Publication: A double-blind phase III trial of immunomodulating nutritional formula during adjuvant chemoradiotherapy in head and neck cancer patients: IMPATOX. American Journal of Clinical Nutrition. 2020 Dec 10;112(6):1523-1531. doi: 10.1093/ajcn/nqaa227. PMID: 32936874.
Reviewer: Vijaya Surampudi, MD, MS
Why is this paper important? Head and neck cancer (HNC) accounts for 3% of the malignancies in the United States(1). The most common sites for HNC are the oral cavity, the pharynx and the larynx which are all contribute to the process of mastication. The therapeutic approach for HNC involves a combination of surgery, radiotherapy and chemotherapy and these treatments can result in mucositis, odynophagia, dysphagia, xerostomia, dysgeusia, nausea, vomiting, and anorexia. The multimodal treatment approach to HNC can also contribute decreased oral intake resulting in malnutrition(2). The severity of the adverse side effects may contribute to the need for enteral nutrition. Many patients would prefer to remain on oral nutritional supplements if side effects could be managed or prevented. This study investigates the use of an immunonutrient supplement to help reduce severe side effects resulting from treatment with cisplatin and concomitant radiotherapy.
Summary: This study was a double-blind phase III multicenter trial involving 180 HNC patients who were eligible for chemoradiation after surgery with curative intent. The patients were assigned to drink oral supplementation three times/day 5 days prior to each cycle of cisplatin and randomized to the immunonutrient supplement enriched with L-arginine, omega 3 fatty and ribonucleic acids (treatment arm) or an isocaloric isonitrogenous supplement (control group). There were 90 patients in each arm and four patients were excluded in each arm due to ineligibility, consent withdrawal or incomplete chemoradiation therapy. Median age was 58 years old, 82.8% male and tumor localization was mainly oral cavity and oropharynx.
Primary objective of the study was to evaluate efficacy of the immunonutrient supplement on severe mucositis. Secondary objectives included compliance to oral supplementation, progression-free survival and overall survival. At one month, after terminating chemoradiotherapy, the immunonutrient supplement failed to reduce severe mucositis. Grade 3-4 mucositis was reported in 33.7% in the treatment arm and 34.9% in the control group. Overall no difference was observed for severe toxicities reported during chemoradiation treatment between the two arms. After a median follow up of 38.3 months (95% CI: 37.9, 38.6 months) no significant difference was noted in overall survival or progression-free survival.
However, the study did note improvements in overall survival and progression to free survival in patients who were >75% compliant with the immunonutrient supplement. Of the 172 patients treated with chemoradiation, 112 patients (65%) were classified with >75% compliance. Of that 50.9% took the immunonutrient supplement. In this group overall survival was significantly improved in the immunonutrient group (81%; 95% CI: 67%, 89%) compared with controls (61%; 95% CI: 46%, 73%; p=0.034), as well as progression free survival (73%; 95% CI: 58%, 83% compared with 50%; 95% CI: 36%, 63%; p= 0.012).
Commentary: The use of supplements in addition to standard cancer treatment regimens to reduce adverse side effects and improve overall survival is an active area of cancer research. The intervention with the immunonutrient supplement did not reduce severity of mucositis during chemoradiation but noted improvement in overall survival and progression-free survival who were compliant with the supplement. A major challenge in this study was compliance was self reported by the patient without correlation with biomarkers. It is possible the lack of effectiveness to reduce severity of mucositis was related to lack of nutritional counseling in the study design. Adequate protein intake is linked with reduced severity of mucositis. Studies published with HNC patients that nutritional counseling in conjunction with oral nutritional supplements resulted in better protein intake and improved treatment tolerance(3). Providing a nutritional supplement without nutritional counseling may have contributed to lack of improvement in mucositis. In addition, it would be of interest to review the data on the patients’ body weight and body composition through the study duration. Weight loss and sarcopenia in HNC and can possible predict negative clinical outcomes and treatment toxicity(4). Changes in body composition could be linked to the positive outcomes of survival noted in this study.
This trial highlights the need for ongoing investigations of types of oral nutritional supplements, ideal time of administration during the clinical course and determining which biomarkers are important prognostic markers for the clinical course in HNC.
- R. L. Siegel, K. D. Miller, H. E. Fuchs, A. Jemal, Cancer Statistics, 2021. CA: A Cancer Journal for Clinicians 71, 7-33 (2021).
- A. Yanni et al., Malnutrition in head and neck cancer patients: Impacts and indications of a prophylactic percutaneous endoscopic gastrostomy. European Annals of Otorhinolaryngology, Head and Neck Diseases 136, S27-S33 (2019).
- E. Cereda et al., Nutritional counseling with or without systematic use of oral nutritional supplements in head and neck cancer patients undergoing radiotherapy. Radiotherapy and Oncology 126, 81-88 (2018).
- B. Ferrão et al., Body composition changes in patients with head and neck cancer under active treatment: a scoping review. Supportive Care in Cancer 28, 4613-4625 (2020).
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