherapie-radiotherapie qui ont permis une amelioration de la survie globale et de la survie sans metastases au cours des dernieres annees. Neanmoins, meme dans les formes limitees, la survie a 5 ans varie entre 10 et 15 % et ne depasse guere 25 % dans les meilleures series. Le risque de rechute est en effet eleve : si pres de 70 % des patients avec une forme limitee parviennent a une reponse complete, seul 15 a 20 % d’entre eux survivront de facon prolongee. En effet, la plupart rechutent, et le risque de dissemination cerebrale par exemple est particulierement eleve, puisqu’il atteint pres de 50 % a 2 ans meme chez des patients mis en reponse complete. Ainsi, l’irradiation prophylactique cerebrale a egalement pris place dans la prise en charge standard des patients ayant un CPC en reponse complete suite aux resultats d’une meta-analyse ayant montre que la survie a 3 ans etait amelioree de 5 %. Malgre l’amelioration de la survie globale grâce aux traitements combines, les resultats mediocres observes en termes de survie a long terme devraient stimuler plus d’essais therapeutiques, afin de trouver les chimiotherapies et les modalites de radiotherapie optimales, la meilleure facon d’associer ces deux traitements ainsi que la place de nouvelles therapeutiques.

Due to their rarity, only few trials have studied the role of the doxorubicin-streptozotocin (DS) combination in advanced well-differentiated pancreatic endocrine carcinomas (AWDPEC). However, the published results are inconsistent. We reviewed all AWDPEC (5-year period, 45 patients) treated in our institution with the DS combination for: objective response rate (ORR), progression-free survival, overall survival (OS) and toxicity. An ORR of 36% (95% Confidence Interval (CI) 22-49) was obtained, with 16 partial responses (PR). The mean duration of PR was of 19.7 months. Two and 3-year OS rates were 50.2 and 24.4%, respectively. Toxicities were mainly digestive (grade > or =3 vomiting, 13%) and haematological (grade > or =3 neutropenia, 24%). Previous systemic chemotherapy and malignant hepatomegaly were associated with a poorer ORR (P=0.033, P=0.016) and OS (P=0.008, P=0.045). Multivariate analysis demonstrated previous chemotherapy as the only independent predictive-factor for survival (P=0.013). In conclusion, our data confirm the sensitivity of AWDPEC to the DS combination, with an ORR of 36% and a remarkable median response duration of 19.7 months, and suggests that it could be considered as a valid option in first-line therapy.

Purpose: The aim of this open-label phase II study was to evaluate the activity of raltitrexed (Tomudex; AstraZeneca, Cergy, France) and oxaliplatin combination therapy in patients with diffuse malignant pleural mesothelioma. Patients and Methods: Fifteen pretreated and 55 chemotherapy-naive patients (median age, 60 years; World Health Organization performance status of ≤ 2) were enrolled. Most patients (66%) had advanced disease. Patients received raltitrexed 3 mg/m2 followed by oxaliplatin 130 mg/m2 every 3 weeks. Results: Twenty-four patients (34%) were classified as having a poor prognosis. In the overall study population, 14 patients (20%) had a partial response, and 32 patients (46%) had stable disease. The symptomatic response rates were as follows: shortness of breath, 36%; pain, 30%; activity, 23%; appetite, 21%; and asthenia, 20%. Median time to disease progression was 18 weeks (95% confidence interval [CI], 13 to 22 weeks). In chemotherapy-naive patients, median survival was 31 weeks (95% CI, 23 to 40 weeks) from the start of treatment and 49 weeks (95% CI, 40 to 52 weeks) from diagnosis of mesothelioma. In pretreated patients, median survival was 44 weeks (95% CI, 24 to 40 weeks) from the start of treatment and 226 weeks (95% CI, 63 to 292 weeks) from the diagnosis of mesothelioma. Overall 1-year survival was 26% (95% CI, 15.5% to 36.4%), survival was 22% (95% CI, 10.9% to 33.2%) in chemotherapy-naive patients and 40% (95% CI, 15.2% to 64.8%) in pretreated patients. Hematologic toxicity was mild, and there was no alopecia. The most common adverse events were asthenia, nausea/vomiting, and paraesthesia, and no treatment-related deaths were reported. Conclusion: The raltitrexed and oxaliplatin combination is an active outpatient regimen in malignant mesothelioma and has an acceptable tolerability profile.

Background The aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC). Methods Gemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m2, respectively. Results Forty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m2) and oxaliplatin (85 mg/m2) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated(167 cycles) at that dose level. Thirteen cycles were associated with grade 3–4 non-febrile neutropenia in six patients, and eight cycles with grade 3–4 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m2 experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2′,2′-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70–100 mg/m2. Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients. Conclusions The combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m2 and oxaliplatin 85 mg/m2 every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.

