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© 2001 American Society for Clinical Oncology Synchronous and Metachronous Squamous Cell Carcinomas of the Head and Neck Mucosal Sites . ErkalFrom the Department of Radiation Oncology, Inönü University Faculty of Medicine, Malatya, Turkey; and Departments of Radiation Oncology and Otolaryngology, University of Florida College of Medicine, Gainesville, FL. Address correspondence to William M. Mendenhall, MD, Department of Radiation Oncology, University of Florida Health Science Center, PO Box 100385, 2000 SW Archer Road, Gainesville, FL 32610-0385; email: mendewil{at}shands.ufl.edu
PURPOSE: The present study presents the experience at the University of Florida with synchronous and metachronous squamous cell carcinomas of the head and neck mucosal sites. PATIENTS AND METHODS: This study included 1,112 patients with squamous cell carcinomas of the oropharynx, hypopharynx, and supraglottic larynx treated with radiation therapy with curative intent from 1964 to 1997. All patients had follow-up for at least 2 years. No patients were lost to follow-up. RESULTS: The overall survival rate was 45% and the disease-specific survival rate was 67% at 5 years after initial diagnosis of carcinoma of the head and neck mucosal sites. Seventy-seven patients (7%) presented with synchronous carcinomas of the head and neck mucosal sites and 103 patients (9%) developed metachronous carcinomas of the head and neck mucosal sites at 0.6 to 21.7 years (median, 3.6 years). The overall survival rate was 31%, and the disease-specific survival rate was 50% at 5 years after metachronous carcinomas of the head and neck mucosal sites. Seven patients (1%) developed metachronous carcinomas of the thoracic esophagus at 1 to 11.1 years (median, 2.8 years), 15 patients (1%) presented with synchronous carcinomas of the lung, and 83 patients (7%) developed metachronous carcinomas of the lung at 0.6 to 17.6 years (median, 3.5 years). CONCLUSION: Development of synchronous and metachronous squamous cell carcinomas of the head and neck mucosal sites are in part responsible for failure to improve overall survival rates for patients with squamous cell carcinomas of the head and neck mucosal sites, justifying rigorous follow-up and studies on chemoprevention.
ADVANCES IN THE management of squamous cell carcinomas of the head and neck mucosal sites have improved disease control rates and have translated into improved disease-specific survival rates. Despite improved disease-specific survival rates, the development of synchronous and metachronous squamous cell carcinomas of the head and neck mucosal sites occurs in a significant proportion of patients and is at least partially responsible for failure to improve overall survival rates.1-3 This study presents the experience at the University of Florida with synchronous and metachronous squamous cell carcinomas of head and neck mucosal sites (for patients with squamous cell carcinomas of the head and neck mucosal sites).
This study included 1,112 patients with previously untreated squamous cell carcinomas of the oropharynx, hypopharynx, and supraglottic larynx treated with radiation therapy (RT) with curative intent at the University of Florida from 1964 to 1997.4-9 All patients had follow-up for at least 2 years, and 956 patients (86%) had follow-up for at least 5 years. No patient treated with planned continuous-course RT with curative intent during this time period was excluded. No patients were lost to follow-up. Eight hundred eighty-two patients (79%) were male, and 230 patients (21%) were female. Their ages ranged from 26 to 90 years (median, 61 years). One thousand eleven patients (91%) were white, and 101 patients (9%) were black. Eight hundred thirty-seven patients (75%) had a history of tobacco use, 75 patients (7%) had no history of tobacco use, and the history of tobacco use was not specified in 200 patients (18%). Six hundred twenty patients (56%) had a history of alcohol use, 292 patients (26%) had no history of alcohol use, and the history of alcohol use was not specified in 200 patients (18%). There were 717 patients who had carcinomas of the oropharynx. The distribution of carcinomas of the oropharynx according to site of involvement was as follows: base of tongue, 215 patients (30%); tonsillar fossa, 257 patients (36%); anterior tonsillar pillar, 135 patients (19%); posterior tonsillar pillar, eight patients (1%); and soft palate, 102 patients (14%). There were 192 patients with carcinomas of the hypopharynx. The distribution of carcinomas of the hypopharynx according to site of involvement was as follows: pyriform sinus, 97 patients (51%); lateral pharyngeal wall, 27 patients (14%); and posterior pharyngeal wall, 68 patients (35%). There were 203 patients with carcinomas of the