Ayumu Matsuoka

Bevacizumab Exacerbates Paclitaxel-Induced Neuropathy: A Retrospective Cohort Study

Background Bevacizumab (BEV), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, enhances the antitumor effectiveness of paclitaxel (PTX)-based chemotherapy in many metastatic cancers. A recent study in mice showed that VEGF receptor inhibitors can interfere with the neuroprotective effects of endogenous VEGF, potentially triggering the exacerbation of PTX-induced neuropathy. In clinical trials, exacerbation of neuropathy in patients who received PTX combined with BEV (PTX+BEV) has generally been explained by increased exposure to PTX owing to the extended duration of chemotherapy. We investigated whether the concurrent use of BEV is associated with the exacerbation of PTX-induced neuropathy. Methods Female patients with breast cancer who had received weekly PTX or PTX+BEV from September 2011 through May 2016 were studied retrospectively. PTX-induced neuropathy was evaluated at the same time points (at the 6th and 12th courses of chemotherapy) in both cohorts. A multivariate Cox proportional-hazards model was used to assess the independent effect of BEV on the time to the onset of neuropathy. Results A total of 107 patients (median age, 55 years; range, 32–83) were studied. Sixty-one patients received PTX as adjuvant chemotherapy, 23 received PTX for metastatic disease, and 23 received PTX+BEV for metastatic disease. Peripheral sensory neuropathy was worse in patients who received PTX+BEV than in those who received PTX alone: at the 6th course, Grade 0/1/2/3 = 4/13/4/0 vs. 25/42/6/0 (P = 0.095); at the 12th course, 2/3/11/3 vs. 7/30/23/2 (P = 0.016). At the 12th course, the incidence of Grade 2 or higher neuropathy was significantly higher in patients treated with PTX+BEV than in those treated with PTX alone (74% vs. 40%; P = 0.017). In multivariate analysis, BEV was significantly associated with an increased risk of neuropathy (HR 2.32, 95% CI 1.21–4.44, P = 0.012). Conclusions The concurrent use of BEV could worsen PTX-induced neuropathy in patients with breast cancer.

Quantitative assessment of chemotherapy‐induced peripheral neurotoxicity using a point‐of‐care nerve conduction device

Chemotherapy‐induced peripheral neurotoxicity (CIPN) seriously impairs patients’ quality of life cumulatively and dose‐dependently. Because assessment of CIPN usually depends on patients’ subjective evaluation of symptoms, objective and quantitative measures are needed. We evaluated a point‐of‐care nerve conduction device (POCD), previously validated for the assessment of diabetic peripheral neuropathy. Sensory nerve action potential (SNAP) amplitude and sensory nerve conduction velocity (SNCV) of the sural nerve were measured using a portable, automated POCD (DPNCheck; NeuroMetrix Inc., Waltham, MA, USA) in patients with a clinical diagnosis of CIPN of grade 1 or higher. We compared SNAP and SNCV among patients with different grades of CIPN according to the Common Terminology Criteria for Adverse Events. A total of 50 patients (22 men, 28 women; median age, 64 years; grade 1/2/3, 21/18/11) were evaluated. Anticancer drugs responsible for CIPN were cisplatin in five patients, oxaliplatin in 15, carboplatin in 5, paclitaxel in 16, docetaxel in 14, nab‐paclitaxel in 7, vincristine in 6, and bortezomib in 3. Unadjusted SNAP was 8.45 ± 3.67 μV (mean ± SD) in patients with grade 1 CIPN, 5.42 ± 2.68 μV with grade 2, and 2.45 ± 1.52 μV with grade 3. Unadjusted SNCV was 49.71 ± 4.77 m/s in patients with grade 1 CIPN, 48.78 ± 6.33 m/s with grade 2, and 44.14 ± 7.31 m/s with grade 3. The adjusted SNAP after controlling for age significantly differed between each CTCAE grade (P < 0.001, ancova). The adjusted SNCV after controlling for age and height also differed significantly (P = 0.027). Differences in the severity of CIPN could be detected objectively and quantitatively using this POCD.

