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10.1245/s10434-006-9296-1
Annals of Surgical Oncology 14:1449-1457 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Comorbidity Is a Prognostic Factor in Elderly Patients with Head and Neck Cancer

Alvaro Sanabria, MD, MSc1,2, André Lopes Carvalho, MD, PhD1, José Guilherme Vartanian, MD1, José Magrin, MD, PhD1, Mauro Kasuo Ikeda, MD, PhD1 and Luiz Paulo Kowalski, MD, PhD1

1 Department of Head and Neck Surgery and Otorhinolaringology, Hospital do Câncer AC Camargo, Fundação Antonio Prudente, São Paulo, Brazil
2 Department of Surgery, School of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia

Correspondence: Address correspondence and reprint requests to: Alvaro Sanabria, MD, MSc; Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Hospital do Câncer AC Camargo, R. Professor Antonio Prudente, 211, 01509-900, São Paulo, Brazil; E-mail: alvarosanabria{at}gmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The number of aged patients with head and neck cancer is increasing. Comorbidities are common in this population. It is necessary to evaluate the effect of comorbidities as measured with the ACE-27 index on recurrence and survival of elderly patients with head and neck cancer, adjusting by other prognostic factors as age, clinical stage and functional status index.

Patients: Three hundred and ten patients greater than 70 years of age with head and neck cancer in a referral cancer center were studied. Comorbidity measured with the ACE-27 index was the main independent variable. The outcomes were recurrence and survival.

Results: Comorbidities were present in 75% of patients. Five-year disease-free survival, overall survival and cancer-specific survival were 63.1, 42.8 and 55.8%, respectively. Advanced clinical stage and Karnofsky index ≤70 were associated with recurrence. Age >80 years, male gender, Karnofsky index ≤80, advanced clinical stage, and ACE value ≥2 were independently associated with overall survival. The ACE-27 value was not associated with cancer-specific survival. The Karnofsky performance index was associated with overall survival and mortality and acted as a confounding factor on multivariable analysis on overall and cancer-specific survival.

Conclusions: Comorbidity measured with ACE-27 was a prognostic factor for overall survival in patients older than 70 years with head and neck cancer. The Karnofsky performance index could be included in multivariable analysis of survival for older patients with head and neck cancer.

Key Words: Head and neck neoplasms • Aged • Comorbidity • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Head and neck cancer is the eighth leading cause of cancer mortality worldwide. In the United States, 39,000 new cases and 12,000 deaths were registered in 2006.1 Head and neck cancer has a higher incidence in people older than 50 years, primarily because of its relationship with chronic tobacco and alcohol exposure.2 Besides cancer, these exposures are also associated with other significant systemic comorbidities such as pulmonary, cardiovascular, hepatic and metabolic diseases, which modify treatment tolerance and influence short-term prognosis.

As the world population ages, the number of patients with head and neck cancer surpassing the age of 70 is increasing. Some authors have argued that age is not an independent prognostic variable in head and neck oncology because comorbidities that are associated with increasing age are the main reasons for long-term prognosis modification.3–5 However, others have shown an important independent effect of age on long-term prognosis, even in the absence of comorbidities.6,7 On the other hand, the prognostic effect of comorbidities has been assessed in general populations with small sample sizes of patients older than 70 years. The comorbidity effect in this specific population of aged patients with an intrinsic survival bias is unknown. In response to the controversy related to the isolated effect of age as a prognostic marker, assessing comorbidities in a select population of older patients could help in isolating the effect of comorbidity relative to age.

