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Asia-Pacific Journal of Clinical Oncology 2015; 11: 228–235
doi: 10.1111/ajco.12323
ORIGINAL ARTICLE
Chemoradiotherapy in elderly patients with advanced head and neck cancer under intensive nutritional support Pei-Hung CHANG,1 Kun-Yun YEH,1 Jen-Seng HUANG,1 Eric Yen-Chao CHEN,2 Shih-Wei YANG,3 and Cheng-Hsu WANG1,4 1
Division of Hematology/Oncology, Department of Internal Medicine, and Departments of 2Radiation Oncology and Otolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Taiwan and 4Cancer Center, Chang Gung Memorial Hospital, Keelung, Taiwan 3
Abstract Aim: To evaluate treatment tolerance, toxicities and survival in elderly patients with advanced head and neck cancer who received inpatient-based intensive nutritional support with concurrent chemoradiotherapy in comparison with younger patients undergoing the same treatment. Methods: We retrospectively analyzed the records of 126 stage III, IVA and IVB head and neck cancer patients who were treated with concurrent chemoradiotherapy between 2007 and 2009 under an inpatientbased nutritional support program. The clinical characteristics, treatment tolerance, toxicities and survival of patients older than 65 years were compared with those of identically treated patients younger than 65 years. Results: There were 21 patients older than 65 years and 105 patients younger than 65 years. Clinical characteristics and treatment toxicities were similar between the groups, except that the elderly were less likely to tolerate cisplatin, experienced more weight loss, required more feeding tube support and tended to have >grade 3 hematological toxicities and to develop sepsis during the period of chemoradiotherapy. The 1- and 2-year disease-free survival and disease-specific survival rates were nearly identical. Conclusion: Age alone should not be considered a contraindication to aggressive chemoradiotherapy for advanced head and neck cancer. Older patients require more careful multidisciplinary assessment of their supportive care needs to ensure successful completion of treatment and avoid further treatment-related toxicity. Key words: chemoradiation, elderly, head and neck cancer, nutrition, survival.
INTRODUCTION The percentage of elderly people with head and neck cancer is increasing owing to an overall increase in life Correspondence: Dr Cheng-Hsu Wang, MD, Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Taiwan. No. 200, Lane 208, Jijin 1st Road, Keelung 20445, Taiwan. Email: [email protected] 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 Accepted for publication 14 October 2014.
© 2014 Wiley Publishing Asia Pty Ltd
expectancy.1 Concurrent chemoradiotherapy has become one of the standard definitive treatments for patients with locally advanced stage head and neck cancer and has shown a significant survival benefit, higher laryngectomy-free survival rate, increased locoregional control rate and lower distant metastasis rate than radiation alone.2–4 However, its efficacy comes with substantial toxicities that have the potential to be severe. There is limited information about the effectiveness of cancer treatment in elderly patients, partially because they are often underrepresented and excluded from clinical trials.5,6 Although age is not an independent negative prognostic factor in head and neck cancer treatment,7,8 nonstandard treatment is used more frequently to treat elderly patients.9–11 Single modality
Nutrition in elderly receiving CRT
treatment, such as radiotherapy alone, is more likely to be chosen by clinicians because of the toxicity of concurrent chemoradiotherapy.12 Chemoradiotherapy negatively affects the patient’s nutritional status. Malnourishment at the time of diagnosis and during chemoradiotherapy has adverse consequences, including poor quality of life, decreased immune function and shorter survival.13–16 Optimized nutritional intervention programs such as dietitic consultation, periodic monitoring, appropriate nutritional supplements and feeding tube placement throughout the treatment period markedly improved treatment tolerance and outcomes in head and neck cancer patients.17,18 In 2007, an early and intensive nutritional support program was established within a multidisciplinary management unit at our institution for head and neck cancer patients undergoing chemoradiotherapy.19 Patients with non-metastatic stage IV oral cavity cancers who received chemoradiotherapy with this nutritional support programs experienced many benefits such as minimal body weight loss, improved treatment tolerance and probable survival benefits compared with patients admitted before 2007 (who were not routinely referred to this nutrition program).19 It is reasonable to infer that the maintenance of a good nutritional status is important for patients with advanced stage head and neck cancer undergoing concurrent chemoradiotherapy, especially the elderly one. The purpose of this study was to evaluate and compare treatment tolerance, toxicities, and survival in older and younger patients with advanced head and neck cancer who received inpatient-based nutritional support with concurrent chemoradiotherapy.
