Early nutritional support in non-metastatic stage IV oral cavity cancer patients undergoing adjuvant concurrent chemoradiotherapy: analysis of treatment tolerance and outcome in an area endemic for betel quid chewing
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- Wang, CH., Wang, HM., Pang, YP. et al. Support Care Cancer (2012) 20: 1169. doi:10.1007/s00520-011-1192-y
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Non-metastatic stage IV oral cavity cancer patients undergoing concurrent chemoradiotherapy (CCRT) are at risk of malnutrition because of postoperative eating problems and CCRT-related complications. A high percentage of betel quid use, which is associated with metabolic disorders, is found in oral cavity cancer patients in Taiwan. The aim of this study is to evaluate the effect of an early and intensive nutritional support program, comprising individualized counseling, nasogastric tube feeding, and mandatory hospitalization, throughout the CCRT period for such cases in an area where betel quid use is prevalent.
We retrospectively analyzed 35 patients with nutritional support (NI) and 23 patients with no specifically designed nutrition program (NC).
The NI group had better maintenance of body weight (p < 0.001) and higher serum albumin levels (p < 0.002) than the NC group. There was no difference in the total dose of radiation completed in the two groups; in contrast, the percentage of NI group patients who had radiation therapy (RT) breaks was lower and who completed planned chemotherapy was higher than in the NC group. Furthermore, more NC group patients suffered from sepsis during the treatment period, and fewer were alive 2 years after treatment.
An early and intensive nutrition support may be beneficial to minimizing body weight loss, offering better treatment tolerance and probable survival benefits for patients with non-metastatic stage IV oral cavity cancers undergoing CCRT in endemic betel quid chewing areas.
KeywordsOral cavity cancer Combined modality therapy Nutrition therapy Nasogastric intubation Betel nut
The incidence of oral cavity cancer in Taiwan is one of the highest in the world and is approximately 20 per million among the male population in the country [1, 2]. Over one third of oral cavity cancer patients are diagnosed as non-metastatic stage IV status at presentation in Taiwan [1, 3]. Surgery is the mainstay treatment of choice, since a wide excision margin ensures good locoregional control. Postoperative concurrent chemoradiotherapy (CCRT) has been considered a part of standard of treatment for cases where a positive surgical margin exists or where extracapsular spread to regional lymph nodes is present [4, 5]. Nonetheless, the treatment for these patients remains a clinical challenge, since the rates for local recurrence and distant metastases are high, and patient acceptance of subsequent complications is poor, even if there is a good treatment response .
Appropriate nutritional support plays an important role in the postoperative care of stage IV oral cavity cancer patients undergoing CCRT, and the treatment plan should integrate a nutritional component as early as possible for several reasons. First, it is estimated that more than 50% of patients with head and neck cancers had developed protein-energy malnutrition at the time of diagnosis and before beginning treatment because of locally advanced cancer status and their frequent history of excessive smoking, betel quid chewing, dietary indiscretions, and alcohol abuse [3, 6]. Of particular concern is the statistic that in Taiwan, approximately 85% of oral carcinoma patients are habitual users of betel quid, which is strongly associated with adult metabolic syndrome [1, 7]. These factors of cancer-related malnutrition and carcinogen exposure have a significantly negative prognosis . Furthermore, the surgery for stage IV oral cavity cancer patients is much more destructive than for early-stage patients so that postoperative chewing/swallowing problems and cosmetic damage are inevitable. Their devastating effects often lead to worsened nutritional status and increased risk of infection . Importantly, CCRT-induced toxicities including emesis, anorexia, mucositis, dysphagia, and xerostomia have a negative impact on nutrition and functional ability, thereby compromising treatment tolerance and efficacy, and increasing health care costs [9, 10]. Finally, preoperative low body mass index (BMI) and serum albumin levels are associated with a poorer prognosis for oral cancer patients in Taiwan, suggesting that a good nutritional status is crucial in improving their survival .
