Short term fasting (STF) protects from toxicity, while enhancing the efficacy of chemotherapy in cancer bearing mice and is a promising strategy to enhance the efficacy and tolerability of chemotherapy in humans. A specifically designed low calorie, low amino acid substitution diet (“Fasting Mimicking Diet”, FMD) has similar effects in vivo during chemotherapy as STF. The DIRECT trial evaluates the impact of FMD on toxicity and efficacy of neoadjuvant chemotherapy in women with HER2-negative early breast cancer.

Patients and methods:

Eligible patients had histologically confirmed, HER2-negative, stage II/III early breast cancer, adequate bone marrow, liver and renal function, BMI > 19kg/m2 and absence of diabetes mellitus. Women receiving 8 neo-adjuvant AC-T courses (adriamycin/cyclophosphamide - docetaxel) or 6 FEC-T courses (5-fluorouracil, epirubicin and cyclophosphamide - docetaxel); day 1, q 3 weeks, were randomized to receive FMD or regular diet for 3 days prior to and at the day of chemotherapy and 3 days prior to surgery. The FMD group received no dexamethasone during the AC or FEC courses. The primary endpoint of the phase II part was feasibility and grade III/IV toxicity and of the phase III pathological complete response (pCR) rate. Additionally, in a side study increase in DNA damage in lymphocytes before and three hours after chemotherapy was compared between the 2 arms.


From February 2014 to January 2018 131 patients from 11 participating Dutch centers were randomized, whereof 100 received AC-T and 31 received FEC-T. Sixty-six of the patients received FMD. Compliance to the diet was low as 32% fasted at least half of the cycles and 24% of patients fasted during all of cycles. The main reasons of non-compliance were food aversion induced by chemotherapy and the taste of the diet. Intention to treat grade III/IV toxicity was not significantly different between the standard arm (67,2%) and in the FMD arm (79,4%), although the majority of the toxicities in the FMD arm were assessed in patients that did not complete the FMD diet preceding the measurements. The total overall pCR rate was 12,8%, lower than assumed in the sample size calculation and would therefore need minimally a doubling in patient numbers to be able to reach the expected pCR difference between both arms. Due to the poor compliance, slow accrual rate and low overall pCR rate the DIRECT study terminated after completion of the phase II part. Subgroup analysis will be presented at SABCS. In a side study, DNA damage after chemotherapy was significantly less increased in lymphocytes in the FMD group as compared to the control group (p=0.043).


The effect of STF on toxicity and efficacy of chemotherapy was not established due to poor compliance, however STF by FMD reduced a transient increase in chemotherapy induced DNA damage. Close monitoring of patients by nutritionists with expertise in low calorie diets as well as diets with a more variable taste are probably needed to successfully examine the impact on adverse effects and tumor biology.

Citation Format: de Groot S, Lugtenberg RT, Welters MJ, Ehsan I, Vreeswijk MP, Smit VT, de Graaf H, Heijns JB, Portielje JE, van de Wouw AJ, Imholz AL, Kessels LW, Vrijaldenhoven S, Baars A, Meershoek-Klein Kranenbarg E, Duijm-de Carpentier M, van Leeuwen-Stok E, Putter H, Longo VD, van der Hoeven JJ, Nortier JW, Pijl H, Kroep JR. DIetary REstriction as an adjunct to neoadjuvant ChemoTherapy for HER2-negative breast cancer: Final results from the DIRECT trial (BOOG 2013-04) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-20.