In the period 1989-1991, 612 patients with inoperable stage IIIA/B and IV non-small cell lung cancer (NSCLC) were randomized in a phase III trial comparing three chemotherapy regimens. Survival data at five and six years of follow-up confirm the overall benefit of treatment with a combination of vinorelbine and cisplatin compared to vindesine plus cisplatin or vinorelbine alone. Of the 612 patients randomized at the start of the study, 17 have survived beyond five years. Of these patients, eight had entered the trial with metastatic disease. Multivariate analysis to detect prognostic factors suggested a possible interaction between the effect of having cisplatin in the chemotherapy received and baseline performance status. Subgroup analysis subsequently confirmed that the survival benefit of the vinorelbine plus chemotherapy regimen is evident only in patients with initial World Health Organization performance status (PS) of 0-1. Among these patients, the one-year survival rate is 38% for the vinorelbine/cisplatin arm, 29% for vindesine/cisplatin and 34% for vinorelbine alone. The corresponding figures for median survival are 43, 33 and 36 weeks. Among inoperable NSCLC patients with a PS of 2, who appear from this trial not to have benefited from the presence of cisplatin in their chemotherapy, use of single agent vinorelbine is an appropriate treatment option.

Summary Since the development of the first immunoassay for circulating chromogranin A in 1984, a lot of studies have evaluated its clinical impact in neuroendocrin e tumors. Initially studied in pheochromocytoma patients, the clinical impact of chromogranin A has rapidly extended to most neuroendocrine tumours, sometimes in combination with other eutopic or ectopic secretions. In our experience, CgA demonstrates a variable sensitivity between NET primary and a high specificity. Our results suggest that CgA should be routinely screened in foregut-derived NET and abandoned in the routine screening of medullary thyroid carcinoma. In addition, in phaeochromocy toma and ileumNET patients, CgA demonstrates a comparable sensitivity with urinary reference markers and its impact on the followup will form a key point when recommending routine screening. Both tumor burden and secretory activity should be taken into account when interpreting CgA results. Neuroendocrine tumors (NET) constitute a tumor network scattered in the body. They are characterized by common features including secretion of hormones, association as part of hereditary syndrome, impact of functioning imaging and, in one subgroup, poor aggressiveness. Secretion of hormones is a main feature of neuroendocrine tumors (NET) with multiple consequences for the diagnosis and prognosis of these tumors. Since 1984, the chromogranin A (CgA), a glycoprotein of the core of storage vesicles, has emerged as a potential general marker of these tumors [1]. CgA plays major roles in the storage and secretion of several hormones within the neuroendocrine cell vesicles. Furthermore, its impact on the pathological diagnosis of NET is well established [2]. This review article summarizes our experience with CgA measurement in the diagnostic biological work-up of NET.

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

The aim of this study was to review the experience of the Institut Gustave Roussy in 163 patients with malignant mesothelioma over a 9-year period. Data from seven consecutive prospective trials, four of chemo-immunotherapy and three of chemotherapy were reviewed. The rationale, methods and results of these trials are summarised and discussed. 98 patients were included in four phase II trials of chemo-immunotherapy whose common denominator was a combination of cisplatin and alpha-interferon. The response rate ranged from 15% to 40%. High-dose weekly cisplatin combined with alpha-interferon yielded the highest response rate but the toxicity of this regimen was considered unacceptable. Neither higher doses of alpha-interferon or the addition of mitomycin C or interleukin-2 to the regimen were able to enhance the activity of this combination. 18 patients were included in a paclitaxel-cisplatin phase II trial. The response rate was only 6% (95% confidence interval (CI): 0-24) and toxicity was also significant. This regimen was, therefore, considered ineffective. Of 17 patients with mesothelioma included in a phase I trial that combined raltitrexed and oxaliplatin, 6 (35%) obtained a partial response. Responses were seen even in cisplatin-refractory mesothelioma. Preliminary results of a subsequent ongoing phase II trial using raltitrexed (3 mg/m(2)) and oxaliplatin (130 mg/m(2)) have confirmed this promising activity with a 30% (9/30) response rate (95% CI: 15-49). The tolerance of this outpatient regimen is acceptable (no significant haematological toxicity and no alopecia) and compares favourably with that of our previous regimens. The final results concerning response and survival are required to confirm the efficacy of this combination. The preliminary results of two studies suggest promising activity with the combination of raltitrexed-oxaliplatin in malignant mesothelioma. The efficacy/toxicity ratio of this combination compares favourably with that of our previous chemotherapy and chemo-immunotherapy regimens.

