Abstract
Background
This retrospective review examines demographic/clinical characteristics and overall survival of patients with squamous cell carcinoma of the oropharynx (SCCOP) at a tertiary cancer center and reports the characteristics influencing any observed survival trends over time.
Methods
The study included 3891 newly diagnosed, previously untreated patients presenting to our institution between 1955 and 2004.
Results
Over time, patients presented at younger ages and were more likely to have base of tongue or tonsil tumors and to be never or former smokers. Patients diagnosed in 1995–2004 were almost half as likely to die as those diagnosed before 1995 (HR,0.6; 95% CI,0.6–0.8). In both multivariable and recursive partitioning survival analyses, the TNM staging system predicted survival of patients treated before 1995 but not of patients treated in 1995–2004.
Conclusion
Survival among patients with SCCOP improved substantially over the past 50 years. The main contributing factors were changes in clinical characteristics, in particular surrogates for HPV positivity. The current TNM staging system for SCCOP is inadequate. Incorporation of HPV status and perhaps smoking status is encouraged.
Keywords: head and neck cancer, head and neck neoplasms, human papillomavirus, oropharyngeal cancer, neoplasm staging
INTRODUCTION
The incidence of cancer at most head and neck sites has been decreasing in the U.S.,1–6 but the incidence of squamous cell carcinoma of the oropharynx (SCCOP) has been increasing, especially among middle-aged white men.2,4,5 These trends have also been observed in Europe and Canada7–10 and are suspected to be due to a decrease in smoking prevalence11 and an increase in human papillomavirus (HPV) infections of the oropharynx.4
The strong association between SCCOP and HPV infection is now well established.12–14 Furthermore, in both the U.S. and Europe, the proportion of archived SCCOP tumor specimens positive for HPV DNA has increased from the 1970s to the present, suggesting an epidemic of HPV-associated SCCOP.7–10,15
Within the National Cancer Data Base for the years 1985–2001, an increase in the use of chemoradiation for SCCOP was observed that suggested an acceptance of nonsurgical multidisciplinary therapy for local-regionally advanced SCCOP.16 Over the same time period, significant increases in 5-year survival rates for patients with SCCOP have been reported,5 and patients with SCCOP now appear to have better 5-year survival rates than patients with cancers of the oral cavity or larynx.17 Additionally, most case series have demonstrated a favorable impact of HPV infection on survival of SCCOP patients.18–20 This has been confirmed in a meta-analysis21 as well as in population-based studies.15,22 Finally, a phase II and 4 phase III studies have all found improved overall and progression-free survival for HPV-positive patients.23–27
The first goal of this study was to examine trends over time in demographic and clinical characteristics and overall survival in patients with newly diagnosed SCCOP at a tertiary cancer center to determine how our institutional experience compared with the current national trends. The second goal was to analyze and report the demographic and clinical characteristics (especially stage) influencing observed overall survival trends.
MATERIALS AND METHODS
All patients with newly diagnosed, previously untreated SCCOP who presented to The University of Texas MD Anderson Cancer Center between 1955 and 2004 were included (N=3891). For survival analysis, only patients who presented without evidence of distant metastases and who were subsequently treated at MD Anderson were included (N=2299). Patients’ medical records and the institutional tumor registry were reviewed for demographic characteristics, including smoking and alcohol exposures; clinical characteristics, including treatment; and overall survival. The 6th edition of the American Joint Committee on Cancer TNM staging system was used to determine stage at presentation for all patients. A patient was considered a smoker if they had smoked at least 100 cigarettes in their lifetime and a drinker if they had consumed at least 1 alcoholic beverage per week for at least 1 year. Patients who had not smoked or consumed alcohol in the year prior to their cancer diagnosis were considered former smokers and former drinkers. This retrospective review was approved by the Institutional Review Board. Because recurrence of SCCOP is highly correlated with subsequent death and to circumvent misclassifications and missing documentation of causes of death, we chose overall survival as the most reliable outcome.
Statistical Analysis
Statistical analyses were carried out using Stata 11.0 (StataCorp., College Station, TX). A P-value of .05 was used to determine statistical significance and all tests were two-sided. Categorical variables were created for age (young, ≤45 years; middle-aged, 46–55 years; historically typical age at SCCOP diagnosis, 56–65 years; or old, >65 years); smoking status (never/former/current); pack-years for smokers (1–19, 20–39, or ≥40); alcohol drinking status (never/former/current); and decade of diagnosis (1955–1964, 1965–1974, 1975–1984, 1985–1994, 1995–2004). A nonparametric test for trend was used to detect significant trends over time.28 Chi-square and Fisher’s exact tests were performed to detect statistically significant differences between groups. For the survival analyses, overall survival was defined as the time from first appointment to death from any cause. Kaplan-Meier curves and log-rank tests were used to detect statistically significant differences in survival. Cox proportional hazards models were generated to calculate hazard ratios to detect any differences in survival with respect to decade of diagnosis. We performed recursive partitioning analysis using the survival tree program S-Tree to determine the most important factors affecting survival.29 Patients were divided into overall survival risk groups on the basis of median survival (Group 1: low-risk, median survival >90 months; Group 2: low-intermediate, 60.1–90 months; Group 3: high-intermediate, 30.1–60 months; Group 4: high-risk, ≤30 months).