supraglottic larynx. The distribution of carcinomas of the supraglottic larynx according to site of involvement was as follows: suprahyoid epiglottis, 47 patients (23%); infrahyoid epiglottis, 73 patients (36%); aryepiglottic fold, 28 patients (14%); false vocal cord, 49 patients (24%); arytenoid, five patients (2%); and pharyngoepiglottic fold, one patient (1%). All patients were staged according to the 1983 American Joint Committee on Cancer staging system.10 Three hundred eighty-two patients (34%) had limited disease (stage I and stage II), and 730 patients (66%) had advanced disease (stage III and stage IV). Seven hundred thirty-two patients (66%) were treated with RT alone, and 380 patients (34%) were treated with RT followed by planned neck dissection. Carcinomas presenting at the time of RT or within 0.5 years after RT were defined as synchronous carcinomas, and carcinomas developing later than 0.5 years after RT were defined as metachronous carcinomas.11 Cancer developing at the site of the initial malignancy at any time after treatment was scored as a recurrence, regardless of the length of follow-up. The rates of developing metachronous carcinomas, overall survival, and disease-specific survival were calculated using the product-limit method.12 Significance levels among the rates were calculated using the log-rank test.13 Multivariate analyses were performed using the forward step-wise log-rank tests of association of covariates.14 Variables evaluated in univariate analyses and multivariate analyses included sex, age (continuous variable), race, history of tobacco use, history of alcohol use, head and neck mucosal site, and extent of disease. Two hundred patients for whom history of tobacco use and history of alcohol use were not specified were excluded from univariate analyses and multivariate analyses.
Overall survival rates after initial carcinomas according to initial head and neck mucosal sites are shown in Fig 1. The overall survival rate at 5 years was 48% after carcinomas of the oropharynx, 33% after carcinomas of the hypopharynx, and 46% after carcinomas of the supraglottic larynx. Disease-specific survival rates after initial carcinomas according to initial head and neck mucosal sites are shown in Fig 2. Disease-specific survival at 5 years was 68% after carcinomas of the oropharynx, 61% after carcinomas of the hypopharynx, and 70% after carcinomas of the supraglottic larynx.
There were 77 patients (7%) presenting with synchronous carcinomas of the head and neck mucosal sites. Distribution of synchronous carcinomas according to initial head and neck mucosal sites was as follows: oropharynx, 54 patients (70%); hypopharynx, 18 patients (23%); and supraglottic larynx, five patients (7%). Distribution of synchronous carcinomas according to involved head and neck mucosal sites was as follows: oral cavity, 27 patients (35%); oropharynx, 18 patients (23%); hypopharynx, 17 patients (22%); glottic larynx, nine patients (12%); supraglottic larynx, five patients (7%); and cervical esophagus, one patient (1%). Forty-seven patients (61%) with synchronous carcinomas of the head and neck mucosal sites had limited disease, and 30 patients (39%) had advanced disease. There were 103 patients (9%) who developed metachronous carcinomas of the head and neck mucosal sites at 0.6 to 21.7 years (median, 3.6 years). The distribution of metachronous carcinomas according to initial head and neck mucosal sites was as follows: oropharynx, 79 patients (77%); hypopharynx, 17 patients (16%); and supraglottic larynx, seven patients (7%). Distribution of metachronous carcinomas according to involved head and neck mucosal sites was as follows: oral cavity, 44 patients (43%); oropharynx, 17 patients (16%); hypopharynx, 20 patients (19%); glottic larynx, two patients (2%); supraglottic larynx, 10 patients (10%); and cervical esophagus, 10 patients (10%). Fifty-seven patients (55%) with metachronous carcinomas of the head and neck mucosal sites had limited disease, and 46 patients (45%) had advanced disease. The rates of developing metachronous carcinomas according to initial head and neck mucosal sites are shown in Fig 3. The rate of developing metachronous carcinomas at 5 years was 11% after carcinomas of the oropharynx, 12% after carcinomas of the hypopharynx, and 3% after carcinomas of the supraglottic larynx. Multivariate analysis revealed that sex (P = .02), history of alcohol use (P = .0007), and head and neck mucosal site (P = .04) significantly affected the rate of developing metachronous carcinomas of the head and neck mucosal sites. Age (P = .49), race (P = .80), history of tobacco use (P = .28), and extent of disease (P = .33) did not significantly affect the rate of developing metachronous carcinomas of the head and neck mucosal sites in multivariate analysis.
