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A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55&ndash, 109) vs. 658 days (222-not reached), HR: 4.12 (1.95&ndash, 8.71), p = 0.0002) and OS (HR: 3.99(1.63&ndash, 9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17&ndash, 6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive, therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30&ndash, 0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21&ndash, 0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

The incidence of cancer increases with age, especially for urological cancers. The frailty of the elderly persons may expose them to more postoperative complications resulting in prolonged hospitalization, increased morbidity or even increased mortality, and delayed or impossible return to normal life. In such cases, the benefit of surgery and therefore its realization can be questioned.This article reports the experience of a pre-operative risk assessment in a population of elderly patients treated for urologic cancer. This retrospective study aims to report the feasibility and the main results of this systematic preoperative multi-professional evaluation.Between April 2016 and February 2017, 31 elderly patients were evaluated. The evaluation revealed: moderate to severe malnutrition in 59 % of cases, a patient judged from a geriatric point of view fit, intermediate or fragile in respectively 25 %, 35 % and 40 % of cases. This evaluation led to propose a modification of an element of care for 66 % of patients and to propose therapeutic abstention for only 3 patients.An evaluation whose purpose is to adapt to the physiological age of patients and their overall state of health, surgical treatment and postoperative management is feasible and seems to help unmask elements of fragility usually not detected.4.

Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards. These medications are conditioned to the expression of biomarkers that require specific tools in routine to measure them. We will detail in this chapter several techniques of anatomopathology, cytogenetics and molecular biology necessary for the detection of biomarkers in lung cancers, and their applications in thoracic oncology in 2018.

Immune checkpoint inhibitors (ICI), targeting the PD1/PD-L1 axis has shown their efficacy in lung cancer but only in a restricted population of patients, thus it is mandatory to identify biomarkers predicting the clinical benefit. In this article we will describe and analyzed biomarkers already published, from protein, to RNA and at last DNA markers, discussing each markers feasibility and interest. In the future, combined analysis of several markers will probably be proposed, particularly with the increasing complexity of therapy schema with molecules association.

Background Use of chemotherapy near the end of life in patients with metastatic cancer is often ineffective and toxic. Data about the factors associated with its use remain scarce, especially in Europe. Methods Nationwide, register-based study including all hospitalized patients aged ≥20 years who died from metastatic solid tumors in France between 2010 and 2013. Results A total of 279 846 hospitalized patients who died from metastatic cancer were included. During the last month before death, 19.5% received chemotherapy (including 11.3% during the last 2 weeks). Female sex (OR= 0.96, 95% CI= 0.93–0.98), older age (OR= 0.70, 95% CI= 0.69–0.71 for each 10-year increase) and higher number of chronic comorbidities (OR= 0.83, 95% CI= 0.82–0.84) were independently associated with lower rates of chemotherapy. Although patients with chemosensitive tumors were statistically more likely to receive chemotherapy during the last month before death (OR= 1.21, 1.18–1.25), this association was mostly fueled by testis and ovary tumors and we found no obvious pattern between the expected chemosensitivity of different cancers and the rates of chemotherapy use close to death. Compared with university hospitals, patients who died in for-profit clinics/hospital (OR= 1.40, 95% CI= 1.34–1.45), or comprehensive cancer centers (OR= 1.43, 95% CI= 1.36–1.50) were more likely to receive chemotherapy. Finally, high-volume centers and hospitals without palliative care units reported greater-than-average rates of chemotherapy near the end of life. Conclusion among hospitalized patients with cancer, young individuals, treated in comprehensive cancer centers or in high-volume centers without palliative care units were the most likely to receive chemotherapy near the end of life. We found no evident pattern between the expected chemosensitivity of different cancers and the probability for patients to receive chemotherapy close to death.

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small&ndash, cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman&rsquo, s rank test was used to investigate the relationship between Cmin and grade &gt, 2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 &plusmn, 6.0 &micro, g/mL (n = 76), 25.6 &plusmn, 10.2 &micro, g/mL (n = 64) and 33.4 &plusmn, 11.3 &micro, g/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02&ndash, 3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78&ndash, 36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46&ndash, 27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.

