CRT indicates chemoradiation therapy; and RT, radiation therapy.
CRT indicates chemoradiation therapy; CT, chemotherapy; and RT, radiation therapy.
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Chen MM, Roman SA, Sosa JA, Judson BL. The Role of Adjuvant Therapy in the Management of Head and Neck Merkel Cell Carcinoma: An Analysis of 4815 Patients. JAMA Otolaryngol Head Neck Surg. 2015;141(2):137–141. doi:10.1001/jamaoto.2014.3052
Merkel cell carcinoma (MCC) is a rare neuroendocrine malignant neoplasm that most commonly occurs in the head and neck and is rapidly increasing in incidence. The role of adjuvant chemoradiotherapy (CRT) in the management of head and neck MCC remains controversial.
To evaluate the association between different adjuvant therapies and survival in head and neck MCC.
Design, Setting, and Participants
Retrospective review of adult patients with head and neck MCC who had surgery recorded in the National Cancer Data Base from 1998 to 2011.
Surgical excision, adjuvant radiation therapy (RT), or adjuvant CRT.
Main Outcomes and Measures
Our main outcome was overall survival (OS). Statistical analysis included χ2, t tests, Kaplan-Meier survival analysis, and Cox proportional hazards regression analysis.
We identified 4815 patients; 92.0% underwent standard surgical excision, and 8.0% underwent Mohs surgery. On multivariate analysis, age at least 75 years (hazard ratio [HR], 2.83 [95% CI, 1.82-4.41]), larger tumor size, positive margins (HR, 1.52 [95% CI, 1.25-1.85]), and metastatic lymph nodes (HR, 2.29 [95% CI, 1.84-2.85]) were independently associated with decreased OS. Postoperative CRT (HR, 0.62 [95% CI, 0.47-0.81]) and RT (HR, 0.80 [95% CI, 0.70-0.92]) provided a survival benefit over surgery alone. Adjuvant CRT was associated with improved OS over adjuvant RT in patients with positive margins (HR, 0.48 [95% CI, 0.25-0.93]), tumor size at least 3 cm (HR, 0.52 [95% CI, 0.30-0.90]), and male sex (HR, 0.69 [95% CI, 0.50-0.94]).
Conclusions and Relevance
To our knowledge, this the first study examining the role of adjuvant CRT in head and neck MCC. Results suggest that adjuvant CRT may help improve survival in high-risk patients, such as males and those with positive margins and larger tumors.
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignant neoplasm that most commonly occurs in the head and neck region.1 Merkel cell carcinoma was initially described by Toker in 1972 and called a “trabecular carcinoma of the skin.”2(p107) From 1986 to 2001, the incidence of MCC has increased 3-fold.3 Merkel cell carcinoma has been shown to be associated with immunosuppression, UV exposure, and mature patient age.4 Recently, a novel Merkel cell polyomavirus has been detected in MCC tumors, suggesting a viral etiology.5
The observed increase in incidence of MCC may at least in part be due to the introduction of the cytokeratin-20 stain in 1994, which decreased the likelihood of a missed diagnosis of MCC.3 In MCC, cytokeratin-20 stains with a characteristic punctate perinuclear pattern.6 The current management of MCC encompasses a broad range of practices: wide local excision, Mohs surgery, sentinel lymph node biopsy, neck dissection (elective or therapeutic), radiation therapy (RT), chemoradiotherapy (CRT), and chemotherapy (CT).7
Head and neck MCC has been shown to have unique prognostic factors that differ from those of non–head and neck MCC.1 There is controversy regarding the role of concurrent CT in patients with MCC who are receiving postoperative RT.8,9 The goal of our study was to evaluate the association between CRT and overall survival (OS) in patients with head and neck MCC.
We used the National Cancer Data Base (NCDB) from 1998 to 2011, which encompasses patients from more than 1500 Commission on Cancer accredited programs.10 Because all patient information is deidentified in the NCDB, our study was granted an exemption by our university institutional review board. The NCDB covers nearly 70% of the incident cases of cancer in the United States.11
We identified patients with head and neck MCC using the International Classification of Diseases for Oncology, Third Edition, topography codes for skin of the lip (C-44.0), eyelid (C-44.1), external ear (C-44.2), other and unspecified parts of the face (C-44.3), and scalp and neck (C-44.4), and the histology code 8247 (MCC). We included all adult patients (aged ≥18 years) who underwent surgery.
Demographic variables included patient age, sex, race, and comorbidity. Age was categorized into younger than 55, 55 to 64, 65 to 74, and at least 75 years. Race was grouped into white, black, and other. The Charlson/Deyo Comorbidity Score12 was used to classify comorbidity as 0 (no comorbid conditions), 1, 2 or more comorbidities, and unknown (Table 1).
