Medical Nutrition Therapy

The patients were prospectively recruited at three tertiary head and neck centers in Sweden. Inclusion criteria were newly diagnosed, curable, untreated HNC with a performance status of 0 to 2 according to the ECOG/World Health Organization (WHO) classification [60 ]. Exclusion criteria included previous treatment for malignant neoplasms within the last 5 years (except for skin cancer), excessive alcohol use, cognitive impairment, and inability to understand Swedish. The Uppsala Regional Ethics Review Board reviewed and approved the study (No. 2014/447). Blood samples were coded and stored in the Uppsala Biobank (approved RCC 2015-0025). This study was carried out as part of a larger prospective study registered on ClinicalTrials.gov, NCT03343236.
All patients were under nutritional surveillance according to local protocols, and supplementary nutritional therapy was offered when indicated. All patients were classified according to the Union for International Cancer Control (UICC) 8 staging system. A study representative met with the included patients and collected blood samples before treatment, 7 weeks after the start of treatment, and 3 and 12 months after the end of treatment. Body weight was monitored at each visit, and the grade of mucositis was evaluated according to the WHO mucositis scale [61 ]. Height was measured and used for the calculation of body mass index (BMI) (kg/m²). Any history of smoking was recorded and documented as pack-years.
The study cohort consisted of 180 patients with HNC. The most common sites were the oropharynx (n = 81), the oral cavity (n = 53), and the larynx (n = 22). Patient characteristics are shown in Table 3. Data from the first 30 patients in this study have previously been reported [16 (link)].
In terms of treatment, the patients were divided into 4 groups:(a)

Surgery only (Surg group), n = 24.

(b)

RT +/− surgery (RT group), n = 94.

(c)

RT and chemotherapy (cisplatin) +/− surgery (CRT group), n = 47.

(d)

RT and targeted therapy (EGFR monoclonal antibody) +/− surgery (RT Cetux group), n = 15.

Radiation therapy was administered with conventional fractionation (2 Gy/fraction), up to 68–70 Gy for primary therapy and 60–70 Gy for adjuvant therapy.
Cisplatin was administered concomitantly with radiation therapy to a total of 47 patients, in weekly doses of 40 mg/m²: 45 patients with oropharyngeal cancer, and 2 patients with laryngeal cancer. Most patients received 5 to 8 courses of cisplatin (n = 34), and the remainder received 1 to 4 courses (n = 13). In addition, 15 patients received weekly cetuximab (Cetux) and concomitant RT. Cetux was administered at a loading dose of 400 mg/m² and then a weekly dose of 250/m² in most cases. Two patients received 9 doses, five patients received 8 doses, four patients received 7 doses, and the remainder received 4–6 doses.
A total of 6 patients received brachytherapy in addition to conventional RT.

The medical history (age, gender, duration of diabetes) was collected from each subject. The subjects continued to receive the PHI70/30 regimen during the 2-week lead-in period, and were then randomly divided into two treatment arms: one arm received the LM25 regimen and the other arm received the LM50 regimen during the first 16-week treatment period, and the two arms then switched regimens for the next 16-week treatment period. The first four weeks of each 16-week treatment phase were the insulin dose titration period, when the patients were asked to self-monitor their blood glucose levels and insulin dose adjustments were made based on their results (the adjustment protocol is shown in Table 1). The next 12 weeks were the steady dose period. Oral hypoglycemic agents were not adjusted throughout the entire period of the study. The targets for glycemic control were blood glucose levels before breakfast and dinner of > 3.9 and ≤ 6.1 mmol/L, respectively.Table 1

Insulin sliding scale

Blood glucose (mmol/L)	Insulin dose adjustment
≤ 3.9	− 1 ~ 2 U
> 3.9 and ≤ 6.1	Unchanged
> 6.1 and ≤ 7.8	+ 1 ~ 2 U
> 7.8	+ 2 ~ 4U

