Outcome differences in younger and older patients with laryngeal cancer: A retrospective case-control study

Outcome Differences in Younger and Older Patients With Laryngeal Cancer: A Retrospective Case-Control Study B h u v a n e s h Singh, MD, * A n t o n i o Alfonso, MD, f Steven Sabin, MD, * A s h o k Poluri, MD, * A s h o k R. Shaha, MD, * K r i s n a m u r t i S u n d a r a m , MD, * a n d F r a n k E. Lucente, MD* Purpose: Younger or older age has a significant impact on the outcome of patients with head and neck cancer. However, the data regarding outcomes based on age are conflicting. The aim of this article is to determine the impact of age on the outcome of laryngeal cancer. Materials and Methods: A retrospective study was performed including all patients with squamous cell carcinoma of the larynx for over a 9-year period. The patients were divided into 3 groups based on age. The younger age group included patients 40 years of age and younger, the older group included patients over 80 years of age, and the remaining patients served as the control group. Descriptive statistics were used to summarize study data. Nonparametric quantitative and qualitative analyses were performed using the Mann-Whitney U test and Fisher's exact test, respectively. Survival analysis was performed using the generalized Wilcoxon test. The Cox proportional hazards model was used for multivariate analysis. Results: Of the 209 patients with laryngeal carcinoma presenting to our institution over a 9-year period, 20 (10%) were -<40 years and 15 (7%) were ->80 years of age. No differences in TNM stage at presentation, treatment, or treatment-associated complications were observed based on age. However, younger patients were less likely to report tobacco (50%; P < .001) or alcohol (57%; P = .03) use and more likely to have human immunodeficiency virus infection (50%; P < .001). Older patients showed a trend toward having a worse baseline medical status. Recurrence was significantly more common in older patients (P = .02) and cause-specific survival significantly poorer for both younger and older patients (P = .0O2). Conclusions: The presentation and outcome of laryngeal cancer is influenced by the age at presentation. The differences may be related exact reason for the observed survival differences needs to be determined. (Am J Otolaryngol 2000;21:92-97. Copyright © 2000 by W.B. Saunders Company)

Age has a significant impact on the development and progression of cancer. 1,2 Although several studies have shown outcome differences in both young and older patients with head and neck squamous cell carcinoma (HNSCC), the impact of age on presentation

From the *Departments of Otolaryngology and l-Surgery, State University of New York--Health Science Center at Brooklyn and The Long Island College Hospital, Brooklyn, NY. Presented at the 43rd Annual Meeting of the Society for Head and Neck Surgery, Cancun, Mexico, April 10-12, 1997. Address reprints requests to Bhuvanesh Singh, MD, Head and Neck Service, 1275 York Ave, New York, NY 10021. Copyright © 2000 by W.B. Saunders Company 0196-0709/00/2102-0004510.00/0 92

and outcome remains conflicting. 3-12The inclusion of multiple histologies, anatomic locations, and/or limitations in sample size have confounded the findings in the majority of these studies. 9 In addition, the control group in many studies has included the entire age spectrum, not accounting for differences at polarized ends of the spectrum. Only 2 studies to date have focused on laryngeal cancer in younger patients, and no studies have specifically addressed this issue in older patients. 11,.3 The present study was undertaken to analyze differences in the management and outcome of head and neck cancer in younger and older patients, at a single anatomic site (larynx) and to identify factors responsible for these differences.

