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Consensus and clinical recommendations for nutritional intervention for head and neck cancer patients undergoing chemoradiotherapy in Taiwan
Oral Oncology 81 (2018) 16–21
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Review
Consensus and clinical recommendations for nutritional intervention for head and neck cancer patients undergoing chemoradiotherapy in Taiwan
T
Mei-Chun Lina, Pei-Wei Shuengb,c, Wei-Kuo Changd, Peter Mu-Hsin Change, Hsin-Chun Fengf, ⁎ Muh-Hwa Yange, Pei-Jen Loug, a
Department of Otolaryngology, National Taiwan University Hsin-Chu Branch, Hsin-Chu City, Taiwan Division of Radiation Oncology, Far Eastern Memorial Hospital, New Taipei City, Taiwan c Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan d Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan e Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan f Department of Dietetics and Nutrition, National Taiwan University Hospital, Taipei, Taiwan g Department of Otolaryngology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan b
A R T I C LE I N FO
A B S T R A C T
Keywords: Consensus Head and neck cancer Chemoradiotherapy Nutrition Level of evidence
Because of the anatomical location, patients with head and neck cancer (HNC) frequently experience dysphagia and malnutrition at the time of diagnosis and these conditions are often exacerbated after chemoradiotherapy. There is an emerging medical need to establish a consensus on nutritional intervention for these patients. A panel of 30 senior physicians and experts from multidisciplinary teams drafted clinical recommendations to improve the management of nutritional interventions in Taiwan and to provide updated treatment strategy recommendations in hope of improving the nutritional status of patients with HNC. This clinical review describes the resulting consensus document, including the impact of malnutrition on clinical outcomes, the role of prophylactic tube feeding, the choice of tube feeding, and the benefit of oral nutritional supplements in patients with HNC undergoing chemoradiotherapy. The outcomes of this review will support clinicians in their efforts to improve the nutritional status of patients with HNC.
Introduction Head and neck cancer (HNC) is one of the most common malignancies worldwide [1]. In patients with advanced HNC, the standard of care often involves radical resection, chemotherapy, and radiotherapy [2]. Multidisciplinary treatments invariably cause mucositis, xerostomia, and odynophagia, resulting in swallowing disabilities. In addition, severe malnourishment may interrupt treatment or even cause death. Poor nutritional status increases radiation-induced toxicity and is associated with poor clinical outcome [3]. Therefore, improving the nutritional status of patients with HNC during treatment is one of the major goals of multidisciplinary treatment teams. Taiwan has one of the highest incidence rates of HNC worldwide (41.05 per 100,000) [4]. A large proportion of these patients receive adjuvant or definitive chemoradiation due to either presence of pathological risk factors of recurrence or locally advanced stage. There is an emerging medical need to establish a consensus on nutritional intervention in these patients. The current consensus regarding nutritional intervention in patients with HNC receiving chemoradiotherapy
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varies from experts’ experiences to evidence-based medicine [5]. Thus, we developed this consensus statement to improve the management of nutritional intervention in Taiwan and to provide updated treatment strategy recommendations to improve the nutritional status of patients with HNC. Our recommendations for the population in Taiwan, which has a high prevalence of HNC, may also be helpful for other global regions in their efforts to improve the nutritional status of patients with HNC undergoing chemoradiotherapy. Methods Steering committee set the consensus scope and structure To establish the expert consensus for nutritional intervention in Taiwan, the steering committee was chaired by P.J. Lou (Taiwan Head and Neck Oncology Society) along with five other opinion leaders from the Gastroenterological Society (W.K. Chang), Radiation Oncology Society (P.W. Shueng), Clinical Oncology Society (M.H. Yang), and Clinical Nutrition Society (H.C. Fong and Y.H. Kuo) in Taiwan. The
Corresponding author. E-mail address: [email protected] (P.-J. Lou).
https://doi.org/10.1016/j.oraloncology.2018.03.016 Received 18 February 2018; Received in revised form 25 March 2018; Accepted 26 March 2018 1368-8375/ © 2018 Elsevier Ltd. All rights reserved.
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Consensus statement
Table 1 Levels of evidence and grades of recommendation based on the Oxford Centre for Evidence Based Medicine. Recommendation
Level
Description
A
1a
Systematic review (SR) with homogeneity of randomized controlled trials (RCTs) Individual RCT (with narrow confidence interval) All or none
1b 1c B
2a 2b 2c 3a 3b
Statement 1: Significant weight loss with malnutrition before treatment predicts poor clinical outcomes of patients with HNC.
• Evidence level: 1b • Agreement: 100% • Recommendation grades: A: 96.7%, B: 3.3%, C: 0%, D: 0%
SR (with homogeneity) of cohort studies Individual cohort study (including low quality RCT; for example, < 80% follow-up) “Outcomes” research; ecological studies SR with homogeneity of case-control studies Individual case-control study
C
4
Case series (and poor quality cohort and case-control studies)
D
5
Expert opinion without explicit critical appraisal, or based on physiology, bench research, or “first principles”
Pretreatment evaluation of nutritional status in patients with HNC is very important. A prospective randomized phase III trial showed that significant weight loss before, but not during, treatment was associated with poor survival and clinical outcomes in 224 patients with HNC [6]. In addition, pretreatment weight loss > 10% is an independent prognostic variable for overall survival, with an effect that persists even 10 years after the initial diagnosis and weight loss between 5% and 10% is related to decreased overall survival at two years [7]. The association between weight loss and deterioration in quality of life (QoL) has also been investigated in patients with HNC treated with radiotherapy. These studies have shown that weight loss greater than 10% during radiotherapy is associated with deterioration in QoL, social eating, and social contact [8,9]. Statement 2: Patient-Generated Subjective Global Assessment (PGSGA) is a common method to define the nutritional status of patients with HNC.
steering committee defined the scope sessions of the consensus, conducted a literature search and review, formulated draft statements, and defined the statement evidence level.
