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Marion venema Vene 1401 Jetse Norel Nore 1400



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Datum04.04.2017
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DISCUSSION


Contrary to our hypotheses, neither AET nor RET significantly improved cancer-specific QOL, fatigue, depression, or anxiety, although the trends favored the exercise groups. Consistent with our hypotheses, AET significantly improved self-esteem, preserved aerobic fitness, and maintained body fat levels, whereas RET significantly improved self-esteem, muscular strength, and lean body mass. Unexpectedly, RET significantly improved chemotherapy completion rate. Neither intervention caused lymphedema or significant adverse events.

Few published studies are available for direct comparisons. A recent meta-analysis5of 14 exercise randomized controlled trials in breast cancer patients/survivors revealed that published trials have either focused on the postadjuvant therapy setting or combined breast cancer patients on various adjuvant therapies (eg, chemotherapy, radiation therapy, hormonal therapy). Trials in the postadjuvant setting have shown that both aerobic22 and resistance23 exercise can improve cancer-specific QOL. Only one trial in the adjuvant therapy setting reported data separately for patients on chemotherapy, although it was not powered for such a subanalysis.24 In that trial, there were no effects of 26 weeks of lower intensity supervised or self-directed aerobic exercise on QOL.

The failure of our exercise interventions to significantly improve cancer-specific QOL may be, in part, a result of the wide variability in QOL change scores we found during chemotherapy (standard deviation = 25). Many uncontrollable factors influence QOL during chemotherapy, and a global measure of cancer-specific QOL may be too broad to detect the likely narrower effects of exercise training. A more appropriate and realistic primary end point in exercise trials may be the physical functioning component of QOL.25 It is also possible that the effects of our exercise interventions were partly diluted by inadequate adherence and/or an insufficient volume/intensity of exercise. However, it is unclear whether better adherence or a greater volume/intensity of exercise can be achieved in this clinical setting. Our adherence rate is within the range commonly reported in exercise RCTs in breast cancer patients receiving adjuvant therapy5 and older adults without cancer.26Nevertheless, there is clearly still room for improvement, and we plan a full report of the predictors of exercise adherence in our trial to facilitate this improvement.

Changes in fatigue, depression, and anxiety also favored the exercise groups but did not achieve statistical significance. These findings are consistent with three recent meta-analyses5-7 that have reported modest effects on these outcomes and noted that the stronger and more consistent effects appear in the postadjuvant setting. Conversely, both exercise interventions improved self-esteem, which is an important outcome for breast cancer patients going through difficult treatments.27 There is no identified important difference for our scale, but the standardized effect size was small to moderate (d = 0.30). Previous exercise trials have not examined self-esteem during chemotherapy but have noted improvements in the postadjuvant therapy setting with aerobic exercise.22

Although patient-rated outcomes primarily showed trends in favor of the exercise groups, the objectively measured outcomes were reliably changed. AET blunted a decline in maximal oxygen consumption in the UC group of approximately 2.0 mL/mg/kg, or 8%. Training studies in other populations show slightly larger improvements of 10% to 30%,8 although few have conducted intent-to-treat analyses. Segal et al24 reported no effects of a lower intensity exercise program on aerobic fitness in the subanalysis of breast cancer patients receiving chemotherapy. Our trial demonstrates that a higher intensity exercise program can preserve aerobic fitness in breast cancer patients even in the face of a downward trajectory in aerobic fitness, possibly caused by chemotherapy effects such as anemia, tachycardia, dehydration, and cardiac dysfunction.3,28 Preserving aerobic fitness in breast cancer patients receiving chemotherapy may be beneficial. In our trial, improved aerobic fitness was associated with improved QOL, fatigue, depression, and anxiety, suggesting that greater increases in aerobic fitness may have resulted in better patient-rated outcomes. Aerobic fitness is also an established predictor of disease and mortality.29

RET increased muscular strength by 25% to 35%, which is consistent with research in other populations.9 To our knowledge, our study is the first to test the effects of an isolated resistance training program in breast cancer patients receiving chemotherapy. Schmitz et al30 demonstrated improvements in muscular strength of 30% to 50% in the postadjuvant setting. The clinical implications of improved muscular strength for breast cancer patients are unknown, but we did observe a modest correlation between increased muscular strength and improved QOL, as did Ohira et al.23 In other populations, muscular strength is associated with improved physical functioning, reduced mobility limitations and lower risk of falling,23,31,32 and lower mortality.33

Neither exercise intervention prevented weight gain, but each altered body composition as hypothesized. AET prevented fat gain, and RET added lean body mass. Weight gain after a breast cancer diagnosis has been associated with earlier recurrence and shorter survival,34 with most explanations focusing on adiposity rather than body weight per se.35 Moreover, in our trial, improvements in body composition were associated with improvements in QOL, self-esteem, and depression, suggesting that body composition may have implications for psychosocial functioning in addition to clinical outcomes. Schmitz et al30 reported similar improvements in body composition with resistance training in the postadjuvant setting but also found no change in body weight. Associations between improved lean body mass and QOL were also reported.23 A systematic review of 14 exercise intervention studies in breast cancer patients/survivors concluded that there were few changes in body weight but some improvements in body composition.36

Unexpectedly, RET improved chemotherapy completion rate. Clinical trials support the importance of sustaining full dose-intensity in adjuvant chemotherapy for early-stage breast cancer with evidence of a threshold effect of approximately 85%.37-39The clinical implications of an RDI difference of 5.7% found in our study are unclear, but most studies have noted a steep association between RDI and clinical outcomes to the 85% threshold.37-39 The explanation for the difference in chemotherapy completion rate is unclear. The groups were balanced on chemotherapy regimens, and the UC group actually received more granulocyte colony-stimulating factor than the RET group (P = .013) after excluding prophylactic granulocyte colony-stimulating factor use. Acute exercise is known to cause demargination of neutrophils and a temporary increase of 25% to 100% in peripheral-blood neutrophil count lasting up to 6 hours,40 which, theoretically, could alter chemotherapy delivery decisions. Given the exploratory nature of this finding, it should be replicated before it is considered reliable.

Neither AET nor RET caused arm swelling or other adverse events. To our knowledge, our trial is the first to report lymphedema data for the adjuvant chemotherapy time period, but it is consistent with previous smaller studies in the postadjuvant therapy setting.16,41-43 Few exercise trials in breast cancer patients have reported adverse events, but our trial suggests that adverse events may be minimal.

Our trial's strengths include the direct comparison of aerobic and resistance exercise, the largest sample size to date, the well-defined population, the multicenter recruitment, the supervised exercise, a comprehensive assessment of important end points with validated measures, intent-to-treat analysis, and limited loss to follow-up. Limitations include the 70% adherence rate, the 33% recruitment rate, and the well-educated, racially homogenous sample. Moreover, given the 22 group comparisons we made at the α = .05 level, we would expect one false discovery by chance if all of these comparisons were actually null.

In summary, our trial demonstrates important improvements in self-esteem, physical fitness, body composition, and possibly chemotherapy completion rate from exercise training in breast cancer patients receiving chemotherapy. Our findings may help explain a recent observational study reporting a positive association between physical activity and survival in breast cancer survivors.44 Cancer care professionals should consider recommending either AET or RET to breast cancer patients receiving chemotherapy. A combined intervention may be optimal, but research is needed to confirm this assumption, especially given the challenges of exercise adherence in this clinical setting.

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