The clinical implications of a head and neck cancer (HNC)-specific frailty index focusing on respiratory and swallowing functions were investigated in 165 elderly patients with HNC. Pretreatment functional disabilities related to respiration and swallowing were significantly associated with early morbidity and mortality.
Keywords: Elderly, Frailty, Head and neck cancer, Respiration, Swallowing
Abstract
Introduction.
Frailty refers to a decreased physiologic reserve in geriatric patients and its importance in terms of treatment planning and outcome prediction has been emphasized in oncologic practices for older patients with cancer. We investigated the clinical implications of a head and neck cancer (HNC)-specific frailty index suggested by prospective clinical and functional evaluations of HNC patients.
Materials and Methods.
We analyzed data on 165 elderly patients with HNC who were prospectively enrolled in our hospital from 2010 to 2013. Pretreatment functional evaluations were performed according to all comprehensive geriatric assessment (CGA) domains. We additionally evaluated the patients’ respiratory and swallowing functions using pulmonary function tests, voice handicap index (VHI), MD Anderson Dysphagia Inventory (MDADI), and other associated tests. Factors affecting the 2-year morbidity and mortality were also analyzed.
Results.
Respiratory and swallowing problems were major causes of 2-year morbidity. Pretreatment performance status, VHI ≥8, MDADI <70, dental problems, and chemotherapy were significantly associated with early morbidity and mortality (all p < .05). CGA-assessed frailty was found in 72 patients (43.6%) and was significantly associated with 2-year mortality (p = .027) but not with morbidity (p = .716). The high-risk group according to our new HNC-specific frailty index that included functional evaluations of respiration and swallowing showed significantly higher 2-year morbidity (p = .043) and mortality (p < .001).
Conclusion.
Pretreatment functional disabilities related to respiration and swallowing were significantly associated with early morbidity and mortality. The suggested index would be more useful for assessing frailty in elderly HNC patients.
Implications for Practice:
This study is the first report in terms of suggesting a new frailty index focusing on respiratory and swallowing functions in elderly patients with head and neck cancer. This study shows that functional disabilities associated with respiration and swallowing significantly affected early morbidity and mortality in these elderly patients. The head and neck cancer-specific frailty index described in this report, which includes functional evaluations of respiration and swallowing, significantly predicted both early morbidity and mortality.
Introduction
Cancer incidence has been rising as the average human life expectancy increases. Patients older than 65 years, commonly considered elderly, occupy a larger and larger proportion of patients with cancer. Hence, cancer treatment in geriatric populations is a concern of oncology practitioners, with a particular focus on the “frail oldster” [1]. Frailty in geriatrics generally means a decreased physiologic reserve and function, defined as meeting three of five phenotypic criteria: unintentional weight loss, exhaustion, low physical activity, slowness, and weakness of grip strength [2]. Frailty may lead to a higher susceptibility to adverse outcomes during the disease course (e.g., treatment-related side effects, hospital admission, morbidity, and even mortality) [2]. Therefore, it is important when planning treatment in elderly cancer patients to consider residual life expectancy with frailty.
Comprehensive geriatric assessment (CGA), a diagnostic model used worldwide to evaluate the “functional” age of geriatric patients, has also been used in the oncology field [3]. CGA consists of nine domains with numerous associated subassessment items for multidimensional evaluation of older cancer patients. It is currently used to guide treatment planning and as a prognostic indicator. However, given the busy clinical environment, it is practically difficult and time consuming to evaluate all CGA items. Therefore, diverse CGA-related screening methods focusing on ease of applicability and aiming to accurately assess frailty (e.g., Vulnerable Elders Survey-13 [VES-13], Geriatric 8 [G8], and Groningen Frailty Index [GFI]) have been introduced and their predictive values have been reviewed [4, 5].
The head and neck are critical for respiration and swallowing. Head and neck cancer (HNC) may disturb a number of essential functions, and the cancer itself and its treatment are associated with significant patient morbidity. Older HNC patients have a relatively higher incidence of coexisting pulmonary diseases or degenerative neuromuscular disorders that can aggravate treatment-related complications and may lead to insufficient treatment or even treatment discontinuation [6]. Importantly, HNC itself and its associated aerodigestive complications during patient follow-up can lead to early death and noncancerous demises [7–9]. Therefore, pretreatment evaluation of the functional age of geriatric HNC patients should include assessment of swallowing and respiration abilities.