Unconvincing Benefit of Combination Therapy With Gefitinib and Pemetrexed in Advanced Non–Small-Cell Lung Cancer

TO THE EDITOR: In a recent issue of Journal of Clinical Oncology, the study by Cheng et al was interesting because it showed that first-line therapy with pemetrexed plus gefitinib significantly improved progression-free survival (PFS) compared with gefitinib alone in patients with epidermal growth factor receptor (EGFR) –mutation positive advanced nonsquamous non–small-cell lung cancer. The Kaplan-Meier curves for PFS overlapped during the first 7 to 8 months and subsequently started to diverge. The coinciding curves at the beginning showed that the addition of pemetrexed did not provide any synergistic or additive benefit. The subsequent divergence at later time points implies that the beneficial effect on PFS was attributed solely to pemetrexed. The similar high response rates in both arms are comparable to those obtained in a previous study of EGFR-mutation–positive advanced-stage non–small-cell lung cancer treated with singleagent EGFR tyrosine kinase inhibitor therapy, suggesting that gefitinib in the study by Cheng et al had extremely dominant activity, irrespective of the combination with pemetrexed. Hence, we believe it is not the combination per se that provided the PFS gains. The antitumor effects seen in the combination arm after the divergence of the curves could simply reflect the effect of pemetrexed alone. Given that the combination is associated with a substantial increase in toxicity and that the development of drug resistance to EGFR tyrosine kinase inhibitors is nearly unavoidable after several months, we believe that the difference in PFS in this study suggests that sequential treatment with pemetrexed after the development of resistance to gefitinib is more effective than concurrent treatment with gefitinib plus pemetrexed. It would be interesting to have access to the overall survival data from this study because most patients in the gefitinib monotherapy group who had disease progression probably received second-line chemotherapy (as most likely did those in the pemetrexed plus gefitinib group). Access to the overall survival data would allow us to determine whether there was a difference in overall survival between the treatment groups.

Clinical effectiveness of geriatric assessment for predicting the tolerability of outpatient chemotherapy in older adults with cancer

Oncologists have increasing opportunities to treat older adults with cancer in clinical practice. However, the tolerability of chemotherapy in older patients is not supported by adequate evidence because such patients have long been underrepresented in routine clinical trials [1]. Older patients are less likely to receive standard chemotherapy; alternative regimens supposed to be less toxic than the standard regimens tend to be selected according to the chronologic age and performance status (PS) of older patients. However, since the aging process is highly variable among individuals, chronologic age is not a sufficient biomarker for this heterogeneous population [2]. Healthcare provider-assessed PS tends to underestimate the degree of functional impairment in older patients [3]. Therefore,more reliablemethods for evaluating older adults with cancer are needed to predict the tolerability of chemotherapy. The Geriatric Assessment (GA) is a multidimensional, interdisciplinary process for evaluating the health status of older individuals. In patients with cancer, two large multicenter studies have recently shown that GA can predict grade 3 or higher toxicities due to chemotherapy [4,5]. However, since older patients are generally reluctant to compromise their quality of life only to achieve survival benefits [6], predicting only severe toxicity provides an insufficient basis for decision-making in older adults with cancer. In other words, even grade 2 or lower toxicity might result in the harmful discontinuation of successful chemotherapy. Weprospectively validatedGA for predicting the tolerability of outpatient chemotherapy in older adults with cancer (UMIN000015991).

Modified docetaxel, cisplatin and capecitabine for stage IV gastric cancer in Japanese patients: A feasibility study

AIM To evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients. METHODS We performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage IV gastric cancer. In particular, 30 or 40 mg/m2 of docetaxel on day 1, 60 mg/m2 of cisplatin on day 1, and 2000 mg/m2 of capecitabine for 2 wk were administered every three weeks. RESULTS Three patients were treated with modified DCX (mDCX) with 30 mg/m2 docetaxel, and five patients were treated with this regimen with 40 mg/m2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes. CONCLUSION mDCX was well tolerated by Japanese patients with stage IV gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.