Short-Term Fasting Enhances Chemotherapy Response in Advanced Ovarian Cancer

CHICAGO — Patients who fasted during chemotherapy for ovarian cancer had significantly longer progression-free survival (PFS) compared with patients who ate a normal diet, a small randomized study from Italy showed.

Fasting led to significantly lower insulin levels at the end of neoadjuvant therapy (9.59 vs 18.5 µIU/mL), the study’s primary endpoint. Additionally, patients assigned to a regular diet had significantly greater variation in insulin levels after neoadjuvant therapy.

Investigators hypothesized that insulin helps fuel cancer growth and that reducing insulin via fasting might enhance the effect of chemotherapy via metabolic modulation. Subsequently, patients randomized to fasting had a significantly higher rate of pathologic complete response (pCR) and a median PFS of 38 months versus 24 months for the control group.

The pilot study (41 patients total in both arms) demonstrated the feasibility and tolerability of short-term fasting, and the results warrant validation in larger studies, said Claudia Marchetti, MD, PhD, of the Fondazione Policlinico Universitario Agostino Gemelli in Rome, during a press briefing prior to the American Society of Clinical Oncology (ASCO) annual meeting.

“Short-term fasting results in a favorable metabolic shift with a decrease in insulin,” said Marchetti. “It is also feasible and well tolerated and helps in achieving better response and longer progression-free survival. We observed preliminary signals of immune response, and we are undergoing other analyses with regards to lymphocytes. We are waiting for longer follow-up, and we are planning a larger randomized multicenter trial to further validate our findings.”

ASCO President Eric Small, MD, of the University of California San Francisco, called the study an example of “very, very interesting translational science,” showing biologic effects of short-term fasting on insulin and the immune environment.

“What’s so interesting about this study, and why we’ve selected it for the program, is that it had significant clinical impact,” said Small. “This is a great example of a very simple intervention that has benefit and can be undertaken and implemented anywhere in the world. It’s not an expensive new drug, and yet it has the potential to really have an impact on this cancer. While this is a small study, the findings are very encouraging, support earlier data, and are a very promising area of research.”

Context and Study Design

Providing context for the study, Marchetti noted that despite advances in surgery and chemotherapy for advanced ovarian cancer, outcomes remain poor for many patients. Half of the patients are not suitable for primary surgery, necessitating neoadjuvant therapy followed by interval debulking surgery. An urgent need exists for safe, low-cost, and easily implemented strategies to enhance treatment efficacy and improve prognosis.

“One of our major challenges is to improve neoadjuvant chemotherapy response and also to increase the rate of complete cytoreductive surgery,” Marchetti said. “In this regard, preclinical evidence suggests that short-term fasting may enhance chemotherapy efficacy through metabolic modulation. In particular, fasting reduces insulin levels and also the level of IGF [insulin-like growth factor]-1, which are involved in tumor growth and also in chemotherapy resistance. A lower level of insulin may create a more favorable environment for chemotherapy response.”

To test their hypotheses, Marchetti and colleagues conducted a prospective, open-label, exploratory randomized trial. They enrolled patients with newly diagnosed advanced high-grade serous ovarian cancer not suitable for primary cytoreduction and requiring neoadjuvant chemotherapy. Patients initially were randomized to three dietary strategies: short-term fasting, a ketogenic diet, and a free diet. The ketogenic arm closed early because of issues with compliance.

Patients assigned to the study arm began fasting 36 hours before the start of each cycle of chemotherapy, continuing until 24 hours after completion of a cycle. During the fasting period, patients had a total daily energy intake of 350 kcal, including unlimited water and herbal tea, 200 cL of vegetable juice (~67 oz), and small quantities of light vegetable broth. No stimulants of any type were allowed.

Patients received three cycles of neoadjuvant chemotherapy, with a 21-day interval between cycles. Between chemotherapy cycles, patients randomized to fasting consumed their regular diet. The day before fasting started, patients were asked to limit total energy intake to <1,000 kcal. Patients in the control arm consumed their regular diet throughout the study.

The primary endpoint was the reduction in mean insulin levels, which were measured at baseline, at the start of each chemotherapy cycle, and at the end of the third cycle.

Key Findings

Data analysis included 36 patients who adhered to assigned treatment, 18 in each arm. The mean baseline insulin level was 8.7 µIU/mL in the control group and 10.7 µIU/mL in the fasting arm, a nonsignificant difference. At the end of neoadjuvant chemotherapy, the mean insulin level was significantly lower in the fasting group (P=0.014), as was variation in insulin level after chemotherapy (+9.76 vs – 1.12 µIU/mL, P=0.010).

The chemotherapy toxicity profile did not differ significantly between arms, although the fasting arm had more grade 3/4 hematologic toxicity (77.8% vs 50%, P=0.083). No grade 3/4 nonhematologic toxicity occurred in either group. The fasting group had a significantly higher pCR rate (defined by chemotherapy response score), at 58.8% versus 17.6% (P=0.011). Rates of cytoreductive surgery were similar between the two groups.

Translational analyses suggested a better anticancer immune response in the fasting group, as reflected by lower levels of suppressor granulocytes and monocytes.

Although patients received standard chemotherapy (carboplatin and paclitaxel), the results are likely applicable to other kinds of therapy and cancers.

“Fasting appears to modulate systemic metabolic pathways involved in tumor growth and treatment sensitivity that are not specific to chemotherapy and may also influence the response to targeted agents,” Marchetti told MedPage Today. “Recently, data on the use of a fasting-mimicking diet in patients with metastatic non-small cell lung cancer have also been published, further supporting the broader potential of this strategy.”

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