We hypothesized that pretreatment swallowing and respiratory dysfunctions in elderly HNC patients would significantly impact early post-treatment morbidity and mortality. We also assumed that frailty assessment comprising these functions would have a greater prognostic significance than conventional CGA. Frailty in HNC patients has rarely been studied and, as explained, development of a modified and simplified HNC-specific screening tool is necessary for frailty evaluation [4, 10, 11]. Thus, in this study, we evaluated respiratory and swallowing frailty in older HNC patients by using symptom questionnaires and objective diagnostic tools. We also sought to develop a new frailty index that included these two functional concepts and to compare its applicability with that of CGA. Finally, we investigated the clinical implications of the HNC-specific frailty index as an indicator of prognostic prediction or optimal treatment selection.
Materials and Methods
Patients
This prospective study was conducted to identify prognostic indicators of treatment outcomes through well-planned and careful clinical, functional, and imaging assessments. The study was approved by the institutional review board of our hospital and informed consent was obtained from each patient. The primary endpoint was all-cause mortality and the secondary endpoints were morbidity and other survival outcomes. The early time point for these endpoints was 2 years. Functional assessments including swallowing and respiration were performed in all patients. We primarily enrolled 173 HNC patients, who were accrued and treated in our hospital from 2010 to 2013, to perform functional assessments. The following inclusion criteria were applied: (a) age ≥65 years at diagnosis; (b) tumor origin in the oral cavity, oropharynx, larynx, or hypopharynx; (c) previously untreated squamous cell carcinoma; (d) no initial distant metastasis; (e) no history of other cancer within the previous 5 years; (f) no synchronous second primary cancer (SPC); (g) treatment with curative intent; and (h) a follow-up duration of survivors ≥1 year. A total of 165 patients were included in the final analyses.
Pretreatment Evaluation Tools
The pretreatment functional status of the patients was identified in accordance with the CGA domains (supplemental online Table 1). That is, the social status domain was estimated by the presence of a caregiver and accessibility to the hospital. The Charlson comorbidity index (CCI) and performance score of the Eastern Cooperative Oncology Group (ECOG) were used to estimate each comorbidity and the physical function domains [12, 13]. Nutritional status was estimated based on recent body weight loss, namely, unintentional weight loss of more than 5% of basal body weight within 6 months, or a body mass index (BMI) of less than 18.5 kg/m2 [1]. Depression was assessed using the second version of the Beck Depression Inventory (BDI-II) [14]. The number of medications (taking five or more medications was considered polypharmacy), cognitive impairment measured by mini-mental-state examination, and the presence of any problems included in geriatric syndrome, such as dementia or osteoporosis, were also investigated to evaluate other CGA domains. Patients with impairment in two or more estimates of the CGA domains were considered “frail” for the purposes of this study [15].
The respiratory capacity of the patients was estimated by the predicted percentage of forced expiratory volume per 1 second (FEV1% predicted), which is one of the parameters in the pulmonary function test and is defined as the FEV1% of the patient divided by the average FEV1% of an age-, sex-, and body composition-matched population. Because a recent prospective study reported that a low FEV1 was a short-term predictor of all-cause mortality and hospitalization in very old adults, independently of comorbidities (including chronic lung diseases), we regarded the FEV1% predicted value as a standard tool for evaluating the respiratory function of our patients [16]. The voice handicap index (VHI), which indirectly reflects the subglottic pressure and pulmonary reserve, was also assessed as an approximation of respiratory function [17]. The swallowing function of the patients was measured using the global assessment scores of the MD Anderson Dysphagia Inventory (MDADI) with a video fluoroscopic swallowing study as an objective confirmative test [18]. In addition, all study patients were examined by professional dentists before treatments, and any dental problems affecting mastication or deglutition function were reported.
Treatments and Follow-Up
All of the patients were primarily treated with curative intent based on the consensus of the tumor board of our hospital. Therapeutic modalities were divided into two major categories: surgical and nonsurgical. In the surgically treated group, postoperative adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) was sometimes administered to patients with advanced stages or adverse features. Definitive RT and CRT were considered nonsurgical modalities, and induction chemotherapy followed by surgery or RT/CRT was also introduced on a case-by-case basis.
After treatment cessation, each patient was regularly followed up with meticulous physical examinations in the outpatient clinic, and imaging tests were carried out according to the follow-up schedules. If cancer recurrence was suspected, the patients were treated in curative or palliative settings according to the status of the disease or the patient. All patients who survived were followed for more than 1 year.