Screening was performed in 130 consecutive patients with apparently sporadic neuroendocrine tumors (NET) to assess the prevalence of multiple endocrine neoplasia type 1 (MEN1) and hormonal production. Screening for MEN1 included measurement of serum calcium and PTH[ PTH-(1–84)], gastrin, PRL, and insulin-like growth factor type I (IGF-I) levels. MEN1 genetic testing was performed in patients with two components of the MEN1 syndrome. Screening for hormonal production included measurement of serum neuron-specific enolase (NSE), calcitonin (CT), glycoprotein α-subunit (GPα), hCG β-subunit (free hCGβ), and somatostatin levels. Twenty-four-hour urinary free cortisol (UFC) and 5-hydroxyindolacetic acid (5-HIAA) determinations were also performed. Four patients had hyperparathyroidism, none of whom had pituitary or familial disease. Hyperprolactinemia was compatible with a pituitary disease in one patient. No acromegalic feature or any increase in IGF-I was found. Hypergastrinemia, compatible with an associated ...

The activity of the combination of intravenous docetaxel 75 mg/m2 plus cisplatin 100 mg/m2 administered every 3 weeks for 3 cycles then every 6 weeks was investigated in 51 chemotherapy naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). The population was 92% male, with a median age of 54 years and median performance status of 1; 80% of patients had metastatic disease, including 37% with bone involvement. All patients received prophylactic premedication (ondansetron, dexamethasone plus cetirizine) and standard hyperhydration. With a median of 4 treatment cycles (range 1-9), 14 of 42 evaluable patients responded (overall response rate 33.3%, 95% CI 19.6-49.6%); the median response duration was 7.3 months, median survival 8.4 months, and 1-year survival rate 35%. The most common adverse event was neutropenia, occurring in two-thirds of patients. Neurosensory effects were cumulative but generally mild. No treatment-related deaths occurred. This combination of docetaxel/cisplatin showed activity in advanced NSCLC. While it was not clearly superior to single-agent docetaxel, due to differences in prognostic factors among the patients in open trials, a randomised study would be needed to demonstrate definitively whether cisplatin adds to the activity of docetaxel or not.

In a pilot study of 29 patients treated for localized small cell lung cancer, three new approaches were introduced, i.e. an increased initial drug dose, an early alternation of chemotherapy and thoracic radiotherapy and initial accelerated and hyperfractionated irradiation. The results were interesting. However, a high rate of fatal toxicity (21%) was observed.

Resume Le diagnostic de mesotheliome pleural epithelial est realise apres une thoracoscopie-talcage chez un homme de 58 ans qui presente une pleuresie. L’evolution est rapidement defavorable malgre une chimiotherapie systemique, avec des douleurs dorsales revelant un envahissement vertebral et du canal rachidien, responsable d’une compression medullaire 3 mois apres le diagnostic du mesotheliome.

Clinical trials investigating new trends in the treatment of stage I and II malignant mesothelioma have shown both intra-pleural immunotherapy and systemic chemo-immunotherapy to be efficacious. Intra-pleural gamma-interferon (γ-IFN) therapy was associated with tolerable toxicity and an overall response (ORR) rate of 19%, while treatment with intra-pleural recombinant interleukin-2 (IL-2) was more toxic, but yielded an ORR of 47% in phase I trial and 55% in a phase II study. The association of intravenous cisplatin and subcutaneous α-interferon (α-IFN) was also associated with an encouraging ORR of 40% and a median survival of 12 months. Treatment with cisplatin, α-IFN and mitomycin C was associated with moderate toxicity and an ORR of 21% and a median survival of 12 months. The association of cisplatin, α-IFN and IL-2 was, however, extremely toxic and resulted in an ORR of 15%. The majority of patients responding to intra-pleural immunotherapy and systemic chemo-immunotherapy had epithelial type mesothelioma. The most encouraging results obtained from trials investigating systemic chemotherapy were following treatment with cisplatin, 5-fluorouracil, mitomycin C and etoposide, where an ORR of 38% and an overall median survival rate of 16 months were achieved. Toxicity was mainly haematological and tolerable.

The triangular test has been used to monitor survival data from a randomized trial in patients with small cell lung cancer. The results of consecutive interim analyses and the problems met by the data monitoring committee and the co-ordinators are described. The methods as well as the consequences of the early stopping on the analysis and the results of this trial are discussed. From this experience, we believe that statistical stopping rules--only one of the factors to be taken into account when deciding to stop a trial--should be used with caution. Independent data monitoring committees may be useful in helping to review the ongoing results and advise the participants in the trial.

