Sanft T, Harrigan M, McGowan C, et al. Randomized trial of exercise and nutrition on chemotherapy completion and pathologic complete response in women with breast cancer: the Lifestyle, Exercise, and Nutrition Early After Diagnosis Study. J Clin Oncol. 2023;JCO2300871.
To determine if an exercise and diet intervention affects chemotherapy dosing as measured by relative dose intensity (RDI) over patients’ entire treatment period. Secondarily, to assess tumor response to chemotherapy (pathological complete response [pCR]) in those who received chemotherapy before tumor removal (neoadjuvant chemotherapy).
The intervention did not affect the amount of chemotherapy delivered (relative dose intensity) between the 2 groups. However, in those who received neoadjuvant chemo, the intervention arm had nearly twice as many cases of pathological complete remission (53%) compared to the usual-care (UC) arm (28%).
This was a 2-arm, randomized trial dubbed the Lifestyle, Exercise, and Nutrition Early After Diagnosis (LEANer) Study.
All participants were invited volunteers who met criteria based on their electronic medical records while receiving treatment at Yale New Haven Hospital or Dana-Farber Cancer Institute. Eligible participants were newly diagnosed with breast cancer, open to being randomly assigned, receiving chemotherapy, and able to walk at moderate to vigorous intensity at least 150 min/week, eat fruits or vegetables daily, and understand instructions.
From the original 425 women screened, 173 women enrolled, with 87 assigned to the intervention group and 86 to the UC group.
After participants completed a baseline questionnaire, computer generation randomly assigned them into the UC or intervention arms. Randomization was stratified by human epidermal growth factor receptor 2 (HER2) status, hormone receptor (HR) status, and the number of chemotherapy cycles planned (4 or >4).
Age, race, ethnicity, and tumor type did not differ for enrolled vs those screened and not enrolled. Women were aged 53 ± 11 years. The mean body mass index (BMI) was 29.7 ± 6.7 kg/m2. Participants were 71% nonHispanic White, 14% Black, and 8% Hispanic.
Roughly half the participants in each arm had a stage I tumor. Menopausal status was 55.5% of the participants in the intervention group and 53.5% in the UC group. There were no statistically significant differences in the tumor characteristics or participant characteristics in the 2 arms.
Dietary and physical-activity goals for the participants were set based on the Healthy Eating Index 2015 for diet quality, along with a physical-activity guideline of ≥150 min/wk of moderate to vigorous intensity or 75 min/wk of vigorous intensity along with resistance training 2 times weekly. Intervention sessions of 30 minutes varied based on the length of chemotherapy; registered dieticians met with the patients 4 times in the first month, then for 2 biweekly sessions for months 2 and 3, and then once a month until completion. The registered dieticians were all certified specialists in oncology nutrition and used interventions based on the LEANer study, which is an adaptation from a diabetes study that focused on cognitive therapy and side-effect management.
Study Parameters Assessed
Investigators collected data after each chemotherapy cycle, including the date, dose adjustments if made, and/or delays. Relative dose intensity was a percentage of the actual chemotherapy dose divided by prescribed dose intensity. This was calculated for each drug separately and then averaged for each patient.
For those who received neoadjuvant chemotherapy, investigators also collected the pathology report postsurgery and recorded the pathological complete response if no residual invasive disease was noted in the specimen.
Of note, the other participants in the UC group had access to a dietician and survivorship group anytime if referred but were not assigned.
The primary outcome of this study was to compare an exercise and diet intervention vs usual care on relative dose intensity of chemotherapy. RDI is a measurement of chemotherapy delivered relative to that prescribed, and lower RDIs have been associated with greater mortality. The higher the RDI, the better response and prognosis. This trial’s secondary aim was to evaluate the diet and exercise intervention vs usual care on the rate of complete pathological response in those receiving neoadjuvant chemotherapy.
Not surprisingly, the intervention group had a greater improvement in diet and exercise quality compared to the usual-care group (P<0.05).