Steering committee members to conduct literature search and review
• Evidence level: 2a • Agreement: 100% • Recommendation grades: A: 86.7%, B: 13.3%, C: 0%, D: 0%
Published literature was searched from the Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases. The keywords included head and neck cancer, nutrition, nutritional assessment, weight loss, performance, survivals, enteral feedings, nasogastric tube, gastrostomy, chemotherapy, radiotherapy, and nutritional supplements. The review processes included all primary research studies published in English with peer reviews. Based on the literature review, the draft statements of the consensus were established by the steering committee members. For each statement, the level of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence (Table 1).
A number of methods are used to evaluate the nutritional status of patients with HNC. Among them, the PG-SGA is a reliable, cancerspecific nutritional assessment tool recognized by several international dietetic associations. The combination of weight loss and PG-SGA assessment allows the detection of 18% more true-positive cases of malnutrition and has been frequently utilized in related studies [7,10,11]. Statement 3: Nutritional interventions significantly improve clinical outcomes.
• Evidence level: 1b • Agreement: 96.7% • Recommendation grades: A: 66.7%, B: 33.3%, C: 0%, D: 0%
Expert group meeting to produce a statement of agreement and recommendation grading A total of 30 experts, including the six members of the steering committee and 24 members who accepted the invitation from the steering committee, comprised the expert consensus group. The draft statements were sent to all experts, together with the pertinent literature, prior to the consensus meeting in Tainan in February 2017. During the two-day consensus meeting, the supporting evidence from the keynote literature summary by the steering committee was presented for each draft statement. Based on a modified Delphi process through two separate iterations, all participants voted anonymously for the first round of statements and modified the statements through discussion. The modified statements were followed by a second round of voting with electronic keypads until a consensus was reached, defined as an agreement percentage > 80%. If the agreement was < 80%, the statement was rejected. The expert members also discussed the level of evidence suggested by the steering committee and then graded the recommendation level by voting for each statement. The recommendation grades ranged from A to D. The level of recommendation was defined as the grade with the highest number of votes from the expert group members. The conferences were underwritten by unrestricted grants from the Gastroenterological Society of Taiwan. Mandatory written disclosures of financial conflicts of interest within the period of three years prior to the meetings were obtained from all experts prior to the voting.
Several randomized trials showed that nutritional interventions, e.g., dietary counseling, nutritional supplementation, or prophylactic enteral tube feeding, had benefits on clinical outcomes in patients with HNC [5,12,13]. Early and intensive nutritional interventions improved the deterioration in weight loss, nutritional status, and overall QoL [11]. Weight maintenance led to beneficial outcomes and is an appropriate aim of nutritional interventions. Meta-analysis of randomized trials showed that enteral tube feeding for patients undergoing surgery resulted in a shorter length of hospital stay and lower incidence of surgical complications including infection and sepsis scores [12]. A randomized trial also suggested that prophylactic percutaneous endoscopic gastrostomy (PEG) for enteral nutrition could prevent malnutrition and improve health-related QoL [13]. Studies also supported the use of interventions to optimize the nutritional status in patients with HNC receiving radiotherapy [5,14]. Furthermore, several trials evaluating the effects of different nutritional interventions showed that individualized dietary counseling resulted in superior nutritional status and QoL compared to no counseling or general nutritional advice by nurses. In addition, nasogastric tube feeding had a benefit on nutritional status compared to oral nutritional supplementation [15]. Statement 4: Prophylactic feeding tube placement is not recommended in patients with good performance and nutritional status. 17
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• Evidence level: 2a • Agreement: 96.7% • Recommendation grades: A: 60%, B: 40%, C: 0%, D: 0%
treatment, which results in an incomplete chemoradiation plan and cancer cell repopulation, ultimately leading to an unsatisfactory outcome [29]. In a 2013 expert meeting in Milan to establish a consensus for mucositis in patients with HNC treated with radiotherapy and systemic therapies, both radiation and chemotherapy were listed as treatment-related risk factors that may induce oral mucositis and reduce QoL as well as limit food intake [30]. Considering the severity of oral mucositis in concurrent chemoradiotherapy and bioradiotherapy, there was no conclusion about which causes more severe mucositis [30]. A recent meta-analysis of 31 eligible studies and 4212 patients with HNC compared oral mucositis in patients receiving definitive cisplatin-based chemoradiation or cetuximab-based bioradiation and found no difference between these treatments [31]. Regarding triplecombination biochemoradiotherapy, one randomized phase III trial (RTOG-0522) reported that adding cetuximab to cisplatin-based chemoradiation increased the incidence of oral mucositis compared to that in chemoradiation alone (43.2% vs. 33.3% grade 3–4 radiation mucositis, respectively) [32]. Statement 6b: Accelerated radiation increases oral mucositis and limits oral intake in HNC patients.
