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Adjuvant radiation for T1-2N1 oral cavity cancer survival outcomes and utilization treatment trends: Analysis of the SEER database
Oral Oncology 85 (2018) 1–7
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Adjuvant radiation for T1-2N1 oral cavity cancer survival outcomes and utilization treatment trends: Analysis of the SEER database
T
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Vanessa Torrecillasa, , Hailey M. Shepherda, Sam Francisb, Luke O. Buchmanna, Marcus M. Monroea, Shane Lloydb, Donald Cannonb, Ying J. Hitchcockb, John R. Weisc, Jason P. Hunta, Jeffrey J. Houltond, Richard B. Cannona a
The University of Utah School of Medicine, Otolaryngology Head and Neck Surgery, 50 North Medical Drive 3C-120, Salt Lake City, UT 84132, USA The University of Utah School of Medicine, Department of Radiation Oncology, 1950 Circle of Hope, Salt Lake City, UT 84112, USA c The University of Utah School of Medicine, Division of Oncology, 1950 Circle of Hope, Salt Lake City, UT 84112, USA d The University of Washington School of Medicine, Department of Otolaryngology-Head and Neck Surgery, Seattle, WA, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Adjuvant radiation Oral cavity cancer Survival outcomes Overall survival Disease-specific survival SEER database Population-based study Utilization Treatment trends Improved survival
Objective: Evaluate current practice patterns in the use of adjuvant radiation for T1-2N1 OCSCC patients and investigate its efficacy in the population-based setting. Materials and methods: This study extracted patients who were treated surgically for T1N1 and T2N1 OCSCC without adverse nodal features from the SEER database from 2004 to 2013. Patients with distant metastatic disease, unknown surgery or radiation status, or prior malignancies were excluded. Patients were divided into those who underwent surgical resection with and without adjuvant radiation. Disease-specific survival (DSS) and overall survival (OS) were the primary outcomes measured. Results: 746 patients met inclusion criteria and 70% received adjuvant radiation therapy. Treatment with adjuvant radiation therapy was significantly associated with improved 5-year DSS (65% versus 51%; p < 0.001) and OS (54% versus 44%; p = 0.007) for T1N1 tumors. Likewise, improved 5-year DSS (58% versus 38%; p = 0.009) and OS (48% versus 28%; p = 0.004) was shown in T2N1 tumors. Patients with T2N1 tumors wer significantly more likely to receive adjuvant radiation (75% versus 63%; p < 0.001). Those with insurance and high risk primary subsites: buccal, retromolar trigone, and hard palate were more likely to receive adjuvant radiation. The percent utilization of adjuvant radiation remained constant through the study period for T2N1 tumors (72–74%) but significantly decreased for T1N1 (71–55%) (p = 0.047). Conclusion: Adjuvant radiation therapy is independently associated with a significant survival benefit for patients with both T1N1 and T2N1 OCSCC. However, this study demonstrates that patients with T1N1 cancer are less likely to receive adjuvant radiation and utilization is decreasing.
Introduction In the United States each year, there are an estimated 49,670 new cases and 9700 deaths from oral cavity and oropharyngeal cancers [1,2]. Tobacco and alcohol use are known risk factors for development of squamous cell carcinomas of the oral cavity and oropharynx and when used in concurrence, they have a synergistic effect on cancer development [3–5]. In particular, the incidence of oral cavity squamous cell carcinomas (OCSCC) continues to rise, particularly among black males and white females, and the disease burden remains a significant national public health concern [6–10]. In any head and neck squamous cell carcinoma, it is well known that
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nodal metastasis is a strong predictor of locoregional recurrence, distant metastasis, and survival [11–18]. However, in cases where there is metastasis to just one ipsilateral node without adverse features such as positive margins, extracapsular invasion, or perineural invasion, it has been unclear whether adjuvant radiation therapy improves these survival outcomes. The National Comprehensive Cancer Network (NCCN) provides up to date clinical practice guidelines for treatment of oral cavity cancers based on clinical and pathologic staging algorithms. Currently, for T1-2M0 OCSCC, the NCCN definitively recommends primary surgical excision with or without neck dissection. However, if on pathology there is just one positive node without adverse features, the decision to pursue adjuvant radiation is based on the surgeon’s
Corresponding author at: The University of Utah, Otolaryngology Head and Neck Surgery, 50 North Medical Dr., SOM 3C-120, Salt Lake City, UT 84132, USA. E-mail address: [email protected] (V. Torrecillas).
https://doi.org/10.1016/j.oraloncology.2018.07.019 Received 29 May 2018; Received in revised form 20 July 2018; Accepted 29 July 2018 1368-8375/ Published by Elsevier Ltd.
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judgement [19]. This flexibility in clinical guidelines for adjuvant radiation therapy arises from a nonuniform NCCN consensus due to a low level of evidence regarding adjuvant radiation in N1 classification OCSCC. Recent literature has contributed to the growing pool of evidence supporting the use of adjuvant radiation therapy in patients with T12N1 oral cavity cancer. A study of the Surveillance, Epidemiology, and End Results (SEER) database by Kao et al showed statistically significant increases in overall survival associated with adjuvant radiation for all SCC nodal groups, including N1 disease [20]. However, an analysis by subsite failed to show significant improvement in overall survival for patients with OCSCC of any stage and nodal positivity treated with adjuvant radiation. This study did not specifically evaluate T1-2N1 OCSCC. Another retrospective review of the SEER database from 1983 to 2004 by Shrime et al demonstrated that adjuvant radiation significantly improved overall survival and disease specific survival in patients with T2N1 OCSCC, however their data failed to achieve statistical significance in T1N1 disease [21]. A study with similar aims was then conducted in a review of the National Cancer Database (NCDB) from 2004 to 2013 by Chen et al. [22]. These investigators found that adjuvant radiation significantly improved overall survival in patients with both T1N1 and T2N1 OCSCC, especially in those younger than 70 years of age and in those with T2 disease, however the NCDB is not designed to represent the US population and has an inherit bias of accredited cancer facilities. Overall, the currently published studies demonstrate statistically significant improvement in outcomes for T2N1 OCSCC treated with adjuvant radiation. While evidence suggests there is some survival advantage for T1N1 cancers, this is not strongly demonstrated. Patterns of use for adjuvant radiation are also not well defined in the literature. It is currently not clear what systems, socioeconomic, and patientspecific factors are associated with adjuvant radiation use in T1-2N1 OCSCC. The primary objectives of this study were to, first, use the SEER database to investigate utilization patterns for adjuvant radiation for T1-2N1 OCSCC patients, second, investigate its efficacy in the population-based setting, and finally, to examine factors associated with adjuvant radiation therapy use and survival outcomes.
surgically for T1N1 and T2N1 disease were extracted from the database and the use of adjuvant radiation was compared to those not treated with adjuvant radiation. Clinical and pathologic data, survival outcomes, and recurrences were extracted. Insurance status was collected from years in which it was available, from 2007 to 2013. The percent utilization of adjuvant radiation was analyzed and compared over time. Overall survival (OS) and disease-specific survival (DSS) were calculated.
Statistical analysis Descriptive statistics were performed by independent t-tests and the Mann-Whitney U test for mean comparisons of variables with two groupings. For variables with groupings of three or more, a one-way ANOVA test was utilized. Chi square and Fisher’s exact test were used to analyze categorical variables. Univariate survival estimates were generated by the Kaplan-Meier method and compared with the log-rank test. Multivariate survival analysis was performed using the Cox proportional hazard regression model, utilizing all variables approaching significance (p ≤ 0.2) to control for confounding covariates. Statistical analysis was performed using XLSTAT (version 2018.2, Addinsoft). All tests were two-tailed, and results were considered significant for p ≤ 0.05.