Anemia is frequent in oncology. We debate the decision-making process of erythrocyte transfusion in palliative care situation from a case report. A patient with a prostatic metastatic cancer was in palliative situation with asthenia and coronary symptom. We analyze, in this particular case that does not describe reality of normal practice, the decision-making process of erythrocyte transfusion. These transfusions were based, in this case, on the evaluation of oncology prognosis, the short-term vital threats, life project and clinical safety of the transfusion. The patient has received 5 erythrocyte transfusions in 4 months until a multidisciplinary meeting decided to stop transfusion because of poor prognostic situation and bad tolerance of the act. This patient could be a collegial model used to measure the reasonable nature of prescription depending on the purpose and the goal of the patient but does not allow generalization. Although there is low risk of erythrocyte shortage, it seems important to train doctors to reduce abusive transfusion and define transfusion thresholds. Different levels of erythrocyte transfusion security would raise the issue of management of several stocks. Erythrocyte transfusion in palliative care can be considered subject to prognostic information and the palliative aim of the transfusions, multidisciplinary decision-making, during short hospitalizations and with evaluation of the act and consequences for the patient.

Le corticosurrenalome est un cancer peu chimiosensible. L’association mitotane et chimiotherapie par platine-etoposide constitue le standard therapeutique en premiere ligne metastatique. Le mitotane est un puissant inducteur du CYP3A4 de la BCRP et pourrait interagir avec l’etoposide (susbtrat du CYP3A4 et BCRP), et limiter son efficacite. Objectif Evaluer l’interaction pharmacocinetique entre mitotane et etoposide, et la faisabilite d’une escalade de dose d’etoposide. Patients et methodes Nous avons inclus 5 patients traites par platine-etoposide (120–150 mg/m2 J1J2J3 au premier cycle) pour un corticosurrenalome metastatique. En l’absence de toxicite, une escalade de dose progressive etait proposee des le deuxieme cycle. Les concentrations d’etoposide ont ete mesurees par chromatographie liquide 0, 4 et 24 heures apres chaque perfusion. Resultats Deux a 6 cycles de chimiotherapie ont ete administres, en association au mitotane (residuelle mediane 14,2 mg/L) pour 4 patients et apres arret du mitotane pour 1 patient (residuelle mediane 1 mg/L). La clairance de l’etoposide etait plus elevee sous mitotane (4,95 L/h [2,67–6,20]) que sans mitotane (2,53 L/h [2,02–2,78], Wilcoxon p = 0,014) ou que dans une population de reference (1,81 L/h). Une escalade de dose d’etoposide a ete realisee pour les 4 patients sous mitotane, avec 2 reponses tumorales mineures a 300 mg/m2 d’etoposide, et une toxicite severe (aplasie febrile). Discussion La prescription concomitante de mitotane entraine une sous-exposition plasmatique a l’etoposide, pouvant expliquer en partie son inefficacite aux doses standards. L’arret prealable du mitotane ou l’escalade de dose d’etoposide pourrait permettre d’augmenter l’efficacite de la chimiotherapie.

Resume L’arsenal therapeutique des cancers s’est considerablement etoffe avec le developpement des therapies ciblees. Parmi ces traitements, des molecules anti-angiogeniques inhibant la voie de l’angiogenese disposent deja d’une autorisation de mise sur le marche dans differentes indications. Le sorafenib, un des representants de cette classe, est indique dans le traitement du carcinome hepatocellulaire avance et du carcinome renal avance. Cet article fait le point sur le profil de tolerance du sorafenib et sur les modalites de prevention et de prise en charge des effets indesirables les plus frequemment rencontres.

On peut distinguer, dans l’organisation des soins, deux dimensions: la relation medecin (ou soignant)-soigne et les actes de soins. Ces deux aspects de la medecine sont totalement bouleverses depuis quelques annees: modifications legislatives, expression claire des nouvelles attentes des malades, reduction des ressources disponibles dans l’action. Relation, information et actes sont scandes par les prises de decision. Organiser la prise de decision conditionne toutes les autres organisations. Le medecin doit gerer le temps (augmentation exponentielle du nombre de malades, de leur vulnerabilite avec l’âge et appauvrissement de la population, reduction des conditions d’accueil et des moyens de reponse), les emotions (du malade, de l’entourage, des soignants, les siennes), le poids des responsabilites (la prise de decision et ses consequences, pour le malade, l’hopital, son service, pour la Securite sociale), l’evolution des attentes avec la montee en force du principe ethique d’autonomie aux depens du principe de bienveillance. Le medecin est amene a gerer des injonctions paradoxales: le malade reclame plus d’attention a sa personne tandis que ce temps est nie et chasse au profit de l’efficience organisationnelle vis-a-vis d’une suite d’actes. L’etablissement de soins lui demande des comptes sur son activite (les actes techniques), ses depenses (en personnel, en medicaments etmateriel), aucun sur la qualite reelle du soin et l’humanite du soin supposees aller de soi.

