Sloan, Jeff A.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10−8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10−8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10−8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN.

Abstract Background Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation. Materials and Methods The Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib. Results Sixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported. Conclusion Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. Implications for Practice Regorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.

Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10−23; financial concerns: p = 4.8 × 10−40) and mental health (age: p = 3.5 × 10−7; financial concerns: p = 2.0 × 10−69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10−8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10−8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p < 10−6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL.

Background: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library designed for eliciting patient-reported adverse events in oncology. For each adverse event, up to three individual items are scored for frequency, severity, and interference with daily activities. To align the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events with other standardized tools for adverse event assessment including the Common Terminology Criteria for Adverse Events, an algorithm for mapping individual items for any given adverse event to a single composite numerical grade was developed and tested. Methods: A five-step process was used: (1) All 179 possible Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events score combinations were presented to 20 clinical investigators to subjectively map combinations to single numerical grades ranging from 0 to 3. (2) Combinations with <75% agreement were presented to investigator committees at a National Clinical Trials Network cooperative group meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability, and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating adverse events between study arms was measured in two Phase III clinical trials (NCT02066181 and NCT01522443). Results: In Step 1, 12/179 score combinations had <75% initial agreement. In Step 2, majority consensus was reached for all combinations. In Step 3, five grades were adjusted to assure directional consistency. In Steps 4 and 5, composite grades performed well and comparably to individual item scores on validity, reliability, sensitivity, and between-arm delineation. Conclusion: A composite grading algorithm has been developed and yields single numerical grades for adverse events assessed via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, and can be useful in analyses and reporting.

Evidence for massage therapy (MT) in hospice patients remains limited. We conducted a prospective pilot study on MTs impact on quality of life of hospice patients and caregivers. Patient-caregiver dyads were enrolled if patients scored ≥5 on pain, depression, anxiety, or well-being using the revised Edmonton Symptom Assessment System Revised (ESAS-r). The patient received MT weekly for up to 3 massages with assessments completed at baseline, after each massage, and 1 week after the final massage for patients and at baseline and 1 week after final massage for caregivers. A satisfaction survey was completed at study completion. A pro-rated area under the curve (AUC) was utilized to assess the primary endpoints of change in ESAS-r for patient ratings of pain, depression and anxiety as well as the Linear Analogue Self-Assessment (LASA). Median difference scores (end of study value)-(baseline value) for each participant and caregiver were calculated. Of 27 patients and caregivers enrolled, 25 patients received MT. Fifteen patients completed all 3 MT sessions and were given the final symptom assessment and satisfaction survey and their caregivers completed final assessments. The proportion of patients considered success (AUC > baseline) in the primary endpoints were the following: pain 40.9%, depression 40.9%, anxiety 54.5%, LASA 54.5%. Median difference scores were largely zero indicating no significant temporal change in symptoms. Patients were highly satisfied with MT. This pilot study indicated that MT was a feasible and well-received intervention in our population of patients with inadequately controlled symptoms.

Abstract Background Two methods combining survival and health-related quality of life (HRQoL) data in glioma trials to calculate the “net clinical benefit” were evaluated: Quality-adjusted effect sizes (QASES) and joint modeling (JM). Methods The net clinical benefit in two trials was calculated as proof of concept for other trials. With the QASES method, effect sizes for differences in progression-free survival (PFS) or overall survival (OS) and HRQoL between the experimental arm and standard treatment arm were calculated, while the relative emphasis placed on survival/HRQoL varied. JM allows simultaneous modeling of HRQoL and OS/PFS. Results In the EORTC 26951 trial, combined radiochemotherapy significantly prolonged OS (difference 11.7 months), but also resulted in more patients experiencing clinically relevant worsening (≥10 points) in appetite loss and nausea/vomiting shortly after treatment. Using QASES, the survival benefit of additional procarbazine, lomustine, and vincristine (PCV) decreased from 42.3 months to 29.5 and 28.2 months when accounting for appetite loss and nausea/vomiting, respectively. JM analyses resulted in a loss of the beneficial effect of additional PCV between 13% and 24% when adjusting for different HRQoL parameters. The EORTC 22033 trial showed no significant PFS difference between radiotherapy or temozolomide alone (46 vs 39 months), nor clinically relevant differences in HRQoL. JM analyses also showed no significant association between PFS and HRQoL scales/items, whereas QASES showed that temozolomide alone was more favorable when considering symptom burden (47–49 instead of 39 months). Conclusions Both methods resulted in different outcomes, but adjusting for the impact of treatment on HRQoL resulted in theoretically reduced survival benefits.