During the study, the subjects were assigned diets recommended by nutritionists based on the 2013 China Medical Nutrition Therapy Guidelines for Diabetes [14 ]. The diets led to 45–60% of the total daily energy being derived from carbohydrates, 25–35% from dietary fat, and 15–25% from protein. The total daily energy intake was calculated based on the height and weight of each subject. Subjects were also required to exercise regularly during the study. During the 3 days of CGM at the end of each treatment phase, the subjects were given high-carbohydrate test meals (with 56.8–58.4% of the total energy deriving from carbohydrate, 15.7–17.2% from protein, and 24.4–26.7% from fat) on day 1 and high-fat test meals (with 39.8–40.7% of the total energy deriving from carbohydrate, 23.0–24.4% from protein, and 33.0–36.1% from fat) on day 2. They continued their habitual diets in day 3.

The outcome parameters (weight, NRS, phase angle) on the nutritional status were collected during dietary counseling by the nutritionist. Weight was measured with a calibrated body scale (seca 769), and patients wore light clothing. Phase angle, as a marker for the quality of the muscle mass, was collected by bioelectrical impedance analysis. For this purpose, the multifrequency impedance analyzer Nutriguard-MS Version 2 (Data Input GmbH; Pöcking, Germany) was used. The implementation of the BIA measurement was based on the specifications of Data Input GmbH and official guidelines [20 (link)]. It is worth mentioning that the NRS 2002 serves as an evaluated and validated screening tool to determine the risk of malnutrition, taking into account nutritional history (food intake, current weight, weight loss) and disease severity and higher risk in elderly patients [21 (link),22 (link)]. It is important to mention that nutritional counseling was irregular in the preoperative and postoperative periods, so the parameters were not standardized over time. As CGs did not receive preoperative nutritional counseling, their outcome parameters on nutritional status were omitted. Instead, the postoperative parameters were compared between the study groups. The medical parameters used to assess the effects of nutritional therapy include postoperative complications, hospitalization, and mortality. The postoperative complications were evaluated using the Clavien–Dindo classification, and a score of IIIb and/or higher was classified as severe complication. The parameter for hospital stay was subdivided into different levels of care (ICU: intensive care unit, MCU: medium care unit, normal ward). The NRS was used to combine the severity of the disease with the nutritional status.

IG patients were consulted (at least once pre- and postoperatively) for detailed nutritional counseling, which lasted approximately 45 min. However, a few additional counseling sessions were also provided at the request of physicians. Nutritional history, including anthropometric data, such as weight, disease-related weight loss, and height, was obtained by the dietitian. Quantitative and qualitative food intake, appetite, and gastrointestinal symptoms were also asked. In case of persistent nutritional problems, such as low food intake or malnutrition, high-caloric fluid supplements (2–3 potions (200 mL) per day with 2.0 kcal/mL) and enteral or parenteral nutrition were prescribed. In addition to the changes in nutritional physiology and/or possible complications from the surgery, some practical recommendations to avoid gastrointestinal symptoms, the risk of malnutrition, possible symptoms of dumping syndrome, the necessity of pancreatic enzyme supplementation, and possible lactose intolerance were also discussed. We also calculated the energy requirements and derived a recommendation for protein intake, weight maintenance, and weight gain, respectively. The total energy expenditure was calculated as 25–30 kcal/kg body weight per day, depending on patient activity, and recommended protein intake was calculated as 1.2–1.5 g/kg body weight per day, according to DGEM and ESPEN guidelines [1 (link),2 (link)]. Additionally, each patient received written nutritional recommendations related to surgery or individual symptoms, and the contents of the nutritional therapy were documented in the electronic medical record. A standard stepwise introduction to a full diet was further provided to the patients in accordance with the Enhanced Recovery after Surgery (ERAS) Standard Operating Procedure (SOP). All patients received supportive parenteral nutrition (SMOF lipid at 2200 kcal/d) for at least the first 4 postoperative days. All parts of nutritional therapy followed the recommendations of standardized clinical practice guidelines from DGEM and ESPEN. It is worth mentioning that the postoperative nutritional treatment was comparable in both study groups.