Catherine Lhommé

Malignant effusions and immunogenic tumour-derived exosomes.

BACKGROUND Exosomes derived from tumours are small vesicles released in vitro by tumour cell lines in culture supernatants. To assess the role of these exosomes in vivo, we examined malignant effusions for their presence. We also investigated whether these exosomes could induce production of tumour-specific T cells when pulsed with dendritic cells. METHODS We isolated exosomes by ultracentrifugation on sucrose and D(2)O gradients of 11 malignant effusions. We characterised exosomes with Western blot analyses, immunoelectron microscopy, and in-vitro stimulations of autologous T lymphocytes. FINDINGS Malignant effusions accumulate high numbers of membrane vesicles that have a mean diameter of 80 nm (SD 30). These vesicles have antigen-presenting molecules (MHC class-I heat-shock proteins), tetraspanins (CD81), and tumour antigens (Her2/Neu, Mart1, TRP, gp100). These criteria, including their morphological characteristics, indicate the similarities between these vesicles and exosomes. Exosomes from patients with melanoma deliver Mart1 tumour antigens to dendritic cells derived from monocytes (MD-DCs) for cross presentation to clones of cytotoxic T lymphocytes specific to Mart1. In seven of nine patients with cancer, lymphocytes specific to the tumour could be efficiently expanded from peripheral blood cells by pulsing autologous MD-DCs with autologous ascitis exosomes. In one patient tested, we successfully expanded a restricted T-cell repertoire, which could not be recovered carcinomatosis nodules. INTERPRETATION Exosomes derived from tumours accumulate in ascites from patients with cancer. Ascitis exosomes are a natural and new source of tumour-rejection antigens, opening up new avenues for immunisation against cancers.

Cutaneous side-effects of kinase inhibitors and blocking antibodies.

Although kinase inhibitors raise hope for people with cancer, patients and their clinicians are commonly confronted with the cutaneous side-effects that are associated with the use of these drugs. This review is the result of collaborations between dermatologists, medical oncologists, and pathologists, and discusses the cutaneous side-effects seen after treatment with the inhibitors of epidermal-growth-factor receptor (EGFR), imatinib, sorafenib, and sunitinib. Some of the side-effects caused by these agents are very distressing, partly because they are chronic owing to the long duration of treatment. Therefore, patients need early and appropriate dermatological management. Moreover, several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side-effects. Elucidation of this connection could lead to the identification of crucial predictive factors for tumour response.

Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.

BACKGROUND Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. METHODS For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. FINDINGS 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). INTERPRETATION Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. FUNDING Amgen.

The growing teratoma syndrome: results of therapy and long-term follow-up of 33 patients

Growing teratoma syndrome (GTS) is defined as an increase in tumour size during or after chemotherapy for germ cell tumour (GCT), and only mature teratoma at histological analysis of the resected tumour specimen. Between 1985 and 1997, 30 male patients fulfilling GTS criteria were included in the present study. 3 female patients were also included but analysed separately. A mature teratoma component was found in 86% of the primary GCT. 3 male patients (10%) had a complication at diagnosis of GTS. One male patient (4%) having undergone complete resection (n=24) had a recurrent GTS, compared with all but 1 patient (83%) in whom resection was partial (n=6) (P<0.001). 2 (8%) and 3 (50%) male patients treated with complete and partial resection subsequently developed a malignant NSGCT respectively (P=0.01). 2 female patients treated with partial resection presented a recurrent GTS. One of them died of this recurrent GTS. GTS is an entity in its own right with respect to complications and the natural history of the disease. Complete surgical resection is the treatment of choice for GTS.

Antimüllerian hormone as a serum marker of granulosa cell tumors of the ovary: Comparative study with serum α-inhibin and estradiol ☆ ☆☆ ★ ★★

OBJECTIVE Our purpose was to evaluate serum antimüllerian hormone as a marker for granulosa cell tumors. STUDY DESIGN Serum antimüllerian hormone concentrations were determined in 16 patients with an adult-type granulosa cell tumor; in female patients with ovarian adenocarcinoma, benign ovarian cysts, or extraovarian cancers; and in normal premenopausal and postmenopausal women. Serum antimüllerian hormone, alpha-inhibin, and estradiol levels were compared in 10 patients with a granulosa cell tumor during 6 to 47 months of follow-up. RESULTS Serum antimüllerian hormone was undetectable in normal postmenopausal women and was <5 micrograms/L in premenopausal women. Normal serum levels were found in patients with ovarian cancers or cysts or with extraovarian cancers. Levels were between 6.8 and 117.9 microg/L in eight of nine patients with a progressive granulosa cell tumor. In the remaining case antimüllerian hormone, alpha-inhibin and estradiol concentrations were normal. Serum antimüllerian hormone and alpha-inhibin levels became elevated at least 11 months before the recurrence was clinically detectable. During clinical remission serum antimullerian hormone, beta-inhibin, and estradiol were normal in most cases. CONCLUSION Serum antimüllerian hormone is a sensitive, specific, reliable marker of adult-type granulosa cell tumors and is useful to evaluate the efficacy of treatment and to detect recurrences early.