We report the results observed in a large randomized study comparing radiotherapy alone to combined radiotherapy and chemotherapy in unresectable squamous cell and large cell lung carcinoma. Radiation dose was 65 Gy in both groups and chemotherapy included vindesine, cyclophosphamide, cisplatin and lomustine. One hundred seventy-seven patients received radiotherapy alone, and 176 received the combined treatment. The 2-year survival rate was 14% for patients receiving radiotherapy vs. 21% for patients receiving the combined treatment (P = 0.02). The distant metastasis rate was significantly lower in the group receiving the combined treatment (P < 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively) and remains a major problem in locally advanced non-small cell lung cancer.

IntroductionThe value of a nonanthracyclin regimen in thymic carcinoma and malignant thymoma is not well defined. These regimens may be useful in some patients, particularly with cardiac diseases. The objective of this study is to evaluate the response rate, progression free survival, overall survival and toxicity of combined etoposide, ifosfamide, and cisplatin in patients with advanced thymoma and thymic carcinoma.MethodsFrom October 1995 to April 2001, 18 patients with advanced thymoma or thymic carcinoma were entered on trial, and receive etoposide (100 mg/m2 on days 1–3), ifosfamide (1500 mg/m2 on days 1–3), s and cisplatin (30 mg/m2 on days 1–3). Cycles were repeated every 3 weeks for a total of six cycles.ResultsAmong 16 evaluable patients, there were no complete responses and four partial responses (complete and partial responses rate, 25%; confidence interval [CI] 95, 7–48%). The median follow-up was 32.6 months (range

Two chemotherapy regimens for patients with extensive small-cell lung cancer were prospectively compared in a randomized multicentric trial with crossover. Every four weeks, 60 consecutive previously untreated patients received either DPE (doxorubicin, cisplatin and etoposide), or CIV (carboplatin, ifosfamide and vincristine) with crossover as soon as progression or end of response were observed. Pretreatment characteristics were similar in the two groups. Fifty-seven patients were evaluated for response. The response rate was higher with the DPE regimen both in first-line (for DPE: response rate 62% (18/29), including 17% (5/29) of complete response (CR), and for CIV: response rate 29% (8/28) with no CR, p < 0.02) and in second-line after crossover (for DPE: response rate 45% (9/20) including 5% (1/20) of CR, and for CIV response rate 0%, p < 0.02). Major toxicities were equally frequent in both groups. No significant difference was found between median survival times (9.7 months for the DPE group and 10.4 months for the CIV group). We conclude that: 1) DPE is a more active regimen than CIV, both in first- and second-line; 2) no alternating scheme may be considered with these two combinations. Of particular note is the similar median survival times in the two groups, contrasting with the different activities of the two regimens.

The authors report their experience with the MVP (mitomycin/vindesine/cisplatin) regimen of the Memorial Sloan-Kettering Cancer Center (MSKCC) which showed the highest response rate in non-small cell lung cancer (NSCLC). The aim was to respect the original reported schedule to appreciate its activity, because the same drug combination with dose and schedule variations used by other investigators has failed to reproduce the original report results. 82 consecutive previously untreated patients with unresectable and/or metastatic NSCLC received mitomycin (8 mg/m2 days 1, 29, 71), vindesine (3 mg/m2, days 1, 8, 15, 22, 29, 43, 57, 71) and cisplatin (120 mg/m2, days 1, 29, 71), with evaluation on day 71. 24 objective responses were noted (29%) (2 complete response/22 partial response) (95% CI 19%-39%), without differences according to histology. Differences in median survival were noted according to the performance status and type of response. Overall survival rates in responding patients were similar to those noted with the original schedules. Analysis of selection criteria showed that there were more patients with bone (P less than 0.01) or liver metastases (P less than 0.05), less women (P less than 0.001) and less adenocarcinoma (P less than 0.001) than the MSKCC trial. A dose intensity analysis showed only a minimal difference in the average weekly doses of vindesine (10% lower than MSKCC trial: 1.8 mg/m2 vs. 2.25 mg/m2). Disease improvement, a subjective response criterion used in the MSKCC trial, was probably underestimated in the current study. We conclude that the potential benefit of chemotherapy with a three-drug combination in NSCLC is greatest in patients with stage IIIa and IIIb disease or stage IV disease with a good performance status and a low metastatic volume.

48 patients with colorectal cancer metastatic to the liver were implanted with a subcutaneous access system allowing hepatic intra-arterial perfusion. Regional chemotherapy used 5-fluorouracil, while 17 patients also received low-dose mitomycin at the beginning of the study. Responses to the treatment occurred in 29 patients (60%) and median survival was 14.4 months. Toxicity included gastroduodenal erosions in 12.5% of the patients, leucopenia in 20.8%, catheter thrombosis in 42% and arterial thrombosis in 50%. 2 patients died of digestive haemorrhage probably related to treatment. When individually analysed, four factors were found to significantly affect survival: presence of hepatomegaly (defined as palpable liver edge exceeding the right costal margin by more than 5 cm) (P = 0.006), percentage of hepatic replacement superior to 50% (P = 0.003), more than four metastases (P = 0.025) and hypovascularised metastases at radionuclide liver scan with 99mtechnetium-labelled macroaggregate albumin (MAA) (P = 0.04). The effect of the four variables on the observed survival time was analysed using a Cox regression model. Two variables were found to have simultaneously influenced survival. Presence of hepatomegaly emerged as the more significant (P = 0.0001), the other being hypovascularised metastases at 99mTc-MAA.