L’institut national du cancer encourage la mise en place de reunions de concertation de recours et de reseaux nationaux structures pour la prise en charge des cancers rares. Les osteosarcomes de l’adulte sont un exemple de maladie qui entre dans cette dynamique. L’objectif est de permettre une amelioration de la qualite des soins, une facilitation de l’acces aux expertises tres specialisees et une dynamisation de la recherche clinique. Les professeurs Gouin (orthopedie, Nantes) et Anract (orthopedie, Paris) coordonnent ce projet. Cet article est une revue centree sur la prise en charge de l’osteosarcome de l’adulte et ses specificites.

Les enzymes topo-isomerases I interviennent pour resoudre des contraintes topologiques de l’ADN. Les topo-isomerases I coupent transitoirement un seul des deux brins d’ADN et transferent l’autre brin au travers de la coupure transitoire, avant de relier. Les poisons de topo-isomerase I en clinique sont les derives de la camptothecine: irinotecan ou 7-ethyl-10-[4-(I-piperidino)-I-piperidino]carbonyloxy-camptothecine (Campto®), topotecan ou 9-(dimethylamino)methyl-10-hydroxycampto-thecine (Hycamtin®). Les principales proprietes pharmacologiques et cliniques des derives de camptothecine sont revues.

Patient information and advance directives (AD) are described in the French laws of 4 March 2002 and 22 April 2005, which concern the decisions of subjects regarding end-of-life treatment. At present, practitioners rarely seek the opinion of patients on this matter. The Claeys-Leonetti law requires doctors to identify any advance directives by patients, which are binding upon medical staff. The present study sought to analyse the extent of application of the laws of 2002 and 2005 and to collect the observations of clinicians in dermato-oncology regarding the new legislation.We contacted members of the French dermato-oncology group by email and asked them to assess their practices with regard to information provision, patient surrogates and advance directives.To 111 requests we received 34 replies from hospital dermatologists, i.e. a response rate of 31 %. In all, 85 % of clinicians informed patients with metastasis that their disease was incurable, and 94 % stated that they have procedures in place concerning the appointment of a patient surrogate. One third of respondents reported having a procedure in place for provision of information or collection of advance directives. According to 91 % of clinicians, the binding nature of advance directives did not constitute any loss of chance for the patient in question; 59 % felt that the new law would affect their practices, but of these, paradoxically, 60 % felt that this would have no impact on their therapeutic decision-making. In all, 26 clinicians (76.5 %) did not intend to modify their decision-making process.The law of 2002 is generally better known than that of 2005. Dermato-oncologists are not aware of the practical consequences of the new binding nature of advance directives with regard to the doctor-patient relationship and the actual decision-making process.

Pegylated liposomal doxorubicin (PLD) is widely used in relapsing ovarian carcinoma. Its original formulation is metabolized by the monocyte–macrophage system. One of its main toxicities is the palmoplantar erythrodysesthesia (PPE) syndrome. To date, no predictive factors of PPE have been identified. Data of patients (pts) treated with PLD between 2005 and 2014 were retrospectively collected. A case–control study was performed, comparing main baseline clinical and biological characteristics of pts experiencing PPE and those who did not, after at least three cycles of PLD. A pilot analysis of blood monocyte subpopulations (classical, intermediate and non-classical) was performed by FACS in selected pts. Among 88 pts treated with PLD, 28 experienced PPE of any grade (31, 95 % CI 21–41). The first occurrence of PPE was at first cycle in only 11 % of pts, peaked at cycle 2 (32 %) and represented 57 % of cases after cycle 3. Baseline characteristics of pts with PPE were compared to 27 control pts who received at least 3 cycles. Older pts represented 61 % of pts with PPE and 15 % of pts without PPE (p = 0.04 by Chi-square test). Monocyte count and inflammatory parameters were not associated with PPE. However, the analysis of monocyte subpopulations revealed a large inter-patient variability. Contrary to most acute toxicities, PPE occurred more frequently after several cycles, suggesting a PLD body accumulation through repeated cycles. PPE was more frequent in pts older than 70 years. Monocyte subpopulations may have different roles on PLD metabolism and warrant further studies.

