Quick, non-invasive and quantitative assessment of small fiber neuropathy in patients receiving chemotherapy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4%), Paclitaxel only (14.8%), another drug only (28.4%) or two drugs (11.4%) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin mean hands ESC changed from 73 ± 2 to 63 ± 2 and feet ESC from 77 ± 2 to 66 ± 3 µS (p < 0.001) while TNSc changed from 2.9 ± 0.5 to 4.3 ± 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 ± 2 and 73 ± 2 µS respectively while they were 59 ± 1.4 and 64 ± 1.5 µS with a corresponding TNSc ≥ 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.

A clinical experience of single agent bevacizumab in relapsing ovarian cancer.

OBJECTIVE: The objective of this study is to report the efficacy and tolerance of single agent bevacizumab (BEVA) in relapsing ovarian cancer patients treated in a single institution outside a clinical trial. METHODS: To receive single agent BEVA, patients must have to relapse after at least one previous line of chemotherapy and to not have clinical conditions associated with high risk of gastrointestinal perforation. Dose-intensity of BEVA was 2.5mg/kg/week. RESULTS: 37 previously treated patients (33 with platinum resistant disease) were included in this retrospective analysis. The median number of BEVA infusion by patient was 5 (range: 1-61). The most frequent adverse effect was arterial hypertension, observed in 23 patients (62%), including 11 with G3 (30%) and 1 with G4. No intestinal perforation was reported. Tumor response rate according to CA 125 level (GCIG criteria) was 37% (11 of 30 patients). The median PFS and OS were 4 (range: 1 to +56) and 16 (range: 1 to +65) months (ms), respectively. 12-ms PFS was 25% (95% CI: 11-39%). The PFS tended to be better in patients who experienced grade 3-4 arterial hypertension during the first month of treatment (median: 10ms) compared to patients who did not (median: 3ms) (HR: 0.49 (95% CI: 0.18-1.03), p=0.06 by log rank test). CONCLUSION: Single agent BEVA could be a reasonable option with favorable therapeutic index in pretreated ovarian cancer patients who do not want to suffer the side effects of chemotherapy provided to exclude those with high risk of intestinal perforation and carefully monitor blood pressure.

High-dose irinotecan plus LV5FU2 or simplified LV5FU (HD-FOLFIRI) for patients with untreated metastatic colorectal cancer: a new way to allow resection of liver metastases?

UNLABELLED: The antitumor efficacy of irinotecan may be dose dependent. This study aimed to determine the safety and efficacy of high-dose (HD) irinotecan combined with LV5FU2 or simplified LV5FU (LV5FUs) in first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Patients with unresectable and measurable metastatic colorectal cancer, not pretreated for metastatic disease, were given irinotecan 260 mg/m(2) combined with LV5FU2 in the first 25 patients, then with LV5FUs (HD-FOLFIRI) in 35 patients. G-CSF was given in case of febrile neutropenia, grade 4 neutropenia >7 days or neutropenia grade >1 at day 15. RESULTS: The response rate was 57% (95% confidence interval 43-69%). Second surgery with curative intent was performed in 28% of patients, leading to 20% radiological complete response. Median response duration, time to progression and overall survival were 11, 9 and 22 months, respectively. The median dose intensity of irinotecan was 117 mg/m(2)/week. G-CSF was given to 45% of patients over 33% of cycles. Usual toxicity of irinotecan and 5-FU were observed without major increased frequency, except hematological toxicity. Tolerance was similar with LV5FU2 and LV5FUs, though more asymptomatic grade 3-4 neutropenia was observed with LV5FU2. CONCLUSION: HD-irinotecan plus LV5FU2 or HD-FOLFIRI is feasible and achieved a high response rate and postsurgery complete response rate.

Oxaliplatin combined with 5-FU in second line treatment of advanced pancreatic adenocarcinoma. Results of a phase II trial.

BACKGROUND: The efficacy and benefit of second-line chemotherapy in advanced pancreatic adenocarcinoma has never been demonstrated although it is regularly used. PATIENTS AND METHODS: A randomized phase II study evaluating oxaliplatin alone (OXA), infusional 5-fluorouracil alone (5-FU) and an oxaliplatin/infusional 5-FU combination (OXFU) in untreated advanced pancreatic adenocarcinoma has been conducted. In this trial, a second-line treatment with the OXFU regimen (OXA 130 mg/m2 2-h intravenous (i.v.) infusion combined with 5-FU (1000 mg/m2/day, continuous i.v., days 1-4), every 3 weeks) was offered to patients progressing after single agent treatment. RESULTS: Eighteen out of 32 patients (12 males, median age 57 years) treated in the single agent arms received the OXFU combination in second-line treatment. WHO performance status was at least 2 in 61% of the patients. There was no objective response and 3 patients (17%) had a disease stabilisation. Median time to progression from the start of second-line treatment was 0.9 months. Median overall survival was 4.9 months from the start of front-line therapy and 1.3 months from the start of second-line therapy. CONCLUSION: The results of this trial bring arguments to support a modest value of second-line chemotherapy for advanced pancreatic adenocarcinoma.