METHODS This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital. Patients who had biopsy-proven stage III, IVA or IVB head and neck squamous cell carcinoma (TNM (Tumor, node, metastasis) stage reclassified according to the American Joint Committee on Cancer staging system published in 2002) of the oral cavity, oropharynx, and hypopharynx, and who were treated with primary chemoradiotherapy were eligible for this study. Patients with recurrent cancer, distant metastasis or another concomitant active cancer were excluded from the study. From January 2007 to December 2009, we retrospectively reviewed the records of 134 patients with stage III, IVA and IVB head and neck squamous cell carcinoma who had undergone concurrent chemoradiotherapy at our institution. Eight patients were excluded from the study. Four patients dropped out
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during the chemoradiotherapy schedule and were lost to follow-up because of unavoidable family reasons, such as divorce (one patient), poor financial support (two patients) and moving out of town (one patient). Two patients were treated with re-chemoradiation for recurrent disease and two were diagnosed with a concomitant active cancer upon diagnosis. A total of 126 patients who received concurrent chemoradiotherapy were included in the analysis. All patients received intensity-modulated or arc technique radiotherapy on 5 consecutive days/week at a conventional fractionated daily dose of 1.8 or 2 Gy. The total prescribed dose of radiotherapy was 70–74 Gy. The initial treatment volume included the tumor bed and regional lymphatics. After receiving 46–50 Gy, the treatment area was reduced to irradiate the tumor bed and regional nodes. The chemotherapy regimens including cisplatin 40 mg/m2 every week or 100 mg/m2 every 3 weeks were administered according to the treatment guidelines at our institution. All patients were routinely referred to an early and intensive nutritional support program established in 2007 at our institution.19 This inpatient-based program includes biweekly dietitian visits, mandatory feeding tube placement, timely caloric supplementation and blood transfusion as needed, and continues on a regular basis throughout the chemoradiation period. Feeding tube placement, including nasogastric tube or percutaneous gastrostomy, is performed for all the patients if their body weight loss is more than 5% during the treatment course. The daily nutritional intake of patients is monitored closely in the hospital throughout the treatment period, and their oral intake is supplemented to fulfill their energy requirements. During the chemoradiation therapy period, all patients are prescribed analgesics, antibiotics, vitamin supplements, mouth rinse and topical steroid ointments. More than 90% of head and neck cancer patients undergoing concurrent chemoradiotherapy remain in the hospital to complete the treatment. Patients are admitted to receive chemoradiation therapy along with the inpatient-based nutritional support program. Our patients have government-supported health care via the National Health Insurance Program in Taiwan. The following clinical parameters of patients in both groups were retrospectively analyzed in this study before the initiation of treatment and at the end of treatment: age, gender, primary site of disease, TNM stage of cancer at diagnosis (American Joint Committee on Cancer), Eastern Cooperative Oncology Group performance status, comorbid disease as Charlson Comorbidity Index, body mass index and serum albumin level. According to the World Health Organization,20 the age
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of 60 or 65, equivalent to the retirement ages in most developed countries, is considered to be the beginning of old age. We defined those aged 65 years or older as older patients in our study, according to the retirement age in Taiwan. Treatment tolerance was evaluated by the total dose of radiation completed, the total dose of cisplatin received, the occurrence of sepsis (cultures from the bloodstream were used to detect the presence of pathogens that made the patients ill and febrile), hematological toxicity grade ≥3 (including leukopenia, neutropenia, thrombocytopenia and anemia), mucositis/ pharyngitis grade ≥3 and nausea/vomiting grade ≥3, according to the RTOG (Radiation Therapy Oncology Group) toxicity criteria.21 Treatment outcome was assessed by the 1- and 2-year disease-free survival, disease-specific survival and overall survival rates. Disease-free survival was defined as the time spanning from the initiation of chemoradiation to the first evidence of recurrence of the primary tumor. Diseasespecific survival was defined as the time from the initiation of chemoradiation to death from either disease or toxicity. Overall survival was defined as the time from the initiation of chemoradiation to death from any cause. 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 two groups and various clinical and pathological features of patients in each group. The differences in body mass index, serum albumin level, weight loss, total dose of radiotherapy and dose of cisplatin received were evaluated by independent Student’s t-tests. The Kaplan–Meier method was used to analyze survival, and the log-rank test was used to examine the differences. All P-values were derived from two-tailed statistical tests. A P-value of < 0.05 was considered statistically significant.
P-H Chang et al.
significant difference in the total dose of radiation completed. However, the older group received a significantly lower accumulated cisplatin dose than the younger patients (151.2 ± 78.7 mg/m2 vs 199.0 ± 90.1 mg/m2, P = 0.042). Weight loss during the chemoradiotherapy period (−7.2 ± 5.1% vs −3.7 ± 6.7%, P = 0.047) and feeding tube placement (80.1% vs 52.3 %, P = 0.020) was more significant among the older patients. The rate of toxic death (grade 5 toxicity) was similar in both groups. In the older patient group, one patient died from sepsis caused by ischemic bowel. In the younger patient group, three patients died from neutropenic sepsis, one from aspiration pneumonia, one from empyema and one from tumor bleeding. There was no difference in > grade 3 mucositis/pharyngitis, > grade 3 nausea/vomiting, > grade 3 any hematological toxicities or sepsis during the chemoradiotherapy period. Although not significant, the older group tended to have a higher percentage of patients with > grade 3 hematological toxicities (38.1% vs 20.1%, P = 0.092) and sepsis (38.1% vs 18.1%, P = 0.076) during the chemoradiation therapy period (Table 2). There was also no statistically significant difference between the two groups in 1- and 2-year diseasefree survival (75.2% vs 71.4%, and 60.0% vs 52.4% in the older vs younger patients, respectively), 1- and 2-year disease-specific survival (84.8% vs 80.1%, and 66.7% vs 57.1% in older vs younger patients, respectively), and 1- and 2-year overall survival (82.8% vs 76.2%, and 64.8% vs 52.4% in older vs younger patients, respectively). The survival outcomes are detailed in Table 2 and graphically portrayed in Figures 1–3. Except for the fact that the older group tended to have worse overall survival (P = 0.117), the disease-related outcomes, including disease-free and disease-specific survival, were not statistically different.