Absolute survival rates after metachronous carcinomas according to involved head and neck mucosal sites are shown in Fig 4. The absolute survival rate at 5 years was 54% after carcinomas of the oral cavity, 29% after carcinomas of the oropharynx, 0% after carcinomas of the hypopharynx, 50% after carcinomas of the glottic larynx, 0% after carcinomas of the supraglottic larynx, and 0% after carcinomas of the cervical esophagus. Multivariate analysis revealed that race (P = .0001), history of tobacco use (P = .03), and extent of disease (P = .02) significantly affected the rate of overall survival. Sex (P = .56), age (P = .41), history of alcohol use (P = .36), and head and neck mucosal site (P = .99) did not significantly affect the rate of overall survival in multivariate analysis.
Disease-specific survival rates after metachronous carcinomas according to involved head and neck mucosal sites are shown in Fig 5. Disease-specific survival rates at 5 years were 80% after carcinomas of the oral cavity, 26% after carcinomas of the oropharynx, 29% after carcinomas of the hypopharynx, 100% after carcinomas of the glottic larynx, 14% after carcinomas of the supraglottic larynx, and 0% after carcinomas of the cervical esophagus. Multivariate analysis revealed that race (P = .0001) and history of tobacco use (P = .03) significantly affected the disease-specific survival rates. Sex (P = .80), age (P = .50), history of alcohol use (P = .78), head and neck mucosal site (P = .57), and extent of disease (P = .12) did not significantly affect the disease-specific survival rate in multivariate analysis.
Seven patients (1%) developed metachronous carcinomas of the thoracic esophagus at 1 to 11.1 years (median, 2.8 years). The distribution of metachronous carcinomas of the thoracic esophagus according to initial head and neck mucosal site was as follows: oropharynx, five patients (71%); and hypopharynx, two patients (29%). Fifteen patients (1%) presented with synchronous carcinomas of the lung, and 83 patients (7%) developed metachronous carcinomas of the lung at 0.6 to 17.6 years (median, 3.5 years). In cases where it was unclear whether the lung cancer represented a distant metastasis as opposed to a second primary cancer, the malignancy was scored as a distant metastasis. The distribution of synchronous and metachronous carcinomas of the lung according to initial head and neck mucosal sites was as follows: oropharynx, 58 patients (59%); hypopharynx, 13 patients (13%); and supraglottic larynx, 27 patients (28%).