Variables
Patient information, including sex, age at diagnosis, educational level, and residence, was collected. Patients with a smoking history of ≥20 pack-years were considered heavy smokers and those with daily alcohol use of ≥15.6 mL of pure ethanol (1 or more drinks per day) were defined as heavy drinkers [19]. The primary tumor site and stage of disease were classified according to the Tumor-Node-Metastasis staging system of the American Joint Committee of Cancer [20]. Follow-up information, including primary tumor recurrence, SPC development, and patient survival, was investigated. Adverse events were also identified during or after initial treatments, with their causes and severities graded according to the Common Terminology Criteria for Adverse Effects (CTCAE, version 4.0) [21].
Statistical Analysis
Characteristics were compared between “fit” and “frail” patients. The Fisher’s exact test and Student t test or Mann-Whitney U test were used for categorical and continuous variables, respectively. Severe morbidity requiring hospitalization (i.e., CTCAE grade ≥3 complications requiring admission) and overall mortality during follow-up were identified. Factors associated with these events were analyzed with a Cox proportional hazards model, and the cutoff values of these factors were obtained using the area under the time-dependent receiver operating characteristic (ROC) curve. Kaplan-Meier survival plots were depicted and the log-rank test was used for comparisons according to the presence of frailty or among the newly defined risk groups. All statistical analyses were performed with IBM SPSS Statistics Software (version 21.0; IBM Corp., Armonk, NY, http://www.ibm.com), and statistical significance was defined as two-sided p < .05.
Results
Patient Characteristics
Table 1 lists the demographic and clinical data for the study patients. A total of 173 patients were initially accrued; 5 were excluded because they refused functional assessments and 3 were excluded because of voluntary loss of follow-up within 1 year. Hence, the final study population comprised 137 men (83.0%) and 28 women (17.0%), with a median age of 71 years (range: 65–84 years). Significant pretreatment body weight losses were found in 29 patients (17.6%), and 13 subjects (7.9%) had an ECOG performance score ≥2. Sixty-four patients (38.8%) had a CCI ≥1, and polypharmacy was identified in 81 patients (49.1%). Only 3 patients (1.8%) had dementia or osteoporosis, one of whom had both conditions. The median FEV1% predicted, VHI, MDADI, and BDI-II values were 89, 7, 74, and 6, respectively. Dental problems requiring amendment were found in 27 subjects (16.4%). The larynx (38.2%) was the most common primary tumor site, followed by the hypopharynx (24.2%), oral cavity (20.0%), and oropharynx (17.6%). Advanced tumors (stages T3–4) were found in 64 patients (38.7%) and a positive nodal stage was identified in 77 patients (46.7%). Surgical and nonsurgical treatments were performed in 93 (56.4%) and 72 (43.6%) patients, respectively.
Table 1.
Patient characteristics (n = 165)
The median follow-up duration of survivors was 30.3 months. During this period, index HNC recurrences were found in 29 patients (17.6%), as well as 5 (3.0%) newly detected metachronous SPCs. A total of 42 deaths (25.5%) were identified, 26 (15.8%) from the index HNC and 16 (9.7%) from noncancerous causes. Two patients (1.2%) were alive with HNC at the last follow-up. After the initial treatment, readmission due to noncancer causes occurred in 40 patients (24.2%) with 68 cumulative events. Respiratory complications such as aspiration pneumonia or dyspnea were the most common reasons for hospitalization, and dysphagia was another major cause of severe post-treatment morbidity.
Prevalence of Frailty and Its Association With Other Clinical Factors
Frailty based on the CGA was identified in 72 of our study subjects (43.6%); fit and frail patients are compared in Table 2. The mean age of the frail group was higher than that of the fit group (p = .004), and other factors associated with the definition of frailty itself (BMI, body weight loss, ECOG performance score, CCI, polypharmacy, and BDI-II) were different between the two groups (p < .05). However, indices of pretreatment respiratory and swallowing functions were not significantly different between the two groups. Moreover, there were no significant differences in the stages of the index HNC or treatment modalities between the two groups.
Table 2.