DISCUSSION RESULTS The study cohort of locally advanced head and neck cancer patients before chemoradiotherapy included 21 patients older than 65 years (older group) and 105 patients younger than 65 years (younger group). The clinical and tumor characteristics of these 126 patients are listed in Table 1. No significant differences were found in gender, tumor location, TNM stage, performance status, Charlson Comorbidity Index, pretreatment body mass index or serum albumin level between the older and younger groups (Table 1). As shown in Table 2, we compared the treatment tolerance and outcomes between the groups and found that there was no
© 2014 Wiley Publishing Asia Pty Ltd
Head and neck cancer and its treatment is associated with a marked symptom burden and functional impairment.22 Supportive care is crucial in enabling patients to complete their prescribed course of treatment without breaks and to recover safely from toxicities. In an analysis of five cross-sectional studies of patients with head and neck cancer, there was a statistical correlation between age, overall symptom burden and nutritional dysfunction during therapy.22 Chemoradiation therapy negatively impacts on patient’s nutritional status.23 Numerous reports have found that malnutrition has adverse associations, including poor quality of life, decreased immune function and shorter survival.14–16
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Nutrition in elderly receiving CRT
Table 1
Demographic characteristics of the patients before treatment according to age 1 BMI (mean ± SD), kg/m2 Albumin (mean ± SD), g/dL
≥65 years
105 48 (26–64)
21 68 (65–76)
97 (92.4%) 8 (7.6%)
19 (90.5%) 2 (9.5%)
17 (16.2%) 88 (83.8%)
7 (33.3%) 14 (66.7%)
12 (11.4%) 26 (24.8%) 19 (18.1%) 36 (34.3%) 12 (11.4%)
1 (4.8%) 9 (42.9%) 4 (19.0%) 5 (23.8%) 2 (9.5%)
22 (21.0%) 14 (13.3%) 8 (7.6%) 31 (29.5%) 20 (19.0%) 9 (8.6%)
7 (33.3%) 6 (28.6%) 2 (9.5%) 4 (19.0%) 2 (9.5%) 0 (0.0%)
43 (40.1%) 36 (34.3%) 26 (24.8%)
10 (47.6%) 4 (19.0%) 7 (33.3%)
93 (88.6%) 12 (11.4%)
16 (76.2%) 5 (23.8%)
85 (81.0%) 20 (19.0%) 22.9 ± 4.1 3.5 ± 0.6
16 (76.2%) 5 (23.8%) 22.3 ± 3.75 3.6 ± 0.4
P-value
0.672
0.123
0.482
0.209
0.376
0.160
0.565
0.518 0.698
BMI, body mass index; SD, standard deviation.
The use of optimized nutritional intervention programs such as dietitian consultations, periodic monitoring, appropriate nutritional supplements and feeding tube placement throughout the treatment period markedly improved treatment tolerance and outcomes in head and neck cancer patients.17,18 Therefore, it is reasonable to infer that the maintenance of a good nutritional status is important for patients with advanced stage head and neck cancer who are undergoing concurrent chemoradiotherapy, especially for elderly patients. In 2007, we set up an early and intensive nutritional support program within a multidisciplinary management unit at our institution for head and neck cancer patients undergoing chemoradiation. We offered intensive nutritional support, including scheduled counseling, prompt tube
Asia-Pac J Clin Oncol 2015; 11: 228–235
feeding and mandatory hospital care, throughout the treatment period on an inpatient basis.19 Using this early and intensive nutritional support program, we analyzed treatment tolerance, toxicities and survival in older versus younger patients with advanced head and neck cancer undergoing concurrent chemoradiotherapy. We found that clinical characteristics and treatment toxicities were similar between the older and younger patients, except that the older patients were less likely to tolerate cisplatin, experienced more weight loss, required more feeding tube support and tended to develop >grade 3 any hematological toxicities and sepsis during the chemoradiotherapy period. Except for overall survival, the disease-related outcomes, including disease-free survival and disease-specific survival, were
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Table 2
P-H Chang et al.
