Loprinzi, Charles L.

AbstractPaclitaxel‐induced peripheral neuropathy (PIPN) cannot be predicted from clinical parameters and might have a pharmacogenomic basis. Previous studies identified single nucleotide variants (SNV) associated with PIPN. However, only a subset of findings has been confirmed to date in more than one study, suggesting a need for further re‐testing and validation in additional clinical cohorts. Candidate PIPN‐associated SNVs were identified from the literature. SNVs were retested in 119 patients selected by extreme phenotyping from 269 in NCCTG N08C1 (Alliance) as previously reported. SNV genotyping was performed by a combination of short‐read sequencing analysis and Taqman PCR. These 22 candidate PIPN SNVs were genotyped. Two of these, rs7349683 in the EPHA5 and rs3213619 in ABCB1 were found to be significantly associated with PIPN with an Odds ratios OR = 2.07 (P = 0.02) and OR = 0.12 (P = 0.03), respectively. In addition, three SNVs showed a trend toward a risk‐ or protective effect that was consistent with previous reports. The rs10509681 and rs11572080 in the gene CYP2C8*3 showed risk effect with an OR = 1.49 and rs1056836 in CYP1B1 showed a protective effect with an OR = 0.66. None of the other results supported the previously reported associations, including some SNVs displaying an opposite direction of effect from previous reports, including rs1058930 in CYP2C8, rs17222723 and rs8187710 in ABCC2, rs10771973 in FGD4, rs16916932 in CACNB2 and rs16948748 in PITPNA. Alliance N08C1 validated or supported a minority of previously reported SNV‐PIPN associations. Associations previously reported by multiple studies appeared to have a higher likelihood to be validated by Alliance N08C1.

Purpose Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation. Methods Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. Results Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001). Conclusion Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

Erythropoiesis‐stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients with cancer chemotherapy‐associated anemia (CAA). Extended‐interval ESA dosing (administration less than once weekly) is common with DA, but previous studies suggested that EA might also be administered less often than weekly. In this multicenter prospective trial, 239 CAA patients with Hb <10.5 g/dL were randomized to receive EA 40,000 U subcutaneously once weekly (“40K” arm), EA 80,000 U every 3 weeks (“80K”), EA 120,000 U every 3 weeks (“120K” arm), or DA 500 mcg every 3 weeks (“DA”), for 15 weeks. The primary endpoint was the proportion of patients achieving Hb ≥ 11.5 g/dL or increment of Hb > 2.0 g/dL from baseline without transfusion. Secondary endpoints included transfusion requirements, adverse events (AEs), and patient‐reported outcomes (PROs). There were no significant differences between treatment arms in the proportion of patients achieving Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; P > 0.41 for all comparisons) or requiring RBC transfusion, but the median Hb increment from baseline was higher in the 40K and DA arms compared to the two extended dosing EA arms, and Hb response was achieved soonest in the weekly EA arm. There were no differences in PROs or AEs. The FDA‐approved schedules tested—weekly EA 40,000 U, and every 3 week DA 500 mcg—are reasonable standards for CAA therapy. Am. J. Hematol. 90:877–881, 2015. © 2015 Wiley Periodicals, Inc.

Abstract Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several chemotherapy drug classes, including taxanes. Peripheral neuropathies have been shown to lead to pain, falls, and difficulty in walking and performing activities of daily living in a variety of patient populations. Although the prevalence of CIPN has been noted in cancer patients, the development of self-reported symptoms, gait changes and balance changes during treatment have not been well explored to date. We hypothesized that the use of taxane-based chemotherapy will result in significant changes in spatiotemporal gait and balance parameters, as well as self-reported quality of life and function. Methods We characterized the alterations in gait and balance that occur in non-metastatic breast cancer patients during taxane chemotherapy. We evaluated (1) spatiotemporal gait parameters, including cadence and step length, and (2) balance parameters, including time-to-contact and 95% ellipse area, using each patient as her own control. Laboratory assessment of gait and balance was conducted at baseline and at completion of therapy in selected patients. We compared the natural history of changes in gait and balance parameters with changes in CIPN status as measured by validated patient reported outcomes, including EORTC QLQ-C30, CIPN-20, and Brief Pain Inventory Short Form (BPI-SF), and the Duke Activity Status Index (DASI). Time points included pre-chemotherapy, after each cycle of chemotherapy, and one month after the end of therapy to collect information on neuropathy, pain and functional capacity. The preliminary data were illustrated using individual plots; trend lines (changing over time) were based on least square means at each time point, which were estimated using the linear mixed models for repeated measures. Results To date, 15 patients with localized breast cancer have been enrolled; patient recruitment is ongoing. The median age is 42 years (range 25-67). Ten patients (67%) received weekly paclitaxel, 1 patient (7%) received paclitaxel every 2 weeks, and 4 patients (27%) received docetaxel every 3 weeks. Preliminary results with these 15 patients, based on least square means at each timepoint, showed trends in several parameters. As treatments progressed, patients tended to develop more difficulty in quiet balance and in their ability to actively shift weight in the sagittal and frontal planes. From the CIPN-20, they also tended to develop increased difficulty with sensory and motor systems. From the QLQ-C30, their global health status also tended to worsen. For most of these parameters, the largest changes were observed between the 2nd and 3rd treatments, though some changes were not observed until the 4th treatment. From the BPI-SF, no trends in pain symptoms or pain interference were observed within this preliminary cohort. Conclusions Gait and balance testing is feasible in the clinical setting. Preliminary observations suggest that balance, function and quality of life may all be affected by taxane therapy, even without pain symptoms. The findings of this study will enable us to better characterize the neurotoxic effect of taxanes and to ultimately test the effectiveness of preventative measures and interventions. Funding by NCI R03CA182165-01. Citation Format: Maryam B Lustberg, Scott Monfort, Janani Singaravelu, Raquel E Reinbolt, Xueliang Pan, Bhuvaneswari Ramaswamy, Rachel M Layman, Robert Wesolowski, Ewa Mrozek, Erin Macrae, Charles Shapiro, Robyn Patrick, Charles L Loprinzi, Ajit Chaudhari. Longitudinal evaluation of taxane-induced neuropathy in early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-04.