Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study.

BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

Preliminary experience with umbilical stoma in transumbilical single-port colorectal surgery.

BACKGROUND: The umbilicus, an embryological natural orifice, is increasingly used as the only access route during single-incision laparoscopic surgery (SILS) for colorectal disease. As a part of some of these procedures, a temporary, diverting ostomy could be exteriorized through the umbilicus itself. Theoretical advantages include better preservation of the abdominal wall and potentially superior cosmetic results. The aim of the present study was to evaluate our preliminary experience in SILS colorectal resection with umbilical stoma (u-stoma). METHODS: We retrospectively reviewed all colorectal patients operated using SILS for benign or malignant disease at Paris Poissy Medical Center. Patients were selected for consideration of u-stoma with our stoma therapists. RESULTS: Between January 2010 and December 2016, 234 patients underwent colorectal SILS procedures. In 74 patients (31.6%), an ileostomy (n = 41) or a colostomy (n = 33) was fashioned. Of these, 20 (27% of all ostomies) were umbilical stomas. The 20 u-stoma patients, 10 men and 10 women, received either a loop ileostomy (n = 14) or an end (n = 4) or loop (n = 2) colostomy. The mean age was 52 years (range 29-81 years). There was no mortality. Operative stoma-related morbidity occurred in only 5% of patients (n = 1: ileal torsion volvulus). Median follow-up after stoma formation was 30 months (range 12-59 months). Adjustment to the stoma and quality of life were satisfactory as estimated by both the patient and the stoma therapist. All stomas were reversed. At a median follow-up of 27.5 months (range 7-55 months) after stoma reversal, two patients had reoperation for incisional hernia. CONCLUSION: This preliminary experience showed that u-stoma is a feasible and safe alternative to more conventional ostomy after SILS.

Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.

Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours.

BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine. METHODS: This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates.

A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆.

BACKGROUND: Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). PATIENTS AND METHODS: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. RESULTS: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. CONCLUSION: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.

Assessing oncologic benefit in clinical trials of immunotherapy agents.

BACKGROUND: USA Food and Drug Administration approval for cancer therapy requires demonstration of patient benefit as a marker of clinical efficacy. Prolonged survival is the gold standard for demonstration of efficacy, but other end points such as antitumor response, progression-free survival, quality of life, or surrogate end points may be used. DESIGN: This study was developed based on discussion during a roundtable meeting of experts in the field of immunotherapy. RESULTS: In most clinical trials involving cytotoxic agents, response end points use RECIST based on the premise that 'effective' therapy causes tumor destruction, target lesion shrinkage, and prevention of new lesions. However, RECIST may not be appropriate in trials of immunotherapy. Like other targeted agents, immunotherapies may mediate cytostatic rather than direct cytotoxic effects, and these may be difficult to quantify with RECIST. Furthermore, significant time may elapse before clinical effects are quantifiable because of complex response pathways. Effective immunotherapy may even mediate transient lesion growth secondary to immune cell infiltration. CONCLUSIONS: RECIST may not be an optimal indicator of clinical benefit in immunotherapy trials. This article discusses alternative clinical trial designs and end points that may be more relevant for immunotherapy trials and may offer more effective prediction of survival in pivotal phase III studies.

[Pleuro-pericarditis developed under a leflunomide therapy]. / Pleuro-péricardite développée au décours d'un traitement par léflunomide.

Leflunomide is an immunosuppressant drug used in rheumatoid arthritis and psoriatic arthritis. This product may cause rare but serious interstitial lung disease that appear at the beginning of treatment. This is why leflunomide should be prescribed and monitored in hospital. We present the case of a 71 years old woman who presented a pleuro-pericarditis with an increase of CA 125 during a treatment with leflunomide. This is the second case reported in the literature. The outcome was favorable after discontinuation of leflunomide.

[Malignant pleural mesothelioma after radiation treatment for Hodgkin lymphoma]. / Mésothéliome pleural malin après irradiation pour maladie de Hodgkin.

Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the role of ionizing radiation is more controversial. We report the case of a 41-year-old male who developed pleural mesothelioma. He had both, a prior short asbestos exposure and a thoracic radiotherapy for Hodgkin's disease 26years before. The evidence for radiotherapy as cause for mesothelioma is expanding and the diagnosis of mesothelioma in patients who had previous irradiation should be kept in mind.

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer.

BACKGROUND: Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC). METHODS: Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH). RESULTS: Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes. CONCLUSIONS: The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting.

[Clonal eosinophilia revealed by recurrent Staphylococcus aureus infection]. / Hyperéosinophilie clonale révélée par une infection récurrente à Staphylococcus aureus.

Acquired eosinophilia is currently classified into secondary (reactional to underlying diseases), clonal (presence of a bone marrow histological, cytogenetic or molecular marker of a myeloid malignancy) and idiopathic (neither secondary nor clonal) categories. We report the case of a 47-year-old male who was admitted to the hospital for Staphylococcus aureus recurring infections. An hypereosinophilia was discovered and led to molecular analysis. The identification of FIP1L1-PDGFRA fusion gene permitted the diagnostic of clonal eosinophilia. Treatment by imatinib mesylate induced an haematological remission, the control of the infection and thoracotomy cicatrization. This case is original because of its infectious presentation and the efficacy of imatinib mesylate to control the infectious process.