This Phase II study evaluated the combination of two active agents in small cell lung carcinoma (SCLC): carboplatin and ifosfamide. Thirty previously untreated patients (27 men and 3 women) with a median age of 59 years were included in this study. Twelve patients had one metastatic site and 18 had two or more metastatic sites. The median performance status was 80%. The chemotherapy (CT) regimen administered during the course of this study consisted of carboplatin (300 mg/m2) and ifosfamide (4 g/m2) plus mesna every 4 weeks. All 30 patients were evaluable: 1 achieved a complete remission (CR) and 18 achieved a partial remission (PR) (objective response rate, 63%). The median response time was 3 months and the median survival time was 8 months (range, 1 to 25+ months). Bone marrow toxicity was Grade III in three patients and Grade IV in four patients. The carboplatin and ifosfamide combination was well tolerated. No cross-resistance with the doxorubicin and etoposide regimen was established because 4 of 11 patients responded to this combination (+/- cisplatin) after failing to respond to the ifosfamide and carboplatin regimen. The ifosfamide and carboplatin combination may be considered for inclusion in non-cross-resistant alternating CT schedules.

We report the results observed in a large, randomized study that compared the effects of radiotherapy alone (the standard therapy) with those of a combination of radiotherapy and chemotherapy in nonresectable squamous cell and large-cell lung carcinoma. The radiation dose was 65 Gy in each group, and chemotherapy included vindesine, cyclophosphamide, cisplatin, and lomustine. In this study, 177 patients received radiotherapy alone (group A), and 176 patients received the combined treatment (group B). The 2-year survival rate was 14% in group A and 21% in group B (P = .08). The distant metastasis rate was significantly lower in group B (P less than .001). Local control was poor in both groups (17% and 15%, respectively) and remained the major problem.

One-hundred seventy-three patients with limited small cell lung cancer were included in three consecutive protocols alternating radiotherapy and chemotherapy. The alternating schedule consisted of six courses of chemotherapy (doxorubicin, VP16213, cyclophosphamide, and methotrexate in the first protocol; methotrexate being replaced by cisplatinum in the other two protocols) and three series of thoracic radiotherapy delivering a total dose of 45, 55, and 65 Gy in each consecutive protocol. Radiotherapy was started after the second course of chemotherapy. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy. Seventy percent of patients were in complete remission at the end of the induction treatment. The actuarial 5-year local control was 60% and the 5-year overall survival was 18%. Sixty percent of patients developed distant metastases. The death rate unrelated to cancer was 10%. These results show that alternating radiotherapy and chemotherapy schedules are reproducible, and provide a consistent long-term local control and a long-term survival rate exceeding 15% in limited disease.

Management of advanced malignant mesothelioma (MM) still requires innovative systemic therapy as its prognosis is poorly affected by currently available chemotherapy. The combination cisplatin and alpha-interferon (alpha-INF) has synergistic antitumoral activity in preclinical models and interesting activity in phase I-II clinical trials. Weekly CDDP (60 mg/m2) and alpha-IFN (3 MUI/d: d1-d4) in combination was tested in a previous phase I-II study in 23 MM patients, with a 36% objective response rate (ORR). A trial with higher doses of alpha-IFN in the same combination schedule was conducted to explore an incrementalist hypothesis. Thirty patients with MM received the same CDDP dose (60 mg/m2/w) and doubled doses of alpha-IFN (6 MUI/d: d1-d4). The treatment protocol consisted of two cycles of 4 weeks on/4 weeks off followed by two shorter cycles of 3 weeks on/3 weeks off, in the absence of life-threatening toxicity or progressive disease. All patients were evaluable for toxicity. The main treatment-limiting side-effects were digestive intolerance (nausea, vomiting) and severe asthenia. Antitumoral efficacy was not increased (ORR = 27%). Haematological and neurological toxicities were moderate and manageable. The antitumoral activity of the CDDP-alpha-IFN combination with higher doses of the latter is similar to our previous experience, but tolerance issues make it a poorer choice for eventual comparative trials, or as a standard therapeutic indication.