RESULTS
Trends over Time in Demographic and Clinical Characteristics
The demographic and clinical characteristics of the 3891 patients with SCCOP diagnosed between 1955 and 2004 by decade of diagnosis are presented in Table 1. Over time, patients presented at significantly younger ages (median age 60 years, 1955–1994 and median age 55 years, 1995–2004; P<0.001, Ptrend<.001). Before 1995, less than one-third of patients were never or former smokers, whereas in 1995–2004, almost two-thirds of patients were never or former smokers (Ptrend<.001). Furthermore, among smokers, intensity of smoking also decreased over time (Ptrend<.001). No obvious changes in alcohol drinking patterns over time were observed. Before 1995, SCCOP cases were relatively evenly distributed between tonsil, base of tongue, and other sites, whereas since 1995, over 85% of SCCOP cases were found in either the tonsil or the base of tongue. We also observed significant trends over time for the following: (1) lower T categories (Ptrend<.001); (2) higher N categories (Ptrend<.001); and (3) higher TNM stage (Ptrend<.001).
Table 1.
Demographic Characteristics of All Incident SCCOP Patients by Decade of Presentation (n=3891).
| 1955–1964 (n=473)
|
1965–1974 (n=666)
|
1975–1984 (n=657)
|
1985–1994 (n=850)
|
1995–2004 (n=1,245)
|
P for Trend | |
|---|---|---|---|---|---|---|
| N(%) | N(%) | N(%) | N(%) | N(%) | ||
| Age, years | <.001 | |||||
| <46 | 23(4.9) | 42(6.3) | 52(7.9) | 91(10.7) | 174(14.0) | |
| 46–55 | 135(28.5) | 176(26.4) | 142(21.6) | 218(25.7) | 462(37.1) | |
| 56–65 | 173(36.6) | 257(38.6) | 262(39.9) | 291(34.2) | 346(27.8) | |
| >65 | 142(30.0) | 191(28.7) | 201(30.6) | 250(29.4) | 263(21.1) | |
| Sex | .724 | |||||
| Male | 386(81.6) | 503(75.5) | 465(70.8) | 614(72.2) | 995(79.9) | |
| Female | 87(18.4) | 163(24.5) | 192(29.2) | 236(27.8) | 250(20.1) | |
| Race | .001 | |||||
| White | 424(89.6) | 596(89.5) | 582(88.6) | 707(83.2) | 1068(85.8) | |
| Nonwhite | 49(10.4) | 70(10.5) | 75(11.4) | 143(16.8) | 177(14.2) | |
| Smoking status | <.001 | |||||
| Never-smoker | 47(15.2) | 78(14.1) | 83(16.8) | 102(20.0) | 356(31.1) | |
| Former-smoker | 22(7.1) | 75(13.6) | 63(12.7) | 90(17.7) | 342(29.9) | |
| Current-smoker | 240(77.7) | 400(72.3) | 349(70.5) | 318(62.4) | 446(39.0) | |
| Missing | 164 | 113 | 162 | 340 | 101 | |
| Pack-years for smokers | <.001 | |||||
| 1–19 | 7(6.0) | 18(6.6) | 9(4.7) | 21(6.9) | 127(18.5) | |
| 20–39 | 37(31.6) | 64(23.5) | 35(18.1) | 71(23.2) | 215(31.3) | |
| 40+ | 73(62.4) | 190(69.9) | 149(77.2) | 214(69.9) | 346(50.3) | |
| Missing | 356 | 394 | 464 | 544 | 557 | |
| Alcohol drinking status | .205 | |||||
| Never drinker | 100(34.5) | 109(19.9) | 121(25.1) | 142(28.3) | 344(31.1) | |
| Former drinker | 50(17.2) | 79(14.4) | 50(10.4) | 64(12.8) | 130(11.8) | |
| Current drinker | 140(48.3) | 360(65.7) | 312(64.6) | 296(59.0) | 631(57.1) | |
| Missing | 183 | 118 | 174 | 348 | 140 | |
| Tumor site | <.001 | |||||
| Tonsil | 93(19.7) | 173(26.0) | 195(29.7) | 308(36.2) | 515(41.4) | |
| Base of tongue | 169(35.7) | 244(36.6) | 244(37.1) | 304(35.8) | 552(44.3) | |
| Other | 211(44.6) | 249(37.4) | 218(33.2) | 238(28.0) | 178(14.3) | |
| T category | <.001 | |||||
| T1-T2 | 126(39.7) | 254(42.6) | 233(41.7) | 283(52.3) | 574(53.8) | |
| T3-T4 | 191(60.3) | 342(57.4) | 326(58.3) | 258(47.7) | 493(46.2) | |
| Missing | 156 | 70 | 98 | 309 | 178 | |
| N category | <.001 | |||||
| N0-N1 | 170(50.2) | 328(53.8) | 325(57.7) | 289(53.3) | 403(37.6) | |
| N2-N3 | 169(49.8) | 282(46.2) | 238(42.3) | 253(46.7) | 668(62.4) | |
| Missing | 134 | 56 | 94 | 308 | 174 | |
| TNM stage | <.001 | |||||
| I–II | 52(16.7) | 131(22.1) | 110(20.0) | 126(23.7) | 120(11.9) | |
| III–IV | 259(83.3) | 461(77.9) | 439(80.0) | 405(76.3) | 890(88.1) | |
| Missing | 162 | 74 | 108 | 319 | 235 |
Survival over Time
The overall survival of the 2299 patients with SCCOP who presented without distant metastases and were treated at MD Anderson by decade of diagnosis is presented in Figure 1. The most significantly improved survival was seen in the most recent decade (1995–2004 vs. 1955–1994; P<.001).