Results There were 746 patients who met inclusion criteria. The average age was 63, 80% of patients were white, and 67% were male. Complete patient demographics, tumor characteristics, and treatment details are summarized in Table 1, as well as factors associated with treatment with adjuvant radiation. Insurance status category was not significantly different between the two cohorts (p = 0.198), however, analyzing the percentage of uninsured patients that received adjuvant radiation versus those that did not receive adjuvant radiation resulted in a significant difference (4.0% versus 8.3%; p = 0.045). Utilization of adjuvant radiation therapy was statistically significantly higher in high risk subsites: buccal, retromolar trigone, and hard palate (p < 0.001). Age (p = 0.286), sex (p = 0.741), race (p = 0.944), marital status (p = 0.990), and histological grade (p = 0.989) were not significantly different between the two treatment cohorts. Treatment with adjuvant radiation therapy was significantly associated with improved 5-year DSS (65% versus 51%; p < 0.001) and OS (54% versus 44%; p = 0.007) for patients with T1N1 tumors (Figs. 1 and 2, respectively). Treatment with adjuvant radiation therapy was also significantly associated with improved 5-year DSS (58% versus 38%; p = 0.009) and OS (48% versus 28%; p = 0.004) for patients with T2N1 tumors (Figs. 3 and 4, respectively). Multivariate analysis demonstrated that adjuvant radiation was an independent factor associated with improved DSS (HR: 0.62 [0.47–0.81]; p < 0.001) and OS (HR: 0.63 [0.50–0.80]; p < 0.001) after controlling for other known covariates (Table 2). In addition, Black ethnicity, unmarried status (single, widowed, or divorced), uninsured status, subsites including buccal, hard palate, oral cavity, and NOS subsites, poorly differentiated histology, and T2 classification were independent factors associated with a reduction in both DSS and OS. Patients with T2N1 tumors were significantly more likely to receive adjuvant radiation than patients with T1N1 tumors (75% versus 63%; p < 0.001). The percent utilization of adjuvant radiation has remained constant for T2N1 OCSCC: from 72% averaged over the first 3 years of the study (2004–2006) to 76% (2007–2010) to 74% (2011–2013). On the contrary, the percent utilization of adjuvant radiation has significantly decreased for T1N1 OCSCC: from 71% averaged over the first 3 years of the study (2004–2006) to 60% (2007–2010) to 55% (2011–2013) (p = 0.047) (Fig. 5).
Materials and methods Data source The SEER Program Database is a population- based registry of the National Cancer Institute that currently collects data from approximately 28% of the US population. Data is collected prospectively from registries and includes incidence and population data associated by age, sex, race, year of diagnosis, and geographic areas. During the time of our study period, the 7th edition of the SEER database was used, and there were 18 registries reporting data. These registries included Atlanta, Los Angeles, San Francisco-Oakland, Seattle-Puget Sound, San Jose-Monterey, Rural Georgia, Greater Georgia, Greater California, the Alaska Native Tumor Registry, and the states of Connecticut, Detroit, Hawaii, Iowa, Kentucky, Louisiana, New Jersey, New Mexico, and Utah. This study was exempt from the University of Utah institutional review board approval. Study populations and outcomes Study population and outcomes of all patients with resectable T1N1 and T2N1 OCSCC without adverse nodal features were extracted from the SEER database from 2004 to 2013 using the AJCC Staging 7th Edition. Patients with distant metastatic disease, those with unknown surgery or radiation status, and patients with previous malignancies were excluded. There were 746 patients who met this inclusion criteria. Treatment groups included surgical resection without adjuvant radiation and surgical resection with adjuvant radiation. Patients treated 2
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OCSCC. Furthermore, there is scant data addressing socioeconomic and clinicopathologic factors which may influence the decision to utilize radiotherapy in this patient population. Our study demonstrates a clear survival benefit in patients with T12N1 OCSCC who underwent post-operative adjuvant radiation therapy. A statistically significant improvement in DSS and OS was found for patients with T2N1 OCSCC, which has been illustrated in prior studies [20–22]. Notably, this study also demonstrated a statistically significant improvement in DSS and OS for T1N1 OCSCC with adjuvant radiation therapy. This differs from previous studies which demonstrated no improvement or non-statistically significant improvement [20–22]. These disparities in outcomes may be due to differences in study design (Kao et al evaluated nodal stages but did not evaluate outcomes with tumor stage and nodal stage together), differences in data reporting to NCDB (Chen) versus SEER, or differences in study populations (this study included patients from the SEER database from 2004 to 2013 versus the study by Shrime which included patients from 1983 to 2004) [20–22]. It is important to note that although data from NCDB is very valuable, it is not designed to represent the US population and has an inherit bias of accredited cancer facilities. SEER data is populationbased and our results reinforces the survival benefit of adjuvant radiation therapy when utilized for T1-2N1 disease, with improvements in both DSS and OS. Our study also analyzed patterns in utilization of adjuvant radiation therapy for T1-2N1 OCSCC. We found that patients with T1N1 tumors received less radiation therapy than those with T2N1 disease. T2N1 tumors were about 1.2 times more likely to be treated with adjuvant radiation therapy, and this was statistically significant. Furthermore, our findings indicate a substantial decline in the utilization of adjuvant radiation in T1N1 tumors over the past 10 years. The reason for this decline is unclear. Of note, the study published by Shrime et al which reported no statistically significant improvement in survival from adjuvant radiation in T1N1 tumors coincides with this timeline [21]. It is possible this study may have negatively influenced use of adjuvant radiation therapy following this publication, and thus contributed to the continued decline in utilization for this population. Also, this treatment trend corresponds to the intense de-escalation of therapy for HPV positive oropharyngeal cancers, however these two cancers are clearly different entities and require different treatment. By conducting an analysis of patient and tumor characteristics, we discovered several factors associated with increased utilization of adjuvant radiation therapy: insurance status, tumor subsite, and clinical stage. Other factors such as age (p = 0.286), sex (p = 0.784), race (0.944), marital status (p = 0.990), and histologic grade (p = 0.989) did not appear to significantly influence the decision to pursue adjuvant radiation therapy. Association between insurance status and adjuvant radiation therapy in patients with head and neck cancer is not well documented, and there is a paucity of data regarding insurance status and outcomes in T1-2N1 OCSCC. However, it has been shown that patients who are uninsured or insured by Medicare/Medicaid have a higher incidence of postoperative complications and reduced survival from head and neck cancer than patients who have private insurance [23–25]. Our study demonstrates that uninsured patients with T1-2N1 OCSCC are less likely to undergo adjuvant radiation therapy than patients with any Medicaid or private insurance, and these patients who were not treated with adjuvant radiation had decreased DSS and OS. Therefore, it may be hypothesized that patients with T1-2N1 OCSCC who are uninsured are at risk for increased morbidity and mortality given lower rates of use of adjuvant radiation therapy. Our study found a statistically significant higher use of adjuvant radiation therapy based on tumor subsite with the most use in tumors of buccal, retromolar trigone, and hard palate origin. Of note, our study also demonstrated a significant reduction in DSS and OS in buccal and hard palate tumors as compared with other subsites. DSS and OS for retromolar trigone tumors were not significantly different than other
Table 1 Patient demographics, tumor characteristic, and treatment factors for patients with T1-2N1 oral cavity cancer and their association with utilization of adjuvant radiation (Bold represent p < 0.05). Number of patients (%) (n = 742) Characteristics
No adjuvant radiation
Adjuvant radiation utilized
Overall Average Age
221 (30%) 62.3
521 (70%) 61.1
Sex Male Female
141 (64%) 80 (36%)
339 (65%) 182 (35%)
p = 0.741
183 (83%) 24 (11%) 11 (5%) 1 (0.5%)
422 (81%) 62 (12%) 31 (6%) 3 (0.6%)
p = 0.944
2 (0.9%)
3 (0.6%)
106 (48%) 40 (18%) 35 (16%) 33 (15%) 4 (2%) 3 (1%)
245 (47%) 94 (18%) 89 (17%) 73 (14%) 10 (2%) 10 (2%)
p = 0.990
Insurance status (available 2007+) (n = 534) Insured 119 (75%) Any medicaid 24 (15%) Uninsured 13 (8%) Unknown 3 (2%)
300 (80%) 56 (15%) 15 (4%) 4 (1%)
p = 0.198
Primary subsite Tongue Floor of mouth Alveolar ridge Buccal Retromolar Trigone Lips Hard palate Oral Cavity, NOS
73 (33%) 69 (31%) 27 (12%) 18 (8%) 15 (7%) 7 (3%) 4 (2%) 8 (4%)
146 (28%) 145 (28%) 78 (15%) 57 (11%) 62 (12%) 4 (0.8%) 25 (5%) 4 (0.8%)
p < 0.001
35 (16%) 122 (55%) 51 (23%) 2 (0.9%)
84 (16%) 281 (54%) 120 (23%) 5 (1%)
p = 0.989
Race White Black Asian/Pacific Islander American Indian/Alaskan Native Unknown Marital status Married Single (never married) Widowed Divorced Separated Unknown
Histologic grade I, Well differentiated II, Moderately differentiated III, Poorly differentiated IV, Undifferentiated/ Anaplastic unknown
p value
p = 0.286
11 (5%)
31 (6%)
T Classification T1 T2
119 (54%) 102 (46%)
207 (40%) 314 (60%)
p < 0.001
Survival Mean DSS (months) Mean OS (months)
78.1 61.8
105.3 79.5
p < 0.001 p < 0.001
Discussion Despite the increasing prevalence of OCSCC in the United States and its associated disease burden, there remains a lack of uniform consensus regarding the treatment of T1-2N1 OCSCC. Current utilization of adjuvant radiation therapy in this patient population continues to rely largely on individual clinician discretion. Thus, there remains wide variability in its use. Presently, there is conflicting evidence regarding response to adjuvant radiation therapy in different clinical stages. Prior studies have demonstrated improved survival in patients with T2N1 tumors for which adjuvant therapy was used, but this survival benefit has not been shown for patients with T1N1 tumors at the population level. To our knowledge no prior studies have assessed the treatment trends associated with adjuvant radiation therapy use in T1-2N1
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Survival Function
1
Proportion Surviving
0.8
0.6
0.4
No Radiation
0.2
Radiation
p<0.001
0 0
10
20
30
40
50
60
Disease Specific Survival (months) Fig. 1. Disease-specific survival comparing patients that received adjuvant radiation therapy and those that did not for T1N1 oral cavity cancer.