Most patients with HNC require enteral nutritional support during and after treatment for their cancer. Prophylactic PEG tube placement is beneficial in patients with HNC with significant weight loss prior to treatment, risk of dehydration or malnutrition, risk of aspiration, and risk of swallowing dysfunction [5,12,13]. Evidence-based reviews show that the more advanced the tumor, the more likely the need and benefit from prophylactic PEG tube placement [5,12,13,16]. However, a systematic review of 739 articles did not establish the benefits or harms of prophylactic PEG tube placement in HNC treatment [17]. Another systematic review of prophylactic feeding tubes in patients with locally advanced HNC undergoing combined chemotherapy and radiotherapy also failed to support the effectiveness of prophylactic feeding tubes in these patients [18]. Thus, physicians must carefully assess the tumor and nutritional status of patients before therapy and consider the potential for malnutrition during and after therapy to decide whether to place prophylactic feeding tubes. Statement 5: PEG and NG tube feeding result in similar improvements in nutritional status and clinical outcomes.
• Evidence level: 1b • Agreement: 90% • Recommendation grades: A: 53.3%, B: 46.7%, C: 0%, D: 0%
• Evidence level: 2b • Agreement: 100% • Recommendation grades: A: 53.3%, B: 46.7%, C: 0%, D: 0%
Altered fractionation radiotherapy may improve survival in patients with HNC. Comparison of the different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit [33]. The RTOG- 9003 trial, the largest randomized study of fractionation to date, evaluated the efficacy and toxicity of altered fractionation radiotherapy for patients with locally advanced HNC. The early report showed that all altered fractionations, including hyperfractionation and accelerated fractionation, increased acute oral mucositis compared to the standard fractionation [34]. Furthermore, the results of a randomized trial (GORTEC 99-02) revealed that accelerated radiotherapy with or without chemotherapy increases grade 3–4 acute oral mucosal toxicities and feeding tube intubation rates during treatment [35]. More recently, the RTOG 0129 phase III trial evaluated the toxicity of accelerated fractionation with a concomitant boost versus standard fractionation radiotherapy both combined with cisplatin for locally advanced HNC. The results showed that the accelerated protocol resulted in an increased incidence of severe treatment-related acute oral mucositis [36].Therefore, treatment strategies with accelerated radiotherapy in patients with HNC increase the incidence of oral mucositis and further limit oral intake. Statement 7: Administration of glutamine decreases chemotherapy and radiotherapy-induced mucositis in patients with HNC.
Concurrent chemoradiotherapy is the preferred treatment strategy for patients with HNC [19]. Treatment-related toxicities, including oral mucositis, dysphagia, xerostomia, and weight loss, are common [20]. Many of these patients receive tube feeding via nasogastric (NG) or PEG tubes [19]. The proportion of patients with HNC receiving enteral feeding varies from 60% to 100% [21]. A randomized controlled trial comparing the two different enteral feeding techniques in patients with HNC treated with radiotherapy and/or chemotherapy showed no difference in complication rates or patient satisfaction at six months posttreatment [17]. Another randomized study of PEG vs. NG tubes for enteral feeding in patients with HNC treated with (chemo)radiation observed no differences in overall complication rates, chest infection rates, or overall QoL [18]. In a prospective study of PEG vs. NG tubes for enteral feeding in patients undergoing (chemo)radiation, the PEG patients experienced significantly less weight loss at six weeks posttreatment (p < 0.001), but had high insertion site infection rates and longer duration of use (146 vs. 57 days, p < 0.001). Patient self-assessed general physical condition and overall QoL scores were similar in both groups [22]. A retrospective comparison of NG tube and PEG in patients with advanced HNC showed that similar body weight and body mass index maintenance for both feeding methods at three and six weeks. However, PEG was associated with better QoL [23]. Potential complications, QoL, and feeding tube dependency must be discussed with patients in order to select the proper feeding method (PEG or NG tubes) in patients who require tube feeding. Statement 6a: Radiotherapy with or without chemotherapy is an important treatment-related factor that causes oral mucositis to limit intake and malnutrition in HNC patients.
• Evidence level: 2b • Agreement: 96.7% • Recommendation grades: A: 40%, B: 60%, C: 0%, D: 0% Oral mucositis is associated with swallowing disorders, local pain, malnutrition, and impaired QoL in patients with HNC [37]. A number of clinical trials have evaluated the anti-inflammation properties of glutamine for the reduction of oral mucositis [38,39]. A double-blind, randomized, placebo-controlled trial showed that glutamine significantly decreased the severity of mucositis in the oral cavity, pharynx, and larynx in patients with HNC receiving chemoradiotherapy. Glutamine also decreased the incidence of grade 4 mucositis, which is the most aggressive form of mucositis that often results in unavoidable therapy interruption [40]. A prospective randomized case-control study of oral glutamine for the alleviation and prevention of radiation-induced oral mucositis reported a significantly delayed mean time to mucositis onset in patients who took glutamine compared to that in the control group (p < 0.001). Another study also
• Evidence level: 1a • Agreement: 100% • Recommendation grades: A: 70%, B: 30%, C: 0%, D: 0% Radiotherapy has been considered the standard non-surgical treatment for locally advanced HNC in past decades. In previous studies, the incidence of oral mucositis ranged from 30% to 100% [24]. In patients receiving concurrent chemoradiation, the incidence of oral mucositis increased to up to 90% of patients, 39–66% of whom have grade 3–4 oral mucositis [25–28]. Such toxicities may interrupt radiation 18
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Fig. 1. Flowchart of nutrition management in patients with head and neck cancer.