Figure 1. Survival of SCCOP patients, by decade diagnosed.
Ten-year overall survival of newly diagnosed patients with SCCOP treated at MD Anderson during 1955–2004, by decade diagnosed. Survival improved significantly in the most recent decade studied compared with 1955–1994 (p<.001). Median survival was 25.5 months for the 1955–1964 cohort, 26.5 months for the 1965–1974 cohort, 32.8 months for the 1975–1984 cohort, 44.8 months for the 1985–1994 cohort, and 73.3 months for the 1995–2004 cohort.
On the basis of these findings, we chose to analyze overall survival of this cohort dichotomized by year of diagnosis (before and since 1995) for the following reasons: (1) as just stated, significantly improved overall survival was observed for patients treated since 1995 (Figure 1); (2) the increase in SCCOP incidence in the United States has been most pronounced since 1995;2 (3) the population trend of increasing prevalence of HPV infection in archived specimens of SCCOP has been most pronounced in patients diagnosed since 1995;7–10,15 and (4) within our cohort, we found that the most dramatic shifts in age at presentation, smoking status, tumor site distribution, and stage occurred since 1995.
Survival over Time by Demographic and Clinical Characteristics
To better understand the factors influencing the survival gains observed in 1995–2004, we focused on the subgroup of SCCOP patients who were without distant metastases at diagnosis and who were treated at our institution. We compared demographic and clinical characteristics between patients diagnosed in 1955–1994 and those diagnosed in 1995–2004, and examined differences in overall survival between time periods within various subgroups (Table 2). For patients treated at our institution who were still alive, the median follow-up time was 120 months (120 months, 1955–1994 and 101 months, 1995–2004).
Table 2.
Demographic and Clinical Characteristics by Time Period of Treatment and Relationship with Overall Survival in Incident SCCOP Patients without Distant Metastases Treated at MD Anderson (n=2299).
| Time Period
|
P | Survival Analysis (Earlier Cohort as Referent Category)
|
||||
|---|---|---|---|---|---|---|
| 1955–1994 (Referent)
|
1995–2004
|
Crude Hazard Ratio (95% CI) | Adjusted Hazard Ratioa (95% CI) | P | ||
| N(%) | N(%) | |||||
| All patients | 1609(100) | 690(100) | 0.5(0.4–0.6) | 0.6(0.6–0.8) | <.001 | |
| Age, years | <.001 | |||||
| <46 | 117(7.3) | 99(14.4) | 0.4(0.3–0.7) | 0.6(0.3–1.1) | .086 | |
| 46–55 | 405(25.2) | 244(35.4) | 0.4(0.3–0.6) | 0.6(0.5–0.9) | .003 | |
| 56–65 | 608(37.8) | 201(29.1) | 0.5(0.4–0.7) | 0.6(0.4–0.7) | <.001 | |
| >65 | 479(29.8) | 146(21.2) | 0.6(0.5–0.8) | 0.7(0.5–0.9) | .007 | |
| Sex | .002 | |||||
| Male | 1209(75.1) | 560(81.2) | 0.5(0.4–0.5) | 0.6(0.5–0.7) | <.001 | |
| Female | 400(24.9) | 130(18.8) | 0.6(0.5–0.8) | 0.7(0.5–1.0) | .069 | |
| Race | .016 | |||||
| White | 1431(88.9) | 589(85.4) | 0.4(0.4–0.5) | 0.6(0.5–0.7) | <.001 | |
| Nonwhite | 178(11.1) | 101(14.6) | 0.7(0.5–1.0) | 1.0(0.7–1.5) | .911 | |
| Smoking statusb | <.001 | |||||
| Never-smoker | 223(15.5) | 199(29.8) | 0.3(0.2–0.4) | 0.4(0.3–0.6) | <.001 | |
| Former-smoker | 178(12.3) | 197(29.5) | 0.6(0.5–0.8) | 0.6(0.4–0.8) | .001 | |
