Hypopharyngeal Cancer Incidence, Treatment, and Survival: Temporal Trends in the United States

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1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Hypopharyngeal Cancer Incidence, Treatment, and Survival: Temporal Trends in the United States Phoebe Kuo, BA; Michelle M. Chen, BA; Roy H. Decker, MD, PhD; Wendell G. Yarbrough, MD; Benjamin L. Judson, MD Objectives/Hypothesis: The objective was to characterize incidence, treatment, and survival for hypopharyngeal cancer in the United States between 1988 and 2010, and to analyze associations between changes in treatment modality and survival. Study Design: Retrospective cohort study. Methods: A total of 3,958 adult patients with hypopharyngeal cancer were identified in the Surveillance, Epidemiology, and End Results database. Incidence, treatment, and survival, controlling for patient demographics and disease severity, were analyzed using two-tailed t tests, Kaplan-Meier analysis, and univariate and multivariate Cox regression. Results: The incidence of hypopharyngeal cancer decreased from 1973 to 2010 with an average annual percent change (APC) of 22.0% every year (P <.05). Treatment with laryngopharyngectomy decreased (22.5% APC, P <.001), treatment with radiotherapy without surgery increased (12.0% APC, P <.001), and treatment with neither surgery nor radiotherapy increased (10.5% APC, P <.001) between 1988 and There was a significant increase in the 5-year overall survival between 1988 and 1990 and between 1991 and 1995 (P 5.024) with no other significant temporal trends in survival. Multivariate analysis revealed that age (65 74, 75 84, or 851 relative to years old), race (white relative to non-african races), T stage (T2, T3, or T4 relative to T1), N stage (N2 or N3 relative to N0), and treatment modality (2surgery/ 2radiation, 2surgery/1radiation, and 1surgery/2radiation relative to 1surgery/1radiation) were all significantly associated with worse survival. Conclusions: Hypopharyngeal cancer has had a decreasing incidence with little change in patient or tumor characteristics. Treatment has increasingly involved radiation without laryngopharyngectomy. This has not been associated with a decrease in survival. Controlling for patient demographics and disease severity, radiation with laryngopharyngectomy is associated with improved survival. Key Words: Hypopharynx, hypopharyngeal cancer, survival, head and neck cancer, laryngectomy. Level of Evidence: 2b Laryngoscope, 124: , 2014 From the Department of Surgery (P.K., M.M.C., W.G.Y., B.L.J.), and Department of Therapeutic Radiology (R.H.D.), Yale University School of Medicine, New Haven, Connecticut, U.S.A. Editor s Note: This Manuscript was accepted for publication February 18, This work was supported by the Yale University School of Medicine Medical Student Research Fellowship, Yale University School of Medicine Lowe Endowment. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Benjamin L. Judson, MD, 800 Howard Ave., YPB 425, Department of Surgery, Yale University School of Medicine, New Haven, CT benjamin.judson@yale.edu DOI: /lary INTRODUCTION The hypopharynx is one of the less common subsites for head and neck cancers, with an estimated 2,450 new cases arising in the United States annually. 1 Because of the relative rarity of hypopharyngeal cancers, the hypopharynx has often been grouped with the larynx for oncologic management, and the historic standard of care for both diseases was surgery involving total laryngectomy. Although the anatomic location is similar, cancers in the hypopharynx have poor prognoses compared to laryngeal cancer. 2 4 Hypopharyngeal cancers show a tendency to spread submucosally and are often asymptomatic until they have reached advanced stages, contributing to higher rates of delayed and distant metastatic disease. 5 7 The landmark Veterans Affairs (VA) trial in 1991 found comparable outcomes for adults with laryngeal cancers treated with induction chemotherapy followed by radiation therapy, compared with those who underwent laryngectomy and radiation therapy. 8 Lefebvre et al. similarly did not find differences between induction chemotherapy/radiotherapy and laryngectomy/radiotherapy for hypopharyngeal cancers. 9,10 These trials have led to an increased reliance on larynx-preserving treatment modalities for cancers of the larynx and hypopharynx. 11 Yet, whether larynx-preserving therapies are really as safe as laryngectomies for laryngeal cancers has been challenged Citing worsening survival for laryngeal cancers, concerns have been raised that the subjects in the VA trial may not have been representative of the broader population with this disease. 14 These concerns regarding laryngeal cancers are also relevant to cancers in the hypopharynx. With a similar change in treatment from surgery to organ-preserving, radiation-based therapies, there is a potential risk of worse outcomes as this approach is applied broadly to patients with hypopharyngeal cancer. Our first objective