[45]. However, the observations that these specific nutrients modulate immune function, reduce radiation-induced oral mucositis, and improve the nutritional status of patients with HNC are based on studies with limited case numbers. Further studies with larger sample sizes are needed to verify these findings. Statement 9: Pre-treatment swallowing dysfunction is an important predictor of clinical outcomes and nutritional status in patients with HNC.
demonstrated that oral glutamine reduced the frequency and duration of grades 3 and 4 mucositis [37]. Many topical and systemic medications have been used for the prevention and treatment of oral mucositis in patients with HNC. Although glutamine has been shown to decrease chemotherapy and radiotherapy-induced mucositis, the sample sizes in those studies were relatively small. Further studies with larger sample sizes are needed to verify the efficacy of glutamine in reducing radiation-induced oral mucositis in patients with HNC. Statement 8: Omega 3, arginine, eicosapentaenoic acid (EPA), and glutamine may improve the nutritional status of patients with HNC.
• Evidence level: 2a • Agreement: 90% • Recommendation grades: A: 26.7%, B: 73.3%, C: 0%, D: 0%
• Evidence level: 2b • Agreement: 100% • Recommendation grades: A: 40%, B: 56.7%, C: 3.3%, D: 0%
Because of the primary tumor location, patients with HNC tend to have swallowing dysfunction even before the definitive treatment. Pretreatment swallowing dysfunction results in reduced oral intake and is an independent factor for weight loss and poor nutrition [46,47]. A prospective cohort study on the impact of pre-treatment dysphagia on treatment outcomes and QoL showed that pre-treatment dysphagia was significantly associated with weight loss and poor QoL and was predictive of disease recurrence and disease-related death in patients with HNC who received radiotherapy with or without chemotherapy [48]. Statement 10: Swallowing training is suggested to maintain or improve swallowing function for nutritional intake in patients with HNC during or after treatment.
Impaired nutritional status and immune function are not uncommon in patients with HNC. Although immune impairment in these patients is multifactorial, their immune systems may be supported by specific nutrients such as omega-3 fatty acids and arginine [41]. Arginine plays an important role in the synthesis of nucleotides, promotion of T-cell proliferation, and generation of lymphokine-activated killer cells. Omega-3 fatty acids and EPA inhibit excessive inflammatory responses. The administration of EPA attenuates the activation of NF-κB by upstream stabilization of the IκB/NF-κB complex and reducing nuclear accumulation, which in turn reduces the transcriptional activation of the proteasome subunits involved in protein degradation [42,43]. EPA alone at a dose of 2 g/day was associated with weight stability in cancer patients [44]. Glutamine, a non-essential amino acid widely distributed throughout the body, can function as an essential amino acid in certain clinical settings [44]. A randomized trial demonstrated that a formula containing low-dose glutamine (0.15 g/kg/day) and l-arginine effectively prevented radiation-induced mucositis in patients with HNC
• Evidence level: 2a • Agreement: 96.7% • Recommendation grades: A: 40%, B: 60%, C: 0%, D: 0% In order to maintain or improve swallowing function for nutritional intake in patients with HNC, swallowing training before, during, or 19
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after cancer treatment has been assessed. It is generally accepted that swallowing training during or after cancer treatment may improve swallowing function and nutritional status, prevent or ameliorate longterm complications, and improve QoL of patients with HNC [49]. A case-control study showed that a swallowing preservation protocol helped to maintain or improve swallowing function in patients with HNC undergoing radiotherapy or chemoradiotherapy. Patients who are able to comply with swallowing exercises are less likely to suffer from worsening of diet, gastrostomy tube insertion, or development of stenosis [50]. Other studies also demonstrated the benefit of swallowing training in HNC and nasopharyngeal cancer patients who received radiotherapy or chemoradiation [50–53]. Growing evidence indicates that swallowing exercises and physical therapy may prevent or ameliorate long-term functional deficits. Thus, the management of dysphagia is important for the long-term health of patients with HNC.