Summary Background To evaluate the efficacy and toxicity of a chemotherapy strategy based on histological differentiation, for patients with carcinoma of unknown primary site Patients and methods Forty-eight patients were prospectively included in the trial Thirty patients with poorly-differentiated carcinoma or poorly-differentiated adenocarcinoma (group A) received a combination of cisplatin and etoposide Patients with a responsive or stable disease after two cycles received the same regimen plus bleomycin, Ifosfamide and G-CSF Eighteen patients with well- or moderately-differentiated carcinoma (group B) received cisplatin, continuous infusion 5-fluorouracil (5-FU) and α-interferon. Treatment was maintained in case of response or stable disease for up to six cycles Results The overall response rate (RR) for the entire group is 43% (95% confidence interval (CI) 35 9%–50 1%). seven CR and five PR in group A (RR = 40%) and six CR and two PR in group B (RR = 44%) Grade 4 leucopenia was observed in 22 (46%) patients and sepsis in 3 (6%) Median survival is 9 4 months (range 5–13 7 months) and 16 1 months (range 11 8–20 3 months), respectively Conclusions This chemotherapy strategy is one way to achieve high response rates, particularly for patients with well- or moderately-differentiated adenocarcinoma usually considered poorly chemosensitive

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the raltitrexed plus oxaliplatin combination regimen, to explore its safety and pharmacokinetics, and to assess its antitumor activity in patients with advanced solid tumors. PATIENTS AND METHODS: Forty-eight patients received the combination of raltitrexed plus oxaliplatin. Raltitrexed was administered as a 15-minute infusion followed by oxaliplatin as a 2-hour infusion 1 hour later, repeated every 3 weeks. Seven dose levels were explored, ranging from 2 to 3.75 mg/m2 and from 85 to 130 mg/m2 for raltitrexed and oxaliplatin, respectively. The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at the last three dose levels. RESULTS: Forty-six patients were assessable for toxicity. Severe toxicities usually occurred from dose level V (raltitrexed 3 mg/m2 and oxaliplatin 130 mg/m2). This combination was not myelosuppressive, eliciting only sporadic grades 3 and 4 neutropenia and/or thrombocytopenia without complications. There was no alopecia. DLTs were asthenia and nausea/vomiting, despite systematic antiemetic prophylaxis. Dose level VI (raltitrexed 3.5 mg/m2 and oxaliplatin 130 mg/m2) was deemed to be the MTD. Eight confirmed partial responses were observed: six patients with malignant mesothelioma (both pretreated and nonpretreated), one with fluorouracil-refractory pancreatic carcinoma, and one with renal carcinoma. Evaluation of the pharmacokinetics of both drugs did not suggest any drug interaction. CONCLUSION: The combination of raltitrexed and oxaliplatin given as consecutive short infusions every 3 weeks seems to be an acceptable regimen that allows a dose-intensity as high as the sum of the recommended doses of each agent given alone. The dose recommended for further phase II studies is raltitrexed 3 mg/m2 and oxaliplatin 130 mg/m2 every 3 weeks. Promising antitumor activity has been observed in patients with malignant mesothelioma.

Primary mediastinal seminoma is an uncommon neoplasm, the optimal management of which is still debated. Radiotherapy produces a 65% disease-free survival rate. We assess whether these results have been improved with the advent of cisplatin-based chemotherapy. Data from 14 patients treated at the Institut Gustave-Roussy were reviewed. 9 had received cisplatin-based chemotherapy (Group 1): their outcome was compared with that of 5 patients treated with radiotherapy without chemotherapy (Group 2). We also reviewed data from the English literature using strict criteria, and report results concerning patients who received cisplatin-based chemotherapy and those who received radiotherapy. 8 of the 9 patients (89%) in Group 1 are long-term disease-free survivors and only 3 of 5 patients in Group 2. The patient who died in Group 1 was the only one who refused surgical resection of residual masses after chemotherapy. The review of the literature revealed that 59 of 68 (87%) patients initially managed with cisplatin- or carboplatin-based chemotherapy and for whom sufficient data are available, are long-term survivors and free of disease. Some of these patients had also received radiotherapy. Only 64 of 103 (62%) treated with thoracic radiotherapy without chemotherapy were long-term disease-free survivors. The disease-free survival rate of 51 patients who received cisplatin-based chemotherapy (excluding those who received carboplatin) was 86%. The difference in survival between patients administered cisplatin-based chemotherapy and those who underwent radiotherapy is apparently not due to unbalanced prognostic factors, the effect of time or non-specific medical management. We conclude that cisplatin-based chemotherapy allows long-term disease-free survival in approximately 85% of patients. These results seem to be higher than those obtained without cisplatin-based chemotherapy. However, a randomised study is required for definitive conclusions, but it is very unlikely that such a study will be performed due to the rarity of this neoplasm. Another alternative would be a meta-analysis based on individual data.