with greater mortality from head and neck cancers [32–36]. Reduced survival in OCSCC regardless of stage at presentation has been demonstrated in Black patients, as well [32–36]. Poorer outcomes in these patients may be due to reduced access to healthcare, increased use of tobacco and alcohol, or education status [32–37]. In addition, our study demonstrates that patients without a married relationship status were associated with decreased DSS and OS: single (never married), widowed, and divorced. Marriage has a protective advantage that is welldocumented across cancer literature, and married patients are more likely to undergo definitive treatment for their cancers, and they are less likely to die from their cancers [26,38–40]. There are several limitations of this study which are inherent to the study design and use of the SEER database. The data was analyzed retrospectively and treatments were not randomly assigned. Only data which was reported to the SEER database from the 18 cancer registrars
subsites. Current evidence supporting adjuvant radiation therapy by subsite is scarce, and no study could be found that has readily addressed the above findings. Previously, studies have shown that tumors of the retromolar trigone and hard palate were significantly less likely to be treated with surgery alone and that nonsurgical therapy is increasing over time [9,26–31]. These high risk subsites: buccal, retromolar trigone, and hard palate have worse survival outcomes in this population, and therefore are more likely to require adjuvant radiation therapy after surgery. Although neither race or marital status were characteristics found to be significantly associated with adjuvant radiation therapy, both were associated with poorer survival outcomes. Our study shows significantly worse DSS and OS in patients of Black ethnicity as compared to other races. These findings are congruent with existing literature showing that Black ethnicity has shown to be independently associated
Survival Function 1
Proportion Surviving
0.8
0.6
0.4
0.2
No Radiation
p=0.007
Radiation 0 0
10
20
30
40
50
60
Overall Survival (months) Fig. 2. Overall survival comparing patients that received adjuvant radiation therapy and those that did not for T1N1 oral cavity cancer. 4
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Survival Function 1
Proportion Surviving
0.8
0.6
0.4
No Radiation
0.2
p=0.009
Radiation
0 0
10
20
30
40
50
60
Disease-Specific Survival (months) Fig. 3. Disease-specific survival comparing patients that received adjuvant radiation therapy and those that did not for T2N1 oral cavity cancer.
suggests that their OCSCC and the associated treatment is the main driver of their survival, not their comorbidities. Despite the above limitations, the SEER database is thought to represent a heterogeneous population within the United States. This makes it a powerful database to assess population level treatment and utilization patterns. Furthermore, it is a valuable tool to analyze socioeconomic, patientspecific, tumor-specific, and treatment-specific factors that influence survival outcomes. Future studies are needed to further characterize patterns of use for adjuvant radiation therapy in T1-2N1 OCSCC. Although this study identified important characteristics significantly associated with adjuvant radiation utilization and survival outcomes, the full scope of which socioeconomic, geographical, and patient-specific factors which have an influence on outcomes is still unclear.
can be analyzed. In-depth information on comorbidities is lacking in the SEER database. It is likely that patient comorbidities and risk factors contribute to treatment decisions, and these are not completely defined. This information would be valuable because patients with advanced comorbidities may not be able to tolerate radiation therapy. Therefore, radiation may be withheld due to advanced comorbidities in situations where it would otherwise be recommended. Furthermore, a patient’s OS may also be significantly impacted by their advanced comorbidities, and so it is difficult to interpret OS without that data. We controlled for as many confounders as possible on our multivariate analysis. However in this situation, DSS should account for the difference in comorbidities and is a more accurate indicator of the effects of the different treatments in this situation. The fact that there is very little difference between the DSS and OS curves between the different treatment groups
Survival Function 1
Proportion Surviving
0.8
0.6
0.4
0.2 p=0.004
No Radiation Radiation 0 0
10
20
30
40
50
60
Overall Survival (months) Fig. 4. Overall survival comparing patients that received adjuvant radiation therapy and those that did not for T2N1 oral cavity cancer. 5
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Table 2 Multivariate analysis of factors affecting overall and disease specific survival for patients with T1-2N1 oral cavity cancer reported as proportional hazard ratios with 95% confidence interval (Bold represent p < 0.05). Variable
Disease-specific survival
p value
Overall survival
p value
Sex Male Female
1 [Reference] 0.98 (0.78–1.23)
p = 0.855
1 [Reference] 0.95 (0.71–1.19)
p = 0.787
1 [Reference] 1.08 (0.71–1.66) 0.72 (0.45–1.17) 1.42 (1.12–1.78)
p = 0.723 p = 0.185 p = 0.019
1 [Reference] 1.11 (0.68–1.73) 0.75 (0.52–1.19) 1.45 (1.10–1.82)
p = 0.688 p = 0.175 p = 0.022
Marital status Married Single (never married) Widowed Divorced Separated Unknown
1 [Reference] 1.50 (1.11–2.03) 1.86 (1.34–2.58) 1.61 (1.15–2.25) 1.05 (0.43–2.56) 1.20 (0.65–2.21)
p = 0.008 p < 0.001 p = 0.006 p = 0.918 p = 0.570
1 [Reference] 1.45 (1.04–2.19) 1.93 (1.41–2.76) 1.59 (1.07–2.36) 1.14 (0.50–2.42) 1.34 (0.59–2.97)
p = 0.021 p < 0.001 p = 0.027 p = 0.893 p = 0.764
Insurance status Insured Any medicaid Uninsured
1 [Reference] 0.87 (0.49–1.56) 1.47 (1.09–2.40)
p = 0.655 p = 0.012
1 [Reference] 0.82 (0.41–1.89) 1.51 (1.13–2.33)
p = 0.560 p = 0.024
Primary subsite Tongue Floor of mouth Alveolar ridge Buccal Retromolar trigone Lips Hard palate Oral Cavity, NOS
1 [Reference] 1.24 (0.93–1.65) 1.31 (0.85–2.03) 1.51 (1.03–2.22) 1.19 (0.83–1.73) 0.68 (0.44–0.92) 2.21 (1.33–3.46) 1.61 (1.15–1.92)
p = 0.146 p = 0.227 p = 0.036 p = 0.346 p = 0.014 p < 0.001 p = 0.036
1 [Reference] 1.33 (0.97–1.73) 1.23 (0.81–1.86) 1.65 (1.12–2.45) 1.03 (0.71–1.57) 0.70 (0.42–0.96) 2.15 (1.20–3.22) 1.58 (1.11–1.85)
p = 0.067 p = 0.219 p = 0.008 p = 0.219 p = 0.046 p < 0.001 p = 0.024
Histologic grade I, Well differentiated II, Moderately differentiated III, Poorly differentiated IV, Undifferentiated/Anaplastic Unknown
1 [Reference] 0.93 (0.64–1.36) 1.37 (1.02–1.93) 0.78 (0.44–2.62) 1.57 (1.08–2.62)
p = 0.718 p = 0.039 p = 0.987 p = 0.011
1 [Reference] 0.88 (0.55–1.21) 1.35 (1.09–1.87) 0.89 (0.39–2.76) 1.66 (1.21–2.34)
p = 0.680 p = 0.028 p = 0.866 p = 0.003
T Classification T1 T2
1 [Reference] 1.35 (1.07–1.69)
p = 0.011
1 [Reference] 1.43 (1.13–1.75)
p = 0.007
Treatment group No adjuvant radiation Adjuvant radiation
1 [Reference] 0.62 (0.47–0.81)
p < 0.001
1 [Reference] 0.63 (0.50–0.80)
p < 0.001
Race White American Indian/Alaskan Native Asian/Pacific Islander Black Unknown
Adjuvant Radiation Utilization 100% 90% 80% 70% 60% 50% 40% 30% T1N1
20%
T2N1
10% 0% 2004-2006
2007-2010
2011-2013
Year of Diagnosis
Fig. 5. Time trend illustrating the percentage utilization of adjuvant radiation over the time period studied comparing T1N1 tumors versus T2N1 tumors. 6
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Conclusions
[16] Liao C-T, Wang H-M, Chang JT-C, et al. Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity. Cancer 2007;110(7):1501–8. https://doi.org/10.1002/cncr.22959. [17] Chow TL, Chow TK, Chan TTF, Yu NF, Fung SC, Lam SH. Contralateral neck recurrence of squamous cell carcinoma of oral cavity and oropharynx. J Oral Maxillofac Surg 2004;62(10):1225–8. https://doi.org/10.1016/j.joms.2004.03. 013. [18] Liu C-H, Chen H-J, Wang P-C, Chen H-S, Chang Y-L. Patterns of recurrence and second primary tumors in oral squamous cell carcinoma treated with surgery alone. Kaohsiung J Med Sci 2013;29(10):554–9. https://doi.org/10.1016/j.kjms.2013.03. 001. [19] Pfister DG, Ang K, Burntess BA, Cmelak AJ, Colevas D, Dunphy F. Head and neck cancers. J Natl Compreh Cancer Netw 2011;9(6). Retrieved January 31, 2018. [20] Kao J, Lavaf A, Teng MS, Huang D, Genden EM. Adjuvant radiotherapy and survival for patients with node-positive head and neck cancer: an analysis by primary site and nodal stage. Int J Radiat Oncol Biol Phys 2008;71(2):362–70. [21] Shrime MG, Gullane PJ, Dawson L, et al. The impact of adjuvant radiotherapy on survival in T1–2N1 squamous cell carcinoma of the oral cavity. Arch Otolaryngol Head Neck Surg 2010;136:225–8. [22] Chen MM, Harris JP, Hara W, Sirjani D, Divi V. Association of postoperative radiotherapy with survival in patients with N1 oral cavity and oropharyngeal squamous cell carcinoma. JAMA Otolaryngol-Head Neck Surg 2016;142(12):1224. https://doi.org/10.1001/jamaoto.2016.3519. [23] Chen MM, Roman SA, Yarbrough WG, Burtness BA, Sosa JA, Judson BL. Trends and variations in the use of adjuvant therapy for patients with head and neck cancer. Cancer 2014;120(21):3353–60. https://doi.org/10.1002/cncr.28870. [24] Kwok J, Langevin SM, Argiris A, Grandis JR, Gooding WE, Taioli E. The impact of health insurance status on the survival of patients with head and neck cancer. Cancer 2010;116(2):476–85. https://doi.org/10.1002/cncr.24774. [25] Weyh AM, Lunday L, Mcclure S. Insurance status, an important predictor of oral cancer surgery outcomes. J Oral Maxillofacial Surg 2015;73(10):2049–56. https:// doi.org/10.1016/j.joms.2015.04.028. [26] Cannon R, Sowder J, Monroe M, et al. Increasing use of nonsurgical therapy in advanced-stage oral cavity cancer: a population-based study. Head Neck [serial online] 2017;39(1):82–91. Available from: MEDLINE Complete, Ipswich, MA. Accessed April 5, 2018. [27] Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for floor-ofmouth cancer. Laryngoscope 2000;110(10 Pt 1):1764–72. [28] Camilon PR, Stokes WA, Fuller CW, Nguyen SA, Lentsch EJ. Does buccal cancer have worse prognosis than other oral cavity cancers? Laryngoscope 2014;124:1386–91. [29] Ayad T, Gelinas M, Guertin L, et al. Retromolar trigone carcinoma treated by primary radiation therapy: an alternative to the primary surgical approach. Arch Otolaryngol Head Neck Surg 2005;131:576–82. [30] Byers RM, Anderson B, Schwarz EA, Fields RS, Meoz R. Treatment of squamous carcinoma of the retromolar trigone. Am J Clin Oncol 1984;7:647–52. [31] Lee KH, Veness MJ, Pearl-Larson T, Morgans GJ. Role of combined modality treatment of buccal mucosa squamous cell carcinoma. Aust Dent J 2005;50(2):108–13. [32] Gourin CG, Podolsky RH. Racial disparities in patients with head and neck squamous cell carcinoma. Laryngoscope 2006;116:1093–106. [33] Weatherspoon DJ, Chattopadhyay A, Boroumand S, Garcia AI. Oral cavity and oropharyngeal cancer incidence trends and disparities in the United States: 2000–2010. Cancer Epidemiol 2015;39(4):497–504. https://doi.org/10.1016/j. canep.2015.04.007. [34] Chen LM, Li G, Reitzel LR, et al. Matched-pair analysis of race or ethnicity in outcomes of head and neck cancer patients receiving similar multidisciplinary care. Cancer Prev Res (Phila) 2009;2:782–91. [35] Morse DE, Kerr AR. Disparities in oral and pharyngeal cancer incidence, mortality and survival among black and white Americans. J Am Dent Assoc 2006;137:203–12. [36] Ragin CC, Langevin SM, Marzouk M, Grandis J, Taioli E. Determinants of head and neck cancer survival by race. Head Neck 2011;33:1092–8. [37] Osazuwa-Peters N, Adjei Boakye E, Hussaini AS, et al. Characteristics and predictors of oral cancer knowledge in a predominantly African American community. Plos One 2017;12(5):e0177787. https://doi.org/10.1371/journal.pone.0177787. [38] Aizer AA, Chen MH, McCarthy EP, et al. Marital status and survival in patients with cancer. J Clin Oncol 2013;31:3869–76. [39] Rendall MS, Weden MM, Favreault MM, Waldron H. The protective effect of marriage for survival: a review and update. Demography 2011;48:481–506. [40] Inverso G, Mahal BA, Aizer AA, Donoff RB, Chau NG, Haddad RI. Marital status and head and neck cancer outcomes. Cancer 2015;121:1273–8.
Adjuvant radiation therapy is independently associated with a significant survival benefit for patients with both T1N1 and T2N1 OCSCC. For unclear reasons, patients with T1N1 cancer are less likely to receive adjuvant radiation and utilization has been declining. Clinical stage, tumor subsite, and patient-specific factors such as insurance status likely influence the decision to utilize adjuvant radiation therapy. Clinical stage, tumor subsite, and patient-specific factors such as race, relationship status, and insurance status likely influence survival outcomes. Support/Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest None of the authors have a conflict of interest. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: A Cancer J Clin 2015;65:5–29. https://doi.org/10.3322/caac.21254. [2] American Cancer Society. Cancer Facts & Figures 2018. Available at: < http:// www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2018/ > [accessed January 5, 2018]. [3] Rivera C. Essentials of oral cancer. Int J Clin Exp Path 2015;8(9):11884–94. [4] Montero PH, Patel SG. Cancer of the oral cavity. Surg Oncol Clin N Am 2015;24(3):491–508. https://doi.org/10.1016/j.soc.2015.03.006. [5] Spinelli JJ. Epidemiology of smoking-related malignancies. Can Fam Phys 1990;36:940–2. [6] Shiboski CH, Shiboski SC, Silverman S. Trends in oral cancer rates in the United States, 1973–1996. Commun Dent Oral Epidemiol 2000;28(4):249–56. https://doi. org/10.1034/j.1600-0528.2000.280402.x. [7] Shiboski CH, Schmidt BL, Jordan RCK. Tongue and tonsil carcinoma. Cancer 2005;103(9):1843–9. https://doi.org/10.1002/cncr.20998. [8] Patel SC, Carpenter WR, Tyree S, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, Age 18 to 44 Years. J Clin Oncol 2011;29(11):1488–94. https://doi.org/10.1200/jco.2010.31.7883. [9] Funk GF, Karnell LH, Robinson RA, Zhen WK, Trask DK, Hoffman HT. Presentation, treatment, and outcome of oral cavity cancer: a national cancer data base report. Head Neck 2002;24(2):165–80. https://doi.org/10.1002/hed.10004. [10] Courtiss EH, Kalnins IK. Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity. Plastic Reconstruct Surg 1978;61(5). https://doi.org/10.1097/00006534-197805000-00042. [11] Han J, Noble A, Reddy C, et al. The incidence and patterns of failure in patients with stage I/II squamous cell carcinoma of the oral cavity (SCC-OC) treated with surgery alone: implications for adjuvant radiation therapy. Int J Radiation Oncol*Biol*Phys 2013;87(2). https://doi.org/10.1016/j.ijrobp.2013.06.1138. [12] Northrop M, Fletcher GH, Jesse RH, Lindberg RD. Evolution of neck disease in patients with primary squamous cell carcinoma of the oral tongue, floor of mouth, and palatine arch, and clinically positive neck nodes neither fixed nor bilateral. Cancer 1972;29(1):23–30. https://doi.org/10.1002/1097-0142(197201) 29:1<23::aid-cncr2820290104>3.0.co;2-y. [13] Buck G, Huguenin P, Stoeckli SJ. Efficacy of neck treatment in patients with head and neck squamous cell carcinoma. Head Neck 2007;30(1):50–7. https://doi.org/ 10.1002/hed.20657. [14] Woolgar JA, Scott J, Vaughan ED, Brown JS, West CR, Rogers S. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Ann R Coll Surg Engl 1995;77(5):325–31. [15] Huang SH, Hwang D, Lockwood G, Goldstein DP, Osullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. Cancer 2009;115(7):1489–97. https://doi.org/10.1002/cncr. 24161.
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Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Adjuvant radiation for T1-2N1 oral cavity cancer survival outcomes and utilization treatment trends: Analysis of the SEER database
T
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Vanessa Torrecillasa, , Hailey M. Shepherda, Sam Francisb, Luke O. Buchmanna, Marcus M. Monroea, Shane Lloydb, Donald Cannonb, Ying J. Hitchcockb, John R. Weisc, Jason P. Hunta, Jeffrey J. Houltond, Richard B. Cannona a
The University of Utah School of Medicine, Otolaryngology Head and Neck Surgery, 50 North Medical Drive 3C-120, Salt Lake City, UT 84132, USA The University of Utah School of Medicine, Department of Radiation Oncology, 1950 Circle of Hope, Salt Lake City, UT 84112, USA c The University of Utah School of Medicine, Division of Oncology, 1950 Circle of Hope, Salt Lake City, UT 84112, USA d The University of Washington School of Medicine, Department of Otolaryngology-Head and Neck Surgery, Seattle, WA, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Adjuvant radiation Oral cavity cancer Survival outcomes Overall survival Disease-specific survival SEER database Population-based study Utilization Treatment trends Improved survival
Objective: Evaluate current practice patterns in the use of adjuvant radiation for T1-2N1 OCSCC patients and investigate its efficacy in the population-based setting. Materials and methods: This study extracted patients who were treated surgically for T1N1 and T2N1 OCSCC without adverse nodal features from the SEER database from 2004 to 2013. Patients with distant metastatic disease, unknown surgery or radiation status, or prior malignancies were excluded. Patients were divided into those who underwent surgical resection with and without adjuvant radiation. Disease-specific survival (DSS) and overall survival (OS) were the primary outcomes measured. Results: 746 patients met inclusion criteria and 70% received adjuvant radiation therapy. Treatment with adjuvant radiation therapy was significantly associated with improved 5-year DSS (65% versus 51%; p < 0.001) and OS (54% versus 44%; p = 0.007) for T1N1 tumors. Likewise, improved 5-year DSS (58% versus 38%; p = 0.009) and OS (48% versus 28%; p = 0.004) was shown in T2N1 tumors. Patients with T2N1 tumors wer significantly more likely to receive adjuvant radiation (75% versus 63%; p < 0.001). Those with insurance and high risk primary subsites: buccal, retromolar trigone, and hard palate were more likely to receive adjuvant radiation. The percent utilization of adjuvant radiation remained constant through the study period for T2N1 tumors (72–74%) but significantly decreased for T1N1 (71–55%) (p = 0.047). Conclusion: Adjuvant radiation therapy is independently associated with a significant survival benefit for patients with both T1N1 and T2N1 OCSCC. However, this study demonstrates that patients with T1N1 cancer are less likely to receive adjuvant radiation and utilization is decreasing.
Introduction In the United States each year, there are an estimated 49,670 new cases and 9700 deaths from oral cavity and oropharyngeal cancers [1,2]. Tobacco and alcohol use are known risk factors for development of squamous cell carcinomas of the oral cavity and oropharynx and when used in concurrence, they have a synergistic effect on cancer development [3–5]. In particular, the incidence of oral cavity squamous cell carcinomas (OCSCC) continues to rise, particularly among black males and white females, and the disease burden remains a significant national public health concern [6–10]. In any head and neck squamous cell carcinoma, it is well known that
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nodal metastasis is a strong predictor of locoregional recurrence, distant metastasis, and survival [11–18]. However, in cases where there is metastasis to just one ipsilateral node without adverse features such as positive margins, extracapsular invasion, or perineural invasion, it has been unclear whether adjuvant radiation therapy improves these survival outcomes. The National Comprehensive Cancer Network (NCCN) provides up to date clinical practice guidelines for treatment of oral cavity cancers based on clinical and pathologic staging algorithms. Currently, for T1-2M0 OCSCC, the NCCN definitively recommends primary surgical excision with or without neck dissection. However, if on pathology there is just one positive node without adverse features, the decision to pursue adjuvant radiation is based on the surgeon’s
Corresponding author at: The University of Utah, Otolaryngology Head and Neck Surgery, 50 North Medical Dr., SOM 3C-120, Salt Lake City, UT 84132, USA. E-mail address: [email protected] (V. Torrecillas).
https://doi.org/10.1016/j.oraloncology.2018.07.019 Received 29 May 2018; Received in revised form 20 July 2018; Accepted 29 July 2018 1368-8375/ Published by Elsevier Ltd.
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judgement [19]. This flexibility in clinical guidelines for adjuvant radiation therapy arises from a nonuniform NCCN consensus due to a low level of evidence regarding adjuvant radiation in N1 classification OCSCC. Recent literature has contributed to the growing pool of evidence supporting the use of adjuvant radiation therapy in patients with T12N1 oral cavity cancer. A study of the Surveillance, Epidemiology, and End Results (SEER) database by Kao et al showed statistically significant increases in overall survival associated with adjuvant radiation for all SCC nodal groups, including N1 disease [20]. However, an analysis by subsite failed to show significant improvement in overall survival for patients with OCSCC of any stage and nodal positivity treated with adjuvant radiation. This study did not specifically evaluate T1-2N1 OCSCC. Another retrospective review of the SEER database from 1983 to 2004 by Shrime et al demonstrated that adjuvant radiation significantly improved overall survival and disease specific survival in patients with T2N1 OCSCC, however their data failed to achieve statistical significance in T1N1 disease [21]. A study with similar aims was then conducted in a review of the National Cancer Database (NCDB) from 2004 to 2013 by Chen et al. [22]. These investigators found that adjuvant radiation significantly improved overall survival in patients with both T1N1 and T2N1 OCSCC, especially in those younger than 70 years of age and in those with T2 disease, however the NCDB is not designed to represent the US population and has an inherit bias of accredited cancer facilities. Overall, the currently published studies demonstrate statistically significant improvement in outcomes for T2N1 OCSCC treated with adjuvant radiation. While evidence suggests there is some survival advantage for T1N1 cancers, this is not strongly demonstrated. Patterns of use for adjuvant radiation are also not well defined in the literature. It is currently not clear what systems, socioeconomic, and patientspecific factors are associated with adjuvant radiation use in T1-2N1 OCSCC. The primary objectives of this study were to, first, use the SEER database to investigate utilization patterns for adjuvant radiation for T1-2N1 OCSCC patients, second, investigate its efficacy in the population-based setting, and finally, to examine factors associated with adjuvant radiation therapy use and survival outcomes.
surgically for T1N1 and T2N1 disease were extracted from the database and the use of adjuvant radiation was compared to those not treated with adjuvant radiation. Clinical and pathologic data, survival outcomes, and recurrences were extracted. Insurance status was collected from years in which it was available, from 2007 to 2013. The percent utilization of adjuvant radiation was analyzed and compared over time. Overall survival (OS) and disease-specific survival (DSS) were calculated.
Statistical analysis Descriptive statistics were performed by independent t-tests and the Mann-Whitney U test for mean comparisons of variables with two groupings. For variables with groupings of three or more, a one-way ANOVA test was utilized. Chi square and Fisher’s exact test were used to analyze categorical variables. Univariate survival estimates were generated by the Kaplan-Meier method and compared with the log-rank test. Multivariate survival analysis was performed using the Cox proportional hazard regression model, utilizing all variables approaching significance (p ≤ 0.2) to control for confounding covariates. Statistical analysis was performed using XLSTAT (version 2018.2, Addinsoft). All tests were two-tailed, and results were considered significant for p ≤ 0.05.
Results There were 746 patients who met inclusion criteria. The average age was 63, 80% of patients were white, and 67% were male. Complete patient demographics, tumor characteristics, and treatment details are summarized in Table 1, as well as factors associated with treatment with adjuvant radiation. Insurance status category was not significantly different between the two cohorts (p = 0.198), however, analyzing the percentage of uninsured patients that received adjuvant radiation versus those that did not receive adjuvant radiation resulted in a significant difference (4.0% versus 8.3%; p = 0.045). Utilization of adjuvant radiation therapy was statistically significantly higher in high risk subsites: buccal, retromolar trigone, and hard palate (p < 0.001). Age (p = 0.286), sex (p = 0.741), race (p = 0.944), marital status (p = 0.990), and histological grade (p = 0.989) were not significantly different between the two treatment cohorts. Treatment with adjuvant radiation therapy was significantly associated with improved 5-year DSS (65% versus 51%; p < 0.001) and OS (54% versus 44%; p = 0.007) for patients with T1N1 tumors (Figs. 1 and 2, respectively). Treatment with adjuvant radiation therapy was also significantly associated with improved 5-year DSS (58% versus 38%; p = 0.009) and OS (48% versus 28%; p = 0.004) for patients with T2N1 tumors (Figs. 3 and 4, respectively). Multivariate analysis demonstrated that adjuvant radiation was an independent factor associated with improved DSS (HR: 0.62 [0.47–0.81]; p < 0.001) and OS (HR: 0.63 [0.50–0.80]; p < 0.001) after controlling for other known covariates (Table 2). In addition, Black ethnicity, unmarried status (single, widowed, or divorced), uninsured status, subsites including buccal, hard palate, oral cavity, and NOS subsites, poorly differentiated histology, and T2 classification were independent factors associated with a reduction in both DSS and OS. Patients with T2N1 tumors were significantly more likely to receive adjuvant radiation than patients with T1N1 tumors (75% versus 63%; p < 0.001). The percent utilization of adjuvant radiation has remained constant for T2N1 OCSCC: from 72% averaged over the first 3 years of the study (2004–2006) to 76% (2007–2010) to 74% (2011–2013). On the contrary, the percent utilization of adjuvant radiation has significantly decreased for T1N1 OCSCC: from 71% averaged over the first 3 years of the study (2004–2006) to 60% (2007–2010) to 55% (2011–2013) (p = 0.047) (Fig. 5).
Materials and methods Data source The SEER Program Database is a population- based registry of the National Cancer Institute that currently collects data from approximately 28% of the US population. Data is collected prospectively from registries and includes incidence and population data associated by age, sex, race, year of diagnosis, and geographic areas. During the time of our study period, the 7th edition of the SEER database was used, and there were 18 registries reporting data. These registries included Atlanta, Los Angeles, San Francisco-Oakland, Seattle-Puget Sound, San Jose-Monterey, Rural Georgia, Greater Georgia, Greater California, the Alaska Native Tumor Registry, and the states of Connecticut, Detroit, Hawaii, Iowa, Kentucky, Louisiana, New Jersey, New Mexico, and Utah. This study was exempt from the University of Utah institutional review board approval. Study populations and outcomes Study population and outcomes of all patients with resectable T1N1 and T2N1 OCSCC without adverse nodal features were extracted from the SEER database from 2004 to 2013 using the AJCC Staging 7th Edition. Patients with distant metastatic disease, those with unknown surgery or radiation status, and patients with previous malignancies were excluded. There were 746 patients who met this inclusion criteria. Treatment groups included surgical resection without adjuvant radiation and surgical resection with adjuvant radiation. Patients treated 2
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OCSCC. Furthermore, there is scant data addressing socioeconomic and clinicopathologic factors which may influence the decision to utilize radiotherapy in this patient population. Our study demonstrates a clear survival benefit in patients with T12N1 OCSCC who underwent post-operative adjuvant radiation therapy. A statistically significant improvement in DSS and OS was found for patients with T2N1 OCSCC, which has been illustrated in prior studies [20–22]. Notably, this study also demonstrated a statistically significant improvement in DSS and OS for T1N1 OCSCC with adjuvant radiation therapy. This differs from previous studies which demonstrated no improvement or non-statistically significant improvement [20–22]. These disparities in outcomes may be due to differences in study design (Kao et al evaluated nodal stages but did not evaluate outcomes with tumor stage and nodal stage together), differences in data reporting to NCDB (Chen) versus SEER, or differences in study populations (this study included patients from the SEER database from 2004 to 2013 versus the study by Shrime which included patients from 1983 to 2004) [20–22]. It is important to note that although data from NCDB is very valuable, it is not designed to represent the US population and has an inherit bias of accredited cancer facilities. SEER data is populationbased and our results reinforces the survival benefit of adjuvant radiation therapy when utilized for T1-2N1 