Billroth15 described the concept of multiple neoplasms in 1889. Warren and Gates11 defined the criteria classifying multiple neoplasms in 1932, and Moertel16 defined the criteria for distinguishing multiple neoplasms from multicentric neoplasms in 1966. In 1953, Slaughter et al17 proposed the process of "field cancerization," referring to continuous exposure of the upper aerodigestive tract epithelium to unknown carcinogenic agents, in an attempt to define carcinogenesis of multiple neoplasms of the upper aerodigestive tract. Tobacco and alcohol have been demonstrated as carcinogenic agents involved in field cancerization of the upper aerodigestive tract epithelium, leading to pronounced genetic changes responsible for extensive histologic changes ultimately resulting in synchronous and metachronous neoplasms.18 For patients with carcinomas of the head and neck mucosal sites, the rates of developing synchronous and metachronous carcinomas range from 8% to 21%.2,3,19-21 Parker and Enstrom21 reported on 2,151 patients with carcinomas of the head and neck mucosal sites treated with surgery alone, RT alone, or surgery in combination with RT. Synchronous and metachronous carcinomas developed in 8% of patients. Cooper et al2 reported on 928 patients with carcinomas of the head and neck mucosal sites treated with RT alone. Synchronous and metachronous carcinomas developed in 12% of patients, and 18% of metachronous carcinomas developed in head and neck mucosal sites. Schwartz et al3 reported on 851 patients with carcinomas of the head and neck mucosal sites treated with RT alone. Synchronous carcinomas developed in 8% of patients, metachronous carcinomas developed in 11% of patients, and 31% of metachronous carcinomas developed in head and neck mucosal sites. In the present study, synchronous carcinomas developed in 8% of patients, metachronous carcinomas developed in 17% of patients, and 53% of metachronous carcinomas developed in head and neck mucosal sites. For patients with carcinomas of the head and neck mucosal sites, the rates of developing synchronous and metachronous carcinomas of the head and neck mucosal sites correlate with initial head and neck mucosal sites.3,22,23 Roberts et al22 reported on 218 patients with carcinomas of the glottic larynx treated with RT alone or surgery in combination with RT. Synchronous and metachronous carcinomas of the head and neck mucosal sites developed in 2% of patients. Fijuth et al23 reported on 600 patients with carcinomas of the oral cavity and oropharynx treated with RT alone. Synchronous and metachronous carcinomas of head and neck mucosal sites developed in 12% of patients. In the present study, synchronous and metachronous carcinomas of the head and neck mucosal sites developed in 10% of patients with carcinomas of the oropharynx, in 18% of patients with carcinomas of the hypopharynx, and in 6% of patients with carcinomas of the supraglottic larynx. Disease control and survival rates after synchronous and metachronous carcinomas of the head and neck mucosal sites are influenced by involved head and neck mucosal sites and extent of disease.24 Metachronous carcinomas of the lung and thoracic esophagus are associated with advanced disease, correlating with poor disease control and survival rates.3,25 On the contrary, metachronous carcinomas of the head and neck mucosal sites, the oral cavity in particular, are associated with improved disease control and survival rates on early detection of limited disease.3,23 In the present study, 55% of metachronous carcinomas of head and neck mucosal sites were associated with limited disease, correlating with a 50% disease-specific survival rate at 5 years. Development of synchronous and metachronous squamous cell carcinomas of head and neck mucosal sites is, in part, responsible for failure to improve overall survival rates for patients with squamous cell carcinomas of head and neck mucosal sites. Rigorous follow-up is indicated after treatment of the initial cancer so that second primary cancers can be detected while they are limited and treated with a high likelihood of cure. Although there is considerable interest in developing effective, nontoxic chemoprevention drugs to reduce the risk of developing second cancers, to date there are no agents that are indicated for routine use, and further studies are warranted.26