The presence of comorbidities could modify the long-term prognosis of cancer patients because these patients often experience postoperative complications and undergo conservative and less radical procedures.7–9 Various instruments have been developed to assess the effect of comorbidities on patient survival.6,10 The NCI comorbidity index describes the number of diseases but does not consider the severity. Charlson11 and ACE-278 index incorporate a measure of severity and have been validated in select cancer populations. The ACE-27 index, a modification of the Kaplan–Feinstein index, has been widely validated in head and neck cancer patients. This index is simple, requires little training and has been demonstrated to be reliable in a variety of studies.12,13 The aim of this study is to evaluate the effect of comorbidities measured with the ACE-27 index on recurrence and survival of elderly patients with head and neck cancer, while adjusting for other prognostic factors such as age, clinical stage and functional status index.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was approved by the Hospital Committee of Ethics. The medical charts of all patients older than 70 years with untreated head and neck cancer admitted to the Hospital do Cancer A. C. Camargo, Sao Paulo, Brazil, between January 1, 1990, and December 31, 2003, were reviewed. During this period, surgeons followed homogeneous and stable therapeutic approaches, which decreased the effect of bias related to therapy. The following inclusion criteria were used in this study: a histologically confirmed diagnosis of malignant disease, no distant metastasis, no recurrence and intention of treatment with a curative intent, exclusive or as a part of multidisciplinary approach. Patients who underwent surgery for thyroid cancer, skin cancer, melanoma and orbit tumors were excluded.

Data collection from the medical records was performed using a specially designed survey form. The survey form included demographic information, smoking and alcohol consumption, TNM staging (Union Internationale Contre le Cancer or American Joint Committee on Cancer classification, 2002), tumor site, treatment type, neck dissection, comorbidities measured with the ACE-27 index, functional status measured using the Karnofsky Performance Index and final stage at last visit. Outcome measures were recurrence, overall and specific mortality. As these are time-to-event outcomes, the time period was calculated from the first treatment date until the last objective information was registered in the clinical charts. Disease-free survival was defined as the time from initial treatment to the first evidence of recurrence of the primary tumor. The overall survival was defined as the time from initial treatment to death from any cause. Cancer-specific survival was defined as the time from initial treatment to death from the index cancer, including cancer deaths related to surgical treatment.

A sample size calculation was made using information from Life Tables from the United States Center for Disease Control and Prevention from 1989 to 1991 and an article by Piccirillo et al.14 For Americans up to 70 years of age, the risk of death was 28.6% and for those between the ages of 70 and 80, the risk increased to 52.9%. We selected a basal death risk of 50%. Piccirillo et al.14 estimated an increase in the death risk 1.9- to 2.5-fold for patients with moderate or severe comorbidities. We selected an increase in the death risk of 1.2-fold. A power of 80%, an alpha error of 0.05 and a time-to-event period of 5 years were used for 331 patients using the Lachin formula.15

The information from the forms was entered into a database (EPI-INFO, WHO). For the statistical analysis, commercially available software (Stata 8.0, Stata Corporation, Texas, USA) was used. Descriptive statistics were used to show the distribution of variables in the population. Univariate analysis (Kaplan–Meier method) was conducted to explore the relationship between the baseline variables and the outcome events, and the results were reported using a Mantel–Cox hazard risk (HR) with a 95% confidence interval (95% CI). The log-rank test was used to define statistical significance. Continuous and discrete variables were categorized to facilitate data analysis and presentation. In cases of ordinal variables, an indicator variable was created for each level in order to use it in the Cox proportional hazard regression analysis.

The Cox proportional hazard regression analysis was used to assess the independent effect of comorbidity for recurrence, overall and specific mortality. The selection of variables was made by using the results of univariate analysis and clinical criteria. A stepwise backward Cox regression was then used to prove the independent contribution of variables in the final model, using a P = 0.2 for entry into the model. After multivariate analysis, only variables with a P < 0.05 were considered associated with the outcome. For statistically significant variables, HR (hazard ratio) with a 95% IC was reported. For all statistical tests, P < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical charts of 477 patients greater than 70 years of age were examined at the Hospital Medical Archives; 330 patients fulfilled the inclusion and exclusion criteria. The reasons for exclusion were previous treatment at the first visit (30.1% with oral cancer, 16.8% with larynx cancer and 23.1% with other tumor sites), metastatic disease at diagnosis (7%), lymphoma or melanoma (18.2%) and other reasons (synchronic cancer, incomplete information) in 4.8%. In order to keep a homogeneous population, we decided to exclude patients with a histological type different from squamous cell carcinoma too. Finally, we analyzed 310 patients.

The mean age was 76.0 ± 5.3 years (range 70–93; median 75 years); 68 patients (21.9%) were older than 80 years; 226 patients were men (72.9%) and 278 (90.0%) were Caucasians. The duration of follow-up was 34.3 ± 32.9 (0–141, median 22.5 months).