American Journal of Otolaryngology,Vo121, No 2 (March-April),2000: pp 92-97

OUTCOME DIFFERENCES IN LARYNX CANCER

93

TABLE1. Outcome Characteristics of Patients With Laryngeal Cancer by Age Group

was determined for all patients. Tumor information, including anatomic location and TNM stage, were determined from review of the tumor maps and operative records. Tumor staging was based on the criteria established by the American Joint Committee on Cancer (AJCC). 14 Treatment information, including type of treatment, incidence of treatmentassociated complications, radiation breaks, and radiation noncompletion was also ascertained. Cause-specific survival was determined as the period of time between the onset of treatment and the date of the last follow-up. For survival analysis, the survival data was included to the point that the patient was lost to follow-up, died, or lived to the end of the study. Survival information was censored for patients lost to follow-up during the study period, died of causes unrelated to cancer, or lived beyond the end of the study. The development of recurrent and/or second primary cancer was also determined over the follow-up period. Statistical significance was accepted as a 2-tailed P value equal to or less than .05. Fisher's exact test was used for exact nonparametric inference. Survival curves were estimated using the Kaplan-Meier (product-limit) analysis, allowing the maximal use of censored observations. Survival comparisons were performed using the generalized Wilcoxon test, a distribution-free method for comparing survival curves.

<41 yrs

41-79 yrs

>79 yrs

P Value

Sample size 20 (9.5%) 174 (83.3%) 15 (7.2%) #= Median follow-up 23.4 mos 25 mos 13 mos NSc Recurrence 7/20 (35%) 45/174 (26%) 9/15 (60%) ~02A Second primary 0 14/174 (8%) 2/15 (13%) NSA Median survival 45 mos 79 mos 13 mos .002 B NOTE. A, Fisher's exact test; B, Generalized Wilcoxon test for survival curves; c, Mann-Whitney U test; NS, not significant.

METHODS

The study population included patients with biopsy-proven squamous cell carcinoma of the larynx, presenting to 2 tertiary care centers over a 9.5-year period beginning lanuary 1, 1985. Patients with prior treatment for head and neck cancer or inadequate documentation were excluded from the study. The study population was divided into 3 groups based on age at presentation. Group 1 included patients 40 years of age and younger, group 2 included those between the age of 41 and 79 years, and group 3 included patients 80 years of age and older. The study data was obtained through the review of tumor registry abstracts, clinical records, and pathology reports. Demographic data, including the age at presentation, gender, and ethnicity, was recorded for each case. Pretreatment patient characteristics, including history of tobacco or alcohol use, presence of h u m a n immunodeficiency virus infection (HIV), presence of anemia (hematocrit less than 37% for men and 34% for women), albumin level, and the need for tracheostomy TABLE2.

RESULTS

The study population included 209 patients ranging from 20 to 92 years, with a median age of 58 years. Twenty patients (9.5%) were included in group 1; 174 (83.3%)were included in group 2; and 15 (7.2%) were included in group 3. The patient characteristics by group

Treatment Characteristics of Patients With Laryngeal Cancer by Age Group Group I <41 yrs

Sample size No treatment Treatment-associated complications (n = 202*) Pre-treatment tracheostomy Radiation break (n = 139") Incomplete radiation treatment (n = 139")

20 (9.5%) 0 5/20 (25%) 5 (25%) 2/9 (22%) 1/9 (11%)

Group 2 41-79 yrs 174 5 43/169 43 18/121 11/121

(83.3%) (3%) (25%) (25%) (15%) (9%)

NOTE. A, Fisher's exact test; *, number of patients with available data; NS, not significant.

Group 3 >79 yrs

P Value

15 (7.2%) 2 (13%) 3/13 (23%) 5 (33%) 2/9 (22%) 2/9 (22%)

4= NSA NSA NSA NSA NSA

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SINGH ET AL

DISCUSSION Unknown

Transglottic

Subglottic

Glottic

Supraglottic

0

10

20

30

40

50

60

Percent

Fig 1. Location of laryngeal lesions by age group. (Fisher's e x a c t test; P > .05,)

are given in Table 1. The patients were similar in all study characteristics, with the exception that group i patients had a lower prevalence of tobacco and alcohol use and a higher prevalence of HIV infection. In addition, older patients (group 3) showed a trend toward a higher American Society of Anesthesiologists stage, with the median stage being 3. The tumor characteristics are given in Table 2. No difference in tumor stage, pathological grading, or anatomic location was observed between the groups (Fig 1). Only 7 patients (3.3%) in the study population did not receive any treatment and were equally distributed between the groups. Treatment characteristics of patients undergoing treatment are outlined in Table 3. No significant difference in the primary treatment modali~y was observed between the groups, although a trend toward decreased treatment aggressiveness, for medical reasons, was noted in older patients. Several significant differences in outcome were observed (Table 4). The recurrence rate was significantly higher for older patients (group 3). In addition, the survival rate was significantly poorer for both younger and older patients (Fig 2). TABLE 3,

