The impact of comorbidity and age on survival with laryngeal cancer.

Reprint requests: Steven L. Sabin, MD, Otolaryngology Associates of Central New Jersey, B-3 Cornwall Dr., East Brunswick, NJ 08816. Phone: [phone]; fax: [phone].

Abstract

Previous studies have evaluated the effects of comorbidity on survival in patients with cancer. We applied the Charlson comorbidity index (CCI) to a cohort of patients with laryngeal cancer to validate its use and to assess the prognostic impact of age. Our study population consisted of 152 patients with laryngeal cancer who were seen over a 10-year period. Patients were assigned CCI scores and were categorized into low- and high-grade comorbidity groups for comparison. Age adjustments were performed by adding 1 point to the Charlson score for each decade over the median age.

Low- vs. high-grade comorbidity was a valid predictor of survival independent of TNM (tumor, nodes, and metastases) stage. Low-grade comorbidity was present in 126 patients; their median survival was 41 months. High-grade comorbidity was present in 26 patients; their median survival was 8 months (p = 0.0002). The addition of the age factor to the CCI did not improve our prognostic ability. There was no difference in CCI groups with respect to tobacco and alcohol use, gender, treatment modality, or mean time to recurrence. The incidence and severity of complications were also similar in the two groups.

We conclude that the CCI is a strong predictor of survival in patients with laryngeal cancer. The confounding effects of comorbidity should be considered in the TNM staging of laryngeal cancer to improve our prognostic ability. Further investigations are necessary to assess the validity of this index in patients with other head and neck cancers.

Introduction

Cancer is primarily a disease of the elderly. [1] With most cancers, incidence and mortality increase with age. [2] Recent reports have questioned whether or not age and comorbid conditions should be considered as part of the staging system, since both are significant prognostic indicators. [3]

Staging has long been accepted as the best single determinant of survival in patients with laryngeal cancer. [4] However, recent reports suggest that including other clinical variables such as comorbid conditions can improve the prediction of survival in patients with head and neck cancer. [5,6] Elderly patients are more likely to have comorbidities such as cardiovascular disease, pulmonary disease, and renal insufficiency. [7] Previous studies have suggested that age and comorbidity are independent predictors of survival. [8] Age is an important predictor for the risk of death attributable to comorbid disease. [9] Therefore, it is logical to combine age and comorbidity into a prognostic staging system.

The Charlson comorbidity index (CCI) was found to be a good prognostic indicator in patients with head or neck cancer. [6,9] However, no studies have applied the CCI to a cohort of patients whose head or neck cancer was confined to a single anatomic location. The current study was performed to validate the prognostic ability of the CCI for tumor-specific survival in patients with laryngeal cancer. Age was added as a comorbid condition in an attempt to determine whether or not it improves the prognostic ability of the CCI.

Materials and methods

Our study population was drawn from two hospitals in Brooklyn, N.Y. (Kings County Hospital Center and the Long Island College Hospital) during the 10-year period between January 1984 and February 1994. Data were obtained from medical records, tumor registry abstracts, and pathology reports and supplemented by direct patient contact. Only patients who had biopsy-proven squamous cell carcinoma of the larynx were included in the study. We reviewed each patient's demographic data, the type and intent of treatment (ie, curative or palliative), pathologic grading and staging, the incidence and severity of complications, and treatment outcomes. Each patient was evaluated by the CCI based on the admitting history, medical clearance for cancer treatment, preoperative anesthesia evaluation, and/or medical evaluations within 6 months of the initial presentation with cancer. The total CCI score was determined by adding the weighted score of each comorbid condition. CCI grades 1,2,3, and 4 were established for scores of 0 , 1-2, 3-4, and [greater than or equal to]5, respectively. The age-adjusted comorbidity index was calculated by adding 1 point to the CCI for each decade of age over the median of the population. Grades 1 and 2 were classified as low-grade comorbidity, and grades 3 and 4 were considered high-grade. The CCI and the age-adjusted CCI were compared for prognostic ability.

Tumor stage was determined by reviewing tumor maps and operative reports, and was based on the criteria established in 1992 by the American Joint Committee on Cancer. [10] Outcome was determined by assessing the presence or absence of cancer at the time of the last contact and the patient's current status (alive, dead, or unknown). For patients who died, the cause was determined from death certificates, surgeons' records, family contacts, or tumor registry abstracts.