| Current-smoker | 1042(72.2) | 271(40.6) | 0.7(0.6–0.9) | 0.8(0.6–0.9) | .006 | |
| Pack-years for smokersb | <.001 | |||||
| 1–19 | 41(5.8) | 72(17.7) | 0.4(0.2–0.6) | 0.4(0.2–0.9) | .024 | |
| 20–39 | 151(21.5) | 128(31.4) | 0.6(0.4–0.8) | 0.6(0.4–0.9) | .022 | |
| 40+ | 511(72.7) | 208(51.0) | 0.9(0.7–1.1) | 0.9(0.7–1.1) | .334 | |
| Alcohol drinking statusb | .011 | |||||
| Never-drinker | 332(23.6) | 192(29.8) | 0.4(0.3–0.5) | 0.5(0.4–0.7) | <.001 | |
| Former-drinker | 192(13.7) | 82(12.7) | 0.7(0.5–0.9) | 0.8(0.5–1.1) | .162 | |
| Current-drinker | 883(62.8) | 370(57.5) | 0.5(0.4–0.6) | 0.6(0.5–0.8) | <.001 | |
| Tumor site | <.001 | |||||
| Tonsil | 441(27.4) | 260(37.7) | 0.5(0.4–0.6) | 0.6(0.5–0.8) | .001 | |
| Base of tongue | 588(36.5) | 325(47.1) | 0.4(0.4–0.5) | 0.6(0.5–0.8) | <.001 | |
| Other | 580(36.1) | 105(15.2) | 0.8(0.6–1.0) | 0.7(0.5–0.9) | .010 | |
| Treatment | <.001 | |||||
| Surgery alone | 283(17.7) | 39(5.8) | 0.6(0.4–1.0) | 0.8(0.5–1.3) | .382 | |
| Surgery+radiation±chemotherapy | 428(26.8) | 86(12.7) | 0.4(0.3–0.6) | 0.6(0.4–0.9) | .010 | |
| Radiation alone | 759(47.6) | 316(46.7) | 0.5(0.4–0.6) | 0.8(0.6–1.0) | .017 | |
| Radiation+chemotherapy | 125(7.8) | 236(34.9) | 0.3(0.2–0.4) | 0.4(0.3–0.6) | <.001 | |
| T category | .003 | |||||
| T1 | 229(14.2) | 130(18.8) | 0.4(0.3–0.5) | 0.5(0.4–0.8) | .004 | |
| T2 | 481(29.9) | 229(33.2) | 0.5(0.4–0.6) | 0.7(0.5–0.9) | .020 | |
| T3 | 594(36.9) | 224(32.5) | 0.5(0.4–0.6) | 0.5(0.4–0.7) | <.001 | |
| T4 | 305(19.0) | 107(15.5) | 0.8(0.6–1.1) | 0.8(0.6–1.1) | .225 | |
| N category | <.001 | |||||
| N0 | 624(38.8) | 131(19.0) | 0.6(0.6–1.0) | 1.0(0.7–1.3) | .891 | |
| N1 | 271(16.8) | 117(17.0) | 0.4(0.3–0.6) | 0.5(0.4–0.8) | .001 | |
| N2 | 531(33.0) | 368(53.3) | 0.4(0.3–0.4) | 0.5(0.4–0.6) | <.001 | |
| N3 | 183(11.4) | 74(10.7) | 0.6(0.5–0.9) | 0.8(0.5–1.2) | .207 | |
| TNM stage | <.001 | |||||
| I | 128(8.0) | 22(3.2) | 1.1(0.6–1.9) | 1.2(0.6–2.3) | .666 | |
| II | 224(13.9) | 48(7.0) | 0.9(0.6–1.3) | 1.2(0.8–1.9) | .421 | |
| III | 410(25.5) | 153(22.2) | 0.4(0.3–0.6) | 0.5(0.4–0.8) | <.001 | |
| IV | 847(52.6) | 467(67.7) | 0.4(0.4–0.5) | 0.5(0.4–0.6) | <.001 | |
Estimates for each covariate adjusted for all other covariates except for pack-years and
TNM stage.
Totals less than total number of patients because of missing data.
Demographic Characteristics
Similar to what we observed in the entire cohort, those diagnosed in 1995–2004 were more likely to be younger male never or former smokers than patients diagnosed before 1995 (Table 2). We found that patients diagnosed in 1995–2004 were less likely to die within 10 years of their diagnosis regardless of age or sex than were patients diagnosed in 1955–1994. White patients diagnosed in 1995–2004 had a 40% decreased risk of death compared to patients diagnosed earlier; however, patients of other ethnicities had no apparent survival advantage associated with more recent diagnosis. Regardless of smoking or drinking status, survival improved over time. Never smokers had the greatest improvement in survival, and smokers with the highest pack-years did not have a demonstrable improvement in survival.