Patients with HNSCC, at either end of the age spectrum, have significant alterations in cancer presentation, behavior, and outcome. Although the exact reasons for these differences remain unclear, several trends have become evident based on our data and a review of the literature. Patients less than 40 years of age account for only 1% to 4.3% of all patients with head and neck squamous cell carcinoma. 7,9,15 However, as reported by Lipkin et al 6 and confirmed in this article, younger patients account for approximately 10% of HNSCC in the lower socioeconomic strata. In addition, reports have shown a trend toward increased prevalence of Afro-American patients in the younger HNSCC population. 6,16 Lipkin reported that 67% of younger patients were Afro-American, similar to the 55% rate reported by Slotman. 6,16 Several reports have also indicated an equalization of the male to female ratio in the young HNSCC population, ranging from 1 to 2:1. Lurid 7 suggested that this ratio represents the naturally occurring sex distribution of head and neck cancer. This observation was prompted by the lack of association of carcinogen exposure in the development of HNSCC in young patients. This lack of importance of carcinogen exposure has been observed in the majority of reports in the literature. 3,4,8,9,11 However, one report that included mainly Afro-Americans and patients of lower socioeconomic strata, suggested there was an equal or increased prevalence of tobacco/alcohol usage in this age group. 16 This is in contrast to our findings in a similar study population, which showed a significantly lower prevalence of tobacco/alcohol exposure. In addition, younger patients in our study population had an increased prevalence of HIV infection (50% of cases). The increased rate of HIV

Tumor Characteristics of Patients With Laryngeal Cancer by Age Group

Sample size Tumor size (median) TNM stage (median) Pathological grade (median) Most common tumor location

<41 yrs

41-79 yrs

>79 yrs

20 (9.5%) T3 III Moderately differentiated Glottic (40%)

174 (83.3%) T2 III Moderately differentiated Glottic (46%)

15 (7.2%) T2 II Moderately differentiated Supraglottic (60%)

NOTE: A, Fisher's exact test; B, Kruskal-Wallis analysis of variance; NS, not significant.

P Value NSB NSB NS B

NS A

OUTCOME DIFFERENCES IN LARYNX CANCER

95

TABLE4. TumorCharacteristics by Age Group

Sample size Male gender Tobacco use (n = 179") Alcohol use (n = 151") HIV positive ASA stage (median) Anemia (n = 181") Albumin level (median; n = 108") Race (n = 199")

<41 yrs

41-79 yrs

>79 yrs

PValue

20 (9.5%) 13/20 (65%) 8/16 (50%) 8/14 (57%) 10/20 (50%) 2 3/18 (17%) 3.9

174 (83.3%) 139/174 (80%) 143/151 (95%) 110/127 (87%) 6/174 (3.4%) 2 43/153 (28%) 4.0

15 (7.2%) 14/15 (93%) 11/12 (92%) 0/15 3 4/10 (40%) 3.7

#= NSA <.001A .03A <.001A NS B NSA NS c

16 (80%) 2 (10%) 2 (10%)

97 (56%) 14 (24%) 53 (30%)

5 (33%) 2 (24%) 8 (53%)

NSA

Afro-American Caucasian Hispanic/other

9/10 (90%)

A Fisher's Exact test; B Kruskal-Wallis analysis of variance; c, Mann-Whitney U test; *, Number of patients with available data; NS, not significant. NOTE:

infection has been suggested in other reports, but its implications for the general population have yet to be determined27,18 Many authors have shown an increase in advanced TNM stage and more anaplastic disease in younger patients, relating changes in survival to these alterations. 3,4,19In contrast, other reports suggest that these patients present with earlier stage lesions and have improved survival. 5,8 In our study population, the stage at presentation was similar for all age groups, but the survival was significantly lower for younger patients compared with the stand a r d age- population. It is important to note that the presence of HIV infection has a significant impact on outcome that is unique to the younger population. Consequently, AJCC staging parameters appear to have less prognostic significance in the young patients, with even early stage cancers portending a poor outcome.