Risk factors for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia over time: assessment of monocyte count and baseline clinical parameters.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Investigational therapies up to Phase II which target PDGF receptors: potential anti-cancer therapeutics.

INTRODUCTION: The platelet-derived growth factor receptor (PDGFR) pathway has important functions in cell growth and, by overexpression or mutation, could also be a driver for tumor development. Moreover, PDGFR is expressed in a tumoral microenvironment and could promote tumorigenesis. With these biological considerations, the PDGFR pathway could be an interesting target for therapeutics. Currently, there are many molecules under development that target the PDGFR pathway in different types of cancer. AREAS COVERED: In this review, the authors report the different molecules under development, as well as those approved albeit briefly, which inhibit the PDGFR pathway. Furthermore, the authors summarize their specificities, their toxicities, and their development. EXPERT OPINION: Currently, most PDGFR kinase inhibitors are multikinase inhibitors and therefore do not simply target the PDGFR pathway. The development of more specific PDGFR inhibitors could improve drug efficacy. Moreover, selecting tumors harboring mutations or amplifications of PDGFR could improve outcomes associated with the use of these molecules. The authors believe that new technologies, such as kinome arrays or pharmacologic assays, could be of benefit to understanding resistance mechanisms and develop more selective PDGFR inhibitors.

Combination of topotecan and oxaliplatin in inoperable hepatocellular cancer patients.

Unresectable hepatocellular carcinoma (UHCC) is considered a chemoresistant disease. Moreover, because the liver underlies the disease, it decreases the tolerance to anticancer agents. Topotecan has shown some clinical activity in UHCC using the 5 days every 3 weeks schedule but is limited by severe hematotoxicity. Oxaliplatin is a diamino-cyclo-hexane-platin that exhibits in vitro synergy with topotecan. Thirteen UHCC patients received topotecan (0.5-1.5 mg/m(2) /d days 1-5) and oxaliplatin (85-110 mg/m(2) /d, day 1) every 21 days. All patients had liver biology within normal limits; 11 had World Health Organization performance status less than 2. Seven patients had received previous chemotherapy. Nine patients without cirrhosis received a median number of six cycles (range: 3-12). The main dose-limiting toxicity was severe thrombocytopenia observed in three patients and 4% of cycles. One objective response and eight stabilizations were observed. Conversely, among 4 patients with cirrhosis receiving a median number of 2.5 cycles (range: 1-6), severe thrombocytopenia occurred in 2 patients and 25% of cycles. Three patients with progressive disease and one with stabilization were observed. Overall, the median duration of stabilizations was 27 weeks (range: 16-97 weeks). Four of seven patients treated with 1 mg/m(2) /d or more topotecan experienced severe toxicity. These results warrant a phase II study of this combination in noncirrhotic patients with UHCC. The recommended doses for further studies should be 0.5 mg/m(2) /d to 0.75 mg/m(2) /d of topotecan with 85 mg/m(2) of oxaliplatin.

Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules.

BACKGROUND: New therapies are needed to improve the prognosis of patients with advanced hepatocellular carcinoma (HCC). Various gemcitabine-oxaliplatin combinations have been tested recently in patients with ovarian and pancreatic carcinoma, yielding interesting results with little toxicity. Therefore, the authors evaluated the activity and toxicity of two such combinations in patients with HCC. METHODS: Twenty-one patients were enrolled prospectively in the study. Eleven patients received gemcitabine 1000 mg/m2 on Day 1 and oxaliplatin 100 mg/m2 on Day 2 (GEMOX-1), and 10 patients received gemcitabine 1500 mg/m2 on Day 1 followed by oxaliplatin 85 mg/m2 on Day 1 (GEMOX-2). Treatment was repeated every 2 weeks until disease progression developed or until unacceptable adverse effects occurred. RESULTS: All patients were assessable for response and toxicity. Four patients (19%) achieved objective responses (95% confidence interval, 13-26%), including 3 patients in the GEMOX-1 group and 1 patient in the GEMOX-2 group. Ten patients (48%) had stable disease, and 7 patients (33%) experienced disease progression. The median progression-free survival was 5 months, and the median overall survival was 12 months. Fifty-four percent of patients in the GEMOX-1 group and 50% of patients in the GEMOX-2 group had received previous systemic chemotherapy or cisplatin-based chemoembolization. Grade 3-4 hematologic toxicity, according to National Cancer Institute Common Toxicity Criteria, consisted of thrombocytopenia (GEMOX-1 vs. GEMOX-2, 18% vs. 40%) and neutropenia (0% vs. 30%). No Grade 3-4 nonhematologic toxicity was observed, except for 1 episode of Grade 3 diarrhea. Grade 1 neurotoxicity and Grade 2 neurotoxicity (specific scale), respectively, were observed in 4 patients and 7 patients receiving GEMOX-1 and in 7 patients and 1 patient receiving GEMOX-2. CONCLUSIONS: Gemcitabine-oxaliplatin combination therapy is feasible in patients with advanced HCC. The GEMOX-1 regimen was tolerated better than the GEMOX-2 regimen. Currently, the GEMOX-1 regimen is being evaluated in a Phase II study in previously untreated patients with HCC.