Comparison of treatment tolerance and outcomes
Total dose of RT completed (mean ± SD), Gy Total dose of cisplatin completed (mean ± SD), mg/m2 Weight loss (mean ± SD), % Feeding tube placement Toxic death (grade 5 toxicity) > Grade 3 mucositis/pharyngitis > Grade 3 nausea/vomiting > Grade 3 any hematological toxicities > Grade 3 leukopenia > Grade 3 neutropenia > Grade 3 anemia > Grade 3 thrombocytopenia Sepsis during CCRT 1-year disease-free survival rate 2-year disease-free survival rate 1-year disease-specific survival rate 2-year disease-specific survival rate 1-year overall survival rate 2-year overall survival rate
grade 3 hematological toxicities and to develop sepsis during
Asia-Pac J Clin Oncol 2015; 11: 228–235
chemoradiotherapy in our study. This warrants great attention from clinicians because sepsis can increase the risk of death during chemoradiation therapy.16 Earlier identification of infection symptoms and signs is needed and the administration of prophylactic antibiotics should be considered in elderly patients due to the higher morbidity and mortality rates of elderly patients who develop sepsis.31 Second, the older patients in our study received relatively limited doses of cisplatin, which is consistent with previous reports.32 The relatively lower doses of cisplatin in the older group may be due to the relative higher percentage of > grade 3 hematological toxicities and sepsis in our study. However, similar radiotherapy doses were achieved in both age groups under full nutritional support. This suggests that maintenance of adequate nutritional status enables better treatment tolerance, which may lead to equivalent disease-specific survival in the older and younger patient groups. Choosing the therapy and care for older patients with advanced head and neck cancer remains a challenge. With our intensive nutritional support program, age alone should not be considered a contraindication to aggressive chemoradiotherapy for advanced head and neck cancer. However, older patients still require more careful multidisciplinary assessment of their supportive care needs to ensure successful completion of treatment and to reduce the grade of toxicity. Further studies that explore the value of geriatric assessments of older patients with advanced head and neck cancer should be considered and may allow clinicians to improve triage systems for intensive multimodality treatment.
ACKNOWLEDGMENT The authors thank all the members of the Cancer Center, Chang Gung Memorial Hospital, Keelung, for their invaluable help.
REFERENCES 1 Kruse AL, Bredell M, Luebbers HT, Gratz KW. Head and neck cancer in the elderly: a retrospective study over 10 years (1999–2008). Head Neck Oncol 2010; 2: 25. 2 Forastiere AA, Goepfert H, Maor M et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349 (22): 2091–8. 3 Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated
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individual data. MACH-NC Collaborative Group. MetaAnalysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355 (9208): 949–55. Pignon JP, le Maitre A, Bourhis J. Meta-Analyses of Chemotherapy in Head and Neck Cancer (MACH-NC): an update. Int J Radiat Oncol Biol Phys 2007; 69 (2 Suppl): S112–4. Lewis JH, Kilgore ML, Goldman DP et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 2003; 21 (7): 1383–9. Kumar A, Soares HP, Balducci L, Djulbegovic B. Treatment tolerance and efficacy in geriatric oncology: a systematic review of phase III randomized trials conducted by five National Cancer Institute-sponsored cooperative groups. J Clin Oncol 2007; 25 (10): 1272–6. Barzan L, Veronesi A, Caruso G et al. Head and neck cancer and ageing: a retrospective study in 438 patients. J Laryngol Otol 1990; 104 (8): 634–40. Leon X, Quer M, Agudelo D et al. Influence of age on laryngeal carcinoma. Ann Otol Rhinol Laryngol 1998; 107 (2): 164–9. Kowalski LP, Alcantara PS, Magrin J, Parise Junior O. A case-control study on complications and survival in elderly patients undergoing major head and neck surgery. Am J Surg 1994; 168 (5): 485–90. Hirano M, Mori K. Management of cancer in the elderly: therapeutic dilemmas. Otolaryngol Head Neck Surg 1998; 118 (1): 110–4. Sarini J, Fournier C, Lefebvre JL, Bonafos G, Van JT, Coche-Dequeant B. Head and neck squamous cell carcinoma in elderly patients: a long-term retrospective review of 273 cases. Arch Otolaryngol Head Neck Surg 2001; 127 (9): 1089–92. Peters TT, van der Laan BF, Plaat BE, Wedman J, Langendijk JA, Halmos GB. The impact of comorbidity on treatment-related side effects in older patients with laryngeal cancer. Oral Oncol 2011; 47 (1): 56–61. van Wayenburg CA, Rasmussen-Conrad EL, van den Berg MG et al. Weight loss in head and neck cancer patients little noticed in general practice. J Prim Health Care 2010; 2 (1): 16–21. van Bokhorst-de van der S, van Leeuwen PA, Kuik DJ et al. The impact of nutritional status on the prognoses of patients with advanced head and neck cancer. Cancer 1999; 86 (3): 519–27. Brookes GB. Nutritional status–a prognostic indicator in head and neck cancer. Otolaryngol Head Neck Surg 1985; 93 (1): 69–74. Chang PH, Yeh KY, Huang JS et al. Pretreatment performance status and nutrition are associated with early mortality of locally advanced head and neck cancer patients undergoing concurrent chemoradiation. Eur Arch Otorhinolaryngol 2013; 270 (6): 1909–15. Paccagnella A, Morello M, Da Mosto MC et al. Early nutritional intervention improves treatment tolerance and