and

Age Group >40 <80yrs 1 . 0 0

o

:2YrsuS

,

i

10

20

TM

r

.80

.60

.40

t

.20 -

.00 0

30

40

50

60

~ 4 S

Fig 2. Cause-specific survival by age group. (Generalized Wilcoxon test for survival curves; P = .002.)

R e p o r t s have suggested that the increased cancer aggressiveness in younger patients may reflect an altered tumor or host biology. 1° This theory is supported by the lack on importance of carcinogen exposure, with one study reporting a complete absence of tobacco/alcohol exposure in patients younger than 30 years of age. 4 The theory is further substantiated by the work of Schantz et al, 1° which showed that young adult with HNSCC had a higher susceptibility to mutagen-induced chromosomal damage, suggesting a predisposition to cancer development. Furthermore, the increased prevalence of HIV infection in young patients with HNSCC may also contribute to both cancer development and poorer outcomes./7,~8 The 7.2% rate of HNSCC, in patients over 80 y e a r s of age in this study, is similar to that for the younger age group. However, studies have shown that the age-specific incidence of cancer is actually higher in older patients than all other age groups) The outcome of these older patients is especially poor with higher rates of recurrence and poorer survival. Although a trend toward a higher proportion of supraglottic cancer was seen in older patients, the difference was not significant. Moreover, because this finding is not supported by population based studies, it likely represents random variations in presentation patterns based on age in our study population. It a p p e a r s that t h e r e a s o n for the poorer outcome in older patients centers around the impact of host factors, mainly comorbid diseases. This is indirectly suggested in our study, with elderly patients showing a trend toward

96

higher anesthesia risk. Studies by Kowalski et al 2°,21 also showed that survival was most often related to comorbid conditions, rather than cancer, in older patients. In addition, our previous work in younger patients with head and neck cancer has shown that comorbidity impact on tumor-specific outcomes. 12,22 It is likely that the findings of this study extend to older patients. Unfortunately, m a n y physicians have suggested that advanced age is a direct contraindication to aggressive treatment of head and neck cancer. This was evident in our study population, in which no treatment was given to 13% of the patients older than 79 years of age in contrast to only 3% of the remaining populations. This therapeutic nihilism may not be warranted because the elderly population did not have a high risk for the development of complications or treatment-associated mortality. 23 However, it is important to understand that when they occur, complications tend to be more severe in the older population. In a study by McGuirt and Davis, 24 major complications including death accounted for 31% of all complications in patients ->80 years of age. However, as was the case in a study of younger patients, complications in older patients likely relate to the presence and severity, of comorbid conditions rather than age itself. Accordingly, the surgical treatment of head and neck cancer in the elderly requires early detection and aggressive management of complications. Modification of treatment should be guided by the presence and severity of comorbid conditions rather than age. The results of this study require some qualifications. The retrospective design has known limitations centering around the availability and accuracy of the medical records. In addition, the follow-up is limited, and treatment factors could not be adequately controlled. A prospective, longitudinal study and molecular biological evaluations are likely to provide more insight into the age-associated differences in laryngeal cancer. Nonetheless, the present data suggests that younger and older patients may need to be evaluated differently from other laryngeal cancer patients. Younger patients may have genetically distinct cancers, given that they have a lower prevalence of carcinogen exposure and a higher prevalence