To determine the biological reproducibility and estimate relevant covariates for candidate circulating biomarkers of angiogenesis, we conducted 3 sub-studies with ≤ 15 subjects each. In study 1, 6 healthy subjects provided 13 blood samples across 14–24 days. In study 2, 15 advanced solid tumor patients provided single blood samples before, and approximately 8 and 40 days after sorafenib treatment. In study 3, 4 healthy subjects provided blood samples on 3 occasions over 14 days, processed simultaneously in 2 different laboratories at a single institution. Vascular endothelial growth factor (VEGFA), soluble VEGF receptor-2 (sVEGFR2), and angiopoietin-2 (Ang2) concentrations in plasma and serum were determined by standard immunoassays. Ang2 and sVEGFR2 demonstrated low variance within and high variance across individuals reflected by the high intraclass correlation coefficient (for Ang2: 0.86 for plasma, 0.89 for serum; for sVEGFR2: 0.91 for plasma, 0.87 for serum). Repeated measures linear modeling from 15 patients demonstrated increased Ang2 (P ≤ 0.05) and decreased sVEGFR2 (P ≤ 0.05) after exposure to sorafenib. VEGFA had high intraindividual variance, and study 3 demonstrated the laboratory to have significant effects on plasma measurements (P ≤ 0.05). The biological reproducibility of sVEGFR2 and Ang2 support further use of these markers in studies of vasculature-targeted therapeutics.

Endometriosis is considered as a tumor-like lesion under the World Health Organization (WHO) classification of ovarian tumors. Data from large cohort and case-control studies indicate that patients with a history of endometriosis have an increased risk of ovarian cancer. Recent findings suggest an association between endometriosis and the entire type 1 ovarian tumors group including clear-cell, endometrioid and low-grade serous carcinomas. However, current evidence is lacking to draw definitive conclusion whether this association represents causality or the sharing of common risk factors. Nevertheless, assumption that endometriosis could be a precursor of malignancy raises many issues about serial screening, surgical management and surveillance of endometriosis. Beyond these concerns, endometriosis-associated ovarian cancers seem to be a genuine clinical entity as regards clinicopathological features. In view of the high incidence of endometriosis (10 % of women of childbearing age), the low incidence of endometriosis-associated ovarian cancers and the psychological consequences for those women, systematic screening and surgical exploration seem very questionable in this context.

Resume Les metastases oculaires (MO) sont devenues moins rares depuis que les traitements systemiques de certains cancers permettent de prolonger la survie des patients. Les cancers les plus frequemment en cause sont les cancers du sein pour lesquels la frequence des localisations ophtalmiques atteindrait selon certains auteurs 30%, avec une prevalence de 11 000 cas par an aux Etats-Unis. Le cancer du sein est suivi par ordre de frequence du cancer bronchique et des adenocarcinomes metastatiques de primitif inconnu. Le diagnostic doit etre suspecte precocement devant l'apparition d'une baisse de l'acuite visuelle ou de tout autre symptome oculaire. Le diagnostic est confirme par le fond d'œil, l'echographic orbitaire, la tomodensitometrie, l'imagerie par resonance magnetique et la biopsic lorsqu'elle est possible. Le traitement local repose sur la radiotherapie qui permet une recuperation suffisante de l'acuite visuelle dans 72 a 94% des cas traites precocement. Le diagnostic et le traitement precoce des MO des cancers participent a l'amelioration de la qualite de vie des patients ayant un cancer metastase. Nous rapportons quatre observations de patientes ayant une metastase ophtalmique d'un cancer du sein.

Combinations of topoisomerase I (topo I) poisons and platinum derivatives have synergistic antitumoral effects. However, their clinical development is limited by supra-additive haematological toxicity. The aim of this study was to determine whether sustained doses of topotecan and oxaliplatin could be achieved using a synergistic sequence. 34 advanced cancer patients and 186 cycles were evaluable for toxicity over five dosing levels. Oxaliplatin at 85-110 mg/m(2) was given on day 1, followed by topotecan 0.5-1.25 mg/m(2)/day x 5 from day 1 to 5, every 3 weeks. Plasma pharmacokinetics (PK) of total and ultrafiltrable platinum, total and lactone forms of topotecan were determined in the first cycle. The dose-limiting toxicity (DT) was identified as grade 4 thrombocytopenia. The occurrence of grade 4 thrombocytopenia did not correlate with topotecan PK, but it did with the patient's characteristics. Severe thrombocytopenia was seen in 1/8 of patients without clinical or biological evidence of malnutrition, with a creatinine clearance higher than 1 ml/s, and no more than two previous chemotherapy regimens, while it was seen in 8/10 patients with one of these characteristics (P0.004). In conclusion, the recommended doses of oxaliplatin 110 mg/m(2) and topotecan 1 mg/m(2)/day, every 3 weeks can be administered to patients with a favourable general status and pretreatment characteristics and a phase II study is worthwhile in ovarian cancer patients.