2 Fig. 1. Incidence of hypopharyngeal cancer over time per 100,000 person-years. was to determine if any temporal trends exist in the incidence, patient characteristics, tumor characteristics, treatment modalities, and overall survival of hypopharyngeal cancers. Second, we wanted to evaluate if the decreased reliance on laryngopharyngectomies for hypopharyngeal cancers over time is associated with a difference in survival. Cases of hypopharyngeal squamous cell carcinoma from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed for treatment trends and survival, controlling for patient demographics and disease severity. 16 MATERIALS AND METHODS The SEER database contains data from tumor registries from 1973 to SEER registries originate from 20 geographic regions that represent 28% of the US population and are selected to be representative of the entire US population. To describe temporal trends in this study, we only included cases from SEER-9 registries, which have been participating in SEER for the longest amount of time and represent 9.4% of the US population. Seven of these registries (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, and Utah) contain cases from 1973 to 2010, with Seattle added in 1974 and Atlanta in Incidence rates were age adjusted to population data from We identified all cases of squamous cell cancer with a primary site in the hypopharynx by histology codes and topography codes C12.9-C13.9. Only cases from 1988 to 2010 were included, because staging and treatment information is not recorded in SEER for hypopharyngeal cancers prior to Patients <18 years old or whose primary tumors could not be found were excluded, resulting in a cohort of 3,958 cases. For the Cox survival regression, 2,334 of these cases were analyzed because patients with distant metastases, with incomplete follow-up, whose treatment was unknown, or who received larynx-preserving surgeries that were difficult to classify based on the available data were excluded. Variables of interest pertained to patient demographics, tumor characteristics, treatment modality, and survival. Demographic variables were gender, year of diagnosis (stratified into , , , and ), age at diagnosis (stratified into 18 54, 55 64, 65 74, 75 84, and 851 years old), and race (recoded into white, black, and other). Tumors were classified according to American Joint Commission of Cancer 7th edition staging guidelines. T stage was derived from the tumor size and extension. N stage prior to 2004 was determined from a single variable encoding lymph node involvement, whereas N stage from 2004 to 2010 was derived from two variables encoding lymph node size and lymph node involvement. For M stage, metastatic tumors included metastases to distant sites. Surgery was categorized into three groups: surgery (laryngopharyngectomy/radical excision), larynx-preserving surgery (other cancer-directed surgeries), and no surgery (including patients who received non cancer-directed surgeries). Radiation therapy was categorized into two groups: radiotherapy (defined only as external-beam radiation therapy) and no radiation. Chemotherapy status was not known, so patients who received neither surgery nor radiation could have received palliative chemotherapy and did not necessarily receive no treatment. We first determined the overall incidence of hypopharyngeal cancers and the incidence over time. Summary statistics were found to describe the proportions of patients with hypopharyngeal cancers based on patient demographics, TNM stage, and treatment modality. Temporal trends in these proportions were analyzed by linear regression to find the annual percent change (APC) of the proportions. Treatment modalities for M0 and M1 patients were compared by a two-tailed t test. Overall survival was evaluated by first using a univariate Kaplan- Meier analyses, compared by log rank tests, and 5-year survival rates, compared by two-tailed t tests. Univariate and multivariate Cox regressions compared differences in survival associated with patient characteristics, tumor characteristics, and treatment modality. All tests were two-sided, and statistical significance was determined at the P <.05 level. Incidence rates and trends were analyzed using SEER* Stat (version 8.0.4, National Cancer Institute Surveillance Research Program, All other data analysis was performed using SPSS (version 21.0; IBM, Armonk, NY). This study was determined to be exempt from institutional review by the Yale Human Investigation Committee. RESULTS Incidence The overall incidence of hypopharyngeal cancer in the last 38 years has been 1.0 per 100,000 person-years (Fig. 1). The incidence from 1973 to 2010 has been decreasing with an average annual percent change (APC) of 22.0% every year (P <.05). Most recently, the average incidence from 2006 to 2010 has been 0.7 per 100,000 person-years. Temporal Trends in Demographics, Presentation, and Treatment From 1988 to 2010, there have not been large changes in the patient or tumor characteristics (Table I). Seventy-eight percent of patients were male and 76.7% were Caucasian. There was a slight increase in the proportion of older patients, with 10.3% APC for patients in the 75 to 84 years old range (P 5.002) and 10.1% APC for patients 851 years old (P <.001). There have also not been large changes in the T or N stage of hypopharyngeal cancers. There was a 10.2% APC of T1 tumors (P 5.029), a 10.7% APC of T3 tumors (P <.001), and a 20.7% APC of T2 tumors (P <.001). The APC for N0 tumors was 20.6% (P <.001), 1.4% for N1 tumors (P 5.003), and 10.3% for N2 tumors (P 5.006). Four percent of patients had distant metastases. For subsequent analyses involving treatment modality, patients with 2065

3 TABLE I. Temporal Trends in Patient and Tumor Characteristics. Characteristic Proportion Annual Percent Change (APC) in Proportion P Value Age % 10.1% % 20.2% % 20.5% < % 10.3% % 10.1% <.001 Male 78.0% 0%.89 Race White 76.7% 20.2%.06 Black 16.3% 10.1%.38 Other 7.0% 10.1%.08 AJCC T stage Tis 1.3% 0%.48 T1 9.8% 10.2%.03 T2 39.1% 20.7% <.001 T3 17.3% 10.7% <.001 T4 32.5% 20.1%.48 AJCC N stage N0 38.0% 20.6% <.001 N1 16.1% 10.4%.003 N2 40.4% 10.3%.006 N3 5.5% 20.1%.38 Treatment Surgery (6XRT) 34.7% 22.5% <.001 XRT (Surgery) 52.9% 12.0% <.001 XRT/Surgery 12.4% 10.5% <.001 AJCC 5 American Joint Committee on Cancer; XRT 5radiotherapy. distant metastases (n 5 156) as well as patients who received tumor debulking or larynx-preserving surgeries difficult to classify based on the available data (n 5 459) were excluded. Of the patients, 34.7% received laryngopharyngectomies, composed of 8.2% who received surgery with radiotherapy, 26.0% who received surgery without radiotherapy, 52.9% who received radiotherapy without surgery, and 12.4% who received neither surgery nor radiotherapy. There was a 22.5% APC in laryngopharyngectomies between 1988 and 2010 (P <.001), a 12.0% APC in radiotherapy without surgery (P <.001), and a 0.5% increase in patients receiving neither surgery nor radiotherapy (P <.001) (Fig. 2). Patients with distant metastases who had been excluded had a higher rate of neither surgery nor radiation (35.6% compared to 12.4% of patients without distant metastases, P <.001) and lower rates of surgery (20.5% compared to 34.7% of patients without distant metastases, P 5.001) and radiation (43.9% compared to 52.9% of patients without distant metastases, P 5.044). excluded because of the presence of distant metastasis was 4.0%. When patients were segregated by year of diagnosis ( , , , and ), there was a significant increase in the 5-year survival between 1988 and 1990 and between 1991 and 1995 (P 5.024); otherwise, there were not any significant temporal trends in survival (Fig. 3). Because the rate of laryngopharyngectomies has been significantly decreasing over time and survival has not changed significantly, we investigated whether treatment modality was correlated with survival (Fig. 4). The 5-year overall survival rate for patients who received surgery and radiotherapy was 34.5%, compared to 22.6% for patients who received radiotherapy without surgery, 18.9% for patients who received surgery without radiotherapy, and 8.8% for patients who received neither. Laryngopharyngectomy alone (P <.001) or radiation alone (P <.001) both had better survival than no surgery or radiation. There was not a significant difference in survival between surgery alone and radiation alone (P 5.309). Surgery and radiation together had better outcomes than both surgery alone (P <.001) and radiation alone (P <.001). In the univariate analysis, year of diagnosis ( relative to ), age (65 74, 75 84, or 851 relative to years old), race (black relative to white), T stage (T2, T3, or T4 relative to T1), N stage (N3 relative to N0), and treatment modality (no surgery or radiation, radiation alone, and surgery alone relative to surgery with radiation) all had a significantly increased hazard ratio (Table II). There was not a significant association when surgery alone was compared to radiation alone (hazard ratio: 1.069; confidence interval: ; P 5.345). A multivariate Cox regression was performed to control for patient demographics and TNM stage that may also affect survival and factor into decisions regarding treatment modality (Table II). All factors that correlated with differences in survival in the univariate analysis were included. Multivariate analysis revealed that age (65 74, 75 84, or 851 relative to years old), race (white relative to other races), T stage (T2, T3, or T4 relative to T1), N stage (N2 or N3 relative to N0), and treatment modality (no surgery or radiation, radiation alone, and surgery alone relative to surgery with radiation) were all significantly associated with worse survival. When Cox regression compared treatment modality to radiation alone (instead of to surgery with Survival The 5-year overall survival rate for patients in our study was 25.5%. The 5-year survival for patients Fig. 2. Temporal trends in treatment modalities. XRT 5radiotherapy. 2066

4 Fig. 3. Five-year survival by year of diagnosis. radiation as the reference variable), there was not a significant difference in survival for surgery alone compared to radiation alone (hazard ratio: 0.941; confidence interval: ; P 5.478). We analyzed temporal trends in survival by treatment modality to elucidate why declining treatment with combined surgery and radiation has not been associated with overall declining survival for hypopharyngeal cancer, given the survival advantage seen with this treatment relative to other treatments. When survival was compared for different time periods ( , , , and ) within each treatment modality, radiation without surgery was the only treatment modality with significant improvement (log rank test P <.001). For radiation without surgery, the 5-year survival was significantly worse in 1988 to 1990 compared to all later time periods (Fig. 5). The 5-year survival for these patients increased from 13.5% in to 21.5% in (P relative to ), to 20.9% in (P 5.039), to 23.7% in (P <.001). Because of the improving trend in survival for patients who receive radiation without surgery, we also repeated the multivariate analysis for patients treated in the last decade ( ). The results of the Cox regression similarly showed a survival advantage for surgery with radiation compared to other treatment modalities when controlling for age, race, year of diagnosis, T stage, and N stage. Relative to surgery with radiation, there were hazard ratios of 3.66 for neither surgery nor radiation (confidence interval: ; P <.001), 1.71 for radiation alone (confidence interval: ; P <.001), and 2.35 for surgery alone (confidence interval: ; P <.001). When radiation alone was used as the regression reference variable for treatment modality, the hazard ratio for surgery alone relative to radiation alone was 1.37 (confidence interval: ; P 5.018). This subset analysis suggests that, even in recent years, surgery with radiation still offers a survival advantage over surgery alone or radiation alone, but radiation alone has better outcomes than surgery alone. 20 years. This is consistent with what has been reported with other smoking-related malignancies and is likely a result of the decrease in smoking incidence over this period. 17 Patient and tumor characteristics of hypopharyngeal cancer have remained relatively constant over this period, with a slight shift toward older patients as might be expected in an aging population. As expected, there has been a significant decrease in the rate of laryngopharyngectomies for hypopharyngeal cancers, accompanied by a significant increase in the rate of radiotherapy treatment. Unlike what has been described with larynx cancer, where there has been controversy about changes in survival during the period in which radiation-based treatments have been adopted, we did not find changes over time in survival for patients with hypopharyngeal cancer. This suggests that the change in treatment patterns for hypopharyngeal cancer was not associated with decreased survival. Despite these overall survival trends, multivariate analysis adjusting for patient and tumor characteristics demonstrated that treatment modality did still correlate with significant differences in survival. There was a hazard ratio of 1.59 for surgery alone relative to surgery and radiation, 1.69 for radiation relative to surgery and radiation, and 4.26 for no surgery or radiation relative to surgery with radiation. The best 5-year overall survival rate was seen with combined surgery and radiotherapy at 34.5%, followed by 22.6% for radiotherapy alone, 18.9% for surgery alone, and 8.8% for neither surgery nor radiotherapy. These findings suggest a survival advantage for combined modality treatment with surgery and radiation. Survival does appear to be improving over time for patients who receive radiation without surgery, which may explain why overall survival is not worsening over time. It is important to note that the chemotherapy status of patients in this cohort was not known, so the patients in the radiation without surgery cohort may have received chemotherapy. Increased use DISCUSSION We report a small decrease in the incidence of hypopharyngeal cancer in the United States over the last Fig. 4. Kaplan-Meier survival curves by treatment modality (2surgery/2radiation, 2surgery/1radiation, 1surgery/2radiation, 1surgery/1radiation). 2067

5 TABLE II. Univariate and Multivariate Analysis of Patient and Tumor Characteristics Associated With Survival. Univariate Multivariate Characteristic Hazard Ratio 95% CI Hazard Ratio 95% CI Year of diagnosis Reference 1 Reference Age Reference 1 Reference Gender Male 1 Reference Not Included Female Race White 1 Reference 1 Reference Black Other AJCC T stage T1 1 Reference 1 Reference T T T AJCC N stage N0 1 Reference 1 Reference N N N Treatment 1XRT/1surgery 1 Reference 1 Reference XRT/1surgery XRT/surgery XRT/surgery AJCC 5 American Joint Committee on Cancer; CI 5 confidence interval; XRT 5radiotherapy. of chemotherapy with radiation may account for improved outcomes for these patients over the time period studied. In the literature, the reported 5-survival rates have ranged from 24% to 33% for surgery alone, and 35% to 52% for combined surgery and radiation. 10,18,22 Comparing surgery with radiotherapy to surgery alone, El Badawi et al. reported better outcomes for combination therapy, with 5-year survival of 40% for surgery with radiation versus 25% for surgery alone. 18 In another retrospective cohort study, Elias et al. reported better overall survival and lower recurrence rates for 47 patients who received both surgery and radiation compared to 45 patients who received radiation alone. 23 Thus, in retrospective studies, there may be a survival benefit to combined surgery and radiotherapy over other treatment modalities. In our study, this potential survival benefit is further supported by the fact that surgery with radiation was still associated with improved survival relative to other treatment modalities when controlling for age, tumor stage, and nodal status. However, when induction chemotherapy/radiotherapy was compared with laryngectomy/radiotherapy in a randomized controlled trial, Lefebvre et al. did not find significant differences in the 5-year survival rate for radiotherapy/chemotherapy (30%) versus surgery/radiotherapy (35%). 10 The difference in this study compared to the findings of observational studies may be secondary to selection bias. Outcomes reported in clinical trials for organ-preserving therapy may also be better than 2068

6 Fig. 5. Five-year survival by year of diagnosis for patients who received radiation without surgery (2surgery/1radiation). those in the overall population, resulting in decreased transferability to the patient population as a whole. There are limitations inherent to a study that uses secondary source data from a large database. One concern is coding errors, though SEER is a well-validated database, and the National Cancer Institute has quality improvement personnel who perform annual audits to evaluate the consistency and accuracy of coding. Additionally, though we controlled for age and disease severity, potential confounders like payer status, risk factors (smoking, alcohol, and human papillomavirus), and comorbidities are not available in SEER and thereby were not analyzed. Possible selection bias is subsequently a concern because physicians likely selected patients with better general health for combined modality treatment. Finally, the use of chemotherapy is not reported in SEER, and so we were not able to include this in the analysis. CONCLUSION Although demographics and tumor characteristics of hypopharyngeal patients have been relatively constant over time, our study found a significant change in treatment patterns with a decrease in the rate of laryngopharyngectomies for hypopharyngeal cancers. The changes in treatment modality were similar to what has been reported in laryngeal cancers. 13 Over the same time period for the same cohort of patients, there has not been a decrease in survival, and survival may in fact be improving over time as survival for patients who receive radiotherapy without surgery improves. These findings suggest that the increased reliance on larynxpreserving therapy for hypopharyngeal cancers is not associated with a difference in survival. BIBLIOGRAPHY 1. American Cancer Society. Laryngeal and hypopharyngeal cancer Available at: Accessed April 15, Berrino F, Gatta G. 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