PURPOSE Primary mediastinal nonseminomatous germ cell tumors (NSGCT) are uncommon neoplasms and clinically and biologically distinct from other germ cell tumors (GCT). We describe the clinical and biologic features of these patients and evaluate the results of treatment during the cisplatin era. PATIENTS AND METHODS Between 1976 and 1993, 38 patients with mediastinal NSGCT received cisplatin-based chemotherapy as part of their primary treatment. Twenty-nine of them were initially treated at the Institut Gustave-Roussy (IGR), VillejuiF, France, and nine were referred for salvage treatment. RESULTS Of the 29 patients initially treated at IGR, 11 (39%) had metastasis. A complete response (CR) to therapy was obtained in 19 of 29 patients (66%) after chemotherapy and surgery. Ten patients (34.5%) have remained free of disease with a median follow-up of 89 months. All patients who did not achieve a CR died of disease. The 2-year overall survival rate for the IGR patients is 45% and the 2-year disease-free survival is 37%. Only the presence of extrapulmonary metastasis was of prognostic significance in the univariate analysis (P = .0095). None of the 20 patients who required salvage therapy is currently disease-free. Five patients developed and subsequently died of a hematologic malignancy at an interval range of 1 to 47 months from treatment of mediastinal NSGCT. Cytogenetic analysis of leukemic cells found an isochromosome of the short arm of chromosome 12 (12p) in two cases. The incidence of leukemia was 21% in patients who attained a CR. CONCLUSION Primary mediastinal NSGCT is a clinical and biologic entity that should be distinguished from other GCT. About 40% of these patients can envisage long-term survival with modern therapy that includes cisplatin-based chemotherapy followed by surgical resection of residual masses. New strategies are required for patients who do not attain a CR. Predictive factors and improvement in therapy are required for mediastinal NSGCT-associated leukemia.

PURPOSE To identify prognostic factors of improved survival after resection of isolated pulmonary metastases (PM) from colorectal cancer. PATIENTS AND METHODS A retrospective analysis of the records of all patients with PM from colorectal cancer who underwent thoracic surgery with curative intent before December 1992 at a single surgical center was performed. Univariate (log-rank) and multivariate (Cox's model) analyses of survival were used to identify significant prognostic factors. RESULTS Eighty-six patients with PM from colon (n = 49) or rectal (n = 37) cancer underwent 102 thoracic operations, which included 21 bilateral and 10 incomplete resections. The 5- and 10-year probabilities of survival (Kaplan-Meier) after the first thoracic operation were 24% (95% confidence interval [CI], 15% to 35%) and 20% (95% CI, 13% to 31%), respectively. Sex, age, site of the primary tumor (colon or rectum), disease-free interval (DFI), and previous resection of hepatic metastases were found not to be statistically significant prognostic factors. Complete resection, a limited number ( < two) of PM, and a normal prethoracotomy serum carcinoembryonic antigen (CEA) level were predictors of a longer survival duration by univariate analysis, but only complete resection (P = .024) and preoperative CEA level (P = .001) were identified as independent prognostic factors by multivariate analysis. The estimated 5-year survival rate of patients with a normal prethoracotomy CEA level was 60%, as compared with 4% in cases with elevated ( > 5 ng/mL) CEA level. CONCLUSION Besides resectability, the prethoracotomy serum CEA level appears the most reliable predictor of survival in patients with isolated PM from colorectal cancer.

PURPOSE To assess the tolerance, toxicity, and antitumoral activity of the weekly combination of cisplatin (CDDP) and interferon alfa-2a (IFNalpha2a) in advanced diffuse malignant mesothelioma (DMM). PATENTS AND METHODS: Twenty-six patients with DMM (23 pleural and three peritoneal), previously untreated, were enrolled onto this study between August 1991 and December 1992. All patients had measurable disease defined by computed tomographic (CT) scan and diagnostic confirmation by histopathology review panel. IFNalpha2a (3 x 10(6) IU subcutaneously on days 1 to 4) and CDDP (60 mg/m2/wk on day 2) were given weekly. Initially planned as a 5-weeks-on/3-weeks-off treatment cycle, poor patient tolerance observed in the first 12 patients treated (group A) led to schedule adaptation with a shorter treatment sequence and prolongation of the rest period (4 weeks on/4 weeks off) in the following 14 patients (group B). At least two cycles were administered to each patient in the absence of tumor progression. RESULTS Twenty-six patients were assessable for toxicity and 25 for efficacy (World Health Organization [WHO] criteria). Sixty-eight cycles of IFN/CDDP were given, with a median of three cycles per patient (range, one to five). Toxicity was mainly clinical, with progressive anorexia, asthenia, and prolonged nausea/emesis; these side effects have limited treatment acceptance in many patients. Thrombocytopenia and leukopenia were rarely noted as treatment-limiting toxicities. Objective responses (all partial) were obtained in 10 patients (95% confidence interval [CI], 20% to 60%). The median response duration was 11 months (range, 6 to 18). The median time to progression (TTP) for the whole cohort was 6 months and the median survival time was 12 months (range, 5 to 32). Objective responders had a significantly longer median TTP (21 months) and survival time (25 months) than nonresponders (3 and 8 months, respectively). CONCLUSION The results of this pilot phase I-II study show encouraging antitumor activity in this traditionally resistant tumor, even if the specific contribution of IFN remains speculative and needs further clinical research. Our ongoing program is exploring the dose-intensity impact of IFN dose within the same combination.