Clinical Characteristics
Similar to what was observed in the entire cohort, patients treated in 1995–2004 were more likely to have tonsil or base of tongue primary tumors and T1-2, N1-3 tumors (Table 2). Major shifts in treatment of SCCOP were also observed: in 1995–2004 compared with earlier time periods, surgery was less frequently used and the combination of radiation and chemotherapy was used more frequently. Typically, stage I/II patients were treated with either surgery alone or radiotherapy alone, while those with advanced stage disease were more likely to receive combined therapy (typically surgery + radiation before 1995 and radiation + concurrent chemotherapy after 1994). While not a part of this review, intensity modulated radiotherapy was introduced at our institution in late 1999 but did not become our standard practice until 2004.
The risk of death was decreased for patients treated in 1995–2004 regardless of cancer site and was particularly decreased (40%) for those with tonsil or base of tongue cancers. No survival improvement over time was seen among patients treated with surgery alone, but among patients treated with combined radiation/chemotherapy, the risk of death was reduced by 60% in 1995–2004 compared with 1955–1994.
Improved overall survival for patients treated in 1995–2004 was observed in some staging subgroups but not others (Table 2). No clear improvements in overall survival were observed for patients with T4 tumors, patients without nodal metastases (N0), or patients with the most advanced nodal metastases (N3). The most dramatic observation was that although there was no change in overall survival for patients with stage I–II SCCOP (5-year survival rates were 52% for patients diagnosed before 1995 and 56% for those diagnosed in 1995–2004; log-rank P=.718), the risk of death fell 50% for those with stage III–IV SCCOP (Table 2 and Figure 2). Among patients diagnosed before 1995 (Figure 2a), as expected, those with stage I–II disease had the best and those with stage IV disease had the worst overall survival. However, among patients diagnosed since 1995 (Figure 2b), those with stage III disease did significantly better than those with stage I–II disease (5-year survival rate 68% vs. 56%; log-rank P=.011), and those with stage IV disease did slightly better than those with stage I–II disease (5-year survival rate 61% vs. 56%; log-rank P=.115).
Figure 2.
(a) Survival of SCCOP patients by stage, 1955–1994
(b) Survival of SCCOP patients by stage, 1995–2004.
Panel A shows the ten-year overall survival by stage of newly diagnosed SCCOP patients treated at MD Anderson during 1955–1994 (stage I/II vs. IV, p<0.001). Panel B shows the ten-year overall survival by stage of newly diagnosed SCCOP patients treated at MD Anderson during 1995–2004 (stage III vs. I/II, p<.001 and stage IV vs. I/II, p=.115).
Factors Influencing Survival by Time Period of Treatment
Patients diagnosed in 1995–2004 had a 40% decreased risk of death compared with patients diagnosed before 1995 (Table 2). To determine whether the factors affecting overall survival of SCCOP patients before and since 1995 were different, we created Cox proportional hazards models (Table 3). Treatment type did not appear to have a major impact on survival either before or since 1995. For the earlier cohort, the most important independent factors affecting survival were T category, N category, TNM stage, age, smoking status, and tumor site. Interestingly, for the most recent decade, neither N category nor TNM stage appeared to affect survival, although other factors common to HPV-associated SCCOP were associated with improved survival (younger age, white race, less smoking exposure, tonsil or base of tongue tumor site, and low T category) (Table 3).
Table 3.
Impact of Clinical and Pathologic Factors on Overall Survival by Time Period of Treatment (n=2299).