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concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99–02): an open-label phase 3 randomised trial. Lancet Oncol 2012;13:145–53. Nguyen-Tan PF, Zhang Q, Ang KK, Weber RS, Rosenthal DI, Soulieres D, et al. Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity. J Clin Oncol: Off J Am Soc Clin Oncol 2014;32:3858–66. Chattopadhyay S, Saha A, Azam M, Mukherjee A, Sur PK. Role of oral glutamine in alleviation and prevention of radiation-induced oral mucositis: a prospective randomized study. South Asian J Cancer 2014;3:8–12. Ogawa T, Washio J, Takahashi T, Echigo S, Takahashi N. Glucose and glutamine metabolism in oral squamous cell carcinoma: insight from a quantitative metabolomic approach. Oral surgery, Oral medicine, Oral pathology and Oral radiology 2014;118:218–25. Machon C, Thezenas S, Dupuy AM, Assenat E, Michel F, Mas E, et al. Immunonutrition before and during radiochemotherapy: improvement of inflammatory parameters in head and neck cancer patients. Supportive Care Cancer: official J Multinat Associat Supportive Care Cancer 2012;20:3129–35. Tsujimoto T, Yamamoto Y, Wasa M, Takenaka Y, Nakahara S, Takagi T, et al. Lglutamine decreases the severity of mucositis induced by chemoradiotherapy in patients with locally advanced head and neck cancer: a double-blind, randomized, placebo-controlled trial. Oncol Rep 2015;33:33–9. Fearon KC, Von Meyenfeldt MF, Moses AG, Van Geenen R, Roy A, Gouma DJ, et al. Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 2003;52:1479–86. Fearon KC, Barber MD, Moses AG, Ahmedzai SH, Taylor GS, Tisdale MJ, et al. Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol: Off J Am Soc Clin Oncol 2006;24:3401–7. Vasson MP, Talvas J, Perche O, Dillies AF, Bachmann P, Pezet D, et al. Immunonutrition improves functional capacities in head and neck and esophageal cancer patients undergoing radiochemotherapy: a randomized clinical trial. Clinical
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Consensus and clinical recommendations for nutritional intervention for head and neck cancer patients undergoing chemoradiotherapy in Taiwan
T
Mei-Chun Lina, Pei-Wei Shuengb,c, Wei-Kuo Changd, Peter Mu-Hsin Change, Hsin-Chun Fengf, ⁎ Muh-Hwa Yange, Pei-Jen Loug, a
Department of Otolaryngology, National Taiwan University Hsin-Chu Branch, Hsin-Chu City, Taiwan Division of Radiation Oncology, Far Eastern Memorial Hospital, New Taipei City, Taiwan c Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan d Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan e Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan f Department of Dietetics and Nutrition, National Taiwan University Hospital, Taipei, Taiwan g Department of Otolaryngology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan b
A R T I C LE I N FO
A B S T R A C T
Keywords: Consensus Head and neck cancer Chemoradiotherapy Nutrition Level of evidence
Because of the anatomical location, patients with head and neck cancer (HNC) frequently experience dysphagia and malnutrition at the time of diagnosis and these conditions are often exacerbated after chemoradiotherapy. There is an emerging medical need to establish a consensus on nutritional intervention for these patients. A panel of 30 senior physicians and experts from multidisciplinary teams drafted clinical recommendations to improve the management of nutritional interventions in Taiwan and to provide updated treatment strategy recommendations in hope of improving the nutritional status of patients with HNC. This clinical review describes the resulting consensus document, including the impact of malnutrition on clinical outcomes, the role of prophylactic tube feeding, the choice of tube feeding, and the benefit of oral nutritional supplements in patients with HNC undergoing chemoradiotherapy. The outcomes of this review will support clinicians in their efforts to improve the nutritional status of patients with HNC.
Introduction Head and neck cancer (HNC) is one of the most common malignancies worldwide [1]. In patients with advanced HNC, the standard of care often involves radical resection, chemotherapy, and radiotherapy [2]. Multidisciplinary treatments invariably cause mucositis, xerostomia, and odynophagia, resulting in swallowing disabilities. In addition, severe malnourishment may interrupt treatment or even cause death. Poor nutritional status increases radiation-induced toxicity and is associated with poor clinical outcome [3]. Therefore, improving the nutritional status of patients with HNC during treatment is one of the major goals of multidisciplinary treatment teams. Taiwan has one of the highest incidence rates of HNC worldwide (41.05 per 100,000) [4]. A large proportion of these patients receive adjuvant or definitive chemoradiation due to either presence of pathological risk factors of recurrence or locally advanced stage. There is an emerging medical need to establish a consensus on nutritional intervention in these patients. The current consensus regarding nutritional intervention in patients with HNC receiving chemoradiotherapy
⁎
varies from experts’ experiences to evidence-based medicine [5]. Thus, we developed this consensus statement to improve the management of nutritional intervention in Taiwan and to provide updated treatment strategy recommendations to improve the nutritional status of patients with HNC. Our recommendations for the population in Taiwan, which has a high prevalence of HNC, may also be helpful for other global regions in their efforts to improve the nutritional status of patients with HNC undergoing chemoradiotherapy. Methods Steering committee set the consensus scope and structure To establish the expert consensus for nutritional intervention in Taiwan, the steering committee was chaired by P.J. Lou (Taiwan Head and Neck Oncology Society) along with five other opinion leaders from the Gastroenterological Society (W.K. Chang), Radiation Oncology Society (P.W. Shueng), Clinical Oncology Society (M.H. Yang), and Clinical Nutrition Society (H.C. Fong and Y.H. Kuo) in Taiwan. The
Corresponding author. E-mail address: [email protected] (P.-J. Lou).
https://doi.org/10.1016/j.oraloncology.2018.03.016 Received 18 February 2018; Received in revised form 25 March 2018; Accepted 26 March 2018 1368-8375/ © 2018 Elsevier Ltd. All rights reserved.
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Consensus statement
Table 1 Levels of evidence and grades of recommendation based on the Oxford Centre for Evidence Based Medicine. Recommendation
Level
Description
A
1a
Systematic review (SR) with homogeneity of randomized controlled trials (RCTs) Individual RCT (with narrow confidence interval) All or none
1b 1c B
2a 2b 2c 3a 3b
Statement 1: Significant weight loss with malnutrition before treatment predicts poor clinical outcomes of patients with HNC.