The treatment of malignancies in transplanted patients has become an emerging issue. The anticancer agent CPT-11 is hydrolysed to the active metabolite SN-38 and many drugs interact with its metabolism and toxicity.We studied the clinical and pharmacological interactions between CPT-11 and FK506 in a liver transplant patient. Serial plasma samples of FK506, CPT-11, SN-38 and SN-38 glucuronide were assayed by high-performance liquid chromatography.While no CPT-11 toxicity was observed pre-operatively, several post-operative cycles of CPT-11 were complicated with severe diarrhea. No change in FK506 plasma concentrations was noted in the presence of CPT-11 but the pharmacokinetics of CPT-11 was altered in the presence of FK506. SN-38 glucuronidation was reduced for up to 12 hours following CPT-11 infusion. This increase in plasmatic exposure to unbound SN-38 might account for diarrhea.The starting dose of CPT-11 should be reduced in FK506-treated liver transplant patients.

Aim: The WHO Performance Status (PS) of cancer patients (pts) correlates with survival and with anticancer treatments tolerability. However, PS is subject to inter-observer variability and is not sensitive to detect pts with high-risk of treatment toxicity. We studied the relationship between Rest Metabolic Rate (RMR) and PS. Methods: A prospective observational, monocentric study was conducted. Before treatment initiation, RMR was measured using indirect calorimetry (Fitmate®, Cosmed srl) and compared to estimated RMR obtained by the modified Harris and Benedict equation. Hypermetabolics (Hm) pts were defined as having measured RMR ≥110% of calculated RMR and Not Hypermetabolics (NoHm) pts Results: A total of 161 consecutive pts were analyzed : 58% males, median age : 64 years (20-94). Primary tumor: genito-urinary (23%) gastro-intestinal (20%), lung (17%); 10% were PS ≥3; median weight loss : 4.1% (-14.9–+18.5); mean energetic gap: +80 kcal/d; mean RMR : 1676 kcal/d; 60% of the pts were Hm with mean RMR= 1815 kcal/d vs 1433 kcal/d in NoHm pts (P 5% in 52% vs 32% of the pts (p = 0.03). Hm pts had more inflammation: a1-GP 1.5 vs 1.1 g/L (t=3.41, p Conclusions: Hypermetabolism may account for cancer-induced asthenia and development of cachexia. The measurement of RMR allows to detect pts at high-risk of malnutrition amongst pts with PS Disclosure: All authors have declared no conflicts of interest.

Aim: Lean body mass (LBM) better than body surface area (BSA), predicts epirubicin's clearance and its toxicity in breast cancer patients (pts) (Prado et al, 2010). Since the dose-intensity of anthracycline-based chemotherapy may be critical in sarcoma pts, we studied whether sarcopenia was associated with the occurrence of acute severe toxicity (AT) in this population. Methods: Sarcoma pts treated with doxorubicin-based chemotherapy and having a CT scan at the 3rd lumbar vertebrae prior chemotherapy were selected. Skeletal muscle cross-sectional area were measured and sarcopenia was defined using standardized thresholds (Antoun et al, 2010.). Acute severe toxicity was defined as any grade 4 toxicity or febrile neutropenia (FN) or grade≥3 gastrointestinal (GI) toxicity, according to the NCI-CTC occurring at 1st cycle. Sarcopenic and non-sarcopenic pts were compared (k-2 test or Fischer's exact test for qualitative data). Results: 42 consecutive soft tissue (n=24; 57%) and bone sarcoma (n=18; 43%) pts were eligible (57.1% males, median age 48yrs, range 22-68), and received a median doxorubicin dose of 112 mg at first cycle (range 84-148). 24 pts (57.1%) were sarcopenic at baseline. 13 (54%) of the sarcopenic patients had a normal body mass index (BMI), 11 (46%) were overweight. During the first cycle, AT were hematologic (11 pts 26.2%), FN (8 pts 19.0%), and GI toxicity (6 pts 14.3%). Sarcopenic pts had significantly more ATs (11/24 versus 3/18, p=0.04), more grade 4 hematotoxicity (9/24 versus 2/18, p=0.05), more FN (7/24 versus 1/18, p=0.05). Pts with sarcopenia and BMI Conclusions: The evaluation of sarcopenia prior to doxorubicin-based chemotherapy in sarcoma patients identifies patients with high-risk of acute toxicity. Disclosure: All authors have declared no conflicts of interest.