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outcomes in head and neck cancer patients undergoing concurrent chemoradiotherapy. Support Care Cancer 2010; 18 (7): 837–45. Isenring EA, Capra S, Bauer JD. Nutrition intervention is beneficial in oncology outpatients receiving radiotherapy to the gastrointestinal or head and neck area. Br J Cancer 2004; 91 (3): 447–52. Wang CH, Wang HM, Pang YP, Yeh KY. 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. Support Care Cancer 2012; 20 (6): 1169–74. World Health Organization. Definition of An Older or Elderly Person. WHO, Geneva, Switzerland 2010. [Cited 17th August 2014] Available from URL: http:// www.who.int/healthinfo/survey/ageingdefnolder/en/. Rubin P, Wasserman TH. International clinical trials in radiation oncology. The late effects of toxicity scoring. Int J Radiat Oncol Biol Phys 1988; 14 (Suppl 1): S29– 38. Murphy BA. Advances in quality of life and symptom management for head and neck cancer patients. Curr Opin Oncol 2009; 21 (3): 242–7. Chang PH, Wang CH, Huang JS et al. Low body mass index at 3 months following adjuvant chemoradiation affects survival of postoperative locally advanced oral cavity cancer patients. Laryngoscope 2012; 122 (10): 2193–8. Michal SA, Adelstein DJ, Rybicki LA et al. Multi-agent concurrent chemoradiotherapy for locally advanced head and neck squamous cell cancer in the elderly. Head Neck 2012; 34 (8): 1147–52. Rosenthal DI. Consequences of mucositis-induced treatment breaks and dose reductions on head and neck cancer treatment outcomes. J Support Oncol 2007; 5 (9 Suppl 4): 23–31. Merlano MC, Monteverde M, Colantonio I et al. Impact of age on acute toxicity induced by bio- or chemoradiotherapy in patients with head and neck cancer. Oral Oncol 2012; 48 (10): 1051–7. Boscolo-Rizzo P, Muzzi E, Trabalzini F, Gava A, Stellin M, Da Mosto MC. Functional organ preservation after chemoradiotherapy in elderly patients with loco-regionally advanced head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2011; 268 (9): 1349–55. Kennedy BJ. Aging and cancer. Oncology (Williston Park) 2000; 14 (12): 1731–3. Balducci L, Corcoran MB. Antineoplastic chemotherapy of the older cancer patient. Hematol Oncol Clin North Am 2000; 14 (1): 193–212. Bernardi D, Barzan L, Franchin G et al. Treatment of head and neck cancer in elderly patients: state of the art and guidelines. Crit Rev Oncol Hematol 2005; 53 (1): 71– 80.
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31 Lemay AC, Anzueto A, Restrepo MI, Mortensen EM. Predictors of Long-term Mortality After Severe Sepsis in the Elderly. Am J Med Sci 2014; 347 (4): 282– 8.
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32 Derks W, de Leeuw JR, Hordijk GJ, Winnubst JA. Reasons for non-standard treatment in elderly patients with advanced head and neck cancer. Eur Arch Otorhinolaryngol 2005; 262 (1): 21–6.
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Asia-Pacific Journal of Clinical Oncology 2015; 11: 228–235
doi: 10.1111/ajco.12323
ORIGINAL ARTICLE
Chemoradiotherapy in elderly patients with advanced head and neck cancer under intensive nutritional support Pei-Hung CHANG,1 Kun-Yun YEH,1 Jen-Seng HUANG,1 Eric Yen-Chao CHEN,2 Shih-Wei YANG,3 and Cheng-Hsu WANG1,4 1
Division of Hematology/Oncology, Department of Internal Medicine, and Departments of 2Radiation Oncology and Otolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Taiwan and 4Cancer Center, Chang Gung Memorial Hospital, Keelung, Taiwan 3
Abstract Aim: To evaluate treatment tolerance, toxicities and survival in elderly patients with advanced head and neck cancer who received inpatient-based intensive nutritional support with concurrent chemoradiotherapy in comparison with younger patients undergoing the same treatment. Methods: We retrospectively analyzed the records of 126 stage III, IVA and IVB head and neck cancer patients who were treated with concurrent chemoradiotherapy between 2007 and 2009 under an inpatientbased nutritional support program. The clinical characteristics, treatment tolerance, toxicities and survival of patients older than 65 years were compared with those of identically treated patients younger than 65 years. Results: There were 21 patients older than 65 years and 105 patients younger than 65 years. Clinical characteristics and treatment toxicities were similar between the groups, except that the elderly were less likely to tolerate cisplatin, experienced more weight loss, required more feeding tube support and tended to have >grade 3 hematological toxicities and to develop sepsis during the period of chemoradiotherapy. The 1- and 2-year disease-free survival and disease-specific survival rates were nearly identical. Conclusion: Age alone should not be considered a contraindication to aggressive chemoradiotherapy for advanced head and neck cancer. Older patients require more careful multidisciplinary assessment of their supportive care needs to ensure successful completion of treatment and avoid further treatment-related toxicity. Key words: chemoradiation, elderly, head and neck cancer, nutrition, survival.