| Referent category listed second | 1955–1994
|
1995–2004
|
||||
|---|---|---|---|---|---|---|
| Crude Hazard Ratio (95% CI) | Adjusted Hazard Ratio* (95% CI) | P | Crude Hazard Ratio (95% CI) | Adjusted Hazard Ratioa (95% CI) | P | |
| Age(≥56 years vs. <56 years) | 1.4(1.2–1.6) | 1.5(1.3–1.7) | <.001 | 2.0(1.6–2.5) | 1.8(1.4–2.3) | <.001 |
| Sex(male vs. female) | 1.2(1.1–1.4) | 1.2(1.0–1.3) | .058 | 0.9(0.7–1.2) | 1.0(0.8–1.4) | .817 |
| Race(nonwhite vs. white) | 1.1(1.0–1.4) | 1.1(0.9–1.3) | .613 | 1.8(1.4–2.4) | 1.5(1.1–2.0) | .009 |
| Smoking(ever-smoker vs. never-smoker) | 1.3(1.1–1.6) | 1.4(1.2–1.7) | .001 | 3.0(2.3–4.1) | 2.3(1.7–3.2) | <.001 |
| Pack-years of smoking(≥10 vs. <10) | 1.3(1.1–1.5) | 1.3(1.1–1.6) | .003 | 3.2(2.4–4.2) | 2.6(1.9–3.5) | <.001 |
| Alcohol(ever-drinker vs. never-drinker) | 1.2(1.1–1.4) | 1.1(1.0–1.3) | .078 | 1.6(1.2–2.1) | 1.2(0.9–1.6) | .287 |
| Site(other vs. tonsil or base of tongue) | 1.2(1.1–1.3) | 1.3(1.1–1.5) | <.001 | 2.0(1.5–2.6) | 1.4(1.1–2.0) | .018 |
| Treatment(no surgery vs. surgery) | 0.9(0.8–1.0) | 1.0(0.7–1.5) | .971 | 0.9(0.7–1.2) | 1.2(0.6–2.5) | .548 |
| Treatment(no chemotherapy vs. chemotherapy) | 0.6(0.5–0.7) | 0.7(0.5–1.0) | .039 | 1.0(0.8–1.2) | 1.8(0.8–4.0) | .145 |
| Treatment(no radiation vs. radiation) | 1.1(0.9–1.2) | 1.1(0.7–1.7) | .577 | 1.5(1.0–2.3) | 1.9(0.8–4.5) | .122 |
| Treatment(one modality vs. multimodality) | 0.8(0.9–1.2) | 1.0(0.6–1.5) | .870 | 1.0(0.8–1.3) | 0.9(0.4–2.0) | .722 |
| T category(T3-T4 vs. T1-T2) | 1.7(1.5–1.9) | 1.5(1.4–1.8) | <.001 | 2.0(1.6–2.5) | 2.2(1.7–2.9) | <.001 |
| N category(N1-N3 vs. N0) | 1.4(1.3–1.6) | 1.5(1.3–1.7) | <.001 | 0.7(0.6–0.9) | 1.1(0.8–1.4) | .646 |
| TNM stage(III–IV vs. I–II) | 1.6(1.4–1.8) | 1.8(1.5–2.1) | <.001 | 0.7(0.5–1.0) | 1.3(0.9–1.8) | .179 |
Estimates for each covariate adjusted for all other covariates except pack-years and TNM stage
Recursive Partitioning Analysis
Recursive partitioning analysis identified different prognostic factors among patients diagnosed in the 2 time periods (Figure 3a and 3b). For patients diagnosed in 1955–1994, T and N categories were the most important factors affecting survival (Figure 3a). For patients diagnosed since 1995, smoking status was most important. T category, age, and tumor site were also important (Figure 3b). Among smokers with T1-T2 primary tumors (approximately one-third of patients diagnosed since 1995, Figure 3b), a complete discrepancy with the intended prognostic values of the N categories was observed: patients with nodal metastases had a better prognosis than similar patients lacking nodal metastases (log-rank P<.001). Although not shown, among smokers with advanced primary tumors (another 35% of patients, Figure 3b), patients with nodal metastases also had a better (though nonsignificantly so) prognosis than patients without nodal metastases. In summary, among patients diagnosed before 1995, the various stage categories appeared central to prognostication, while among patients diagnosed since 1995, variables likely to represent surrogates for HPV positivity (such as nonsmoking, T1-T2 tumor, and base of tongue or tonsil site)6 appeared central to prognostication. There was a very small subgroup of patients diagnosed before 1995 who had an excellent prognosis (risk group 1, N=26, Figure 3a and 3c), and the characteristics of this subgroup (never smokers <56 years old with small primary tumors) could suggest an early cohort of patients with HPV-associated SCCOP. We did not have HPV data available for the majority of patients in this cohort; however, of the patients in the 1995–2004 cohort for which we did have this data available, 74% (61 of 82) were positive for HPV by polymerase chain reaction (PCR).
Figure 3. Classification of patients with SCCOP into risk-of-death categories and corresponding Kaplan-Meier survival curves. BOT/T, base of tongue or tonsil; OP, oropharyngeal site.
(a) Classification of patients, 1955–1994.
(b) Classification of patients, 1995–2004.
(c) Overall survival for risk groups, 1955–1994.
(d) Overall survival for risk groups, 1995–2004.
Figure 3 shows the classification of patients with SCCOP into risk-of-death categories based on recursive partitioning analysis and corresponding Kaplan-Meier survival curves. Panel A shows the classification of patients diagnosed during 1955–1994, where group 1 corresponds to the lowest risk of death and group 4 corresponds to the highest risk of death. Each node lists the variable with the number of patients and median survival time for each. Panel B shows the classification of patients diagnosed during 1995–2004. Panel C shows the Kaplan-Meier survival curve by risk group for overall survival of OSCC patients diagnosed during 1955–1994. Panel D shows the Kaplan-Meier survival curve by risk group for overall survival of OSCC patients diagnosed during 1995–2004.