140 Background: Prior studies have suggested that patient-reported outcomes may be associated with cancer outcomes. We evaluated the association between clinically significant fatigue (CSF) and adverse events (AEs), quality of life (QOL), and overall survival (OS) during cancer treatment. Methods: Four phase II or III chemotherapy trials, two each in advanced non-small cell lung cancer (NSCLC) and advanced hormone-refractory prostate cancer (HRPC), were used to compare patients with or without baseline CSF. Baseline CSF was defined as a rating of 2 or greater on the FACT fatigue survey question or an EORTC QLQ-C30 fatigue symptom score of 50% or greater. Change in QOL from baseline, AE rates, and survival were compared according to baseline CSF with linear regression models, equality of proportions chi-squared tests, and Kaplan-Meier survival estimates and Cox regression models, respectively, separately for each trial. Results: Of 1,994 participants, 1,907 had complete baseline QOL survey data, with 52% reporting CSF at baseline. Baseline CSF was associated with an increased incidence of grade 3-5 constitutional (16.5% vs 9.4%, p = 0.002 and 13.9% vs 6.3%, p = 0.002) and neurological (11.7% vs 6.1%, p = 0.006 and 9.0% vs 3.9%, p = 0.01) AEs, respectively, in two studies of advanced HRPC. Overall, patients with baseline CSF had significantly lower baseline QOL across all four domains (p < 0.01). Across all four studies, baseline CSF was associated with higher mortality rates, with adjusted hazard ratios (95% confidence interval, p-value): 1.34 (1.14, 1.57, p < .001) and 1.30 (1.02, 1.66, p = 0.03) in NSCLC studies, 1.49 (0.95, 2.35, p = 0.09) and 1.53 (1.12, 2.11, p = 0.008) in HRPC studies. Conclusions: Oncology trial participants with baseline CSF had significantly lower baseline QOL, experienced more adverse events and had poorer survival compared to participants without CSF. We have confirmed previous work indicating that fatigue is an important baseline stratification factor that should be considered in all oncology treatment trials. Consistent with other research, our results indicate that fatigue should be measured and ameliorated wherever possible among advanced cancer patients.

Abstract Background Prior comparisons of chemotherapy adverse events (AEs) by age and performance status (PS) are limited by the traditional maximum grade approach, which ignores low-grade AEs and longitudinal changes. Materials and Methods To compare fatigue and neuropathy longitudinally by age (&lt;65, ≥65 years) and PS (0–1, 2), we analyzed data from a large phase III trial of carboplatin and paclitaxel versus paclitaxel for advanced non-small cell lung cancer (CALGB 9730, n = 529). We performed multivariable (a) linear mixed models to estimate mean AE grade over time, (b) linear regression to estimate area under the curve (AUC), and (c) proportional hazards models to estimate the hazard ratio of developing grade ≥2 AE, as well as traditional maximum grade analyses. Results Older patients had on average a 0.17-point (95% confidence interval [CI], 0.00–0.34; p = .049) higher mean fatigue grade longitudinally compared with younger patients. PS 2 was associated with earlier development of grade ≥2 fatigue (hazard ratio [HR], 1.56; 95% CI, 1.07–2.27; p = .02). For neuropathy, older age was associated with earlier development of grade ≥2 neuropathy (HR, 1.41; 95% CI, 1.00–1.97; p = .049). Patients with PS 2 had a 1.30 point lower neuropathy AUC (95% CI, −2.36 to −0.25; p = .02) compared with PS 0–1. In contrast, maximum grade analyses only detected a higher percentage of older adults with grade ≥3 fatigue and neuropathy at some point during treatment. Conclusion Our comparison of complementary but distinct aspects of chemotherapy toxicity identified important longitudinal differences in fatigue and neuropathy by age and PS that are missed by the traditional maximum grade approach. Clinical trial identification number: NCT00003117 (CALGB 9730) Implications for Practice The traditional maximum grade approach ignores persistent low-grade adverse events (AEs) and changes over time. This toxicity over time analysis of fatigue and neuropathy during chemotherapy for advanced non-small cell lung cancer demonstrates how to use longitudinal methods to comprehensively characterize AEs over time by age and performance status (PS). We identified important longitudinal differences in fatigue and neuropathy that are missed by the maximum grade approach. This new information about how older adults and patients with PS 2 experience these toxicities longitudinally may be used clinically to improve discussions about treatment options and what to expect to inform shared decision making and symptom management.