disease, with improvements in both DSS and OS. Our study also analyzed patterns in utilization of adjuvant radiation therapy for T1-2N1 OCSCC. We found that patients with T1N1 tumors received less radiation therapy than those with T2N1 disease. T2N1 tumors were about 1.2 times more likely to be treated with adjuvant radiation therapy, and this was statistically significant. Furthermore, our findings indicate a substantial decline in the utilization of adjuvant radiation in T1N1 tumors over the past 10 years. The reason for this decline is unclear. Of note, the study published by Shrime et al which reported no statistically significant improvement in survival from adjuvant radiation in T1N1 tumors coincides with this timeline [21]. It is possible this study may have negatively influenced use of adjuvant radiation therapy following this publication, and thus contributed to the continued decline in utilization for this population. Also, this treatment trend corresponds to the intense de-escalation of therapy for HPV positive oropharyngeal cancers, however these two cancers are clearly different entities and require different treatment. By conducting an analysis of patient and tumor characteristics, we discovered several factors associated with increased utilization of adjuvant radiation therapy: insurance status, tumor subsite, and clinical stage. Other factors such as age (p = 0.286), sex (p = 0.784), race (0.944), marital status (p = 0.990), and histologic grade (p = 0.989) did not appear to significantly influence the decision to pursue adjuvant radiation therapy. Association between insurance status and adjuvant radiation therapy in patients with head and neck cancer is not well documented, and there is a paucity of data regarding insurance status and outcomes in T1-2N1 OCSCC. However, it has been shown that patients who are uninsured or insured by Medicare/Medicaid have a higher incidence of postoperative complications and reduced survival from head and neck cancer than patients who have private insurance [23–25]. Our study demonstrates that uninsured patients with T1-2N1 OCSCC are less likely to undergo adjuvant radiation therapy than patients with any Medicaid or private insurance, and these patients who were not treated with adjuvant radiation had decreased DSS and OS. Therefore, it may be hypothesized that patients with T1-2N1 OCSCC who are uninsured are at risk for increased morbidity and mortality given lower rates of use of adjuvant radiation therapy. Our study found a statistically significant higher use of adjuvant radiation therapy based on tumor subsite with the most use in tumors of buccal, retromolar trigone, and hard palate origin. Of note, our study also demonstrated a significant reduction in DSS and OS in buccal and hard palate tumors as compared with other subsites. DSS and OS for retromolar trigone tumors were not significantly different than other
Table 1 Patient demographics, tumor characteristic, and treatment factors for patients with T1-2N1 oral cavity cancer and their association with utilization of adjuvant radiation (Bold represent p < 0.05). Number of patients (%) (n = 742) Characteristics
No adjuvant radiation
Adjuvant radiation utilized
Overall Average Age
221 (30%) 62.3
521 (70%) 61.1
Sex Male Female
141 (64%) 80 (36%)
339 (65%) 182 (35%)
p = 0.741
183 (83%) 24 (11%) 11 (5%) 1 (0.5%)
422 (81%) 62 (12%) 31 (6%) 3 (0.6%)
p = 0.944
2 (0.9%)
3 (0.6%)
106 (48%) 40 (18%) 35 (16%) 33 (15%) 4 (2%) 3 (1%)
245 (47%) 94 (18%) 89 (17%) 73 (14%) 10 (2%) 10 (2%)
p = 0.990
Insurance status (available 2007+) (n = 534) Insured 119 (75%) Any medicaid 24 (15%) Uninsured 13 (8%) Unknown 3 (2%)
300 (80%) 56 (15%) 15 (4%) 4 (1%)
p = 0.198
Primary subsite Tongue Floor of mouth Alveolar ridge Buccal Retromolar Trigone Lips Hard palate Oral Cavity, NOS
73 (33%) 69 (31%) 27 (12%) 18 (8%) 15 (7%) 7 (3%) 4 (2%) 8 (4%)
146 (28%) 145 (28%) 78 (15%) 57 (11%) 62 (12%) 4 (0.8%) 25 (5%) 4 (0.8%)
p < 0.001
35 (16%) 122 (55%) 51 (23%) 2 (0.9%)
84 (16%) 281 (54%) 120 (23%) 5 (1%)
p = 0.989
Race White Black Asian/Pacific Islander American Indian/Alaskan Native Unknown Marital status Married Single (never married) Widowed Divorced Separated Unknown
Histologic grade I, Well differentiated II, Moderately differentiated III, Poorly differentiated IV, Undifferentiated/ Anaplastic unknown
p value
p = 0.286
11 (5%)
31 (6%)
T Classification T1 T2
119 (54%) 102 (46%)
207 (40%) 314 (60%)
p < 0.001
Survival Mean DSS (months) Mean OS (months)
78.1 61.8
105.3 79.5
p < 0.001 p < 0.001
Discussion Despite the increasing prevalence of OCSCC in the United States and its associated disease burden, there remains a lack of uniform consensus regarding the treatment of T1-2N1 OCSCC. Current utilization of adjuvant radiation therapy in this patient population continues to rely largely on individual clinician discretion. Thus, there remains wide variability in its use. Presently, there is conflicting evidence regarding response to adjuvant radiation therapy in different clinical stages. Prior studies have demonstrated improved survival in patients with T2N1 tumors for which adjuvant therapy was used, but this survival benefit has not been shown for patients with T1N1 tumors at the population level. To our knowledge no prior studies have assessed the treatment trends associated with adjuvant radiation therapy use in T1-2N1
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Survival Function
1
Proportion Surviving
0.8
0.6
0.4
No Radiation
0.2
Radiation
p<0.001
0 0
10
20
30
40
50
60
Disease Specific Survival (months) Fig. 1. Disease-specific survival comparing patients that received adjuvant radiation therapy and those that did not for T1N1 oral cavity cancer.
with greater mortality from head and neck cancers [32–36]. Reduced survival in OCSCC regardless of stage at presentation has been demonstrated in Black patients, as well [32–36]. Poorer outcomes in these patients may be due to reduced access to healthcare, increased use of tobacco and alcohol, or education status [32–37]. In addition, our study demonstrates that patients without a married relationship status were associated with decreased DSS and OS: single (never married), widowed, and divorced. Marriage has a protective advantage that is welldocumented across cancer literature, and married patients are more likely to undergo definitive treatment for their cancers, and they are less likely to die from their cancers [26,38–40]. There are several limitations of this study which are inherent to the study design and use of the SEER database. The data was analyzed retrospectively and treatments were not randomly assigned. Only data which was reported to the SEER database from the 18 cancer registrars
subsites. Current evidence supporting adjuvant radiation therapy by subsite is scarce, and no study could be found that has readily addressed the above findings. Previously, studies have shown that tumors of the retromolar trigone and hard palate were significantly less likely to be treated with surgery alone and that nonsurgical therapy is increasing over time [9,26–31]. These high risk subsites: buccal, retromolar trigone, and hard palate have worse survival outcomes in this population, and therefore are more likely to require adjuvant radiation therapy after surgery. Although neither race or marital status were characteristics found to be significantly associated with adjuvant radiation therapy, both were associated with poorer survival outcomes. Our study shows significantly worse DSS and OS in patients of Black ethnicity as compared to other races. These findings are congruent with existing literature showing that Black ethnicity has shown to be independently associated
Survival Function 1
Proportion Surviving
0.8
0.6
0.4
0.2
No Radiation
p=0.007
Radiation 0 0
10
20
30
40
50
60
Overall Survival (months) Fig. 2. Overall survival comparing patients that received adjuvant radiation therapy and those that did not for T1N1 oral cavity cancer. 4
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Survival Function 1
Proportion Surviving
0.8
0.6
0.4
No Radiation
0.2
p=0.009
Radiation
0 0
10
20
30
40
50
60
Disease-Specific Survival (months) Fig. 3. Disease-specific survival comparing patients that received adjuvant radiation therapy and those that did not for T2N1 oral cavity cancer.
suggests that their OCSCC and the associated treatment is the main driver of their survival, not their comorbidities. Despite the above limitations, the SEER database is thought to represent a heterogeneous population within the United States. This makes it a powerful database to assess population level treatment and utilization patterns. Furthermore, it is a valuable tool to analyze socioeconomic, patientspecific, tumor-specific, and treatment-specific factors that influence survival outcomes. Future studies are needed to further characterize patterns of use for adjuvant radiation therapy in T1-2N1 OCSCC. Although this study identified important characteristics significantly associated with adjuvant radiation utilization and survival outcomes, the full scope of which socioeconomic, geographical, and patient-specific factors which have an influence on outcomes is still unclear.
