Aaronson, Neil K.

Objective Animal data suggest that exercise during chemotherapy is cardioprotective, but clinical evidence to support this is limited. This study evaluated the effect of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity. Methods This is a follow-up study of two previously performed randomised trials in patients with breast cancer allocated to exercise during chemotherapy or non-exercise controls. Cardiac imaging parameters, including T1 mapping (native T1, extracellular volume fraction (ECV)), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), cardiorespiratory fitness, and physical activity levels, were acquired 8.5 years post-treatment. Results In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years), of whom 99% and 18% were treated with anthracyclines and trastuzumab, respectively. ECV and Native T1 were 25.3%±2.5% and 1026±51 ms in the control group, and 24.6%±2.8% and 1007±44 ms in the exercise group, respectively. LVEF was borderline normal in both groups, with an LVEF<50% prevalence of 22.5% (n=40/178) in all participants. Compared with control, native T1 was statistically significantly lower in the exercise group (β=−20.16, 95% CI −35.35 to −4.97). We found no effect of exercise on ECV (β=−0.69, 95% CI −1.62 to 0.25), LVEF (β=−1.36, 95% CI −3.45 to 0.73) or GLS (β=0.31, 95% CI −0.76 to 1.37). Higher self-reported physical activity levels during chemotherapy were significantly associated with better native T1 and ECV. Conclusions In long-term breast cancer survivors, exercise and being more physically active during chemotherapy were associated with better structural but not functional cardiac parameters. The high prevalence of cardiac dysfunction calls for additional research on cardioprotective measures, including alternative exercise regimens. Trial registration number NTR7247.

12081 Background: A common conception is that exercise training is cardioprotective for patients with breast cancer receiving adjuvant chemotherapy, but evidence to support this assertion is limited. This study aims to evaluate the effect of exercise training during adjuvant chemotherapy for breast cancer on long-term structural and functional cardiac outcomes. Methods: This is a follow-up study of two previously performed randomized studies in breast cancer patients; the PACT (N = 204) and PACES (N = 230) study. Cardiac outcomes, including extracellular volume fraction (ECV), left ventricular ejection fraction (LVEF) on cardiac MRI and global longitudinal strain (GLS) on echocardiography, were evaluated in patients allocated to moderate-to high-intensity exercise and non-exercise controls using linear and logistic regression models, adjusted for relevant confounders. Additionally, we explored the influence of self-reported PA during chemotherapy on cardiac outcomes, regardless of treatment allocation. Results: In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years, mean time since treatment 8.5±1.1 years). Mean ECV was 25.3±2.5 in the control group and 24.6±2.8 in the exercise group. Mean LVEF was borderline normal in both (54.6±4.9 and 53.0±7.8) with an LVEF < 50% of 17.1% and 27.8% in control and exercise group, respectively. Compared to control, no significant effect of exercise during chemotherapy on ECV (β = -0.61, 95%CI: -1.55;0.32) or on abnormal ECV (OR = 0.80, 95%CI: 0.26;2.45) was found. Native T1 was statistically significantly lower in the exercise group compared to control (β = -16.75%CI: -31.5 ;-1.93). The odds of having an abnormal native T1 appeared lower in the exercise group (OR 0.58, 95%CI: 0.28;1.17). We found no benefit of exercise for LVEF or GLS (β = -1.82, 95%CI: -4.06;0.42 and β = 0.21, 95%CI: -0.87;1.28), nor on the likelihood of having an abnormal LVEF or GLS (OR = 1.78, 95%CI: 0.79;4.16); OR = 1.21, 95%CI: 0.56;2.63), respectively. Higher self-reported physical activity levels during chemotherapy tended to be associated with better cardiac outcomes. Conclusions: Exercise training during chemotherapy was not associated with long-term cardioprotection in patients with early-stage breast cancer. The high prevalence of cardiac abnormalities years post-chemotherapy suggests the need to include cardiac assessment in long-term follow-up programs for breast cancer survivors and calls for more research on cardioprotective measures during adjuvant chemotherapy, including alternative exercise dosing regimens and pharmacological adjuncts. Clinical trial information: NTR7247.

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.

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.

Abstract INTRODUCTION The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to facilitate shared decision making. Two methods that combine survival and health-related quality of life (HRQoL) data: Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM) were applied to gain insight in the net clinical benefit. METHODS The net clinical benefit in one RCT (EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone) was calculated as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (42.3 vs. 30.6 months). The percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. QASES corresponded to a reduction in the median OS difference from 9.7 months up till 5.5 months, given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

Abstract BACKGROUND The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations. MATERIAL AND METHODS We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.