Les metastases intestinales (parietales et mesenteriques) ont le plus souvent une origine gastrique, ovarienne ou renale. Une tumeur primitive intra-thoracique telle qu'un cancer bronchique est parfois en cause [1]. Des metastases digestives peuvent etre egalement suspectees devant un tableau d'occlusion chez un malade ayant un mesotheliome pleural malin (MPM).

Moderate increases in the initial doses of certain chemotherapeutic drugs, such as cisplatin and cyclophosphamide, may prolong overall survival in patients with limited small-cell lung cancer.We conducted a prospective study of 105 patients with limited small-cell lung cancer. The patients were randomly assigned to receive higher or lower initial doses of cisplatin (100 or 80 mg per square meter of body-surface area) and cyclophosphamide (300 or 225 mg per square meter daily for four days); all patients received the same doses of doxorubicin and etoposide. The first course of chemotherapy was followed by five additional courses and by three courses of radiotherapy. All patients received the lower doses of cisplatin and cyclophosphamide and the same doses of doxorubicin and etoposide from the second through the sixth cycle of chemotherapy.The median follow-up was 33 months. The two-year survival rate for the 55 patients who received the higher doses of chemotherapy was 43 percent, as compared with 26 percent for the 50 patients who received the lower doses (P = 0.02). The rates of complete response at six months were 67 percent in the higher-dose group and 54 percent in the lower-dose group (P = 0.16). Disease-free survival at two years was 28 percent in the higher-dose group, as compared with 8 percent in the lower-dose group (P = 0.02). Side effects from treatment were not increased in the higher-dose group.Higher initial doses of cyclophosphamide and cisplatin improve disease-free and overall survival in patients with limited small-cell lung cancer.

32 patients with advanced non-small cell lung cancer previously untreated by chemotherapy were included in a phase I–II study in order to determine the feasibility of the combination of vinorelbine and cisplatin, each administered at its optimal dose, i.e. 30 mg/m 2 weekly and 120 mg/m 2 every 4–6 weeks, respectively. There were 27 males and 5 females with a mean age of 55 years and a median performance status of 80%. 13 had locally advanced disease and 19 had distant metastases at the time of inclusion. Our study demonstrated the feasibility of this protocol. Dose intensities could be maximised by adapting vinorelbine doses rather than by postponing treatment in the event of neutropenia. Both response rate (33%) and overall survival of the population (median 11 months) justify further studies.

Vindesine (VDS) and 5-Fluorouracil (5-FU) administered by continuous infusion have shown an increased therapeutic index in many solid malignancies. On the basis of our encouraging results obtained by the association of Cisplatin (CDDP, bolus) and VDS with 5-FU by continuous infusion, in unresectable non small cell lung cancer (NSCLC) [1], we tested VDS and 5-FU by continuous infusion in combination with CDDP and high doses of leucovorinin in order to enhance the anti tumoral effect of 5-FU [2].

The authors describe the case of a patient with stage II non seminomatous germinal cell tumor of the testis with a generalized sarcoidosis. They review the existing literature and discuss the problem of diagnosis.

7196 Background: CXCR4 is a chemokine receptor which takes part in diverse events like the migration of lymphocytes to sites of inflammation, internalization of the HIV particle by lymphocytes, and homing of metastasizing tumor cells. Recent studies suggest that nuclear -rather than membranous or cytoplasmic- expression of CXCR4 may signify a different function. In this study, we aimed to evaluate the prognostic significance of nuclear CXCR4 expression in patients with malignant pleural mesothelioma (MPM). Methods: The records of 66 MPM patients were reviewed and CXCR4 expression of their tumors were assessed by immunohistochemistry. Prognostic significance of this marker was evaluated using Log rank test and a Cox proportional hazards model. Results: The mean age of patients was 61±10 years (min: 41, max: 85). Fifty-one patients were males (77%), and 15 were females (23%). The median percentage of cells expressing nuclear CXCR4 was 5.1% (min-max: 0–95), and this was used as the cut-off to define CXCR4-po...