Oxaliplatin is approved in Europe for the treatment of metastatic colorectal cancer patients. Its antitumor activity in other solid tumors is ongoing evaluation and is already well established by randomized phase II studies in ovarian cancer. Phase II trials have also suggested a potential role for oxaliplatin in the treatment of non small cell lung cancers, breast cancers and other malignant diseases. Its large spectrum of anticancer activity is explained at least in part by its cytotoxicity in mismatch repair deficient cells. The absence of nephrotoxicity, the low hematotoxicity and the in vitro synergy with antimetabolites, platinums and topoisomerase I inhibitors suggest new chemotherapy combinations, many of them being ongoing evaluation.

Chronotherapy has consisted in the adaptation of chemotherapeutic drug delivery to circadian (approximately 24-hour) rhythms. This can be achieved in fully ambulatory patients using multichannel programmable pumps. Up to approximately 1500 patients with metastatic colorectal cancer have been registered in one of 15 trials testing the relevance of this treatment method with 5-fluorouracil +/- leucovorin +/- oxaliplatin. Chronotherapy was shown as significantly less toxic and more effective than constant rate infusion in 2 consecutive multicenter trials. High efficacy and good tolerability permitted secondary surgical resection of previously inoperable metastases, with apparent survival improvement (3-year survivalor = 20%) and cures in some patients. This strategy is currently undergoing further testing within the European Organization for Research and Treatment of Cancer. Nevertheless, combining chronotherapy with surgery of colorectal cancer metastases can be readily offered to patients as a safer therapeutic option for optimizing outcome.

Ecteinascidin 743 (Et743; NSC 648766) is a potent antitumor agent presently in clinical trials. Et743 selectively alkylates guanine N2 from the minor groove of duplex DNA and bends the DNA toward the major groove. This differentiates Et743 from other DNA-alkylating agents presently in the clinic. To date, the cellular effects of Et743 have not been elucidated. Recently, Et743 DNA adducts have been found to suppress gene expression selectively and to induce topoisomerase I (top1) cleavage complexes in vitro and top1-DNA complexes in cell culture. In the present study, we characterized the DNA damage and the cell cycle response induced by Et743 in human colon carcinoma HCT116 cells. Alkaline elution experiments demonstrated that micromolar concentrations of Et743 produced comparable frequencies of DNA-protein cross-links and DNA single-strand breaks. The single-strand breaks were protein-cross-linked and were not associated with detectable DNA double-strand breaks. By contrast with camptothecin, these lesions persisted for several hours after drug removal and were not formed at 4 degrees C. Et743 treatment induced transient p53 elevation, dose-dependent cell cycle accumulation in G2-M and in G1- and S-phase, and inhibition of DNA synthesis. The sensitivity of camptothecin-resistant mouse leukemia P388/ CPT45 cells, which fail to express detectable top1, was similar to the sensitivity of wild-type P388 cells, suggesting that top1 is not a critical target for the antiproliferative activity of Et743.

CPT-11, a DNA topoisomerase I inhibitor, and oxaliplatin, a diaminocyclohexane platinum derivative, are cytotoxic agents that have demonstrated clinical antitumor activity in colorectal cancer. Given the therapeutic potential of their combination, we studied the cellular pharmacology of SN-38, the active metabolite of CPT-11, and oxaliplatin in the human colon cancer HT29 cell line. Growth inhibition was studied after a 1- or 24-h exposure to SN-38 or oxaliplatin, given alone or in combination. The cytotoxicity analysis by the isobolograms method elicited synergy. SN-38 delayed the reversion of oxaliplatin-induced DNA interstrand cross-links (ISCs), measured in cells by alkaline elution. The amount of detectable ISCs 15 h after a 1-h exposure to 10 microm oxaliplatin was 27% of the ISC peak levels and increased to 68% in the presence of 0.1 microM SN-38. The presence of oxaliplatin DNA adducts led to a 3.3-fold increase in the SN-38-induced DNA elongation inhibition, as measured by pulse-labeling alkaline elution. Inhibition of DNA and RNA synthesis was longer after exposure to the combination of oxaliplatin and SN-38 than after exposure to each agent alone. Consistently, flow cytometry analyses revealed that preexposure to oxaliplatin enhanced SN-38-induced S-phase arrest. Filter binding assays indicated that the cells arrested in S-phase at 48 h were undergoing apoptosis. Hence, supra-additive cytotoxicity appears related to major modifications in the cellular response to DNA damage rather than to changes in DNA damage formation. The combination of CPT-11 and oxaliplatin induced a 2-fold higher tumor growth reduction in vivo than did oxaliplatin alone at feasible nonlethal doses. This study provides a rationale for the optimal use of CPT-11 and oxaliplatin in combination.