SINGH ET AL

of HIV infection. These patients also have a poorer survival, even with aggressive treatment. Similarly, older patients also have significantly poorer survival and increased recurrence rates. However, cancer outcome in older patients is likely to be influenced by host factors rather than alterations in tumor biology. Because these patients do not have an increased incidence of treatment associated complication, radiation breaks, or noncompletion of radiation, age alone should not alter the selection of appropriate treatment. REFERENCES 1. Crawford J, Cohen H: Relationship of cancer and aging. Clin Geriatric Med 3:419-431, 1987 2. Hutchins L, Lipschitz D: Cancer, clinical pharmacology, and aging. C]in Geriatric Med 3:483-503, 1987 3. Byers R: Squamous cell carcinoma of the oral tongue in patients less than 40 years of age. Am J Surg 130:475478, 1975 4. Carniol P, Freid M: Head and neck carcinoma in patients under 40 years of age. A n n Otol Rhinol Laryngol 91:152-155, 1982 5. Lefebvre J, Vankemmel B, Adenis L, et al: Carcinomas of the upper aerodigestive tract before age 40 (excluding children). Apropos of 100 cases. A n n Otolaryngol Chit Cerviofac 104:89-92, 1987 6. Lipkin A, Miller R, Woodson G: Squamous cell carcinoma of the oral cavity, pharynx, and larynx in young adults. Laryngoscope 95:790-793, 1985 7. Lund V, Howard D: Head and neck cancer in the young: A prognostic conundrum? J Laryngol Oto1104:544588, 1990 8. McGregor G, Davis N, Robins R: Squamous cell carcinoma of the tongue and lower oral cavity in patients under 40 years of age. Am J Surg 1983:88-92, 1983 9. Schantz S, Byers R, Goefpert H, et al: The implication of tobacco use in the young adult with head and neck cancer. Cancer 62:1374-1380, 1988 10. Schantz S, Hsu T, Ainslie N, et al: Young adults with head and neck cancer express increased susceptibility to mutagen-induced chromosomal damage. JAMA 262:3313-3315, 1989 11. Shvero ], Hadar T, Segal K, et al: Laryngeal carcin o m a in patients 40 years of age and younger. Cancer 60:3092-3096, 1987 12. Singh B, Bhaya M, Zimbler M, et al: Impact of co-morbidity on the outcome of young patients with head and neck squamous cell carcinoma. Head Neck 20:1-7, 1998 13. Webber P: Carcinoma of the larynx in the young population (With reference to other head and neck sites). J Laryngol Oto198:901-904, 1984 14. American Joint Committee on Cancer: Manual for Staging of Cancer (ed 2). Philadelphia, PA, Lippincott, 1983 15. Mendez P, Maves MD, Panje W: Squamous cell carcinoma of the head and neck in patients under 40 years of age. Arch Otolaryngol 111:762-764, 1985 16. Slotman G, Swaminathan A, Rush B: Head and neck cancer in a young age group, high incidence in young patients. Head Neck 5:293-298, 1983

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17. Singh B, Balwally A, Shaha A, et al: Upper aerodigestive tract squamous cell carcinoma: The h u m a n immunodeficiency virus connection. Arch Otolaryngol Head Neck Surg 122:639-643, 1996 18. Roland J, Rothstein S, Mitta] K, et al: Squamous cell carcinoma in HIV-positive patients under age 45. Laryngoscope 103:509-511, 1993 19. Son Y, Kapp D: Oral cavity and oropharyngeal cancer in a younger population: Review of the literature and experience at Yale. Cancer 55:441-444, 1985 20. Kowalski L, Franco E, Sobrinho JA, et al: Prognostic factors in laryngeal cancer submitted to surgical treatment. J Surg Onco148:87-95, 1991

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21. Kowalski L, Alcantara P, Magrin J, et al: A casecontrol study on complications and survival in elderly patients undergoing major head and neck surgery. A m J Surg 168:485-490, 1994 22. Singh B, Bhaya M, Stern J, et al: Validation of the Charlson co-morbidity index in head and neck cancer patients: A multi-institutional study. Laryngoscope 107: 1469-1475, 1997 23. Jun M, Strong E, Saltzman E, eta]: Head and neck cancer in the elderly. Head Neck 5:376-382, 1983 24. McGuirt W, Davis SP III: Demographic portrayal of outcome analysis of head and neck cancer surgery in the elderly. Arch Otolaryngol Head Neck Surg 121:150-154, 1995