1. Vikram B, Strong EW, Shah JP, et al: Second malignant neoplasms in patients successfully treated with multimodality treatment for advanced head and neck cancer. Head Neck Surg 6: 734-737, 1984[Medline] 2. Cooper JS, Pajak TF, Rubin P, et al: Second malignancies in patients who have head and neck cancer: Incidence, effect on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys 17: 449-456, 1989[Medline] 3. Schwartz LH, Ozsahin M, Zhang GN, et al: Synchronous and metachronous head and neck carcinomas. Cancer 74: 1933-1938, 1994[Medline] 4. Fein DA, Mendenhall WM, Parsons JT, et al: Pharyngeal wall carcinoma treated with radiotherapy: Impact of treatment technique and fractionation. Int J Radiat Oncol Biol Phys 26: 751-757, 1993[Medline] 5. Mendenhall WM, Parsons JT, Mancuso AA, et al: Radiotherapy for squamous cell carcinoma of the supraglottic larynx: An alternative to surgery. Head Neck 18: 24-35, 1996[Medline]
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Mendenhall WM, Amdur RJ, Stringer SP, et al: Radiation therapy for squamous cell carcinoma of the tonsillar region: A preferred alternative to surgery? J Clin Oncol 18: 2219-2225, 2000 8. Amdur RJ, Mendenhall WM, Stringer SP, et al: Organ preservation with radiotherapy for T1-T2 carcinoma of the pyriform sinus. Head Neck (in press) 9. Erkal HS, Serin M, Amdur RJ: Squamous cell carcinomas of the soft palate treated with radiation therapy alone or followed by planned neck dissection. Int J Radiat Oncol Biol Phys (in press) 10. American Joint Committee on Cancer: Manual for Staging of Cancer ( ed 2 ). Philadelphia, PA, Lippincott, 1983, pp 31-36 11. Warren S, Gates DC: Multiple primary malignant tumors: A survey of the literature. Am J Cancer 16: 1358-1414, 1932 12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 13. Lawless JE: Statistical Models and Methods for Lifetime Data. New York, NY, Wiley, 1982, pp 420-422 14. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980 15. Billroth T: Die allgemeine chirurgische pathologie und therapy, an 51 vorlesungen, in Reimer G (ed): Handbuch fur Studirende und Arzte ( ed 14 ). Berlin, Germany, 1889, p 908 16. Moertel CG: Multiple Primary Malignant Neoplasms: Their Incidence and Significance. New York, NY, Springer-Verlag, 1966 17. Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium: Clinical implications of multicentric origin. Cancer 6: 963-968, 1953[Medline] 18. Wu X, Hu Y, Lippman SM: Upper aerodigestive tract cancers, in Neugut AI, Meadows AT, Robinson E (eds): Multiple Primary Cancers. Philadelphia, PA, Lippincott, 1999, pp 319-346 19. Black RJ, Gluckman IL, Shumrick DA: Multiple primary tumours of the upper aerodigestive tract. Clin Otolaryngol 8: 277-281, 1983[Medline] 20. Shons AR, McQuarrie DG: Multiple primary epidermoid carcinomas of the upper aerodigestive tract. Arch Surg 120: 1007-1009, 1985[Abstract] 21. Parker RG, Enstrom JE: Second primary cancers of the head and neck following treatment of initial primary head and neck cancers. Int J Radiat Oncol Biol Phys 14: 561-564, 1988[Medline] 22. Roberts TJ, Epstein B, Lee DJ: Second neoplasms in patients with carcinomas of the vocal cord: Incidence and implications for survival. Int J Radiat Oncol Biol Phys 21: 583-589, 1991[Medline] 23. Fijuth J, Mazeron JJ, Le Pechoux C, et al: Second head and neck cancers following radiation therapy of T1 and T2 cancers of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 24: 59-64, 1992[Medline] 24. Licciardello JT, Spitz MR, Hong WK: Multiple primary cancer in patients with cancer of the head and neck: Second cancer of the head and neck, esophagus, and lung. Int J Radiat Oncol Biol Phys 17: 467-476, 1989[Medline] 25. McDonald S, Haie C, Rubin P, et al: Second malignant tumors in patients with laryngeal carcinoma: Diagnosis, treatment, and prevention. Int J Radiat Oncol Biol Phys 17: 457-465, 1989[Medline] 26. Huber MH, Lippman SM, Hong WK: Chemoprevention of head and neck cancer. Semin Oncol 21: 366-375, 1994[Medline] Submitted August 8, 2000; accepted November 17, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
