Transferring effective interventions for cancer-related fatigue from the adjuvant to the advanced cancer session: does it work?
Authors: A.M. May
Journal: Annals of Oncology (2020)

Fatigue is one of the most prevalent and debilitating side-effects of cancer treatment.1Lawrence D.P. Kupelnick B. Miller K. et al.Evidence report on the occurrence, assessment, and treatment of fatigue in cancer patients.J Natl Cancer Inst Monogr. 2004; 2111: 40-50Crossref Scopus (293) Google Scholar,2Hofman M. Ryan J.L. Figueroa-Moseley C.D. et al.Cancer-related fatigue: the scale of the problem.Oncologist. 2007; 12: 4-10Crossref PubMed Scopus (607) Google Scholar In the adjuvant setting, both cognitive behavioral therapy (CBT) and physical exercise are beneficial interventions for decreasing cancer-related fatigue and are significantly more effective than pharmaceutical options.3Mustian K.M. Alfano C.M. Heckler C. et al.Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue a meta-analysis.JAMA Oncol. 2017; 3: 961-968Crossref PubMed Scopus (419) Google Scholar Evidence for the advanced cancer setting is, however, currently scarce and large studies are lacking. In this issue of Annals of Oncology, Knoop and colleagues report results of a three-arm randomized controlled trial investigating the effects of 12-week CBT or graded exercise therapy (GET) compared with usual care in 134 patients with metastatic breast, colorectal, or prostate cancer.4Poort H. Peters M.E.W.J. van der Graaf W.T.A. et al.Cognitive behavioral therapy or graded exercise therapy compared with usual care for severe fatigue in patients with advanced cancer during treatment: a randomized controlled trial.Ann Oncol. 2020; 31: 115-122Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Forty-six patients were randomized to CBT, 42 patients to GET, and 46 patients received usual care. This study is innovative in two ways: it transfers two promising interventions to the advanced cancer setting and it targets patients at need, i.e. patients with severe levels of fatigue. Both interventions were compared with usual care. Comparisons between interventions were not (pre-)planned. Almost 60% of contacted patients were randomized, which is a reasonable recruitment rate for a CBT or exercise-intervention trial. Nevertheless, timely recruitment appeared challenging and, due to financial reasons, the study included only 82% of the anticipated sample size, which led especially in the GET arm to an underpowered sample. Consequences will be discussed in the following. Results for the CBT intervention are promising. Fatigue levels were clinically relevantly lower directly after the intervention and effects were maintained until 3 months later. The CBT intervention was based on a carefully designed and, in the adjuvant setting, well-studied intervention5Gielissen M.F.M. Verhagen S. Witjes F. et al.Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial.J Clin Oncol. 2006; 24: 4882-4887Crossref PubMed Scopus (260) Google Scholar, 6Abrahams H.J.G. Gielissen M.F.M. Donders R.R.T. et al.The efficacy of Internet-based cognitive behavioral therapy for severely fatigued survivors of breast cancer compared with care as usual: a randomized controlled trial.Cancer. 2017; 123: 3825-3834Crossref PubMed Scopus (72) Google Scholar, 7Goedendorp M.M. Peters M.E.W.J. Gielissen M.F.M. et al.Is increasing physical activity necessary to diminish fatigue during cancer treatment? Comparing cognitive behavior therapy and a brief nursing intervention with usual care in a multicenter randomized controlled trial.Oncologist. 2010; 15: 1122-1132Crossref PubMed Scopus (71) Google Scholar consisting of five modules tailored to patients' specific needs in all domains of quality of life. Interestingly, one of the modules focused on regulation of physical activity, but it is not reported how many patients chose this module. The 12-week intervention with a maximum of ten 1-hour sessions was provided by experienced clinical psychologists, who had received a 3-day training and were supervised by a psychologist throughout the study. Also, results on adherence and compliance show that the intervention is feasible in this advanced cancer setting. Hence, this intervention seems to be ready to be implemented into clinical practice, at least for the studied cancer types. A condition for this, however, is a health care system that enables in-person delivery of the intervention in terms of resources and reimbursement. Another option to yield a broader reach of the intervention would be, as proposed by the authors, to develop an Internet-based version of the current intervention. This has already been done successfully with their CBT intervention in the adjuvant setting.6Abrahams H.J.G. Gielissen M.F.M. Donders R.R.T. et al.The efficacy of Internet-based cognitive behavioral therapy for severely fatigued survivors of breast cancer compared with care as usual: a randomized controlled trial.Cancer. 