• Evidence level: 1b • Agreement: 100% • Recommendation grades: A: 96.7%, B: 3.3%, C: 0%, D: 0%
SR (with homogeneity) of cohort studies Individual cohort study (including low quality RCT; for example, < 80% follow-up) “Outcomes” research; ecological studies SR with homogeneity of case-control studies Individual case-control study
C
4
Case series (and poor quality cohort and case-control studies)
D
5
Expert opinion without explicit critical appraisal, or based on physiology, bench research, or “first principles”
Pretreatment evaluation of nutritional status in patients with HNC is very important. A prospective randomized phase III trial showed that significant weight loss before, but not during, treatment was associated with poor survival and clinical outcomes in 224 patients with HNC [6]. In addition, pretreatment weight loss > 10% is an independent prognostic variable for overall survival, with an effect that persists even 10 years after the initial diagnosis and weight loss between 5% and 10% is related to decreased overall survival at two years [7]. The association between weight loss and deterioration in quality of life (QoL) has also been investigated in patients with HNC treated with radiotherapy. These studies have shown that weight loss greater than 10% during radiotherapy is associated with deterioration in QoL, social eating, and social contact [8,9]. Statement 2: Patient-Generated Subjective Global Assessment (PGSGA) is a common method to define the nutritional status of patients with HNC.
steering committee defined the scope sessions of the consensus, conducted a literature search and review, formulated draft statements, and defined the statement evidence level.
Steering committee members to conduct literature search and review
• Evidence level: 2a • Agreement: 100% • Recommendation grades: A: 86.7%, B: 13.3%, C: 0%, D: 0%
Published literature was searched from the Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases. The keywords included head and neck cancer, nutrition, nutritional assessment, weight loss, performance, survivals, enteral feedings, nasogastric tube, gastrostomy, chemotherapy, radiotherapy, and nutritional supplements. The review processes included all primary research studies published in English with peer reviews. Based on the literature review, the draft statements of the consensus were established by the steering committee members. For each statement, the level of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence (Table 1).
A number of methods are used to evaluate the nutritional status of patients with HNC. Among them, the PG-SGA is a reliable, cancerspecific nutritional assessment tool recognized by several international dietetic associations. The combination of weight loss and PG-SGA assessment allows the detection of 18% more true-positive cases of malnutrition and has been frequently utilized in related studies [7,10,11]. Statement 3: Nutritional interventions significantly improve clinical outcomes.
• Evidence level: 1b • Agreement: 96.7% • Recommendation grades: A: 66.7%, B: 33.3%, C: 0%, D: 0%
Expert group meeting to produce a statement of agreement and recommendation grading A total of 30 experts, including the six members of the steering committee and 24 members who accepted the invitation from the steering committee, comprised the expert consensus group. The draft statements were sent to all experts, together with the pertinent literature, prior to the consensus meeting in Tainan in February 2017. During the two-day consensus meeting, the supporting evidence from the keynote literature summary by the steering committee was presented for each draft statement. Based on a modified Delphi process through two separate iterations, all participants voted anonymously for the first round of statements and modified the statements through discussion. The modified statements were followed by a second round of voting with electronic keypads until a consensus was reached, defined as an agreement percentage > 80%. If the agreement was < 80%, the statement was rejected. The expert members also discussed the level of evidence suggested by the steering committee and then graded the recommendation level by voting for each statement. The recommendation grades ranged from A to D. The level of recommendation was defined as the grade with the highest number of votes from the expert group members. The conferences were underwritten by unrestricted grants from the Gastroenterological Society of Taiwan. Mandatory written disclosures of financial conflicts of interest within the period of three years prior to the meetings were obtained from all experts prior to the voting.
Several randomized trials showed that nutritional interventions, e.g., dietary counseling, nutritional supplementation, or prophylactic enteral tube feeding, had benefits on clinical outcomes in patients with HNC [5,12,13]. Early and intensive nutritional interventions improved the deterioration in weight loss, nutritional status, and overall QoL [11]. Weight maintenance led to beneficial outcomes and is an appropriate aim of nutritional interventions. Meta-analysis of randomized trials showed that enteral tube feeding for patients undergoing surgery resulted in a shorter length of hospital stay and lower incidence of surgical complications including infection and sepsis scores [12]. A randomized trial also suggested that prophylactic percutaneous endoscopic gastrostomy (PEG) for enteral nutrition could prevent malnutrition and improve health-related QoL [13]. Studies also supported the use of interventions to optimize the nutritional status in patients with HNC receiving radiotherapy [5,14]. Furthermore, several trials evaluating the effects of different nutritional interventions showed that individualized dietary counseling resulted in superior nutritional status and QoL compared to no counseling or general nutritional advice by nurses. In addition, nasogastric tube feeding had a benefit on nutritional status compared to oral nutritional supplementation [15]. Statement 4: Prophylactic feeding tube placement is not recommended in patients with good performance and nutritional status. 17
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• Evidence level: 2a • Agreement: 96.7% • Recommendation grades: A: 60%, B: 40%, C: 0%, D: 0%
treatment, which results in an incomplete chemoradiation plan and cancer cell repopulation, ultimately leading to an unsatisfactory outcome [29]. In a 2013 expert meeting in Milan to establish a consensus for mucositis in patients with HNC treated with radiotherapy and systemic therapies, both radiation and chemotherapy were listed as treatment-related risk factors that may induce oral mucositis and reduce QoL as well as limit food intake [30]. Considering the severity of oral mucositis in concurrent chemoradiotherapy and bioradiotherapy, there was no conclusion about which causes more severe mucositis [30]. A recent meta-analysis of 31 eligible studies and 4212 patients with HNC compared oral mucositis in patients receiving definitive cisplatin-based chemoradiation or cetuximab-based bioradiation and found no difference between these treatments [31]. Regarding triplecombination biochemoradiotherapy, one randomized phase III trial (RTOG-0522) reported that adding cetuximab to cisplatin-based chemoradiation increased the incidence of oral mucositis compared to that in chemoradiation alone (43.2% vs. 33.3% grade 3–4 radiation mucositis, respectively) [32]. Statement 6b: Accelerated radiation increases oral mucositis and limits oral intake in HNC patients.