INTRODUCTION The percentage of elderly people with head and neck cancer is increasing owing to an overall increase in life Correspondence: Dr Cheng-Hsu Wang, MD, Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Taiwan. No. 200, Lane 208, Jijin 1st Road, Keelung 20445, Taiwan. Email: [email protected] 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 Accepted for publication 14 October 2014.
© 2014 Wiley Publishing Asia Pty Ltd
expectancy.1 Concurrent chemoradiotherapy has become one of the standard definitive treatments for patients with locally advanced stage head and neck cancer and has shown a significant survival benefit, higher laryngectomy-free survival rate, increased locoregional control rate and lower distant metastasis rate than radiation alone.2–4 However, its efficacy comes with substantial toxicities that have the potential to be severe. There is limited information about the effectiveness of cancer treatment in elderly patients, partially because they are often underrepresented and excluded from clinical trials.5,6 Although age is not an independent negative prognostic factor in head and neck cancer treatment,7,8 nonstandard treatment is used more frequently to treat elderly patients.9–11 Single modality
Nutrition in elderly receiving CRT
treatment, such as radiotherapy alone, is more likely to be chosen by clinicians because of the toxicity of concurrent chemoradiotherapy.12 Chemoradiotherapy negatively affects the patient’s nutritional status. Malnourishment at the time of diagnosis and during chemoradiotherapy has adverse consequences, including poor quality of life, decreased immune function and shorter survival.13–16 Optimized nutritional intervention programs such as dietitic consultation, periodic monitoring, appropriate nutritional supplements and feeding tube placement throughout the treatment period markedly improved treatment tolerance and outcomes in head and neck cancer patients.17,18 In 2007, an early and intensive nutritional support program was established within a multidisciplinary management unit at our institution for head and neck cancer patients undergoing chemoradiotherapy.19 Patients with non-metastatic stage IV oral cavity cancers who received chemoradiotherapy with this nutritional support programs experienced many benefits such as minimal body weight loss, improved treatment tolerance and probable survival benefits compared with patients admitted before 2007 (who were not routinely referred to this nutrition program).19 It is reasonable to infer that the maintenance of a good nutritional status is important for patients with advanced stage head and neck cancer undergoing concurrent chemoradiotherapy, especially the elderly one. The purpose of this study was to evaluate and compare treatment tolerance, toxicities, and survival in older and younger patients with advanced head and neck cancer who received inpatient-based nutritional support with concurrent chemoradiotherapy.
METHODS This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital. Patients who had biopsy-proven stage III, IVA or IVB head and neck squamous cell carcinoma (TNM (Tumor, node, metastasis) stage reclassified according to the American Joint Committee on Cancer staging system published in 2002) of the oral cavity, oropharynx, and hypopharynx, and who were treated with primary chemoradiotherapy were eligible for this study. Patients with recurrent cancer, distant metastasis or another concomitant active cancer were excluded from the study. From January 2007 to December 2009, we retrospectively reviewed the records of 134 patients with stage III, IVA and IVB head and neck squamous cell carcinoma who had undergone concurrent chemoradiotherapy at our institution. Eight patients were excluded from the study. Four patients dropped out
Asia-Pac J Clin Oncol 2015; 11: 228–235
229
during the chemoradiotherapy schedule and were lost to follow-up because of unavoidable family reasons, such as divorce (one patient), poor financial support (two patients) and moving out of town (one patient). Two patients were treated with re-chemoradiation for recurrent disease and two were diagnosed with a concomitant active cancer upon diagnosis. A total of 126 patients who received concurrent chemoradiotherapy were included in the analysis. All patients received intensity-modulated or arc technique radiotherapy on 5 consecutive days/week at a conventional fractionated daily dose of 1.8 or 2 Gy. The total prescribed dose of radiotherapy was 70–74 Gy. The initial treatment volume included the tumor bed and regional lymphatics. After receiving 46–50 Gy, the treatment area was reduced to irradiate the tumor bed and regional nodes. The chemotherapy regimens including cisplatin 40 mg/m2 every week or 100 mg/m2 every 3 weeks were administered according to the treatment guidelines at our institution. All patients were routinely referred to an early and intensive nutritional support program established in 2007 at our institution.19 This inpatient-based program includes biweekly dietitian visits, mandatory feeding tube placement, timely caloric supplementation and blood transfusion as needed, and continues on a regular