For patients diagnosed before 1995, with the exception of risk group 1, survival stratification on the basis of recursive partitioning analysis (Figure 3a and 3c) was not substantially better than traditional TNM staging (Figure 2a). However, for patients diagnosed in 1995–2004, survival stratification on the basis of recursive partitioning analysis (Figure 3b and 3d) was much better than traditional TNM staging (Figure 2b). Compared with patients in the lowest-risk group (Group 1), those in the low-intermediate-risk group (Group 2) had 3 times the risk of death (HR,3.2; 95% CI,2.2–4.7), those in the high-intermediate-risk group (Group 3) had 6 times the risk of death (HR,6.4; 95% CI,4.5–9.3), and those in the highest-risk group (Group 4) had 10 times the risk of death (HR,10.2; 95% CI,7.1–14.8). The difference in the risk of death was statistically significant between all risk groups (P<.001 between any 2 groups).
DISCUSSION
This review of 1 institution’s experience demonstrates clear changes over time in demographic and clinical characteristics of SCCOP that were particularly pronounced since 1995. These findings are consistent with the decrease in the prevalence of smoking in the U.S. along with an increase in the proportion of HPV-positive SCCOP, as well as Surveillance, Epidemiology, and End Results data that the majority of patients with SCCOP are being diagnosed with late-stage disease, particularly disease associated with nodal metastases.4–6
We observed significantly better overall survival among SCCOP patients diagnosed in the most recent decade than in those diagnosed before 1995. This improvement in survival was observed in most subgroups, with the magnitude of effect greater in subgroups likely to be HPV positive and less or zero in subgroups likely to be HPV negative. For instance, no such survival improvement was seen for nonwhite patients, heavy smokers, or patients with T4 primary tumors, N0 or N3 disease, or TNM stage I or II. In analyses of factors contributing to survival both before and since 1995, traditional staging variables accounted for most of the stratification in survival before 1995, while smoking background accounted for much of the stratification in survival since 1995. Given that lower smoking exposures among SCCOP patients can be a surrogate for HPV status and that HPV-associated SCCOP have improved survival outcomes, these findings further suggest the emergence of an HPV-associated SCCOP cohort at our institution. This interpretation is further supported by the national pattern of increasing incidence of SCCOP coupled with falling mortality, a pattern indicative of a change in tumor biology or risk factors rather than improvements in the management of the disease.30
For the most recent decade, the current TNM staging system for SCCOP has not prognostically stratified patients effectively, but smoking status and other surrogates for HPV status have. Unfortunately, the existing clinical trials in which HPV status was documented cannot be used to adequately assess TNM prognostic stratification in a recent cohort of SCCOP patients because enrollment was limited to patients with TNM stage III–IV disease and patients with N0 disease were either excluded and/or grouped together with patients with N1 and N2a disease.23–27 Furthermore, 2 of these trials included only relatively small subsets of patients with SCCOP within a mixed head and neck cancer trial, precluding detailed TNM stage or N category analyses.23,26 However, case series, population-based studies, and clinical trials all support HPV status as an important, independent prognostic factor for SCCOP.15,18–20,22,23,25–27 Additional literature supports smoking as an important prognostic factor,31,32 and recently it was shown that a combination of smoking and HPV status further refined the prognostic significance of HPV status: HPV-positive nonsmokers had an exceptionally good prognosis, HPV-negative patients had a poor prognosis, and HPV-positive ever smokers had an intermediate prognosis.24 Consequently, we interpret the findings presented here and the existing literature as supporting incorporation of HPV status and possibly smoking into the current TNM staging system.
Our study has several limitations. First, HPV status was not available for this retrospective cohort. However, we can confirm that consistent with existing series,15,18,33 a high proportion (74%, 61 of 82) of SCCOP in the 1995–2004 cohort were associated with HPV16 by PCR. Furthermore, utilizing data from ongoing molecular epidemiological studies through 2011, there is a decreasing proportion of HPV-positive tumors with worsening survival risk group as identified by recursive partitioning analysis (Figure 3b and 3d, trend test P=.003, .053, and .092 for p16 immunohistochemistry, HPV16 PCR, and HPV in-situ hybridization, respectively). Second, comparisons of treatment in a retrospective review may be biased by factors influencing treatment assignments, though multivariable adjustment was performed in order to limit such biases. Third, we considered only all-cause mortality. Increased risk of comorbidities in smokers and older individuals may have biased the results as the earlier cohort had a greater proportion of smokers and older patients. However, we found improved outcomes in all age groups as well as when adjusting for age. Fourth, improvements in imaging evaluation over time contribute to stage drift but do not account for the observed findings in multivariable or recursive partitioning analyses for the most recent decade. Finally, several prognostic variables, such as co-morbidity, treatment breaks, surgical margin status, extracapsular spread, etc., were not available for inclusion in our analysis.