Since 2007, an early and intensive nutritional support program has been established for oral cavity cancer patients undergoing CCRT, within a multidisciplinary management of the disease at our institution. Before 2007, these patients were not routinely referred to the dietitians before the beginning of the treatment until the adverse effects of CCRT developed or recent body weight loss more than 10% of usual body weight occurred. Occasionally, patients had no assistance from the Nutrition Unit during the treatment period. The purpose of this study was to evaluate the effects of early and systematic nutritional interventions, including individualized nutrition counseling, nasogastric tube (NG) feeding, and mandatory hospitalization during CCRT, on body weight, serum albumin levels, treatment tolerance, and survival for postoperative non-metastatic stage IV patients with oral cavity cancers undergoing adjuvant CCRT in Taiwan, an area with high betel quid use.
Methods and materials
From January to September 2007, there were 42 consecutive clinically documented postoperative stage IV oral cavity cancer patients undergoing CCRT, with the presence of a positive surgical margin and/or extracapsular spread in the regional lymph nodes, analyzed retrospectively. All 42 patients were treated after implementation of the nutrition support program and were evaluated before the start of CCRT. Out of the 42, 35 were designed as the nutrition support (NI) group. Seven patients refused hospitalization, tube feeding, or the scheduled follow-up and were not included in the study. All 35 patients were equipped with NG tubing and were hospitalized throughout the CCRT period. They were compliant to the nutritional program. The nutrition support program for oral cavity cancer patients includes individualized nutrition counseling before the beginning of the treatment and scheduled visits every 2 weeks throughout the CCRT period. Each evaluation recorded dietary intake, current weight, usual weight, height, BMI, treatment-related adverse effects, and serum albumin levels. Patients were informed about potential eating difficulties due to CCRT-induced toxicity and about the importance of maintaining a good nutritional status. The patient’s total energy requirement was estimated using the Harris Benedict equation, applying an activity factor of 1.2–1.5 and a stress factor of 1.2 . All postoperative oral cavity cancer patients undergoing CCRT were required to place the NG tube and to monitor closely the daily nutritional intake in the hospital throughout the treatment period to complement their oral intake to fulfill their energy requirement. A commercial supplement was used for oral intake and consisted of ready-to-use liquid polymeric formulas (Isocal, Nestle Taiwan Ltd, 1.05 kcal/mL, 13.0% proteins, 37.0% lipids, and 50.0% carbohydrates; Jevity, Abbot, USA, 1.05 kcal/mL, 16.7% proteins, 29.0% lipids, and 54.3% carbohydrates). For no nutrition support (NC) group, there were 127 postoperative oral cavity cancer patients who had been treated with CCRT between 2005 and 2006, and 59 patients were matched for age, gender, tumor, node, metastasis (TNM) stage, body weight record, the time to record serum albumin levels, and radiotherapy schedule (total dose, fractionation, and volume treated). In my institution, patients undergoing CCRT were regularly visited at hemato-oncology and radiotherapy units every week during the treatment course. Physicians were suggested to record the patient information, including the body weight, mean daily calorie intake from diet diary, serum albumin level, and treatment-related adverse effects at least twice every month. Eventually, only 23 patients were totally matched for this retrospective analysis. Patients in the NC group received a booklet of nutrition advice for CCRT-induced toxicity, the standard practice from hemato-oncology, and radiotherapy units at that time. NG tube feeding and referral to dietitians were usually not suggested unless eating problems or body weight loss was manifested. Patients in this group with less severe side effects seldom received specialized nutritional evaluation.
Tumors were reclassified retrospectively according to the 2002 American Joint Committee on Cancer Staging System based on physical examination, routine laboratory tests, chest X-rays, bone scans, abdominal ultrasonography, and magnetic resonance imaging of the head and neck.
Concurrent chemoradiotherapy and toxicity evaluation
Patients were prescribed radiation of 64–68 Gy in 32–34 fractions over an 8-week period. They received their chemotherapy regimen of a cis-platinum infusion (50 mg/m2) on day 1, plus oral UFT capsule (tegafur plus uracil, 250 mg m−2 day−1) and oral calcium folinate (90 mg/day) on days 1–14 every 2 weeks, concurrently with radiotherapy. The CCRT schedule and standards of care from hemato-oncology and radiotherapy units did not differ between the intervention and the control groups. During the CCRT period, analgesics, antibiotics, vitamin supplements, mouth rinse, and topical steroid ointments were prescribed for all patients. Breaks from radiotherapy were suggested if the following conditions occurred: (1) severe hematological toxicity (neutropenia, grade ≥3 and pancytopenia grade, ≥3) or non-hematological toxicity (mucositis grade, ≥3 and emesis grade, ≥3) according to the Radiation Therapy Oncology Group toxicity criteria ; (2) body weight loss of >10% of pre-treatment value; (3) dehydration due to the onset of absolute dysphagia; and (4) critical medical morbid status including sepsis, hyperglycemia, and unexplained febrile episodes. Before radiotherapy breaks were taken, patients were informed of the benefits and disadvantages of delaying radiotherapy schedules.