There was no difference in RDI between the intervention group (92.9% ± 12.1%) and the UC group (93.6% ± 11.1%; P=0.69).
There was no difference in the percentage of participants in each arm that received >85% RDI, with 81% in the intervention arm and 85% in the UC arm receiving >85% RDI (P=0.55).
The rate of treatment delays and/or dose reduction was 38% in the intervention group and 36% in the UC group (P=0.80). Again, there was no statistically significant difference.
While the intervention did not appear to affect the RDI between the 2 arms, the 72 participants who were receiving neoadjuvant treatment had a remarkable result: There was a complete pathological response (pCR) in 53% of those in the intervention group vs only 28% in the UC group (P=0.037).
The authors did not declare any conflict of interest. The study was registered as NCT03314688.
Practice Implications & Limitations
For integrative clinicians, whether naturopathic or conventionally trained, the role of a healthy diet and exercise is a foundational piece of any optimal health program. The inclusion of diet and exercise extends to active cancer treatment as well. Several studies have been conducted over the years evaluating the effects of diet and exercise on outcomes, and they have shown that higher levels of physical activity and a healthy diet are associated with lower breast cancer mortality,1-3 but no studies until now have evaluated how those interventions may affect relative dose intensity during chemotherapy.
This study ultimately showed that exercise and healthy diet did not greatly impact the RDI but were associated with complete pathological response.
Side effects of chemotherapy are inevitable to some degree, and this sometimes will lead to reducing dosage and even delaying some treatments. This is an opportunity to support the patient during chemotherapy and minimize side effects. One caveat is that the severity of nausea was significantly worse in the intervention group. This could be because, while diets high in fruits and vegetables are great, they may be harder on the gut when enzymes and mucosal lining are altered from chemotherapy. Patients have reported that this can be ameliorated with modified fasting around chemotherapy or eating lighter, more easily digested foods in the window around chemotherapy, and research has backed this up.5
This trial corroborates that exercise and diet interventions are impactful and that patients will follow through with them if given the opportunity and held accountable. The 91% adherence of the intervention group was accomplished through just a few sessions with professionals for guidance. This trial used a plant-focused diet with a daily goal of 5 various fruits and/or veggies, 25 grams or more of fiber, and less than 30 grams of sugar intake. They also recommended limiting processed foods, red meat, and alcohol consumption.
This trial also demonstrated that reaching pathological complete response is not always dependent on the amount of chemo delivered.
Sadly, patients report too often that they’ve been told to eat whatever they want, “a calorie is a calorie,” and that diet doesn’t matter when going through chemotherapy. They are also often told to reduce their activities. We know that moving our bodies is vital for health. We also know that plant-based eating promotes feeling healthy overall. This study suggests it may also lead to less recurrence, since complete pathological response is a good prognostic indicator.
This trial also demonstrates that reaching pathological complete response is not always dependent on the amount of chemo delivered. It is widely accepted that a higher RDI (ie, more chemo) renders better response and better prognosis. This trial showed that other factors are at work. While the mechanism is unknown, we can conjecture that gut health, the microbiome, and its effects on immune function may play a part in the higher rates of pCR seen in the intervention arm. Physical activity status before, during, and after appears to have outcomes as well based on a study that concluded, “Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients.”6
We must ensure that diet and exercise are a part of our conversations with our patients undergoing chemotherapy. For those who receive neoadjuvant chemotherapy, having residual disease at the time of surgery carries with it a worse prognosis than complete pathological response.4 While patients seeing integrative practitioners are given exercise and diet guidelines, many patients are not receiving this information. Perhaps with more trials like this, health practitioners in settings outside integrative health offices will be more likely to focus on diet and exercise.
My hope is that as more trials are conducted, outcomes for women with breast cancer will improve. Adoption of a plant-based diet and an exercise routine during treatment culminates in significant upside potential with no downside risk for those patients undergoing chemotherapy treatment.