9609 Background: Patients undergoing treatment for cancer often report problems with their cognitive function (CF), which is an essential component in maintaining Quality of Life (QoL). We conducted a longitudinal study of lung cancer (LC) patients to systematically evaluate changes in QOL including changes in CF, over time. Methods: Between 2005–2008, we followed 1757 primary LC patients who responded to CF questions at least once within 8 years of diagnosis. Overall QoL measured by LCSS and LASA (scores 0–100 from worst to best) were assessed among 1,604 of 1,757 (91%) who completed the questionnaire at one or both of two time periods: short-term (T1-within 3 years of diagnosis) and long-term follow-up (T2-beyond 5 years of diagnosis). Questions rated overall CF and problems in thinking clearly. Results: The median age at the time of LC diagnosis was 68 years in men (n=834) and 65 years in women (n=770), p<0.0001. At T1, the mean score of patients reporting problems with CF was 63.2 (±22.45) vs 74.4 (±20.38) who reported no problems (p<0.0001). At T2, the mean score was 62.2 (±24.18) for patients who reported CF problems and 78.1 (±18.28) who reported no changes with their CF (p<0.0001). At T1, the mean score of patients reporting problems thinking clearly was 66.1 (±21.65) vs 75.6 (±20.21) reporting no problems with their thinking (p<0.0001). At T2, the mean score was 70.4 (±20.95) for patients reporting problems thinking clearly vs 82.6 (±17.76) who reported no problems (p<0.0001). Conclusions: Self-reported QoL of lung cancer survivors showed substantial deficits with their cognitive function. Prospective and objective assessments are needed to determine if cancer treatments are positively associated with cognitive decline, to identify the patients at risk, and to test appropriate interventions. Funding Source: NIH grants: CA 115857, CA 84354, CA 80127 and CA 77118. No significant financial relationships to disclose.

9587 Background: CIPN is characterized by adjectives not covered directly by most common measures of pain and functional limitations. Possible descriptors include numbness, tingling and shooting/burning pain. A prospective neuropathy treatment trial provided data to explore the relationship between self-reported aspects of this symptom. Methods: Baseline EORTC QLQ CIPN20 data and NCI CTCAE V3.0 (CTC)neuropathy grade (I-IV) were provided for all patients on trial. Spearman correlation coefficients and Kappa's coefficients of agreement were calculated between individual items and subscales of the CIPN20 as well as the CTC neuropathy scale. Simple regression models were applied to examine the association between the sensory symptoms and motor function in the fingers/hands (F/H). 200 patients provided 80% power to detect a correlation coefficient of 0.20 with a 5% Type I error. Results: A majority of patients reported “quite a bit” to “very much” numbness (57%) or tingling (62%) in F/H compared to “a little” or “not at all” (numbness (43%), tingling (38%)) by the CIPN20. In contrast, only 13% of the participants had grade III/IV neuropathy determined by the CTC scale. Fewer patients reported the higher two levels of CIPN20-measured shooting/burning pain in F/H (20% “quite a bit” to “very much”). Numbness and tingling were highly correlated (kappa=0.56), while neither were in high agreement with shooting/burning pain (kappa= 0.05 (tingling) and 0.14 (numbness)). The CIPN20 sensory and motor subscales were significantly associated with each other (p<.0001) but were not or only weakly associated with the CTC. Specifically, tingling, numbness, and shooting/burning pain were not associated with the CTC (R=0.16, 0.18 and 0 .11, respectively). Using the CIPN20, all three sensations; numbness, tingling and shooting or burning pain were strongly associated with motor function. Conclusions: The most common moderate to severe CIPN symptoms were numbness and tingling with shooting/burning pain being less common. Shooting/ burning pain appears to be a separate symptom experience from numbness and tingling. The CTC neuropathy grading scale appears to be less sensitive than the CIPN20 in picking up sensory symptoms. No significant financial relationships to disclose.