Tumor-specific survival was defined as the period of time between the first day of treatment and the day of the last followup. Survival analyses was based on survival until study completion, the duration of followup, or death. The date and location of the first recurrence were also documented. The prognostic ability of the comorbidity indices were compared to the TNM staging system for tumor-specific survival.

Statistical significance was defined as a two-tailed p value less than or equal to 0.05. Fisher's Exact Test was performed for exact nonparametric inference. All other analyses, including survival functions, were performed with the True Epistat software package for medical statistics. Survival curves were estimated by Kaplan-Meier (product limit) analysis to allow for the maximum use of censored observations. (Censored subjects were those who either survived to the end of the study, were lost to followup during the study, or died of a cause unrelated to the cancer.) Survival comparisons were performed with the generalized Wilcoxon's test, a distribution-free method for comparing product-limit survival curves. The Cox proportional hazards model determined the relative risk between survival and each independent variable, adjusted for the effects of all potential confounding variables (eg, TNM stage).

Results

The study population consisted of 114 men and 38 women. Tobacco and alcohol use was reported by 93 and 84%, respectively. Blacks made up 54% of the study population. Tumors were glottic in 52% of the patients, supraglottic in 47%, and subglottic in 1%. The median duration of followup was 19 months; 25% of patients were followed for 38 months or longer, and 25% were followed for less than 8 months. At the time of the last followup, 52 patients (34%) were disease-free, 4 (2.6%) were alive with disease, 69 (45%) had died of their cancer, and 27 (18%) had died of other causes.

The Charlson comorbidity score was low for 126 patients (83%) and high for 26 (17%). Patients with high-grade comorbidity had poorer survival (p = 0.0002), particularly during the first few years of followup (figure 1, table 1). When adjusted for tumor stage (table 2), patients with a high comorbidity index had poorer survival than patients with a low level of comorbidity (p = 0.002). High comorbidity carried a relative risk of 1.57 for death (95% confidence interval: 1.18 to 2.08). There were no differences in survival based on tobacco or alcohol use, gender distribution by pathologic grade, treatment modality, or the mean time to recurrence. There was no difference in the rate or severity of complications based on the comorbidity grade.

Most patients had either stage IV (43%) or stage III (32%) tumors at study entry; stage III was the median. Tumor stage was not associated with survival according to univariate analysis (p = 0.115), although stage IV patients had the poorest survival. When adjusted for comorbidity, tumor stage was significantly associated with outcome (p = 0.025) (table 2).

The median patient age was 59 years (range: 29 to 92; standard deviation: [plus or minus]13.5). According to univariate analysis, age was associated with survival. There was a statistically significant 1.9% decrease in survival for each additional year of age (p = 0.03). This statistical significance, however, was not maintained when adjustments were made for comorbidity grade (p = 0.07). The inclusion of age as a comorbid condition led us to reclassify 18% of our patients from the low- to the high comorbidity group. Consequently, the age-adjusted CCI survival fell from a relative risk of 1.57 before age adjustment to 1.36 afterward. The high comorbidity seen in the elderly patients was not an age-dependent reason for lower tumor-specific survival.

Discussion

The TNM classification scheme is a useful system to describe tumor characteristics and predict survival. However, TNM does not take into account important patient-related factors such as the host's functional status, comorbidities, immunocompetence, and symptom severity. [11,12] Weymuller has suggested that comorbid conditions be included among the prognostic variables in multiinstitutional trials. [13]

Two comorbidity indices have previously been validated for use in head and neck cancer for assessing the impact of comorbid conditions by number and severity. Previous studies have shown that the Kaplan-Feinstein comorbidity index predicts survival in patients with laryngeal cancer. [5] However, the Charlson comorbidity index has not been previously applied to a cohort of patients with laryngeal cancer. Singh et al compared the CCI to the Kaplan-Feinstein index in a cohort of patients younger than 45 who had head or neck cancer. [6] Both indices were found to be prognostic indicators of tumor-specific survival. However, the CCI was more easily applied.

In this study, the CCI was successfully applied to a cohort of patients with laryngeal cancer. Tumor staging did not predict survival until the confounding effects of comorbidity were considered (comorbidity entailed medical illnesses only). Standard cancer treatment plans do not emphasize the confounding effects of comorbidity on survival. Before a treatment plan is chosen for a patient diagnosed with cancer, the disease is assessed on the basis of tumor size, nodal disease, and metastasis, and the prognosis is based on this classification scheme. By factoring comorbidity into the initial staging, the physician can make a more accurate prediction of survival.