Combined radiotherapy and surgery: local control and complications in early carcinoma of the uterine cervix — the Villejuif experience, 1975–1984

From January 1975 to December 1984, 441 patients were treated by combined radiotherapy and surgery at the Institut Gustave Roussy (IGR) for Stage IB (288) and II (proximal) (103) carcinoma of the uterine cervix. Standard treatment consisted of pre-operative utero-vaginal brachytherapy (60 Gy) using a mould technique followed by a colpo-hysterectomy and external iliac lymphadenectomy. Overall 5 year actuarial survival for the whole population was 87% and disease-free survival 85%. Loco-regional relapse occurred in 23 patients (5%). Of these, 12 were central pelvic failures, 8 regional failures and 3 combined central and regional failures. There were 36 systemic relapses (8%) of which 12 relapsed concurrently in the pelvis. Five year actuarial pelvic disease-free, disease-free and overall survival was 87, 85 and 87%, respectively, for the whole population. 340 patients developed one or more complications [Grade 1: 198/441 (44%), Grade 2: 121/441 (27%) and Grade 3 or 4: 21/441 (4.7%)]. Five year actuarial survival for the whole population was poorer for histologically node positive than for node negative (89 vs. 55%, p less than 0.0001). Pre-operative brachytherapy followed by surgery can provide good local control with acceptable morbidity in early cervical cancer.

Phase III Study of Valspodar (PSC 833) Combined With Paclitaxel and Carboplatin Compared With Paclitaxel and Carboplatin Alone in Patients With Stage IV or Suboptimally Debulked Stage III Epithelial Ovarian Cancer or Primary Peritoneal Cancer

PURPOSE To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer. PATIENTS AND METHODS Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m(2), and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m(2) and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability. RESULTS With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC-and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC-treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions. CONCLUSION The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.

Value and cost evaluation of routine follow-up for patients with clinical stage I/II endometrial cancer

The aim of the study was to determine the value and the costs of routine follow-up for the detection of recurrences in patients treated for endometrial cancer. Between 1986 and 1995, 390 women with clinical stage I/II endometrial carcinoma were treated with combined surgery-radiation therapy. After treatment, follow-up was based on the clinical examination, a systematic Papanicolaou (Pap) smear and radiography (chest X-ray and abdomino-pelvic ultrasonography). 27 patients relapsed: 22 patients had symptoms and 5 were asymptomatic. None of the patients had recurrence detected on the routine Pap smear nor on the systematic chest X-ray. In conclusion, the follow-up of patients treated for endometrial cancer based on routine Pap smears and systematic radiography does not permit earlier detection of recurrences. Follow-up should simply include a clinical examination whose frequency should be based on prognostic factors. Approximately two-thirds of this cost was due to systematic examinations (Pap smears and radiography). Our results indicate that such expenditure could be avoided.

Guidelines for the management of ovarian cancer during pregnancy

Adnexal masses may be detected during prenatal ultrasound, and ovarian cancer may be suspected during pregnancy. Even though such masses are rarely malignant (1/10,000 to 1/50,000 pregnancies), the possibility of borderline tumour or cancer must be considered. It is a common assumption by both patients and physicians that if an ovarian cancer is diagnosed during pregnancy, treatment necessitates sacrificing the well-being of the fetus. However, in most cases, it is possible to offer appropriate treatment to the mother without placing the fetus at serious risk. The care of a pregnant woman with cancer involves evaluation of sometimes competing maternal and fetal risks and benefits. These recommendations attempt to balance these risks and benefits; however, they should be considered advisory and should not replace specific interdisciplinary consultation with specialists in maternal-fetal medicine, gynecologic oncology and pediatrics, as well as imaging and pathology, as needed. Second level ultrasound including Doppler is needed. MRI is not often necessary, and CA 125 is of low contribution. We suggest surgery be performed after 15 weeks gestation for ovarian masses which (1) persist into the second trimester, (2) are greater than 5-10 cm in diameter, or (3) have solid or mixed solid and cystic ultrasound characteristics. During the antepartum period surgical staging and debulking, unilateral salpingo-oophorectomy on the side with the tumour, peritoneal cytology and exploration are necessary. Women found to have advanced stage epithelial ovarian cancer should consider having completion of the debulking of the reproductive organs at the conclusion of the pregnancy. If chemotherapy is indicated, we recommend delaying administration, if possible, until after the delivery or at least after 20 weeks in order to minimize the potential fetal toxicity.

A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma

OBJECTIVES Sorafenib, an oral multikinase inhibitor of the VEGFR/PDGFR/Raf/MEK/ERK pathway, has shown potential activity in patients with recurrent ovarian cancer (OC). One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response. A double-blind, randomized, placebo-controlled, phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented. METHODS Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg BID or matching placebo. The primary endpoint was progression-free survival (PFS). RESULTS Of 246 randomized patients, 93% had OC; baseline characteristics were balanced between treatment arms. There was no significant difference between sorafenib and placebo arms for PFS (median 12.7 vs 15.7 months; hazard ratio 1.09; 95% CI 0.72-1.63), although there was a notable imbalance in early censoring. The most common ≥ grade 3 adverse events (AEs) were hand-foot skin reaction (39.0% vs 0.8%) and rash (14.6% vs 0%). More patients receiving sorafenib versus placebo required dose reductions (67.5% vs 30.1%), resulting in a lower than planned median daily dose (median 584.6 vs 800.0mg). Treatment with sorafenib was of shorter duration (median 17.6 vs 51.9 weeks) with more frequent discontinuations due to AEs (37.4% vs 6.5%). CONCLUSIONS Sorafenib 400mg BID cannot be recommended as maintenance therapy for patients with OC in complete remission. Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations.