Abstract
Background
A recent review of the SEER registry suggested that patients with index squamous cell carcinoma (SCC) of the oropharynx (SCCOP) are less likely to develop second primary malignancies (SPM) than patients with index SCC of non-oropharyngeal sites (oral cavity, larynx, hypopharynx). The purpose of this study was to determine the impact of index primary tumor site on SPM risk and explore factors potentially affecting this risk within a large prospectively accrued cohort of patients with index SCC of the head and neck (SCCHN).
Methods
A cohort of 2230 patients with incident SCCHN was reviewed for development of SPM. Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards models were used to detect the impact of various factors, including index tumor site, on SPM risk.
Results
The SPM rate was lower for patients with index SCCOP than for patients with index non-oropharyngeal cancer (P<.001). Among SCCOP patients, former-smokers had a 50% greater risk of SPM and current-smokers had a 100% greater risk of SPM than never-smokers (Ptrend=.008). Among SCCOP patients, those with classic SCCHN phenotype had SPM risk similar to that of patients with index non-oropharyngeal cancers; those with typical HPV phenotype had very low SPM risk. SPM most commonly occurred at non-tobacco-related sites in patients with index SCCOP and at tobacco-related sites in patients with index non-oropharyngeal cancers.
Conclusion
In patients with SCCHN, index cancer site and smoking status affect the risk and distribution of SPM.
Keywords: Head and neck neoplasms, second primary malignancy, smoking, oropharyngeal cancer, oral cancer, laryngeal cancer, human papillomavirus
INTRODUCTION
Squamous cell carcinoma of the head and neck (SCCHN) (oropharynx, oral cavity, larynx, and hypopharynx) is associated with high rates of subsequent second primary malignancy (SPM).1,2 Studies have shown that the incidence of SPM in patients with index SCCHN is 2% to 3% per year and the risk remains constant throughout the life of the patient.1,3–6 While overall survival appears to be improving for some patients with SCCHN because of an evolution in the etiology of the disease, improvements in tobacco control and cessation, and therapeutic advances, SPM remains a major problem.1,7 SPM is a leading cause of long-term mortality among SCCHN patients.2,3 The prognosis for patients who develop SPM is less favorable than the prognosis for patients with index SCCHN alone.6,8,9
A recent analysis of the Surveillance, Epidemiology, and End Results registry has revealed a dramatic shift in the rates of SPM development among patients with SCCHN: whereas patients with squamous cell carcinoma of the oropharynx (SCCOP) previously had high rates of SPM, they now have lower rates of SPM than patients with SCCHN at any other site.10 This change could be another impact of the current epidemic of SCCOP related to human papillomavirus (HPV).10–12
Smoking and alcohol use are the traditional risk factors for SCCHN.13 Smokers with SCCHN have a worse prognosis than nonsmokers,14 because smoking increases the risk of SPM development.4,6,15 In smokers with index SCCHN, the majority of cases of SPM occur in the head and neck, lung, or esophagus. 4,6,16 While the incidence of squamous cell carcinoma of the oral cavity, hypopharynx, and larynx has decreased over the past two decades, the incidence of SCCOP has been rising approximately 5% per year.10,12 At the same time, the proportion of patients with SCCOP who have a limited history of smoking or alcohol use has been increasing, and recent studies have attributed many of these cases to HPV.10,11,17 In contrast to patients with traditional HPV-negative SCCOP, patients with HPV-associated SCCOP present at a younger age with limited or no history of smoking.10,17 Furthermore, patients with HPV-associated SCCOP have a lower incidence of SPM.18,19
In light of the significant risk and increased mortality due to SPM in patients with SCCHN, it is crucial to refine our understanding of SPM risk among patients with index SCCHN to optimize screening and follow-up strategies and improve long-term outcomes. The objective of this study was to determine the impact of index cancer site on the risk of SPM and explore factors potentially affecting this risk within a large cohort of patients with incident SCCHN treated at a tertiary cancer center in the United States.
MATERIALS AND METHODS
Study Subjects
This research was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center. All patients were participants in a prospective molecular epidemiologic protocol of incident SCCHN between 1995 and 2010 and completed an epidemiologic questionnaire. Patients were included if they had previously untreated, pathologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and/or larynx (N=2524). Patients were excluded from the analysis if they were not treated at our center (N=184), received only palliative care (N=89), or had no follow-up after treatment (N=21), leaving a final sample size of 2230 patients.
Throughout their treatment and post-treatment courses, patients had regularly scheduled clinical and radiographic examinations with treating physicians (typically quarterly the first year, 4 months the second year, 6 months the third year, and then annually). On the basis of modified criteria of Warren and Gates, second lesions were considered SPMs if they were of different histopathologic type than the index tumor, occurred more than five years after treatment for the index tumor, and/or were clearly separated from the index tumor by normal epithelium as indicated by findings on clinical and radiographic assessment.20 A synchronous tumor was defined as a malignancy diagnosed at the same time as or during the staging of the index SCCHN. Pulmonary lesions were considered to be SPMs if they had a non-squamous histology or if they were isolated squamous lesions appearing more than five years after the initial SCCHN and were believed to be SPMs by the thoracic medical oncologist and the thoracic surgeon. If there was a difference of opinion or question regarding the origin of a tumor (i.e., recurrence vs. SPM), the second lesion was classified as a recurrence rather than a SPM. SPMs were then categorized as being in one of three classes: SCCHN; tobacco-related cancer, not SCCHN (cancers of the lung and bronchus, esophagus, or urinary bladder); or other. Non-melanoma skin cancers were not recorded or considered SPMs.
Statistical Analysis
Analysis was done using Stata 12 (StataCorp, College Station, TX). The threshold for statistical significance was set at P<0.05, and all tests were two-sided. The Kaplan-Meier failure function was used to calculate the 3- and 5-year rates of SPM within groups. Kaplan-Meier curves were generated to evaluate the proportion of patients with SPM, and log-rank tests were performed to detect statistically significant differences between groups. Time to event was calculated from the date of diagnosis of the index cancer to the date of diagnosis of SPM. Cox proportional hazards models were generated to calculate hazard ratios to detect differences in SPM risk according to demographic and clinical variables in subjects with index SCCOP and those with index non-oropharyngeal cancer (oral cavity, hypopharynx, larynx) as well as to detect differences in SPM risk between patients with and without the classic SCCHN phenotype and patients with and without the typical HPV phenotype. The classic SCCHN phenotype was defined as SCCHN in a male patient over age 50 years who was a current-smoker and ever-drinker. The typical HPV phenotype was defined as SCCOP in a non-Hispanic white male patient under age 60 years who was a never- or former-smoker presenting with a T1-2N1-3 tonsil or base of tongue cancer. Multivariable models were created by minimizing Akaike’s information criterion.
RESULTS
The median follow-up time for patients in the study who were still alive was 33.1 months for all patients, 36.1 months (0.1–170.8 months) for patients with SCCOP, and 28.4 months (0.1–166.8 months) for patients with non-oropharyngeal cancer. Five patients had synchronous SCCOP, seven patients had synchronous non-oropharyngeal cancers (one with synchronous oral cavity cancer, one with synchronous hypopharyngeal cancer, and five with synchronous cancers in more than one non-oropharyngeal subsite), and 19 patients had synchronous tumors of both oropharyngeal and non-oropharyngeal sites.
Relationship between Demographic and Clinical Variables and Risk of SPM
Of the 2230 patients, 236 (10.6%) developed a SPM (7.6% 3-year SPM rate)(Table 1). Older age at diagnosis of index SCCHN was associated with greater risk of SPM. The greater the level of smoking exposure as measured by pack-years or smoking status, the higher the SPM rate (Table 1). Patients with SCCOP had a lower 3-year SPM rate (5.2%) than patients with non-oropharyngeal cancer (8.3%) and a lower incidence of SPM over the course of follow-up (Figure 1). Moderate to severe comorbidity was also associated with a higher rate of SPM.
Table 1.
Factors Associated with Risk of SPM
| Variable | No. of Patients (%) | No. of Patients with SPM (Row %) | 3-year SPM Rate, % (95% CI) | 5-year SPM Rate, % (95% CI) | Log-rank P | P for trend |
|---|---|---|---|---|---|---|
| Total | 2230(100) | 236(10.6) | 7.6(6.4–9.0) | 12.9(11.1–15.0) | ||
| Age, years | <.001 | <.001 | ||||
| <45 | 240(10.8) | 12(5.0) | 2.7(1.1–6.4) | 6.9(3.5–13.4) | ||
| 45–59 | 1065(47.8) | 105(9.9) | 6.5(5.0–8.4) | 10.0(7.8–12.7) | ||
| ≥60 | 925 (41.5) | 119(12.9) | 10.2(8.1–12.8) | 18.4(14.9–22.6) | ||
| Sex | .633 | |||||
| Male | 1701(76.3) | 185(10.9) | 7.5(6.2–9.1) | 13.0(10.9–15.4) | ||
| Female | 529(23.7) | 51(9.6) | 7.8(5.6–11.0) | 12.7(9.1–17.6) | ||
| Ethnicity | .043 | |||||
| Non-Hispanic white | 1922(86.2) | 196(10.2) | 7.0(5.8–8.5) | 12.3(10.4–14.6) | ||
| Other | 308(13.8) | 40(13.0) | 11.1(7.6–16.0) | 16.8(11.7–23.7) | ||
| Smoking | <.001 | <.001 | ||||
| Never smoker | 686(30.8) | 47(6.9) | 4.2(2.7–6.3) | 8.2(5.6–11.8) | ||
| Former smoker | 708(31.8) | 71(10.0) | 6.8(4.9–9.3) | 11.5(8.7–15.2) | ||
| Current smoker | 835(37.5) | 118(14.1) | 11.2(8.9–14.0) | 18.3(14.8–22.5) | ||
| Pack-years* | <.001 | <.001 | ||||
| 1–19 | 448(29.9) | 32(7.1) | 5.4(3.3–8.5) | 7.0(4.5–10.7) | ||
| 20–39 | 385(25.7) | 43(11.2) | 8.5(5.8–12.4) | 16.4(11.5–23.2) | ||
| 40+ | 666(44.4) | 112(16.8) | 12.2(9.7–15.5) | 20.6(16.7–25.3) | ||
| Alcohol use | .011 | |||||
| Never | 597(26.8) | 48(8.0) | 6.7(4.6–9.5) | 10.0(7.1–14.1) | ||
| Ever | 1632(73.2) | 188(11.5) | 7.9(6.5–9.5) | 14.0(11.8–16.6) | ||
| Comorbidity | <.001 | |||||
| None to mild | 1957(87.8) | 198(10.1) | 7.0(5.8–8.4) | 11.7(9.8–13.8) | ||
| Moderate to severe | 273(12.2) | 38(13.9) | 12.2(8.2–17.9) | 24.2(16.7–34.2) | ||
| Index tumor site† | <.001 | |||||
| Oropharynx | 1051(47.1) | 84(8.0) | 5.2(3.9–7.1) | 8.7(6.7–11.3) | ||
| Non-oropharynx | 1160(52.0) | 133(11.5) | 8.3(6.6–10.4) | 15.8(12.9–19.3) | ||
| Synchronous at both sites | 19(0.9) | 19(100.0) | -- | -- | ||
| Histologic grade‡ | .041 | .085 | ||||
| Well or moderately well differentiated | 265(13.6) | 28(10.6) | 5.9(3.4–10.3) | 16.1(10.1–25.2) | ||
| Moderately differentiated | 872(44.6) | 105(12.0) | 9.8(7.7–12.4) | 14.6(11.7–18.2) | ||
| Moderately poorly or poorly differentiated | 819(41.9) | 75(9.2) | 6.1(4.5–8.3) | 9.9(7.5–13.1) | ||
| T category | .036 | |||||
| 1–2 | 1368(61.4) | 134(9.8) | 6.5(5.1–8.1) | 12.1(9.9–14.9) | ||
| 3–4 | 862(38.7) | 102(11.8) | 9.5(7.4–12.1) | 14.2(11.3–17.9) | ||
| N category | .013 | |||||
| 0 | 793(35.6) | 101(12.7) | 7.5(5.7–9.9) | 15.7(12.4–19.9) | ||
| 1–3 | 1437(64.4) | 135(9.4) | 7.6(6.2–9.4) | 11.3(9.3–13.8) | ||
| Overall stage | .165 | |||||
| I–II | 554(24.8) | 66(11.9) | 6.4(4.4–9.2) | 17.3(12.9–22.9) | ||
| III–IV | 1676(75.2) | 170(10.1) | 8.0(6.6–9.6) | 11.5(9.6–13.8) | ||
| Treatment | .833 | |||||
| Single-modality | 864(38.7) | 96(11.1) | 6.5(4.8–8.6) | 13.7(10.8–17.4) | ||
| Multimodality | 1366(61.3) | 140(10.3) | 8.3(6.7–10.2) | 12.2(10.0–14.9) |
For current and former smokers only; pack-years data were missing for 42 patients, of whom two (4.6%) developed SPM.
Non-oropharynx sites were oral cavity, larynx, and hypopharynx.
Grade was unavailable for 274 patients, of whom 28 (10.2%) developed SPM.
Figure 1.
Kaplan-Meier analysis of the proportion of patients with SPM segregated by index cancer site (SCCOP, N=1051; non-oropharynx cancers, N=1160). Log-rank test of equality of survival curves; P<0.001.
Multivariable Analysis of Factors Influencing SPM Risk by Index Primary Tumor Site
Among patients with index SCCOP, age<60 years, being a former- or never-smoker, fewer pack-years of exposure among smokers, lower comorbidity score, N0 nodal category, and TNM stage I or II were associated with lower risk of SPM in univariate analysis, but after multivariable adjustment only smoking status remained a significant predictor of SPM risk (Table 2). In contrast, among patients with index non-oropharyngeal cancer older age, male sex, being a current- or former-smoker, more pack-years of exposure among smokers, and being an ever-drinker were associated with higher risk of SPM in univariate analysis, but after multivariable adjustment only age ≥45 years remained a significant predictor of SPM risk. Among patients with index SCCOP, the risk of SPM increased 1% per year (adjusted hazard ratio [aHR], 1.01; 95% CI, 0.98–1.03), and among patients with index non-oropharyngeal cancer, the risk of SPM increased 2% per year (aHR, 1.02; 95% CI, 1.00–1.03).
Table 2.
Factors Associated with SPM Risk by Index Tumor Site
| Characteristic (Risk Group vs. Reference Group) | Index Tumor Site*
|
|||
|---|---|---|---|---|
| Oropharynx (N=1070)
|
Non-oropharynx (N=1179)
|
|||
| Log-rank P | Adjusted Hazard Ratio§ (95% CI) | Log-rank P | Adjusted Hazard Ratio** (95% CI) | |
| Age, years (≥45 vs. <45) | .319 | 1.1(0.5–2.2) | <.001 | 3.6(1.3–9.7) |
| Age, years (≥60 vs. <60) | .004 | 1.1(0.7–1.7) | .025 | 1.3(0.9–1.9) |
| Sex (male vs. female) | .069 | 0.9(0.5–1.5) | .008 | 1.2(0.8–1.8) |
| Ethnicity (other vs. non-Hispanic white) | .449 | 1.4(0.7–2.7) | .173 | 1.3(0.9–1.9) |
| Smoking (current/former vs. never) | <.001 | 1.7(1.1–2.8) | .003 | 1.4(0.9–2.3) |
| Smoking (current vs. never/former) | <.001 | 1.6(1.1–2.5) | .015 | 1.3(0.9–1.9) |
| Pack-years (≥20 vs. <20)† | .005 | 1.6(0.9–2.7) | .012 | 1.6(0.9–2.8) |
| Pack-years (≥40 vs. <40)† | .006 | 1.2(0.7–2.0) | .010 | 1.3(0.9–1.9) |
| Alcohol use (ever vs. never) | .209 | 1.0(0.6–1.6) | .005 | 1.2(0.8–1.9) |
| Comorbidity (moderate/severe vs. none/mild) | .007 | 1.8(1.0–3.2) | .094 | 1.4(0.9–2.2) |
| T category (T3–4 vs. T1–2) | .331 | 1.1(0.7–1.6) | .114 | 1.2(0.9–1.7) |
| N category (N1–3 vs. N0) | .014 | 1.5(0.9–2.7) | .552 | 0.8(0.6–1.2) |
| Grade (well/moderately well differentiated vs. poorly differentiated)‡ | .142 | 1.0(0.6–1.5) | .949 | 1.3(0.9–2.0) |
| TNM stage (III/IV vs. I/II) | .038 | 1.1(0.4–3.0) | .224 | 0.8(0.4–1.6) |
| Treatment (single-modality vs. multimodality) | .400 | 0.6(0.4–1.0) | .639 | 1.4(0.9–2.2) |
Includes the 19 patients with synchronous index tumors at both oropharyngeal and non-oropharyngeal sites.
Only smokers.
Only those with grade recorded.
Adjusted for age, race, smoking status, alcohol status, comorbidity index, tumor subsite, T category, and N category.
Adjusted for age, race, smoking status, alcohol status, comorbidity index, tumor site, T category, and N category.
Results of detailed subgroup analyses of the impacts of age, smoking, alcohol use, and HPV phenotype on SPM risk are presented in Table 3. Among patients with index SCCOP, those who were ≥60 years of age, current-smokers, or smokers with ≥20 pack-years of exposure had 3-year SPM rates (Table 3) similar to the rate of patients with index non-oropharyngeal cancer (8.3%, Table 1). Similarly, patients with index SCCOP who had a classic SCCHN phenotype had a 3-year SPM rate (Table 3) similar to that of patients with index non-oropharyngeal cancer. Finally, while HPV status was not available for most of the patients in this large retrospective cohort, patients with index SCCOP with a typical HPV phenotype had a very low SPM rate (Table 3, Figure 2). Among patients with index non-oropharyngeal cancer, SPM rates were strongly associated with increased age, and there was a trend toward greater risk with smoking exposure (Table 3).
Table 3.
Selected Factors Associated with Risk of SPM by Index Tumor Site
| Index Tumor Site*
|
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Oropharynx (N = 1070)
|
Non-oropharynx (N = 1179)
|
|||||||||||
| 3-yr SPM Rate, % (95% CI) | 5-yr SPM Rate, % (95% CI) | Log-rank P | P for Trend | Adjusted Hazard Ratio§ (95% CI) | P for Trend | 3-yr SPM Rate, % (95% CI) | 5-yr SPM rate, % (95% CI) | Log-rank P | P for Trend | Adjusted Hazard Ratio**(95% CI) | P for Trend | |
| Age, years | .014 | .008 | .597 | .001 | .001 | .015 | ||||||
| <45 | 3.2 (1.0–9.6) | 8.4(3.8–18.3) | 1.0(ref) | 3.0(1.0–9.4) | 6.0(1.9–17.9) | 1.0(ref) | ||||||
| 45–59 | 5.4(3.7–7.8) | 8.5(6.1–11.9) | 1.0(0.5–2.1) | 9.6(6.9–13.2) | 13.6 (9.9–18.5) | 3.3(1.2–9.1) | ||||||
| ≥60 | 11.1(7.8–15.6) | 14.2(10.1–19.8) | 1.2(0.6–2.4) | 11.4(8.7–14.8) | 22.7(17.8–28.7) | 3.8(1.4–10.5) | ||||||
| Smoking | <.001 | <.001 | .008 | .008 | .002 | .080 | ||||||
| Never | 3.9(2.3–6.7) | 6.1(3.7–9.9) | 1.0(ref) | 5.0(2.6–9.3) | 12.6(7.4–21.1) | 1.0(ref) | ||||||
| Former | 6.6(4.3–10.0) | 9.7(6.5–14.3) | 1.5(0.9–2.5) | 9.1(6.1–13.5) | 16.0(11.1–22.7) | 1.3(0.7–2.2) | ||||||
| Current | 12.2(8.5–17.5) | 18.2(12.8–25.4) | 2.0(1.2–3.4) | 12.4(9.6–16.0) | 20.0(15.7–25.3) | 1.5(0.9–2.6) | ||||||
| Pack-years | .008 | .002 | .196 | .016 | .004 | .093 | ||||||
| 1–19 | 4.9(2.6–9.1) | 6.6(3.7–11.7) | 1.0(ref) | 7.7(4.2–13.9) | 9.1(5.0–16.0) | 1.0(ref) | ||||||
| 20–39 | 9.2(5.3–15.6) | 16.0(9.6–25.9) | 1.7(0.9–3.3) | 9.1(5.7–14.4) | 17.9(11.1–28.2) | 1.5(0.8–2.9) | ||||||
| 40+ | 13.5(9.2–19.5) | 19.3(13.4–27.2) | 1.5(0.8–2.7) | 13.8(10.6–17.9) | 23.3(18.3–29.3) | 1.7(0.9–3.0) | ||||||
| Classic SCCHN phenotype† | .001 | .004 | ||||||||||
| No | 6.1(4.6–8.1) | 8.9(6.8–11.6) | 1.0(ref) | 8.6(6.6–11.1) | 15.2(11.9–19.2) | 1.0(ref) | ||||||
| Yes | 12.5(7.4–20.7) | 21.0(13.0–32.9) | 1.5(0.9–2.4) | 12.9(9.3–17.6) | 22.6(16.6–30.3) | 1.3(0.9–1.8) | ||||||
| Typical HPV phenotype‡ | .001 | |||||||||||
| No | 8.3(6.4–10.8) | 12.8(10.0–16.3) | 1.0(ref) | n.a. | n.a. | n.a. | n.a. | |||||
| Yes | 3.3(1.6–6.5) | 4.0(2.0–7.7) | 0.4(0.2–0.7) | n.a. | n.a. | n.a. | n.a. | |||||
SCCHN, squamous cell carcinoma of the head and neck; HPV, human papillomavirus; n.a., not applicable.
Includes the 19 patients with synchronous index tumors at both oropharyngeal and non-oropharyngeal sites.
Age ≥50 years, male, current smoker, and ever drinker.
Age <60 years, male, non-Hispanic white, never/former smoker, tonsil/base of tongue site, and T1-2N1-3.
Adjusted for age, race, smoking status, alcohol use, comorbidity index, tumor subsite, T category, and N category.
Adjusted for age, race, smoking status, alcohol use, comorbidity index, tumor site, T category, and N category.
Figure 2.
Kaplan-Meier analysis of the proportion of SCCOP patients with SPM segregated by HPV phenotype (age<60 years, male, non-Hispanic white, never-/former-smoker, tonsil/base of tongue cancer site, and stage T1-2N1-3; N=285) vs. all others (N=785). Log-rank test of equality of survival curves; P<0.001.
Locations of SPMs by Index Primary Tumor Site
Among patients with index non-oropharyngeal cancer, the most common sites of SPMs were sites traditionally associated with tobacco-related cancers, including the lung, esophagus, and bladder, and the lung was the most common site (Table 4). In contrast, patients with index SCCOP tended to develop SPMs in other sites. No cases of anogenital SPM developed in this cohort except for one cervical SPM in a woman with an index non-oropharyngeal cancer.
Table 4.
SPM Sites in Patients with Index SCCOP or Non-oropharyngeal Cancer*
| SPM Site | Index Tumor Site
|
||
|---|---|---|---|
| Oropharynx
|
Non-oropharynx
|
||
| Patients with SPM N(%) | Patients with SPM N(%) | P | |
| Total | 85(100) | 142(100) | .482 |
| SCCHN (metachronous) | 16(18.9) | 30(21.1) | .676 |
|
| |||
| Oral cavity | 6 | 18 | |
| Oropharynx | 2 | 5 | |
| Larynx | 6 | 5 | |
| Hypopharynx | 2 | 2 | |
| Tobacco-related, not SCCHN | 31(36.0) | 60(42.3) | .390 |
|
| |||
| Lung and bronchus | 27 | 51 | |
| Esophagus | 2 | 7 | |
| Urinary bladder | 2 | 2 | |
| Others | 38(44.7) | 52(36.6) | .228 |
|
| |||
| Prostate | 13 | 12 | |
| Thyroid | 4 | 11 | |
| Colon | 3 | 6 | |
| Kidney | 4 | 2 | |
| Breast | 1 | 4 | |
| Leukemia | 1 | 3 | |
| Salivary gland | 0 | 3 | |
| Lymphoma | 2 | 1 | |
| Liver | 1 | 2 | |
| Appendix | 1 | 1 | |
| Soft tissue | 1 | 1 | |
| Sinus | 1 | 0 | |
| Stomach | 0 | 1 | |
| Small bowel | 0 | 1 | |
| Ovary | 0 | 1 | |
| Endometrium | 1 | 0 | |
| Bone | 0 | 1 | |
| Brain | 1 | 0 | |
| Merkel cell | 1 | 0 | |
| Melanoma | 0 | 1 | |
| Unknown | 1 | 0 | |
| Nasopharynx | 1 | 0 | |
| Rectum | 1 | 0 | |
| Cervix | 0 | 1 | |
Does not include the 19 patients with synchronous index tumors at both oropharyngeal and non-oropharyngeal sites.
DISCUSSION
In this study, patients with SCCOP had a lower risk of SPM than patients with non-oropharyngeal cancer. Overall, smoking and higher age were associated with risk of SPM. Among patients with SCCOP, being a current- or former-smoker and having greater exposure to smoking were associated with risk of SPM in multivariable analysis. Among patients with non-oropharyngeal cancer, age was a strong predictor of SPM risk in multivariable analysis, but smoking and alcohol use also seemed to modify SPM risk. The most common location of SPMs in patients with index SCCOP was non-tobacco-related sites, while the most common location of SPMs in patients with index non-oropharyngeal cancer was tobacco-related sites.
Dose-response relationships between smoking and risk of SPM were also suggested. The associations between smoking and SPM risk are consistent with previous studies showing a direct association between increased smoking exposure and increased risk of SPM.22 However, the increase in risk may be minimal after patients have exceeded a certain threshold. In our study, while a smoking history of greater than 40 pack-years raised the overall risk of SPM, this risk was only slightly higher than the risk in patients with non-oropharyngeal cancer and was lower in patients with SCCOP who had a history of 20–39 pack-years. Others have reported similar patterns above certain levels of smoking exposure, and these patterns were similar to those observed in other smoking-related cancers, such as lung, esophageal, and bladder cancer.23,24 Tomek and McGuirt concluded that once a critical level of cellular damage due to smoking has occurred, subsequent exposure may not have any further impact on the risk of development of SPM.24
While some studies have shown that tobacco cessation after diagnosis of an index SCCHN reduces the risk of SPM,25,26 other studies have not found a consistent benefit.15,27 Although we did not have data on smoking exposures after diagnosis, we did observe that both in patients with index SCCOP and patients with index non-oropharyngeal cancer, former-smokers had lower SPM rates than current-smokers. While HPV status was not available for most of the patients in this large cohort, it is likely that a high proportion of the cases of SCCOP in the cohort had HPV as the primary etiologic agent given that 38% of these SCCOP patients were never-smokers. We might expect HPV positivity to modify the impact of smoking history and smoking cessation on SPM risk. In light of our observation that both former-smokers and light smokers with index SCCOP had very low SPM rates, HPV positivity may have affected the SPM risk in this subset of patients. Regardless, we actively promote tobacco cessation among patients with index SCCHN, not only because of the potential benefit in terms of reducing SPM risk but also to improve therapeutic outcomes and reduce toxic effects and complications of surgery and radiation therapy.
Previously it was thought that in patients with index SCCHN, most cases of SPM arise in the head and neck region followed by the lung.4,6,28 However, recent studies have shown that the lung is the most common site of SPM in patients with index SCCHN, and our data are in agreement with these findings.16,29 The tendency of patients with SCCHN to develop SPM in sites traditionally associated with tobacco-related cancers is consistent with the concept of field cancerization, first suggested by Slaughter et al.30 However, within the index SCCOP group, we found that a high percentage of SPMs occurred in sites not traditionally associated with tobacco, among which the prostate was the most common site. While some have suggested that patients with SCCOP are at increased risk for SPM at HPV-related sites,16,31 we did not observe an HPV-associated field effect; only a single SPM was observed at an HPV-related site (cervix), in a patient with index non-oropharyngeal cancer.
As suggested by Morris et al., the recent epidemic of HPV-associated SCCOP has altered the incidence and sites of SPMs for patients diagnosed with SCCOP.1 HPV-associated SCCOP often occurs in middle-aged, white, male patients with limited or no history of smoking.11 The different risk factor profile of this population, reflecting a unique oncological process, may result in different clinical presentations, fewer comorbidities, decreased risk of SPMs, and improved outcomes.1,2,17–19 However, within the SCCOP group, we found that patients with the traditional SCCHN risk factors, including smoking history and classic SCCHN phenotype, experienced a high rate of SPM. This is consistent with the traditional behavior and poor outcome of SCCOP prior to the HPV epidemic.7
This study has several limitations. Most important, we were not able to report the results segregated according to HPV status. However, in a recent study by Peck et al. analyzing 182 patients with index SCCOP from this same cohort for whom HPV serology data were available, we observed very low 5-year SPM rates for HPV-seropositive patients (5.6%) and more typical 5-year SPM rates for HPV-seronegative patients (14.6%); furthermore, among the 34 HPV-seropositive patients who were never smokers, the 5-year SPM rate was 0%.32 We also observed that the SPM rate decreased over time for patients with SCCOP while the rate did not change significantly among patients with non-oropharyngeal cancer (data not shown). This is consistent with the concept of increasing prevalence of HPV in SCCOP tumors leading to a lower risk for SPM. Additionally, our findings are similar to those of two smaller reports in which the tumor HPV status in patients with SCCOP was documented.18,19 In all three studies (ours and the preceding two smaller studies), 63% to 75% of SPMs in patients with HPV-negative disease were found in the traditional smoking-associated locations (head and neck, lung and bronchus, esophagus, and bladder). When taken together, only 46% (32 of 70) of the SPMs among patients with HPV-associated disease occurred in smoking-associated locations. While previous studies suggested that SCCOP is also associated with SPMs at sites traditionally associated with HPV, such as the cervix, penis, and anus,16,31 we did not observe any SPMs at anogenital sites among patients with index SCCOP, and only two anogenital cancers (both cervix) out of 60 SPMs were reported among patients with HPV-associated oropharyngeal cancer in the studies by Ang et al. and Huang et al.18,19
Another limitation of our study was that patients’ smoking status was obtained through a prospective epidemiologic questionnaire. Recall bias may have occurred, especially in heavier smokers, who may have underestimated packs smoked per day. A further limitation was that data on continued smoking and alcohol use or tobacco cessation efforts after diagnosis of the index SCCHN were not collected. Finally, while the length of follow-up time was reasonable, this analysis of SPM incidence is a retrospective review of the outcomes of a prospectively accrued patient cohort, and loss to follow-up and lack of standard SPM screening could have biased the outcomes. However, the median follow-up time for patients with index SCCOP was actually greater than that for patients with index non-oropharyngeal cancer (36 months vs. 28 months).
In conclusion, in patients with SCCHN, the index primary tumor site affects the risk of SPM and the sites of SPM. Patients with index SCCOP with limited or no smoking exposure and/or a typical HPV phenotype are at particularly low SPM risk, while smokers with any index SCCHN are at elevated SPM risk, especially current smokers and those with greater smoking exposure. Accurate understanding of the unique risk factors and carcinogenesis of SCCHN at particular subsites is essential to establishing more effective secondary disease prevention strategies and improving long-term patient outcomes.
Acknowledgments
Funding
This research was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant, CA016672. Kristina Dahlstrom was supported by Award Number R25CA057730 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
The authors wish to thank Stephanie Deming for manuscript editing.
Footnotes
Financial Disclosures
None.
References
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