Comparisons of other clinicopathologic parameters between fit and frail patients
Factors Affecting the 2-Year Morbidity and Mortality
The cumulative incidence probabilities of 2-year morbidity (i.e., CTCAE grade ≥3 complications requiring admission) and overall mortality were 24.0% (95% confidence interval [CI]: 20.8%–27.9%) and 22.2% (95% CI: 17.1%–27.3%), respectively. Comparisons among the subjects were done with dichotomized values using time-dependent ROC curves for continuous variables, and heavy smokers (hazard ratio [HR]: 2.62; 95% CI: 1.40–4.88; p = .003) and patients with an ECOG performance score ≥2 (HR: 5.51; 95% CI: 2.60–11.67; p < .001), VHI ≥8 (HR: 2.81; 95% CI: 1.23–6.43; p = .014), MDADI <70 (HR: 2.40, 95% CI: 1.12–5.11; p = .024), BDI-II ≥14 (HR: 3.18; 95% CI: 1.43–7.04; p = .004), and dental problems (HR: 2.81; 95% CI: 1.23–6.43; p = .014) had a significantly higher 2-year morbidity. However, frailty based on the CGA did not show a meaningful relationship with 2-year morbidity (p = .716). In addition, patients with age ≥75 years (HR: 2.07; 95% CI: 1.11–3.87; p = .023), body weight loss (HR: 2.17, 95% CI: 1.11–4.24: p = .024), ECOG performance score ≥2 (HR: 3.50; 95% CI: 1.54–7.96; p = .003), CCI ≥1 (HR: 1.98; 95% CI: 1.08–3.64; p = .028), MDADI <70 (HR: 5.66; 95% CI: 2.48–12.90; p < .001), BDI-II ≥14 (HR: 4.41; 95% CI: 1.90–10.23; p = .001), and frailty (HR 2.01; 95% CI: 1.08–3.72; p = .024) showed significantly greater 2-year mortality (Table 3).
Table 3.
Univariate analysis of factors affecting 2-year morbidity and mortality
Risk Stratification Using the Newly Defined HNC-Specific Frailty Index
Because of the nonsignificant ability of frailty, as defined in this study, to predict early morbidity while considering the importance of respiratory/swallowing functional evaluations, we extracted the factors significantly associated with 2-year morbidity and/or mortality from the above analyses and assembled them for a new risk grouping. Thus, age ≥75 years, heavy smoking, body weight loss, ECOG performance score ≥2, CCI ≥1, dental problems, VHI ≥8, MDADI <70, and BDI-II ≥14 were categories regarded as the “new” 9 domains for functional evaluation of HNC patients, and patients were stratified into 3 groups: low (0–1), intermediate (2–4), and high (5–9) risk, accordingly (Fig. 1). We then analyzed the cumulative incidence probabilities according to the risk group and found that the high-risk group showed significantly higher probability of both 2-year morbidity (39.7% [95% CI: 29.0%–50.4%] vs. 22.3% [95% CI: 18.8%–25.8%]; p = .043) and mortality (59.2% [95% CI: 47.7%–70.7%] vs. 12.2% [95% CI: 9.4%–15.0%]; p < .001) than the low- or intermediate-risk groups (Fig. 2).
Figure 1.
Risk scoring for frailty evaluation in elderly head and neck cancer patients and 2-year morbidity and mortality rates according to the risk group. Body weight loss means unintentional weight loss of more than 5% of the basal body weight within 6 months or a body mass index of less than 18.5 kg/m2.
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
Figure 2.
Cumulative incidence probabilities of 2-year morbidity (A, C) and mortality (B, D). Incidences are compared according to frailty (A, B) or the newly defined risk groups (C, D) with log-rank tests.
Discussion
We have analyzed the effects of diverse pretreatment clinical factors on morbidity and mortality in geriatric HNC patients. We additionally investigated respiratory and swallowing dysfunction beyond the CGA domains, which has not been done in previous studies. Smoking is a well-known carcinogen, especially in HNC. However, it can also cause and aggravate pulmonary diseases, leading to subsequent respiratory morbidity, and we found that patients with a history of heavy smoking had higher risk of early mortality. Initially, we focused on the FEV1% predicted values to estimate early morbidity and mortality, expecting it to be a respiratory prognosticator, but no significant results were found. In contrast, we found that the VHI could predict the risk of early morbidity in elderly HNC patients. It would be somewhat awkward to make a direct link between the VHI and respiratory function, but the VHI can partially reflect respiratory capacity through the use of multidimensional questionnaires that include physical and functional evaluation of the respiratory tract, especially in geriatric subjects [22]. It is also necessary to consider the relatively poor reliability of FEV1 values in elderly patients because of their poor compliance to this objective but self-directed test. Although no other studies have found a strong relationship between the VHI and post-treatment respiratory morbidity, we contend that VHI would be a useful subjective evaluation tool for predicting early morbidity in elderly HNC patients, in the same vein as the MDADI for assessing swallowing function.