basis throughout the chemoradiation period. Feeding tube placement, including nasogastric tube or percutaneous gastrostomy, is performed for all the patients if their body weight loss is more than 5% during the treatment course. The daily nutritional intake of patients is monitored closely in the hospital throughout the treatment period, and their oral intake is supplemented to fulfill their energy requirements. During the chemoradiation therapy period, all patients are prescribed analgesics, antibiotics, vitamin supplements, mouth rinse and topical steroid ointments. More than 90% of head and neck cancer patients undergoing concurrent chemoradiotherapy remain in the hospital to complete the treatment. Patients are admitted to receive chemoradiation therapy along with the inpatient-based nutritional support program. Our patients have government-supported health care via the National Health Insurance Program in Taiwan. The following clinical parameters of patients in both groups were retrospectively analyzed in this study before the initiation of treatment and at the end of treatment: age, gender, primary site of disease, TNM stage of cancer at diagnosis (American Joint Committee on Cancer), Eastern Cooperative Oncology Group performance status, comorbid disease as Charlson Comorbidity Index, body mass index and serum albumin level. According to the World Health Organization,20 the age
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of 60 or 65, equivalent to the retirement ages in most developed countries, is considered to be the beginning of old age. We defined those aged 65 years or older as older patients in our study, according to the retirement age in Taiwan. Treatment tolerance was evaluated by the total dose of radiation completed, the total dose of cisplatin received, the occurrence of sepsis (cultures from the bloodstream were used to detect the presence of pathogens that made the patients ill and febrile), hematological toxicity grade ≥3 (including leukopenia, neutropenia, thrombocytopenia and anemia), mucositis/ pharyngitis grade ≥3 and nausea/vomiting grade ≥3, according to the RTOG (Radiation Therapy Oncology Group) toxicity criteria.21 Treatment outcome was assessed by the 1- and 2-year disease-free survival, disease-specific survival and overall survival rates. Disease-free survival was defined as the time spanning from the initiation of chemoradiation to the first evidence of recurrence of the primary tumor. Diseasespecific survival was defined as the time from the initiation of chemoradiation to death from either disease or toxicity. Overall survival was defined as the time from the initiation of chemoradiation to death from any cause. 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 two groups and various clinical and pathological features of patients in each group. The differences in body mass index, serum albumin level, weight loss, total dose of radiotherapy and dose of cisplatin received were evaluated by independent Student’s t-tests. The Kaplan–Meier method was used to analyze survival, and the log-rank test was used to examine the differences. All P-values were derived from two-tailed statistical tests. A P-value of < 0.05 was considered statistically significant.
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significant difference in the total dose of radiation completed. However, the older group received a significantly lower accumulated cisplatin dose than the younger patients (151.2 ± 78.7 mg/m2 vs 199.0 ± 90.1 mg/m2, P = 0.042). Weight loss during the chemoradiotherapy period (−7.2 ± 5.1% vs −3.7 ± 6.7%, P = 0.047) and feeding tube placement (80.1% vs 52.3 %, P = 0.020) was more significant among the older patients. The rate of toxic death (grade 5 toxicity) was similar in both groups. In the older patient group, one patient died from sepsis caused by ischemic bowel. In the younger patient group, three patients died from neutropenic sepsis, one from aspiration pneumonia, one from empyema and one from tumor bleeding. There was no difference in > grade 3 mucositis/pharyngitis, > grade 3 nausea/vomiting, > grade 3 any hematological toxicities or sepsis during the chemoradiotherapy period. Although not significant, the older group tended to have a higher percentage of patients with > grade 3 hematological toxicities (38.1% vs 20.1%, P = 0.092) and sepsis (38.1% vs 18.1%, P = 0.076) during the chemoradiation therapy period (Table 2). There was also no statistically significant difference between the two groups in 1- and 2-year diseasefree survival (75.2% vs 71.4%, and 60.0% vs 52.4% in the older vs younger patients, respectively), 1- and 2-year disease-specific survival (84.8% vs 80.1%, and 66.7% vs 57.1% in older vs younger patients, respectively), and 1- and 2-year overall survival (82.8% vs 76.2%, and 64.8% vs 52.4% in older vs younger patients, respectively). The survival outcomes are detailed in Table 2 and graphically portrayed in Figures 1–3. Except for the fact that the older group tended to have worse overall survival (P = 0.117), the disease-related outcomes, including disease-free and disease-specific survival, were not statistically different.
