JCO Article Insights: Impact of Physical Activity on Mortality and of BMI on Treatment-Related Adverse Events

Journal of Clinical Oncology (JCO) Podcast

In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects.

In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization.

The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions.

The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration.

So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation.

The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively.

Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants.

Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting.

Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser.

Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death.

The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively.

Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer.

While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis.

All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors.

The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study.

In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial.

Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone.

More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe.

In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression.

No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients.

Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia.

For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity.

Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group.

Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events.

So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment discontinuation. These findings are in line with previous data obtaining the metastatic setting with other CDK4/6 inhibitors, and support the existence of a different pharmacodynamic profile influenced by BMI that translates in a more favorable toxicity profile.

At present, differences in BMI do not seem to affect palbociclib efficacy, but further analysis with additional follow-up time and events, as well as by type of endocrine therapy administered are planned in the PALLAS study. That concludes this episode of JCO Article Insights.

In these episodes, we summarized findings from two studies, the first titled, Pan-Cancer Analysis of Postdiagnosis, Exercise and Mortality by Lavery and colleagues. This trial shows that higher level of exercise are associated with lower risk of all-cause cancer specific and other cause mortality, although with some differences according to cancer site.

The second article titled Impact of BMI in Patients with Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial by Dr. Pfeiler and colleagues observed a significant different side effect profile for palbociclib according to BMI, but no differences in efficacy.

This is Davide Soldato, thank you for your attention and stay tuned for the next episode of JCO Article Insights.

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