Few studies looking at the benefits of exercise in patients with advanced cancer have been published.14Lowe et al15 reviewed six studies of physical activity and palliative cancer patients, all pilots, involving a total of 84 patients. Subsequent studies looking at exercise and late-stage cancer patients included between 21 and 65 individuals,13,16–18 receiving strictly palliative chemotherapy included in heterogeneous groups of patients. This pilot examined 35 patients all with metastatic, incurable malignancy on cytotoxic systemic treatment.
To our knowledge, this is the first exercise pilot using metastatic cancer patients receiving only palliative chemotherapy in a general oncology practice. This pilot did not document any adverse effects, similar to studies with the same patient population.16–18 Two other studies exercising individuals with only multiple myeloma19 and metastatic breast cancer13 reported no injuries. Existing recommendations state that it is safe for cancer survivors to exercise.5,20 Our observations are consistent with observations that exercising patients with metastatic disease is safe.19 Currently, no exercise recommendation exists for this group of patients.
One goal was to determine the participation rate of metastatic cancer patients on chemotherapy in an exercise program: 28% (35/124) of potential candidates. This agrees with many prospective trials, where less than one-third of eligible patients participate.4 This pilot’s potential maximum (according to Table 2, given perceived cancer-related issues precluding participation) includes an additional 37 patients for a total of 72 (35+37) or 58% (72/124). The highest participation rate in the literature was 82% using inpatients in a 4-week program.21 Eleven (8.9%) patients declined the invitation. This pilot study was designed for maximum convenience of the patient: exercise and chemotherapy in the same hospital, clinical appointment shortly after the exercise session, and paid parking on exercise day.
We wanted to understand selection bias as opposed to informal exclusion criteria. While work has been done to assess patient-related factors,4,15,22 health care team biases4 have not been studied as extensively. A palliative chemotherapy candidate may not be an exercise candidate for valid medical reasons. While some patients can successfully exercise, others may fall into a category where a judgment is required by the medical team. A common belief is that cancer patients should rest rather than exercise, especially individuals with metastatic disease. In this pilot study, in the judgment of this particular medical oncologist (JAC), 48% of patients not invited were incapable of effectively taking part in the exercise program. This may be related to the aforementioned thinking. The remaining 52% are biases related to treatment or social factors (Table 2). Our study found that younger patients are more likely to be asked to participate. Further clarification of health care team bias or informal exclusion criteria is needed.
Regarding acceptable tolerability and safety, a study attrition rate of ≤20% and an exercise compliance rate of ≥70% have been suggested as acceptable.23 In this pilot study, the attrition rate was 24% using the previously stated definition. This compares to an attrition rate of 41% in a similar population of incurable metastatic patients in a 6-month program19 and 34% in women with metastatic breast cancer in a 16-week program, 45% of whom were receiving chemotherapy.13 Our study determined that patients stopped participating in the exercise program a median of 100 days prior to death and, for those patients completing palliative chemotherapy, continued to participate in the exercise program for an average of 7.6 days beyond their treatment. The compliance rate for class attendance in our indefinite study was 73.1% (median 73.9%). A compliance rate of 99% has been achieved in a 12-week program in the adjuvant setting.24 Therefore, the attrition rate using a modified definition and the compliance rate are comparable with what is acceptable for therapeutic intervention.
In this study, palliative chemotherapy treatment was not interrupted by the exercise schedule as indicated by preserved DI. Similar findings were seen in the setting of exercise and adjuvant chemotherapy for breast cancer.25
Our study did not show an improvement in the quality of life or reduction in fatigue with exercise, similar to other studies with this patient population.13,17,18 The improvement in physical function with exercise that we found has been reported in this patient population17,18 but not universally.13
How exercise might improve cancer survival is not clear. Medical oncology has moved toward targeted therapy, and exercise oncology must, similarly, determine which patients benefit from exercise as epidemiological data suggest differences with tumor subtype.23 β-Catenin is a candidate biomarker for exercise effect in CRC.8 In surgical and biopsy sections from our metastatic CRC patients, 42% stained strongly for β-catenin in the nucleus where Morikawa et al found 46% for early-stage CRC patients. Morikawa et al showed that strong nuclear staining for β-catenin was associated with a significant reduction in mortality (HR =0.56, 95% CI 0.35–0.90) in patients with early-stage CRC but only among patients with a body mass index (BMI) of ≥30 kg/m2. In our study, strong nuclear staining was associated with a nonsignificant reduction in the risk of death for all patients (HR =0.54, 95% CI 0.14–1.96), but we were unable to confirm Morikawa et al’s finding with respect to BMI given our smaller data set.
Exercise did not affect survival (HR =0.98, 95% CI 0.32–2.97) of patients with metastatic CRC in our study (Figure 2A). However, metastatic CRC patients with weak nuclear staining for β-catenin participating in our exercise program had a nonsignificant mortality reduction (HR =0.39, 95% CI 0.025–6.1) (Figure 2B). This is similar to the mortality reduction described by Morikawa et al for patients with weak nuclear staining, physical activity, and early-stage colon cancer (HR 0.33, 95% CI 0.42–1.09). These results support an intact regulation of the WNT–CTNNB1 pathway being required for exercise to have a beneficial effect on cancer progression, with weak nuclear staining for β-catenin being a potential biomarker. These hypotheses warrant further investigation.
Limitations of this study include the lack of measurement of physical activity including during home exercise where self-reporting can be subjective and lack reliability. Given that there are thresholds of physical activity needed to induce improvements in cancer-specific endpoints,3 this study cannot determine what that might be. Individualized prescriptions that use tenets of exercise treatment such as peak rate of oxygen consumption (peak VO2) and progressive overload have not been used the in the field of exercise oncology26 and were not used in this pilot. The invitation rate was based on the judgment of the medical oncologist and may differ depending on the health care professional. The β-catenin survival study suffers from small sample size, lack of randomization, difficulty in controlling for known prognostic factors in metastatic CRC, and lack of information with respect to activity of nonexercising control patients.
Future work will include a prospective trial looking at referral bias and the development of systematic exclusion criteria, a more careful measurement of physical activity to understand dosing of exercise and possible threshold effects, the use of training effect, a prospective trial of exercise, and β-catenin staining as the biomarker.
This study has tried to address several of the many unsolved issues regarding the effects of exercise in metastatic cancer patients.4 The first is the issue surrounding precision of the data generated with the inclusion of descriptions of the exercise program, and participation, attrition, and compliance rates. We also looked into reasons for referral bias to an exercise program and established a maximum participation rate for metastatic patients. The lack of this sort of data has been responsible for the wide variation in outcomes in previously published literature.4 We have added to the experience that exercise is safe in the metastatic population and that chemotherapy DI is not altered. We offered an exercise program with maximum convenience and safety, available as long as the patient wished to participate. We also looked into a potential biomarker for the efficacy of exercise. This will become especially important as the intracellular signaling pathways involved with exercise and cancer are elucidated, with β-catenin as one such candidate.