Previous cell line comparisons indicated that neither S-phase fraction nor topoisomerase I (top1) levels are sufficient to predict camptothecin (CPT) cytotoxicity (F. Goldwasser el al., Cancer Res., 55: 2116-2121, 1995.). To identify new determinants for CPT activity, two mutant p53 human colon cancer cell lines, SW620 and KM12, that were previously reported to have similar top1 levels and differential sensitivity to CPT were studied. No difference in the kinetics of top1-mediated DNA single-strand breaks or DNA synthesis inhibition were observed after 1 h exposure to 1 microM CPT. Pulse-labeling alkaline elution showed deficiency of damaged replicon elongation in the more sensitive SW620 cells. Consistentiy, flow cytometry analyses showed that KM12 was arrested in G2, whereas SW620 cells were irreversibly blocked in S phase. Aphidicolin protection was minimal in KM12 and more pronounced in the more sensitive SW620 cells. Thus, CPT appears to have two cytotoxic mechanisms, one protectable by aphidicolin and present in SW620 and the other not protectable by aphidicolin and common to both cell lines. SW620 exhibited also a greater capacity to break through the G2 checkpoint after DNA damage. Consistently, SW620 cells failed to down-regulate cyclin B-cdc2 kinase activity, whereas KM12 cells down-regulated cyclin B/cdc2 kinase activity within 30 min to 20 % of control level after CPT treatment. Analysis of the 7 human colon carcinoma cell lines of the NCI Anticancer Drug Screen showed that defects in replicon elongation and G2 breakthrough capability correlate with sensitivity to CPT. Our results suggest that misrepair of damaged replicons and/or alterations in DNA damage checkpoints is critical to defining chemosensitivity to CPT-induced top1-cleavable complexes and that CPT appears to have two cytotoxic mechanisms, one protectable by aphidicolin, and the other not.

Camptothecin (CPT) derivatives are presently in ongoing Phase I/II clinical trials. The interactions between 9-aminocamptothecin (9AC) and cisplatin (CDDP) have been studied in the IGROV-1 human ovarian cancer cell line used in the National Cancer Institute Drug Discovery Anticancer Screen. One-h simultaneous treatment with 9AC and CDDP produced synergistic cytotoxicity. Under these conditions, 9AC delayed the reversal of CDDP-induced DNA interstrand cross-links (ISCs) without modifying the maximum ISC frequency at 6 h after drug treatment. CDDP did not affect the amount and the kinetics of reversion of 9AC-induced DNA single-strand breaks. Simultaneous treatment with CDDP and 9AC prolonged the DNA synthesis inhibition produced by each drug alone. Consistently, flow cytometry analyses showed enhanced S-phase arrest in cells treated with the CDDP-9AC combination. The DNA polymerase inhibitor aphidicolin also increased the residual CDDP-induced ISCs. These results suggest that prolonged inhibition of DNA synthesis by CPTs potentiate the cytotoxicity of CDDP by inhibiting the reversal of CDDP-induced DNA damage. Therefore, the combination of CPTs and CDDP appears to be worthwhile in cancer chemotherapy.

We report a case of non-Hodgkin's lymphoma (NHL) successfully treated with combination chemotherapy during pregnancy. The histological diagnosis was large-cell B-type NHL. Four courses of chemotherapy with epirubicin, vincristine and prednisolone were given before delivery. The patient is in complete remission and her baby, now four years old, has developed normally. To our knowledge, this is the first reported case of epirubicin administration during pregnancy and in which chemotherapy was given safely to NHL patients during the second and third trimester of pregnancy.