Data collection and statistical analysis
The following clinical parameters of patients from both groups were retrospectively analyzed in the study: age, gender, body weight, BMI, co-morbidity status, history of tobacco, alcohol, and betel nut chewing exposure, tumor location, TNM stage, serum albumin level, and daily caloric intake within the CCRT period. The changes in body weight were assessed in both groups at the beginning of CCRT (V0), at the second week of CCRT (V1), at the fourth weeks of CCRT (V2), at the sixth week of CCRT (V3), and at the eighth week of CCRT (V4). The changes in serum albumin levels were evaluated at V0, V2, and V4.
The treatment tolerance was evaluated by the total dose of radiation completed, the percentages of patients with RT breaks, adherence to the planned chemotherapy schedule, occurrence of sepsis (cultures from the bloodstream detected the presence of pathogens that made the patients ill and febrile), mucositis grade ≥3, and emesis grade ≥3. The treatment outcome was assessed by the 1- and 2-year survival rates.
Statistical analyses were performed with the SPSS statistical package, version 13.0 (SPSS Inc., Chicago, IL, USA). The chi-square test was used to determine the associations between the nutrition groups and various clinical and pathological features of patients within the groups. The differences among age, body weight, BMI, serum albumin level, and daily caloric intake were evaluated by independent Student’s t tests. All p values were derived from two-tailed statistical tests. A p < 0.05 was considered statistically significant.
Demographic characteristics of patients according to nutrition support status
NI (N = 35)
NC (N = 23)
55.1 ± 1.9
51.9 ± 2.2
Tumor sites of oral cavity cancer
TNM stage (IVA/IVB)
Betel quid chewing
Mean body weight (kg) before CCRTa
60.9 ± 2.3
64.8 ± 2.4
Mean BMI (kg/m2) before CCRTa
22.7 ± 4.2
22.9 ± 3.8
Mean serum albumin level (g/dL) before CCRTa
3.6 ± 0.5
3.8 ± 0.4
Percentage of patients with NG tube feeding throughout the CCRT period (%)
Percentage of patients who completed the whole CCRT course at hospitalization (%)
Mean daily calorie given within the CCRT period (kcal/day)a
2,145 ± 411
1,888 ± 170
Analysis of percentage change of body weight and serum albumin level from baseline in the nutrition support (NI) group and in the no nutrition support (NC) group
Body weight (kg) change (%)
−0.91 ± 2.23
−3.39 ± 4.23
−0.96 ± 3.54
−4.87 ± 3.64
−1.21 ± 6.56
−7.37 ± 5.81
−1.68 ± 6.33
−6.55 ± 7.28
Albumin level change (%)
−1.05 ± 5.50
−10.61 ± 10.80
−15.05 ± 10.41
−27.38 ± 11.41
Comparison of treatment tolerance and outcome between the nutrition support (NI) group and the no nutrition support (NC) group
Total dose of RT completed (Gy)a
65.8 ± 3.6
64.3 ± 2.3
Patients who had RT breaks (>5 days) for toxicity (%)
Patients who completed planned chemotherapy (%)
Grade 3/4 mucositis (%)
Grade 3/4 emesis (%)
Patient who had sepsis during the CCRT period (%)
1-year survival rate (%)
2-year survival rate (%)
Early-stage oral cancer can be managed by simple excision without a protracted treatment course, but combined modalities using surgery, radiotherapy, and chemotherapy are the standard treatment of choice for late-stage oral cancer and may last for several months. If complications occur, therapeutic duration may be even longer. Liu et al. analyzed 1,010 patients with oral cavity cancer and found that those with a preoperative BMI of <22.8 kg/m2 and serum albumin levels lower than 4.15 g/dL were had a lower rate of survival . Brookes et al. also reported that there was a significant difference in survival rates between well-nourished and under-nourished groups . Several reports suggest that regardless of the treatment modalities used and individualized and intensive support programs for patients with head and neck cancers resulted in minimized body weight loss, reduced treatment-related toxicity, maintenance of a global quality of life, and improved physical function [14, 15, 16]. Hence, it is reasonable to infer that the maintenance of a good nutritional status is important for patients with late-stage oral cavity cancer undergoing treatment. We offered intensive nutritional support, including scheduled counseling, prompt NG tube feeding, and mandatory hospital care, throughout the treatment period for these postoperative stage IV oral cancer patients undergoing CCRT. We found that patients in the NI group experienced less body weight loss, higher levels of serum albumin, and fewer sepsis and emetic episodes than those in the NC group. Consequently, patients in the NI group were able to receive more chemotherapy and radiation doses on time and consequently had higher survival rates. In spite of the small sample size in the current retrospective study, our observations are in accordance with previous reports and further demonstrate that appropriate and intensive nutritional support affects survival for cases characterized by unpleasant treatment-associated sequelae and complications.