Primary tumor localization is shown in Fig. 1Go. The distribution by T and N clinical staging is shown in Table 1Go. Information about tobacco and alcohol consumption was available for 294 patients. Of these, 218 (73.9%) patients were smokers, 120 (40.7%) were alcohol drinkers and 118 patients (38.1%) were simultaneous smokers and drinkers.


Figure 1
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  		FIG. 1. Distribution of primary tumor site.

 

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  		TABLE 1. Distribution by clinical stage
 
Two hundred and forty-seven (75.1%) patients had at least one comorbidity (Table 2Go). The classification of patients’ comorbidity by the ACE-27 index was 0 in 77 (24.9%) patients, 1 in 141 (45.6%) patients, 2 in 48 (15.5%) patients and 3 in 43 (13.9%) patients. The Karnofsky index value was available for 284 patients: ≤60 in 14 (5.0%) patients, 70 in 62 (21.8%) patients, 80 in 70 (24.6%) patients and ≥90 in 138 (48.6%) patients.


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  		TABLE 2. Distribution of type and severity of comorbidities
 
One hundred and eighty-two patients (58.7%) were submitted to surgery. The most common procedures were partial or total glossectomy with/without floor of the mouth and mandibulectomy resection (26.2%) and partial or total laryngectomy (20.5%). Ipsilateral neck dissection was performed in 113 (62.1%) of these patients and bilateral neck dissection was performed in 36 (19.8%) patients. Seventy-eight (42.8%) of the operated patients received postoperative radiotherapy. Criteria for use of postoperative radiotherapy were clinical stage III or IV, positive surgical margins, perineural, lymphatic or vascular invasion, metastatic lymph nodes at the neck dissection or extracapsular invasion in at least one metastatic lymph node.

One hundred and nineteen patients (38.4%) received radiotherapy as an exclusive treatment, while 26 of them received concomitant chemotherapy. The mean dose of radiotherapy was 61 ± 13 Gy (7–76, median 65) and the treatment duration was 6.8 ± 1.7 weeks (1–11, median 7). Platinum- and taxane-based schemes of chemotherapy were used in 19 and 6 patients, respectively.

Nine patients (2.9%) did not receive therapy because of death prior to treatment initiation or the rejection of proposed therapy.

Eighty-five (27.4%) patients experienced tumor recurrence. The distribution of recurrence is as follows: 45 (14.5%) local recurrences; 15 (4.8%) neck recurrences; 8 (2.6%) locoregional recurrences and 17 (5.5%) systemic recurrences (9 in lung, 3 in liver, 2 in brain, 2 in bone and 1 in other organ). The mean disease-free interval was 12.9 ± 11.6 months (range 1.8–49.3; median 8.8 months). The actuarial 5-year disease-free survival was 63.1%.

One hundred and sixty-seven (53.8%) patients died. Death due to cancer occurred in 109 patients (35.2%). The actuarial 5-year overall survival and cancer-specific survival was 42.8 and 55.8%, respectively.

The results of the univariate analysis are displayed in Table 3Go. The multivariable Cox model included gender, age, ACE-27 index, clinical stage, tumor site, neck dissection, Karnofsky index and treatment type for all models.


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  		TABLE 3. Univariate analysis of survival
 
For recurrence, the final model maintained clinical stage IV [HR 2.54 (95% CI 1.61–3.99), P < 0.001] and Karnofsky ≤70 [HR 1.65 (95% CI 1.01–2.72), P = 0.04] as independent significant variables. The ACE-27 index value was not statistically associated with recurrence (P = 0.6).

For overall survival, the final multivariable Cox model maintained age >80 years [HR 1.53 (95% CI 1.02–2.29), P = 0.03], male gender [HR 1.70 (95% CI 1.12–2.58), P = 0.01], Karnofsky index ≤80 [HR 2.0 (95% CI 1.40–2.87), P < 0.001], clinical stage IV [HR 2.13 (95% CI 1.49–3.05), P < 0.001], ACE-27 index value equal or higher than 2 [HR 1.72 (95% CI 1.21–2.43), P = 0.002] and larynx site [HR 0.65 (95% CI 0.43–0.99), P = 0.04] as statistically independent factors (Figs. 2aGo, 3aGo).