Clinical and pathologic variables included surgery type, treatment, tumor size, surgical margins, lymph node status, and pathologic nodal evaluation. Treatment was classified as surgery, adjuvant RT, adjuvant CRT, and adjuvant CT. Tumor size was categorized into less than 2, 2 to less than 3, 3 to less than 4, 4 to less than 5, and 5 cm or greater. Surgical margins were classified into positive margins, negative margins, and unknown. Surgical margins are final margins. Lymph node status was categorized into no positive lymph nodes, positive lymph nodes, and lymph nodes not examined.
Hospital-level variables included hospital type and region. Hospital type was categorized as community, academic, and other cancer programs. Region was grouped into 4 categories: East, South, Midwest, and West.
Our primary outcome of interest was OS. Survival time in years was calculated from the date of diagnosis to death, the last date the patient was known to be alive, or December 31, 2011, whichever came first. Survival data are limited to patients who received a diagnosis from 1998 through 2005.
Bivariate analysis using χ2 tests was used to analyze categorical variables. Kaplan-Meier analysis was used to analyze survival, and the log-rank test was used to determine statistical significance. Cox proportional hazards regression analysis was used to identify prognostic factors associated with OS, and hazard ratios (HRs) and 95% confidence intervals were calculated for the strength of association. All tests were 2-sided, and P < .05 was considered statistically significant.
The analysis was conducted using Statistical Package for the Social Sciences (SPSS) software, version 21.0 (SPSS Inc).
We identified 4815 adult patients with head and neck MCC in the NCDB from 1998 to 2011. The majority of our cohort was male (62.9%) and white (98.1%). A total of 92.0% underwent surgical excision, whereas the remaining 8.0% underwent Mohs surgery. Negative margins were present in 79.1% of the cohort. The 5-year OS rate was 41.3%, the mean (standard error) survival time was 5.50 (0.11) years, and the median (standard error) survival time was 3.41 (0.14) years.
From 1998 to 2011, the proportion of patients who received surgery, adjuvant RT, and adjuvant CRT remained stable (Figure 1). In our cohort, 58.6% of patients with MCC received adjuvant therapy. Most patients who received postoperative therapy had adjuvant RT (82.6%), whereas the remaining patients had either adjuvant CRT (13.9%) or adjuvant CT (3.4%) (Table 1). Compared with patients who had adjuvant therapy, those who had surgery alone were more likely to be aged 75 years or older (69.6% vs 61.6%; P < .001), have multiple comorbidities (3.0% vs 4.1%; P = .03), and have negative surgical margins (83.6% vs 76.0%; P < .001).
Five-year OS rates for patients who had surgery alone, adjuvant RT, adjuvant CRT, and adjuvant CT were 38.5%, 42.8%, 47.5%, and 28.7%, respectively (log-rank test, P < .001) (Figure 2). After multivariate analysis, patient age 75 years or older (HR, 2.83 [95% CI, 1.82-4.41]), increasing tumor size, positive margins (HR, 1.52 [95% CI, 1.25-1.85]), and presence of metastatic lymph nodes (HR, 2.29 [95% CI, 1.84-2.85]) were independently associated with decreased OS (Table 2). Surgery combined with adjuvant RT (HR, 0.80 [95% CI, 0.70-0.92]) or adjuvant CRT (HR, 0.62 [95% CI, 0.47-0.81]) continued to be associated with a better prognosis than surgery alone. However, postoperative CT was associated with decreased OS (HR, 1.74 [95% CI, 1.10-2.75]) when compared with surgery alone.
A subanalysis of 2820 patients who all received postoperative therapy demonstrated an association between improved survival and adjuvant CRT vs RT (HR, 0.79 [95% CI, 0.60-1.03]) that was statistically insignificant on multivariate analysis (Table 3). However, a subanalysis of 457 high-risk patients with positive margins who received postoperative therapy demonstrated that postoperative CRT was associated with improved survival over RT (HR, 0.48 [95% CI, 0.25-0.93]). Postoperative CRT was also associated with improved survival in patients with tumors of size 3 cm or larger (HR, 0.52 [95% CI, 0.30-0.90]) and in male patients (HR, 0.69 [95% CI, 0.50-0.94]).
In this retrospective population-level cohort study, nearly two-thirds of patients with head and neck MCC had adjuvant therapy, and of these, only 13.9% had adjuvant CRT. Older age, male sex, positive margins, and larger tumors were factors independently associated with decreased OS. Compared with surgery alone, both postoperative CRT and postoperative RT were associated with improved OS. Compared with postoperative RT, CRT was associated with improved OS in patients with positive margins and larger tumors. Patients who underwent Mohs surgery had improved survival over those who underwent standard surgical excision.