Most patients with HNC require enteral nutritional support during and after treatment for their cancer. Prophylactic PEG tube placement is beneficial in patients with HNC with significant weight loss prior to treatment, risk of dehydration or malnutrition, risk of aspiration, and risk of swallowing dysfunction [5,12,13]. Evidence-based reviews show that the more advanced the tumor, the more likely the need and benefit from prophylactic PEG tube placement [5,12,13,16]. However, a systematic review of 739 articles did not establish the benefits or harms of prophylactic PEG tube placement in HNC treatment [17]. Another systematic review of prophylactic feeding tubes in patients with locally advanced HNC undergoing combined chemotherapy and radiotherapy also failed to support the effectiveness of prophylactic feeding tubes in these patients [18]. Thus, physicians must carefully assess the tumor and nutritional status of patients before therapy and consider the potential for malnutrition during and after therapy to decide whether to place prophylactic feeding tubes. Statement 5: PEG and NG tube feeding result in similar improvements in nutritional status and clinical outcomes.
• Evidence level: 1b • Agreement: 90% • Recommendation grades: A: 53.3%, B: 46.7%, C: 0%, D: 0%
• Evidence level: 2b • Agreement: 100% • Recommendation grades: A: 53.3%, B: 46.7%, C: 0%, D: 0%
Altered fractionation radiotherapy may improve survival in patients with HNC. Comparison of the different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit [33]. The RTOG- 9003 trial, the largest randomized study of fractionation to date, evaluated the efficacy and toxicity of altered fractionation radiotherapy for patients with locally advanced HNC. The early report showed that all altered fractionations, including hyperfractionation and accelerated fractionation, increased acute oral mucositis compared to the standard fractionation [34]. Furthermore, the results of a randomized trial (GORTEC 99-02) revealed that accelerated radiotherapy with or without chemotherapy increases grade 3–4 acute oral mucosal toxicities and feeding tube intubation rates during treatment [35]. More recently, the RTOG 0129 phase III trial evaluated the toxicity of accelerated fractionation with a concomitant boost versus standard fractionation radiotherapy both combined with cisplatin for locally advanced HNC. The results showed that the accelerated protocol resulted in an increased incidence of severe treatment-related acute oral mucositis [36].Therefore, treatment strategies with accelerated radiotherapy in patients with HNC increase the incidence of oral mucositis and further limit oral intake. Statement 7: Administration of glutamine decreases chemotherapy and radiotherapy-induced mucositis in patients with HNC.
Concurrent chemoradiotherapy is the preferred treatment strategy for patients with HNC [19]. Treatment-related toxicities, including oral mucositis, dysphagia, xerostomia, and weight loss, are common [20]. Many of these patients receive tube feeding via nasogastric (NG) or PEG tubes [19]. The proportion of patients with HNC receiving enteral feeding varies from 60% to 100% [21]. A randomized controlled trial comparing the two different enteral feeding techniques in patients with HNC treated with radiotherapy and/or chemotherapy showed no difference in complication rates or patient satisfaction at six months posttreatment [17]. Another randomized study of PEG vs. NG tubes for enteral feeding in patients with HNC treated with (chemo)radiation observed no differences in overall complication rates, chest infection rates, or overall QoL [18]. In a prospective study of PEG vs. NG tubes for enteral feeding in patients undergoing (chemo)radiation, the PEG patients experienced significantly less weight loss at six weeks posttreatment (p < 0.001), but had high insertion site infection rates and longer duration of use (146 vs. 57 days, p < 0.001). Patient self-assessed general physical condition and overall QoL scores were similar in both groups [22]. A retrospective comparison of NG tube and PEG in patients with advanced HNC showed that similar body weight and body mass index maintenance for both feeding methods at three and six weeks. However, PEG was associated with better QoL [23]. Potential complications, QoL, and feeding tube dependency must be discussed with patients in order to select the proper feeding method (PEG or NG tubes) in patients who require tube feeding. Statement 6a: Radiotherapy with or without chemotherapy is an important treatment-related factor that causes oral mucositis to limit intake and malnutrition in HNC patients.
