Citations

PURPOSE: Patient-reported outcomes may be associated with cancer outcomes. We evaluated clinically significant fatigue (CSF), overall survival, adverse events (AEs), and quality of life (QOL) during cancer treatment. METHODS: We compared outcomes in four phase II or III chemotherapy trials, two advanced non–small-cell lung cancer and two advanced hormone-refractory prostate cancer, with or without baseline CSF. CSF was defined as a rating of two or greater on the Functional Assessment of Cancer Therapy fatigue question or a European Organization for Research and Treatment of Cancer Quality of Life Questionnaire—Core 30 fatigue symptom score of 50% or greater. Survival was compared according to CSF using Kaplan-Meier estimates and Cox regression models. Differences in AE rates by CSF were assessed via chi-squared tests, and QOL changes from baseline to 3 months via linear regression. RESULTS: Of 1,994 participants, 1,907 (median age 69 years, range: 32-91) had complete baseline QOL survey data, with 52% reporting CSF at baseline. For the two hormone-refractory prostate cancer studies, baseline CSF was associated with higher mortality rates, with adjusted hazard ratios of (95% CI, P value) 1.32 (1.13 to 1.55, P < .001) and 1.31 (1.02 to 1.67, P = .03) and with increased incidence of grade 3-5 constitutional (16.5% v 9.4%, P = .002; 13.9% v 6.3%, P = .002) and neurologic (11.7% v 6.1%, P = .006; 9.0% v 3.9%, P = .01) AEs, respectively. Baseline CSF was associated with a higher mortality rate in one non–small-cell lung cancer study: hazard ratio 1.44 and 1.04 to 2.00, P = .03. CONCLUSION: Oncology trial participants with baseline CSF had poorer survival and experienced more AEs than participants without CSF. This indicates fatigue as an important baseline prognostic factor in oncology treatment trials.

AbstractVenetoclax (Ven) is a selective small‐molecule inhibitor of BCL‐2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open‐label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21–day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL‐2) and BCL2L1 (BCL‐XL) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow‐up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF‐kB. VenDex demonstrated efficacy and manageable safety in heavily‐pre‐treated patients with t(11;14) R/R MM.

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.

8038 Background: Bone marrow biopsies (BMB) are performed pre/post therapy to confirm complete response (CR) in patients (pts) with lymphoma on clinical trials. We evaluated 2 prior data sets and concluded that BMB impact response assessment in a minority of pts with follicular lymphoma (FL) (Rutherford BJH 2017; Rutherford ASH abstract 1605, 2018). We sought to establish if BMB add value in assessing response or identify distinct progression free (PFS) or overall survival (OS) outcomes in a large, multicenter, multi-trial cohort. Methods: Data were pooled from 7 trials of 580 pts with untreated FL conducted through the Alliance for Clinical Trials in Oncology and SWOG from 2002-2016. The proportion of pts with positive (+) baseline BMB, CR on imaging after treatment, and (+) repeat BMB was calculated using total pts enrolled as the denominator. We tested against the null hypothesis that the proportion was = 10%, the threshold below which BMB would be considered irrelevant for response assessment, versus (vs) the alternative hypothesis that this proportion was < 10%, using 1-sided exact binomial test. Response criteria were CT-based. Imaging was not used to assess BM involvement. Because confirmatory BMB were not completed in all indicated pts, landmark survival analyses compared PFS/OS of pts with CR on imaging and negative (-) BMB vs pts with CR on imaging without repeat BMB. Pts with CR on imaging were categorized as having (-) repeat BMB or no repeat BMB within 60 days of first CR on imaging. PFS and OS were calculated from time of first CR and estimated using Kaplan-Meier and Cox models adjusting for age, sex, stage, Follicular Lymphoma International Prognostic Index (FLIPI) score, and treatment type (targeted vs chemotherapy plus targeted therapy), and stratified by treatment arm. Results: Median age was 55 with 51% male, 96% stage III-IV, and 88% grade I-II. FLIPI scores were 113 low, 265 intermediate, and 199 high risk. 67% received chemotherapy-based regimens. Baseline BMB was (+) in 321 (55%). Only 5/580 (0.8%) had (+) baseline BMB, CR on imaging, and subsequent (+) BMB (p < 0.0001). Of pts with CR on imaging, PFS and OS were not different among pts with (-) BMB vs pts without repeat BMB (PFS: HR = 1.08, 95%CI 0.61-1.93, p = 0.783; OS: HR = 0.52, 95%CI 0.20-1.40, p = 0.199). Conclusions: BMB requirements may discourage pt participation in trials and add pain, expense and time without providing necessary information. We recommend eliminating BMB for response assessment from FL clinical trials. Clinical trial information: NCT00553501, NCT01145495, NCT01190449, NCT01286272, NCT01829568, NCT00822120, and NCT00770224 .