2017; 123: 3825-3834Crossref PubMed Scopus (72) Google Scholar While the short- and long-term findings for CBT are positive, the comparison between GET and control is methodologically limited and definitive conclusions cannot be drawn, unfortunately. The authors report that fatigue was lower in the GET group as compared with control and effect sizes were comparable to the small-to-moderate effect sizes found in the adjuvant setting,8Furmaniak A. Menig M. Markes M. Exercise for women receiving adjuvant therapy for breast cancer.Cochrane Database Syst Rev. 2016; 9: CD005001PubMed Google Scholar,9Vulpen J.K. van Velthuis M.J. Steins Bisschop C.N. et al.Effects of an exercise program in colon cancer patients undergoing chemotherapy.Med Sci Sport Exerc. 2016; 48: 767-775Crossref PubMed Scopus (76) Google Scholar i.e. 0.39, 0.24, and 0.50 at 14, 18, and 26 weeks post-baseline, respectively. Statistical analyses resulted in a P value of 0.057, which is not surprising, since only 42 of the estimated 51 patients were included. Given the number of patients and the effect size a conclusion of no difference based on the P value is unjustified.10Amrhein V. Greenland S. McShane B. Scientists rise up against statistical significance.Nature. 2019; 567: 305-307Crossref PubMed Scopus (1312) Google Scholar Nevertheless, there are other aspects regarding the GET intervention that need attention and require further studying of exercise interventions in the advanced cancer setting. First, adherence to the intervention was low. This has also been described by Scott et al. who investigated a thrice weekly supervised treadmill walking intervention and concluded that further studies are needed to find the optimal exercise dose.11Scott J.M. Iyengar N.M. Nilsen T.S. et al.Feasibility, safety, and efficacy of aerobic training in pretreated patients with metastatic breast cancer: a randomized controlled trial.Cancer. 2018; 124: 2552-2560Crossref PubMed Scopus (55) Google Scholar In the current study, other reasons for the low adherence could be identified. The GET intervention was newly developed and pilot tested,12van den Dungen I.A. Verhagen C.A. van der Graaf W.T. et al.Feasibility and impact of a physical exercise program in patients with advanced cancer: a pilot study.J Palliat Med. 2014; 17: 1091-1098Crossref PubMed Scopus (36) Google Scholar but the actual intervention deviated from the pilot study in several aspects, such as a longer duration (12 versus 6 weeks), fewer supervised sessions (one versus two per week) and inclusion criteria (fatigued versus no selection on fatigue level). Moreover, the program immediately started with high-intensity interval training, whereas starting with a continuous moderate-to-high-intensity aerobic program and progressing to high-intensity interval training after a couple of weeks might be better in this fatigued population. Indeed, five patients of the 34 patients who started the intervention withdrew within 5 weeks. In addition, the implementation of the exercise intervention could possibly be improved. Currently, physical therapists were only instructed once about the GET protocol and supervision was upon request. Since this is a new patient group, more monitoring and guidance by experienced exercise-oncology trainers is probably needed and might improve adherence. In conclusion, transferring an evidence-based CBT intervention from the adjuvant to the advanced cancer setting worked and yielded very promising results in a severely fatigued population. Regarding exercise, this study provided first insights regarding feasibility and effectiveness in the advances setting, but further research is warranted. The current international PREFERABLE project (https://www.h2020preferable.eu/about/, NCT04120298) will take the results of the present study into account and will study the effect of exercise in 350 patients with metastatic breast cancer. Along with this randomized controlled trial, it will be investigated how health care systems in different EU countries are organized around integrating exercise interventions into cancer care and what patients' preferences and barriers regarding exercise will be in these countries. I thank Prof. Petra Peeters for her valuable comments. No funding was received.