Figure 2
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  		FIG. 2. a Overall survival by ACE-27 value. b Cancer specific survival by ACE-27 value.

 

Figure 3
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  		FIG. 3. a Overall survival by ACE-27 value (categorized in mild (ACE-27 value 0–1) and severe (ACE-27 value 2–3)). b Cancer specific survival by ACE-27 value (categorized in mild (ACE-27 value 0–1) and severe (ACE-27 value 2–3)).

 
For cancer-specific survival, the final multivariable Cox model maintained an age older than 80 years [HR 1.68 (95% CI 1.03–2.73) P = 0.03], Karnofsky index ≤80 [HR 2.28 (95% CI 1.43–3.64), P = 0.001], and clinical stage IV [HR 3.43 (95% CI 2.20–5.36), P = < 0.001]. The ACE-27 index value was not associated with specific survival (Figs. 2bGo, 3bGo, P = 0.11).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Studies exploring prognostic factors related to recurrence and survival in head and neck surgical patients have stated that clinical stage, histological factors and comorbidities have a strong relationship with these outcomes.8,16 However, most of these studies included a wide population with low representation of older patients. As the population ages, the importance of these standard prognostic factors must be reassessed. It is clear that prognostic factors could not have the same burden, or even, their effects can disappear because of the selected sample of survivors.

The significance of age as a prognostic factor in cancer patients has been widely discussed with a number of authors either supporting or denying its importance. Studies detailing larynx,17 thyroid18 and other head and neck tumors4,5 have shown that older patients do not have different outcomes when compared with the younger patients. Other studies have shown results sustaining the prognostic effect of age, even when adjusting for other prognostic factors.6,7 Consequently, we believe that an evaluation of comorbidities in a group of older patients could help in elucidating the prognostic effect of each factor.

The univariate analysis, in this series of older patients, showed a marginal association of age higher than 80 years with an overall and cancer-specific survival, which was confirmed in the multivariate analysis. The relationship with the overall survival is not surprising, because the older patients had a higher probability of death, independent of health status. However, for the case of specific survival, the multivariate analysis demonstrated an important prognostic effect. Patients older than 80 years have a 1.68-fold increased risk of death, even when adjusted by variables such as the severity of comorbidities, clinical stage and functional status. This finding confirms the independent effect of age in cancer survival, but is different from a previous report by Piccirillo8. We think this contradictory finding could result from the small sample size in his study, which included 341 patients with head and neck cancer and a small minority of these patients were elderly. Nonetheless, in a later study with a higher sample size, the prognostic effect of age was confirmed by the same and other authors.6,7

On the other hand, comorbidity has been defined as the presence of disease unrelated to the disease under study.13 Examining the effect of comorbidities is very relevant to cancer patients, because known relationships exist between some chronic diseases and a higher risk of cancer development. Additionally, comorbidities can oftentimes influence the treatment selection and administration.19–21 This is specifically important in head and neck cancer, where smoking and alcohol drinking are the most important risk factors, but they are also risk factors for developing other cardiovascular, pulmonary and metabolic diseases. Comorbidities can act as confounding factors when prognosis is measured. It has been demonstrated that certain therapies such as chemotherapy cannot be offered in the presence of specific comorbidities. Additionally, physicians may be obligated to administer suboptimal treatments to patients with comorbidities. All of these factors contribute to decreases in disease-free survival.22

Several instruments have been developed for comorbidity measurement. Kaplan and Feinstein23 developed a specific index in a group of diabetic patients. Later, Charlson11 built another specific scale to measure comorbidity. This scale was derived and validated in a cohort of medical patients and predicted survival in head and neck cancer surgical patients reliably24. Later, the Kaplan–Feinstein Comorbidity Index was modified by Piccirillo, creating the Adult Comorbidity Evalaution-27 (ACE-27),8 which has been widely validated in head and neck cancer patients.6,8,12–14,25–27 This test is reliable and easy to use, requires little training on the part of the test administrator, and can be calculated retrospectively. All of these variables make the ACE-27 one of the best instruments to assess comorbidity in head and neck cancer patients.12,13

As expected, we found a high frequency of comorbidities (75%) in this series of older patients. Ferrier27 found at least one comorbidity in 59% of 117 patients, where only 28% of patients were older than 70 years. Piccirillo28 in an analysis of the SEER database, found 59% of comorbidities in 7,131 patients reviewed, including approximately 52% of patients older than 70 years.