can be analyzed. In-depth information on comorbidities is lacking in the SEER database. It is likely that patient comorbidities and risk factors contribute to treatment decisions, and these are not completely defined. This information would be valuable because patients with advanced comorbidities may not be able to tolerate radiation therapy. Therefore, radiation may be withheld due to advanced comorbidities in situations where it would otherwise be recommended. Furthermore, a patient’s OS may also be significantly impacted by their advanced comorbidities, and so it is difficult to interpret OS without that data. We controlled for as many confounders as possible on our multivariate analysis. However in this situation, DSS should account for the difference in comorbidities and is a more accurate indicator of the effects of the different treatments in this situation. The fact that there is very little difference between the DSS and OS curves between the different treatment groups
Survival Function 1
Proportion Surviving
0.8
0.6
0.4
0.2 p=0.004
No Radiation Radiation 0 0
10
20
30
40
50
60
Overall Survival (months) Fig. 4. Overall survival comparing patients that received adjuvant radiation therapy and those that did not for T2N1 oral cavity cancer. 5
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Table 2 Multivariate analysis of factors affecting overall and disease specific survival for patients with T1-2N1 oral cavity cancer reported as proportional hazard ratios with 95% confidence interval (Bold represent p < 0.05). Variable
Disease-specific survival
p value
Overall survival
p value
Sex Male Female
1 [Reference] 0.98 (0.78–1.23)
p = 0.855
1 [Reference] 0.95 (0.71–1.19)
p = 0.787
1 [Reference] 1.08 (0.71–1.66) 0.72 (0.45–1.17) 1.42 (1.12–1.78)
p = 0.723 p = 0.185 p = 0.019
1 [Reference] 1.11 (0.68–1.73) 0.75 (0.52–1.19) 1.45 (1.10–1.82)
p = 0.688 p = 0.175 p = 0.022
Marital status Married Single (never married) Widowed Divorced Separated Unknown
1 [Reference] 1.50 (1.11–2.03) 1.86 (1.34–2.58) 1.61 (1.15–2.25) 1.05 (0.43–2.56) 1.20 (0.65–2.21)
p = 0.008 p < 0.001 p = 0.006 p = 0.918 p = 0.570
1 [Reference] 1.45 (1.04–2.19) 1.93 (1.41–2.76) 1.59 (1.07–2.36) 1.14 (0.50–2.42) 1.34 (0.59–2.97)
p = 0.021 p < 0.001 p = 0.027 p = 0.893 p = 0.764
Insurance status Insured Any medicaid Uninsured
1 [Reference] 0.87 (0.49–1.56) 1.47 (1.09–2.40)
p = 0.655 p = 0.012
1 [Reference] 0.82 (0.41–1.89) 1.51 (1.13–2.33)
p = 0.560 p = 0.024
Primary subsite Tongue Floor of mouth Alveolar ridge Buccal Retromolar trigone Lips Hard palate Oral Cavity, NOS
1 [Reference] 1.24 (0.93–1.65) 1.31 (0.85–2.03) 1.51 (1.03–2.22) 1.19 (0.83–1.73) 0.68 (0.44–0.92) 2.21 (1.33–3.46) 1.61 (1.15–1.92)
p = 0.146 p = 0.227 p = 0.036 p = 0.346 p = 0.014 p < 0.001 p = 0.036
1 [Reference] 1.33 (0.97–1.73) 1.23 (0.81–1.86) 1.65 (1.12–2.45) 1.03 (0.71–1.57) 0.70 (0.42–0.96) 2.15 (1.20–3.22) 1.58 (1.11–1.85)
p = 0.067 p = 0.219 p = 0.008 p = 0.219 p = 0.046 p < 0.001 p = 0.024
Histologic grade I, Well differentiated II, Moderately differentiated III, Poorly differentiated IV, Undifferentiated/Anaplastic Unknown
1 [Reference] 0.93 (0.64–1.36) 1.37 (1.02–1.93) 0.78 (0.44–2.62) 1.57 (1.08–2.62)
p = 0.718 p = 0.039 p = 0.987 p = 0.011
1 [Reference] 0.88 (0.55–1.21) 1.35 (1.09–1.87) 0.89 (0.39–2.76) 1.66 (1.21–2.34)
p = 0.680 p = 0.028 p = 0.866 p = 0.003
T Classification T1 T2
1 [Reference] 1.35 (1.07–1.69)
p = 0.011
1 [Reference] 1.43 (1.13–1.75)
p = 0.007
Treatment group No adjuvant radiation Adjuvant radiation
1 [Reference] 0.62 (0.47–0.81)
p < 0.001
1 [Reference] 0.63 (0.50–0.80)
p < 0.001
Race White American Indian/Alaskan Native Asian/Pacific Islander Black Unknown
Adjuvant Radiation Utilization 100% 90% 80% 70% 60% 50% 40% 30% T1N1
20%
T2N1
10% 0% 2004-2006
2007-2010
2011-2013
Year of Diagnosis
Fig. 5. Time trend illustrating the percentage utilization of adjuvant radiation over the time period studied comparing T1N1 tumors versus T2N1 tumors. 6
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Conclusions
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Adjuvant radiation therapy is independently associated with a significant survival benefit for patients with both T1N1 and T2N1 OCSCC. For unclear reasons, patients with T1N1 cancer are less likely to receive adjuvant radiation and utilization has been declining. Clinical stage, tumor subsite, and patient-specific factors such as insurance status likely influence the decision to utilize adjuvant radiation therapy. Clinical stage, tumor subsite, and patient-specific factors such as race, relationship status, and insurance status likely influence survival outcomes. Support/Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest None of the authors have a conflict of interest. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: A Cancer J Clin 2015;65:5–29. https://doi.org/10.3322/caac.21254. [2] American Cancer Society. Cancer Facts & Figures 2018. Available at: < http:// www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2018/ > [accessed January 5, 2018]. [3] Rivera C. Essentials of oral cancer. Int J Clin Exp Path 2015;8(9):11884–94. [4] Montero PH, Patel SG. Cancer of the oral cavity. Surg Oncol Clin N Am 2015;24(3):491–508. https://doi.org/10.1016/j.soc.2015.03.006. [5] Spinelli JJ. Epidemiology of smoking-related malignancies. Can Fam Phys 1990;36:940–2. [6] Shiboski CH, Shiboski SC, Silverman S. Trends in oral cancer rates in the United States, 1973–1996. Commun Dent Oral Epidemiol 2000;28(4):249–56. https://doi. org/10.1034/j.1600-0528.2000.280402.x. [7] Shiboski CH, Schmidt BL, Jordan RCK. Tongue and tonsil carcinoma. Cancer 2005;103(9):1843–9. https://doi.org/10.1002/cncr.20998. [8] Patel SC, Carpenter WR, Tyree S, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, Age 18 to 44 Years. J Clin Oncol 2011;29(11):1488–94. https://doi.org/10.1200/jco.2010.31.7883. [9] Funk GF, Karnell LH, Robinson RA, Zhen WK, Trask DK, Hoffman HT. Presentation, treatment, and outcome of oral cavity cancer: a national cancer data base report. Head Neck 2002;24(2):165–80. https://doi.org/10.1002/hed.10004. [10] Courtiss EH, Kalnins IK. Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity. Plastic Reconstruct Surg 1978;61(5). https://doi.org/10.1097/00006534-197805000-00042. [11] Han J, Noble A, Reddy C, et al. The incidence and patterns of failure in patients with stage I/II squamous cell carcinoma of the oral cavity (SCC-OC) treated with surgery alone: implications for adjuvant radiation therapy. Int J Radiation Oncol*Biol*Phys 2013;87(2). https://doi.org/10.1016/j.ijrobp.2013.06.1138. [12] Northrop M, Fletcher GH, Jesse RH, Lindberg RD. Evolution of neck disease in patients with primary squamous cell carcinoma of the oral tongue, floor of mouth, and palatine arch, and clinically positive neck nodes neither fixed nor bilateral. Cancer 1972;29(1):23–30. https://doi.org/10.1002/1097-0142(197201) 29:1<23::aid-cncr2820290104>3.0.co;2-y. [13] Buck G, Huguenin P, Stoeckli SJ. Efficacy of neck treatment in patients with head and neck squamous cell carcinoma. Head Neck 2007;30(1):50–7. https://doi.org/ 10.1002/hed.20657. [14] Woolgar JA, Scott J, Vaughan ED, Brown JS, West CR, Rogers S. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Ann R Coll Surg Engl 1995;77(5):325–31. [15] Huang SH, Hwang D, Lockwood G, Goldstein DP, Osullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. Cancer 2009;115(7):1489–97. https://doi.org/10.1002/cncr. 24161.
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