The median value of the global assessment score of the MDADI was 74 in our current study patients. The same score was found in the HNC patient cohort that included all ages in our previous study [9]. Similarly, we found that an MDADI <70 was related to a lower 2-year overall survival rate. In addition, we found that an MDADI <70 had prognostic value for increased early morbidity that is severe enough to require readmission. Therefore, a pretreatment MDADI score that directly reflects swallowing function could be an independent prognosticator for geriatric HNC patients. Intriguingly, our current analyses found that geriatric HNC patients with dental problems had a higher risk of early morbidity. Pretreatment dental evaluation is a routine workup before RT, and dental problems causing chewing difficulty can lead to dysphagia and malnutrition, especially in patients with oral/oropharyngeal cancers [23]. A recent prospective study of the effect of dental problems on orodigestive cancer mortality in elderly patients found a significant relationship between dental problems and mortality, but the cause was unclear [24]. There may be a strong association between dental problems and morbidity/mortality in geriatric HNC patients. Hence, a pretreatment dental evaluation with a focus on swallowing dysfunction could be a significant prognostic factor.
In our study patients, frailty based on CGA did not show a significant relationship with 2-year morbidity, possibly because of differences in the characteristics of HNC compared with tumors from other organs. That is, HNC treatments are usually performed by locoregionally focused modalities with uncommon deterioration in the general condition, and systemic therapies are relatively infrequently applied to patients. However, chemotherapy may be used as an induction chemotherapy at radiosensitizing doses that are less likely to cause systemic deterioration, although our patients treated with chemotherapy showed higher risk of early morbidity. Most early morbidity in our patients was confined to those with respiratory/swallowing problems instead of systemic deconditioning. Thus, some CGA domains associated with systemic conditions, such as physical strength, polypharmacy, and geriatric syndrome, may not fully represent frailty in HNC patients. As shown from our current findings, our new risk stratification approach, which incorporates additional evaluations considering respiration with swallowing functions, strongly predicted both early morbidity and mortality. Therefore, our HNC-specific frailty criteria would be more useful than other scales for estimating the vulnerability of geriatric HNC patients.
Our study had some limitations due to its small study population with a relatively short follow-up duration. We also could not evaluate very old patients (older than 85 years) because almost all of them refused to undergo curative treatments because of a limited residual life expectancy or coexisting morbidity. Finally, we could not evaluate which treatment modalities may be better suited for vulnerable patients nor could we perform multivariate analyses, because of the relatively small study population, which made it difficult to control the diverse variables in the statistical process. However, our findings are important in terms of estimating the ability of respiratory and swallowing frailty to predict early morbidity and mortality in elderly HNC patients. Our HNC-specific frailty index was also found to be important as a method of evaluation that complements conventional CGA in the prediction of early morbidity. We hope there will be further investigation into the ability of our HNC-specific frailty index to help assess personalized treatment for elderly patients.
Conclusion
Our study found that functional disabilities associated with respiration and swallowing significantly affect early morbidity and mortality in elderly HNC patients. We observed a relatively high incidence of frailty based on the CGA in our patients, but the presence of frailty was not significantly associated with 2-year morbidity. In contrast, our newly suggested HNC-specific frailty criteria showed a strong ability to predict both early morbidity and mortality. Therefore, functional evaluations of respiration and swallowing could be used to estimate the prognosis of geriatric HNC patients, and our modified frailty index has the potential to be a very useful pretreatment functional evaluation tool.
See http://www.TheOncologist.com for supplemental material available online.
Supplementary Material
Acknowledgments
This study was supported by Grant No. 2015R1A2A1A15054540 from the Basic Science Research Program through the National Research Foundation of Korea, Ministry of Science, ICT, and Future Planning, and Grant No. HI15C2920 from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute, Ministry of Health & Welfare, Seoul, Republic of Korea (Jong-Lyel Roh).
Author Contributions
Conception/Design: Minsu Kwon, Shin-Ae Kim, Jong-Lyel Roh
Provision of study materials or patients: Jong-Lyel Roh, Sang-Wook Lee, Sung-Bae Kim, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim
Collection and/or assembly of data: Minsu Kwon, Shin-Ae Kim, Jong-Lyel Roh
Data analysis and interpretation: Minsu Kwon, Jong-Lyel Roh
Manuscript writing: Minsu Kwon, Jong-Lyel Roh
Final approval of manuscript: Minsu Kwon, Shin-Ae Kim, Jong-Lyel Roh, Sang-Wook Lee, Sung-Bae Kim, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim
Disclosures
Jong-Lyel Roh: National Research Foundation and Korea Health Technology R&D Project (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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