The most frequent comorbidities were cardiovascular diseases (hypertension, congestive heart disease, arrhythmia, myocardial infarct), alcohol abuse, respiratory diseases and diabetes mellitus, which were closely related to a chronic expose of tobacco and alcohol, but also common in geriatric populations. In a group of 40 patients older than 75 years with head and neck cancer, Sesterhenn29 found a similar distribution of comorbidities. However, the severity of disease as measured by ACE-27 was mild in most cases, even considering that all patients were older than 70 years. These findings are comparable to the other studies with a greater proportion of younger patients6,8,27 and suggest that the presence of a comorbidity without a measure of severity is not a reliable indicator of the functional effect of the disease. Hence, instruments that only account for the disease are less useful in a geriatric population.10,30

The ACE-27 index was a good predictor of overall survival and cancer-specific survival in the univariate analysis, but was not associated with higher recurrence. In the multivariate analysis, an ACE-27 index value ≥2 was associated with a 1.72-fold increase in the death risk, even when adjusting for age, clinical stage and functional status. These results confirm the previous findings from other authors.6,8,14,31

However, the ACE-27 index was not statistically associated with specific survival or recurrence in the multivariate analysis. This finding could be explained by the surgical approach implemented at this center where age and the presence of comorbidities were no contraindications to radical surgery and complex reconstruction. If a comorbidity could be compensated, then the patient would receive the standard treatment that would be offered to a patient without comorbidities.

Another explanation is the inclusion of a functional status evaluation in the multivariate analysis. The Karnofsky index was the strongest statistically related variable with overall and specific survival. It has been previously demonstrated that functional status is a different construct that cannot be confounded with comorbidity in geriatric patients and could act as an interaction factor.32–35 The previous studies that were focused on geriatric oncologic patients demonstrated an important effect of functional status on mortality.36,37 Instruments specifically designed to measure the performance of older patients as Activities of Daily Living, Instrumental Activities of Daily Living, Geriatric Depression Scale and pooled instruments as Comprehensive Geriatric Assessment and Preoperative Assessment of Cancer in the Elderly have shown that functional status modifies the prognosis in older cancer patients.38,39 Obviously, the Karnofsky performance index is not as specific as such indices, but these results show that it is an important factor to be included when assessing prognostic factors in the older patients. Even more, its simplicity and wide use makes it an easy instrument that could help clinicians to define treatment approaches during the first clinical visit without the use of extensive laboratory resources.

In conclusion, age was a prognostic factor for overall and specific survival in the older patients with head and neck cancer and its influence is independent of the presence or severity of comorbidities. Comorbidity measured with the ACE-27 index was also a prognostic factor for overall survival in head and neck cancer patients older than 70 years and should be used in longitudinal studies assessing long-term prognosis as an adjusting factor. The Karnofsky performance index was highly associated with survival to a greater extent than the ACE-27, and must be an essential variable that should be considered for clinical and research purposes in older populations. We could not find a significant association between comorbidity and specific survival, but this finding is highly dependent on other factors such as clinical approach and the functional status of evaluated patients. These results can be confirmed in other populations with different treatment approaches.


   ACKNOWLEDGMENTS
 
A. Sanabria has a grant from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico-CNPq-Brasil. CAAE 0005.0.022.000-06.

Received for publication October 30, 2006. Accepted for publication November 9, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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 Cancer Epidemiol. Biomarkers Prev.Home page
J. Hopkins, D. W. Cescon, D. Tse, P. Bradbury, W. Xu, C. Ma, P. Wheatley-Price, J. Waldron, D. Goldstein, F. Meyer, et al.
Genetic Polymorphisms and Head and Neck Cancer Outcomes: A Review
Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 490 - 499.
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 CA Cancer J ClinHome page
N. Choong and E. Vokes
Expanding Role of the Medical Oncologist in the Management of Head and Neck Cancer
CA Cancer J Clin, January 1, 2008; 58(1): 32 - 53.
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