DISCUSSION RESULTS The study cohort of locally advanced head and neck cancer patients before chemoradiotherapy included 21 patients older than 65 years (older group) and 105 patients younger than 65 years (younger group). The clinical and tumor characteristics of these 126 patients are listed in Table 1. No significant differences were found in gender, tumor location, TNM stage, performance status, Charlson Comorbidity Index, pretreatment body mass index or serum albumin level between the older and younger groups (Table 1). As shown in Table 2, we compared the treatment tolerance and outcomes between the groups and found that there was no
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Head and neck cancer and its treatment is associated with a marked symptom burden and functional impairment.22 Supportive care is crucial in enabling patients to complete their prescribed course of treatment without breaks and to recover safely from toxicities. In an analysis of five cross-sectional studies of patients with head and neck cancer, there was a statistical correlation between age, overall symptom burden and nutritional dysfunction during therapy.22 Chemoradiation therapy negatively impacts on patient’s nutritional status.23 Numerous reports have found that malnutrition has adverse associations, including poor quality of life, decreased immune function and shorter survival.14–16
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Table 1
Demographic characteristics of the patients before treatment according to age 1 BMI (mean ± SD), kg/m2 Albumin (mean ± SD), g/dL
≥65 years
105 48 (26–64)
21 68 (65–76)
97 (92.4%) 8 (7.6%)
19 (90.5%) 2 (9.5%)
17 (16.2%) 88 (83.8%)
7 (33.3%) 14 (66.7%)
12 (11.4%) 26 (24.8%) 19 (18.1%) 36 (34.3%) 12 (11.4%)
1 (4.8%) 9 (42.9%) 4 (19.0%) 5 (23.8%) 2 (9.5%)
22 (21.0%) 14 (13.3%) 8 (7.6%) 31 (29.5%) 20 (19.0%) 9 (8.6%)
7 (33.3%) 6 (28.6%) 2 (9.5%) 4 (19.0%) 2 (9.5%) 0 (0.0%)
43 (40.1%) 36 (34.3%) 26 (24.8%)
10 (47.6%) 4 (19.0%) 7 (33.3%)
93 (88.6%) 12 (11.4%)
16 (76.2%) 5 (23.8%)
85 (81.0%) 20 (19.0%) 22.9 ± 4.1 3.5 ± 0.6
16 (76.2%) 5 (23.8%) 22.3 ± 3.75 3.6 ± 0.4
P-value
0.672
0.123
0.482
0.209
0.376
0.160
0.565
0.518 0.698
BMI, body mass index; SD, standard deviation.
The use of optimized nutritional intervention programs such as dietitian consultations, periodic monitoring, appropriate nutritional supplements and feeding tube placement throughout the treatment period markedly improved treatment tolerance and outcomes in head and neck cancer patients.17,18 Therefore, it is reasonable to infer that the maintenance of a good nutritional status is important for patients with advanced stage head and neck cancer who are undergoing concurrent chemoradiotherapy, especially for elderly patients. In 2007, we set up an early and intensive nutritional support program within a multidisciplinary management unit at our institution for head and neck cancer patients undergoing chemoradiation. We offered intensive nutritional support, including scheduled counseling, prompt tube
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feeding and mandatory hospital care, throughout the treatment period on an inpatient basis.19 Using this early and intensive nutritional support program, we analyzed treatment tolerance, toxicities and survival in older versus younger patients with advanced head and neck cancer undergoing concurrent chemoradiotherapy. We found that clinical characteristics and treatment toxicities were similar between the older and younger patients, except that the older patients were less likely to tolerate cisplatin, experienced more weight loss, required more feeding tube support and tended to develop >grade 3 any hematological toxicities and sepsis during the chemoradiotherapy period. Except for overall survival, the disease-related outcomes, including disease-free survival and disease-specific survival, were
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Table 2
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Comparison of treatment tolerance and outcomes
Total dose of RT completed (mean ± SD), Gy Total dose of cisplatin completed (mean ± SD), mg/m2 Weight loss (mean ± SD), % Feeding tube placement Toxic death (grade 5 toxicity) > Grade 3 mucositis/pharyngitis > Grade 3 nausea/vomiting > Grade 3 any hematological toxicities > Grade 3 leukopenia > Grade 3 neutropenia > Grade 3 anemia > Grade 3 thrombocytopenia Sepsis during CCRT 1-year disease-free survival rate 2-year disease-free survival rate 1-year disease-specific survival rate 2-year disease-specific survival rate 1-year overall survival rate 2-year overall survival rate
grade 3 hematological toxicities and to develop sepsis during
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chemoradiotherapy in our study. This warrants great attention from clinicians because sepsis can increase the risk of death during chemoradiation therapy.16 Earlier identification of infection symptoms and signs is needed and the administration of prophylactic antibiotics should be considered in elderly patients due to the higher morbidity and mortality rates of elderly patients who develop sepsis.31 Second, the older patients in our study received relatively limited doses of cisplatin, which is consistent with previous reports.32 The relatively lower doses of cisplatin in the older group may be due to the relative higher percentage of > grade 3 hematological toxicities and sepsis in our study. However, similar radiotherapy doses were achieved in both age groups under full nutritional support. This suggests that maintenance of adequate nutritional status enables better treatment tolerance, which may lead to equivalent disease-specific survival in the older and younger patient groups. Choosing the therapy and care for older patients with advanced head and neck cancer remains a challenge. With our intensive nutritional support program, age alone should not be considered a contraindication to aggressive chemoradiotherapy for advanced head and neck cancer. However, older patients still require more careful multidisciplinary assessment of their supportive care needs to ensure successful completion of treatment and to reduce the grade of toxicity. Further studies that explore the value of geriatric assessments of older patients with advanced head and neck cancer should be considered and may allow clinicians to improve triage systems for intensive multimodality treatment.
ACKNOWLEDGMENT The authors thank all the members of the Cancer Center, Chang Gung Memorial Hospital, Keelung, for their invaluable help.
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