Knee osteoarthritis is one of the most common causes of chronic pain worldwide, and several animal models have been developed to investigate disease mechanisms and treatments to combat associated morbidities. Here we describe a novel method for assessment of locomotor pain behavior in Yucatan swine. We used monosodium iodoacetate (MIA) to induce osteoarthritis in the hindlimb knee, and then conducted live observation, quantitative gait analysis, and quantitative weight-bearing stance analysis. We used these methods to test the hypothesis that locomotor pain behaviors after osteoarthritis induction would be detected by multiparameter quantitation for at least 12 wk in a novel large animal model of osteoarthritis. MIA-induced knee osteoarthritis produced lameness quantifiable by all measurement techniques, with onset at 2 to 4 wk and persistence until the conclusion of the study at 12 wk. Both live observation and gait analysis of kinetic parameters identified mild and moderate osteoarthritis phenotypes corresponding to a binary dose relationship. Quantitative stance analysis demonstrated the greatest sensitivity, discriminating between mild osteoarthritis states induced by 1.2 and 4.0 mg MIA, with stability of expression for as long as 12 wk. The multiparameter quantitation used in our study allowed rejection of the null hypothesis. This large animal model of quantitative locomotor pain resulting from MIA-induced osteoarthritis may support the assessment of new analgesic strategies for human knee osteoarthritis.

Abstract Background Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. Methods Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. Results In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34–0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). Conclusions Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

Objective The aim of this study was to grade cartilage damage in a swine model of osteoarthritis using a whole-body photon-counting detector (PCD) CT. Materials and Methods A multienergy phantom containing gadolinium (Gd) (2, 4, 8, and 16 mg/mL) and hydroxyapatite (200 and 400 mg/cc) was scanned using a PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs, D50 reconstruction kernel) to serve as calibration for material decomposition and to assess quantification accuracy. Osteoarthritis was induced in Yucatan miniswine (n = 8) using 1.2 mg monoiodoacetate (MIA) injected into a randomized knee, whereas the contralateral control knee received saline. Twenty-one days later, a contrast bolus (gadoterate meglumine, 4 mL/knee) was intra-articularly administered into both knees. The knees were simultaneously scanned on the PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs). Multienergy images were reconstructed with a sharp “V71” kernel and a quantitative “D50” kernel. Image denoising was applied to the V71 images before grading cartilage damage, and an iterative material decomposition technique was applied to D50 images to generate the Gd maps. Two radiologists blinded to the knee injection status graded the cartilage integrity based on a modified International Cartilage Repair Society scoring system. Histology was performed on excised cartilage using methylene blue/basic fuchsin. Statistical analysis of grade distribution was performed using an exact test of omnibus symmetry with P < 0.05 considered significant. Results Material decomposed images from the multienergy phantom scan showed delineation and quantification of Gd and hydroxyapatite with a root-mean-squared error of 0.3 mg/mL and 18.4 mg/cc, respectively. In the animal cohort, the radiologists reported chondromalacia in the MIA knees with International Cartilage Repair Society scores ranging from grade 1 (cartilage heterogeneity, n = 4 knees) to grade 3 (up to 100% cartilage loss, n = 4 knees). Grade 1 was characterized by cartilage heterogeneity and increased joint space in the patellofemoral compartment, whereas grade 3 was characterized by cartilage erosion and bone-on-bone articulation in the patellofemoral compartment. All control knees were scored as grade 0 (normal cartilage). Significant difference (P = 0.004) was observed in the grade distribution between the MIA and control knees. Gross examination of the excised knees showed cartilage lesions in the grade 3 MIA knees. The Gd maps from material decomposition showed lower contrast levels in the joint space of the MIA knee compared with the contralateral control knee due to joint effusion. Histology revealed chondrocyte loss in the MIA knee cartilage confirming the chondrotoxic effects of MIA on cartilage matrix. Conclusions We demonstrated a high-resolution and quantitative PCD-CT arthrography technique for grading cartilage damage in a large animal model of osteoarthritis. Photon-counting detector CT offers simultaneous high-resolution and multienergy imaging capabilities that allowed morphological assessment of cartilage loss and quantification of contrast levels in the joint as a marker of joint disease. Cartilage damage in the MIA knees was graded using PCD-CT images, and the image-based findings were further confirmed using histology and gross examination of the excised knees.

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.