By assessing a patient's medical history and examination, the process of assigning a CCI score is simple. Patients can be placed into either a low- or high-grade comorbidity group. Tumor-specific survival can be predicted after determining the comorbidity grade.

Charlson suggested that with longitudinal studies, both age and comorbidity should be taken into account as predictors of death. [9] Older patients have more overall comorbidity. By adding age to the comorbidity index, we were able to reclassify 18% of our patients from low- to high-grade comorbidity. Even so, incorporating age as an additional comorbid condition did not improve the prognostic ability of the CCI. In conclusion, this study suggests that the CCI is an independent predictor of tumorspecific survival. Comorbidity may serve as an indicator of the host's immunologic status. [14] This further supports the concept that comorbidity may have an impact on the behavior of the tumor. Further studies are necessary to confirm the influence of comorbidity on survival, and to combine its effects with the TNM staging system for a more accurate prediction of survival.

References

(1.) Ganz PA. Age and gender as factors in cancer therapy. Clin Geriatr Med 1993 9: 145-55.

(2.) Manton KG, Wrigley JM, Cohen HJ, Woodbury MA. Cancer mortality, aging, and patterns of comorbidity in the United States: 1968 to 1986. J Gerontol 1991;46:S225-34.

(3.) McGuirt WF, Davis SP. Demographic portrayal and outcome analysis of head and neck cancer surgery in the elderly. Arch Otolaryngol Head Neck Surg 1995;121;150-4.

(4.) Kowalski LP, Franco EL, deAndrade Sobrinho J, et al. Prognostic factors in laryngeal cancer patients submitted to surgical treatment. J Surg Oncol 1991;48:87-95.

(5.) Piccirillo JF, Wells CK, Sasaki CT, Feinstein AR. New clinical severity staging system for cancer of the larynx: Five-year survival rates. Ann Otol Rhinol Laryngol 1994:103:83-92.

(6.) Singh B, Bhaya M, Stern J, et al. Validation of the Charlson comorbidity index in patients with head and neck cancer: A multiinstitutional study. Laryngoscope 1997:107:1469-75.

(7.) Nusbaum NJ. How do geriatric patients recover from surgery? South Med J 1996;89:950-7.

(8.) Singh B, Alphonso A, Shaha A, et al. Outcome differences in younger and older patients with laryngeal cancer. Presentation at the Annual Meeting of the Society of Head and Neck Surgeons. Cancun, Mexico, April 1997.

(9.) Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987:40:373-83.

(10.) American Joint Committee on Cancer. Manual for Staging of Cancer. 4th ed. Philadelphia: J.B. Lippincott, 1992.

(11.) Ferlito A, Harrison DF, Bailey BJ, DeSanto LW. Are clinical classifications for laryngeal cancer satisfactory? Ann Otol Rhinol Laryngol 1995;104:741-7.

(12.) Piccirillo JF Purposes, problems, and proposals for progress in cancer staging. Arch Otolaryngol Head Neck Surg 1995;121:145-9.

(13.) Weymuller EA Jr. Clinical staging and operative reporting for multi-institutional trials in head and neck squamous cell carcinoma. Head Neck 1997;19:650-8.

(14.) Satariano WA. Aging, comorbidity, and breast cancer survival: An epidemiological view. Adv Exp Med Biol 1993;330:l-11.

(a.) Department of Otolaryngology, State University of New York Health Science Center at Brooklyn.

             Disease-specific survival rates for 152 patients
              with squamous cell carcinoma of the larynx [*]

             Low        High      Combined
         Comorbidity Comorbidity Comorbidity
Survival     (%)         (%)         (%)
1 year       78          44          73
2 years      63          34          59
3 years      54          32          51
4 years      48          32          45
5 years      47          32          44


(*.)Median survival was 41 months for patients with a low comorbidity index
(n=126) and 8 months for those with a high index (n=26). For all patients
combined, median survival was 37 months.
       Multivariate analysis of factors associated with survival for
          squamous cell carcinoma of the larynx in 152 patients

                       Relative 95% Confidence
Factor                   Risk      Interval    p value
High comorbidity         1.57     1.18-2.08     0.002
(relative to low)
Tumor stage              1.34     1.04-1.73     0.025
(relative to the mean)