• Evidence level: 2b • Agreement: 96.7% • Recommendation grades: A: 40%, B: 60%, C: 0%, D: 0% Oral mucositis is associated with swallowing disorders, local pain, malnutrition, and impaired QoL in patients with HNC [37]. A number of clinical trials have evaluated the anti-inflammation properties of glutamine for the reduction of oral mucositis [38,39]. A double-blind, randomized, placebo-controlled trial showed that glutamine significantly decreased the severity of mucositis in the oral cavity, pharynx, and larynx in patients with HNC receiving chemoradiotherapy. Glutamine also decreased the incidence of grade 4 mucositis, which is the most aggressive form of mucositis that often results in unavoidable therapy interruption [40]. A prospective randomized case-control study of oral glutamine for the alleviation and prevention of radiation-induced oral mucositis reported a significantly delayed mean time to mucositis onset in patients who took glutamine compared to that in the control group (p < 0.001). Another study also
• Evidence level: 1a • Agreement: 100% • Recommendation grades: A: 70%, B: 30%, C: 0%, D: 0% Radiotherapy has been considered the standard non-surgical treatment for locally advanced HNC in past decades. In previous studies, the incidence of oral mucositis ranged from 30% to 100% [24]. In patients receiving concurrent chemoradiation, the incidence of oral mucositis increased to up to 90% of patients, 39–66% of whom have grade 3–4 oral mucositis [25–28]. Such toxicities may interrupt radiation 18
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Fig. 1. Flowchart of nutrition management in patients with head and neck cancer.
[45]. However, the observations that these specific nutrients modulate immune function, reduce radiation-induced oral mucositis, and improve the nutritional status of patients with HNC are based on studies with limited case numbers. Further studies with larger sample sizes are needed to verify these findings. Statement 9: Pre-treatment swallowing dysfunction is an important predictor of clinical outcomes and nutritional status in patients with HNC.
demonstrated that oral glutamine reduced the frequency and duration of grades 3 and 4 mucositis [37]. Many topical and systemic medications have been used for the prevention and treatment of oral mucositis in patients with HNC. Although glutamine has been shown to decrease chemotherapy and radiotherapy-induced mucositis, the sample sizes in those studies were relatively small. Further studies with larger sample sizes are needed to verify the efficacy of glutamine in reducing radiation-induced oral mucositis in patients with HNC. Statement 8: Omega 3, arginine, eicosapentaenoic acid (EPA), and glutamine may improve the nutritional status of patients with HNC.
• Evidence level: 2a • Agreement: 90% • Recommendation grades: A: 26.7%, B: 73.3%, C: 0%, D: 0%
• Evidence level: 2b • Agreement: 100% • Recommendation grades: A: 40%, B: 56.7%, C: 3.3%, D: 0%
Because of the primary tumor location, patients with HNC tend to have swallowing dysfunction even before the definitive treatment. Pretreatment swallowing dysfunction results in reduced oral intake and is an independent factor for weight loss and poor nutrition [46,47]. A prospective cohort study on the impact of pre-treatment dysphagia on treatment outcomes and QoL showed that pre-treatment dysphagia was significantly associated with weight loss and poor QoL and was predictive of disease recurrence and disease-related death in patients with HNC who received radiotherapy with or without chemotherapy [48]. Statement 10: Swallowing training is suggested to maintain or improve swallowing function for nutritional intake in patients with HNC during or after treatment.
Impaired nutritional status and immune function are not uncommon in patients with HNC. Although immune impairment in these patients is multifactorial, their immune systems may be supported by specific nutrients such as omega-3 fatty acids and arginine [41]. Arginine plays an important role in the synthesis of nucleotides, promotion of T-cell proliferation, and generation of lymphokine-activated killer cells. Omega-3 fatty acids and EPA inhibit excessive inflammatory responses. The administration of EPA attenuates the activation of NF-κB by upstream stabilization of the IκB/NF-κB complex and reducing nuclear accumulation, which in turn reduces the transcriptional activation of the proteasome subunits involved in protein degradation [42,43]. EPA alone at a dose of 2 g/day was associated with weight stability in cancer patients [44]. Glutamine, a non-essential amino acid widely distributed throughout the body, can function as an essential amino acid in certain clinical settings [44]. A randomized trial demonstrated that a formula containing low-dose glutamine (0.15 g/kg/day) and l-arginine effectively prevented radiation-induced mucositis in patients with HNC
• Evidence level: 2a • Agreement: 96.7% • Recommendation grades: A: 40%, B: 60%, C: 0%, D: 0% In order to maintain or improve swallowing function for nutritional intake in patients with HNC, swallowing training before, during, or 19
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after cancer treatment has been assessed. It is generally accepted that swallowing training during or after cancer treatment may improve swallowing function and nutritional status, prevent or ameliorate longterm complications, and improve QoL of patients with HNC [49]. A case-control study showed that a swallowing preservation protocol helped to maintain or improve swallowing function in patients with HNC undergoing radiotherapy or chemoradiotherapy. Patients who are able to comply with swallowing exercises are less likely to suffer from worsening of diet, gastrostomy tube insertion, or development of stenosis [50]. Other studies also demonstrated the benefit of swallowing training in HNC and nasopharyngeal cancer patients who received radiotherapy or chemoradiation [50–53]. Growing evidence indicates that swallowing exercises and physical therapy may prevent or ameliorate long-term functional deficits. Thus, the management of dysphagia is important for the long-term health of patients with HNC.
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