We observed that older age, male sex, and tumors of size 3 cm or greater were associated with decreased survival in head and neck MCC. This validates prior studies that have demonstrated that head and neck MCC has unique prognostic factors that differ from those of MCC in other body sites. Smith et al1 analyzed 2104 patients with head and neck MCC and reported that age at diagnosis (HR, 1.02 [95% CI, 1.01-1.03]), male sex (HR, 1.84 [95% CI, 1.44-2.37]), and increasing tumor size were associated with reduced disease-specific survival. They observed that male sex was a prognostic factor that was unique to head and neck MCC.
The current data on adjuvant therapy in head and neck MCC is limited to small single-institution studies investigating the role of adjuvant RT13-16; to our knowledge, there are no studies examining the role of adjuvant CRT. Clark et al14 conducted the largest study to date on the role of adjuvant therapy in patients with head and neck MCC, analyzing 110 patients. Adjuvant therapy was demonstrated to be associated with improved locoregional control and disease-free survival; however, on multivariate analysis, adjuvant RT was not associated with improved disease-specific survival (HR, 0.48 [95% CI, 0.21-1.09]) or OS (HR, 0.52 [95% CI, 0.25-1.07]).14 Gillenwater et al15 studied 66 patients with head and neck MCC and reported that patients who received postoperative RT had improved local (12% vs 44%; P < .01) and regional (27% vs 85%; P < .01) recurrence rates; there was no significant difference in disease-specific survival (P = .30). For MCC in general, it has been shown that there is a survival benefit for postoperative RT17,18 but no difference between postoperative RT and CRT.9 Hasan et al9 conducted a systematic review that encompassed 4475 patients with MCC and reported 3-year OS of 56%, 70%, and 73% for patients who underwent surgery, adjuvant RT, and adjuvant CRT, respectively (P < .001). In our subanalysis of only patients who received postoperative therapy, we demonstrated that adjuvant CRT is associated with improved OS over adjuvant RT in patients with certain high-risk characteristics, such as male sex, tumors with positive margins, and tumors of size 3 cm or greater.
In the NCDB, there is no centralized review of the pathology by an experienced head and neck pathologist. Other limitations to our study include the absence of survival data for cases diagnosed after 2005, so our cohort for the survival analysis is limited to 1998 through 2005. We do not have detailed information on how margins were excised on patients who underwent non-Mohs surgery. Thus, we are unable to compare circumferential pathologic margins after surgical excision with Mohs. Moreover, in comparing patients who underwent Mohs surgery with those who underwent standard surgical excision, there may be a selection bias in which patients with Mohs surgery had different characteristics than those who did not have Mohs surgery. We attempted to adjust for this in our multivariate analysis by controlling for tumor size. The NCDB does not include information on rates of disease-specific survival, disease recurrence, detailed comorbidities beyond the Charlson/Deyo score, and reoperation, so these important outcomes could not be included in the analysis.
Head and neck MCC is a rare and aggressive malignant neoplasm. To our knowledge, our study is the first to examine the role of adjuvant CRT in patients with head and neck MCC, and our findings demonstrate an association between OS and postoperative CRT and RT. Although prior studies have not shown an added survival benefit associated with postoperative CRT over RT, our results suggest that postoperative CRT may be an important tool to use in the management of high-risk patients with head and neck MCC. Further multi-institutional studies are needed to investigate possible systemic treatments and treatment intensification in order to improve outcomes in head and neck MCC.
Submitted for Publication: July 9, 2014; final revision received October 17, 2014; accepted October 22, 2014.
Corresponding Author: Benjamin L. Judson, MD, Section of Otolaryngology, Department of Surgery, Yale University School of Medicine, PO Box 208041, New Haven, CT 06520-8041 (email@example.com).
Published Online: December 4, 2014. doi:10.1001/jamaoto.2014.3052.
Author Contributions: Drs Chen and Judson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chen, Judson.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chen.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Chen.
Obtained funding: Chen.
Administrative, technical, or material support: Judson.
Study supervision: Roman, Sosa, Judson.
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Chen is a recipient of the Hirsch Endowed Medical Student Research Fellowship at Yale University School of Medicine.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentation: A portion of these data was presented at the Fifth World Congress of the International Federation of Head and Neck Oncologic Societies and the Annual Meeting of the American Head & Neck Society; July 27, 2014; New York, New York.
Disclaimer: The data used in the study are derived from a deidentified National Cancer Database file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used, or the conclusions drawn from these data by the investigator.
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