The habitual use of betel quid may raise the risk of metabolic derangement in patients with oral cavity cancer undergoing CCRT. Betel quid was reported to induce metabolic syndrome or insulin resistance via activation of the sympathetic nervous system, induction of inflammation, generation of oxidative stress, and the presence of diabetogenic arecal nitrosamines [17, 18, 19, 20, 21, 22, 23, 24]. CCRT was found to induce a severe alteration in glucose metabolism for patients with locally advanced head and neck cancers, throughout the treatment period . Furthermore, Nan et al. reported that 11 out of 219 of patients with head and neck cancers receiving cis-platinum-based chemotherapy developed diabetes mellitus, with two cases presenting as hyperosmolar coma . Hence, it is critical in Taiwan, an endemic betel quid chewing area, to integrate an intensive nutritional support and regular program monitoring into the care of patients with locally advanced oral cavity cancer to avoid the occurrence of nutrition imbalance and unexpected metabolic disorders. Fortunately, it is common in Taiwan for postoperative head and neck cancer patients undergoing adjuvant chemotherapy or CCRT to remain in hospital for completion of the treatment course. All patients have government support healthcare via Taiwan National Health Insurance Program.
Two possible criticisms exist for the current study: Firstly, the body weight change is a facile but unreliable indicator of nutritional status, as it may not reflect the underlying nutritional status for cancer patients, since their body weight loss could be related to loss of body fat as well as a decline in skeletal muscle protein. Body weight gain is probably attributable to fluid accumulation or cancer growth . Secondly, placement of the NG tube as the main feeding route for enteral nutrition was reported to have more adverse effects and was less acceptable to head and neck cancer patients as compared with percutaneous endoscopic gastrostomy (PEG) . Nonetheless, we utilized the record of body weight change and enteral feeding by NG tube because there is a linear relationship between the percentage of body weight loss from baseline to CCRT completion and RT breaks . Furthermore, both the American Society for Parenteral and Enteral Nutrition and European Society for Parenteral and Enteral Nutrition recommended that body weight stablization remain the goal for cancer nutrition during the treatment period [30, 31]. Thirdly, the short-term 8-week NG tube feeding during CCRT produces fewer episodes of dysphagia and less need for pharyngoesophageal dilation than PEG . Over 90% of patients in the current study were reluctant to have PEG after they were provided information concerning the benefits and complications between these two artificial feeding routes. Lastly, the current national health insurance policy in Taiwan does not either cover the cost of insertion of the PEG apparatus or permit frequent examinations of serum albumin, pre-albumin, and transferrin levels. Taken together, body weight and NG tube placement provide relatively feasible nutrition measurements and a reliable energy intake route, taking into consideration the cost and the preference of the patients.
For stage IV oral cavity cancer patients undergoing CCRT in an endemic betel quid chewing area, the current study suggests that early and intensive nutrition support may be beneficial to minimizing body weight loss, offering improved treatment tolerance and probable survival benefit. A randomized prospective study is warranted to examine these observations.
Conflict of interest
The authors declare that they have no competing interests and no financial relationship with other organizations sponsoring this research. All authors have nothing to disclose.