In conclusion, survival among patients with SCCOP at our institution has improved markedly over the past 50 years, most dramatically since 1995. Although changes in treatment have occurred, they were not the major contributor to the observed improved survival. Instead, changes in clinical characteristics were the most important influence on survival and are likely a result of the changing etiology of SCCOP. The important prognostic factors accounting for the observed improvements in SCCOP survival over time are in part surrogates for HPV status and reflect an emerging epidemic of HPV-associated SCCOP. Our observations indicate that the current TNM staging system for oropharyngeal cancer has limited utility and encourage us to advocate that HPV status and perhaps smoking be incorporated into the staging system for SCCOP.
Acknowledgments
Funding sources: This research was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant, CA016672 and by a cancer prevention fellowship for Kristina Dahlstrom supported by the National Cancer Institute grant R25T CA57730, Shine Chang, Ph.D., Principal Investigator.
The authors wish to thank Stephanie Deming for manuscript editing.
Footnotes
Financial Disclosures: None
References
- 1.Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: Increasing trends in the U.S. population ages 20–44 years. Cancer. 2005;103(9):1843–1849. doi: 10.1002/cncr.20998. [DOI] [PubMed] [Google Scholar]
- 2.Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612–619. doi: 10.1200/JCO.2007.14.1713. [DOI] [PubMed] [Google Scholar]
- 3.Frisch M, Hjalgrim H, Jaeger AB, Biggar RJ. Changing patterns of tonsillar squamous cell carcinoma in the United States. Cancer Causes Control. 2000;11(6):489–495. doi: 10.1023/a:1008918223334. [DOI] [PubMed] [Google Scholar]
- 4.Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: An emerging epidemic of human papillomavirus-associated cancers? Cancer. 2007;110(7):1429–1435. doi: 10.1002/cncr.22963. [DOI] [PubMed] [Google Scholar]
- 5.Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: A site-specific analysis of the SEER database. Int J Cancer. 2005;114(5):806–816. doi: 10.1002/ijc.20740. [DOI] [PubMed] [Google Scholar]
- 6.Sturgis EM, Ang KK. The epidemic of HPV-associated oropharyngeal cancer is here: Is it time to change our treatment paradigms? J Natl Compr Canc Netw. 2011;9(6):665–673. doi: 10.6004/jnccn.2011.0055. [DOI] [PubMed] [Google Scholar]
- 7.Hammarstedt L, Lindquist D, Dahlstrand H, et al. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer. 2006;119(11):2620–2623. doi: 10.1002/ijc.22177. [DOI] [PubMed] [Google Scholar]
- 8.Hammarstedt L, Dahlstrand H, Lindquist D, et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol. 2007;127(9):988–992. doi: 10.1080/00016480601110170. [DOI] [PubMed] [Google Scholar]
- 9.Nasman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: An epidemic of viral-induced carcinoma? Int J Cancer. 2009;125(2):362–366. doi: 10.1002/ijc.24339. [DOI] [PubMed] [Google Scholar]
- 10.Attner P, Du J, Nasman A, et al. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int J Cancer. 2010;126(12):2879–2884. doi: 10.1002/ijc.24994. [DOI] [PubMed] [Google Scholar]
- 11.Giovino GA. The tobacco epidemic in the United States. Am J Prev Med. 2007;33(6 Suppl):S318–26. doi: 10.1016/j.amepre.2007.09.008. [DOI] [PubMed] [Google Scholar]
- 12.Gillison ML, Shah KV. Human papillomavirus-associated head and neck squamous cell carcinoma: Mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol. 2001;13(3):183–188. doi: 10.1097/00001622-200105000-00009. [DOI] [PubMed] [Google Scholar]
- 13.Klussmann JP, Weissenborn SJ, Wieland U, et al. Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer. 2001;92(11):2875–2884. doi: 10.1002/1097-0142(20011201)92:11<2875::aid-cncr10130>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
- 14.D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944–1956. doi: 10.1056/NEJMoa065497. [DOI] [PubMed] [Google Scholar]
- 15.Ernster JA, Sciotto CG, O’Brien MM, et al. Rising incidence of oropharyngeal cancer and the role of oncogenic human papillomavirus. Laryngoscope. 2007;117(12):2115–2128. doi: 10.1097/MLG.0b013e31813e5fbb. [DOI] [PubMed] [Google Scholar]
- 16.Chen AY, Schrag N, Hao Y, Stewart A, Ward E. Changes in treatment of advanced oropharyngeal cancer, 1985–2001. Laryngoscope. 2007;117(1):16–21. doi: 10.1097/01.mlg.0000240182.61922.31. [DOI] [PubMed] [Google Scholar]
- 17.Surveillance, Epidemiology and End Results. Fast stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute; [Accessed Sept 25, 2011]. Available from URL: http://seer.cancer.gov/faststats. [Google Scholar]
- 18.Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–720. doi: 10.1093/jnci/92.9.709. [DOI] [PubMed] [Google Scholar]
- 19.Ritchie JM, Smith EM, Summersgill KF, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer. 2003;104(3):336–344. doi: 10.1002/ijc.10960. [DOI] [PubMed] [Google Scholar]
- 20.Strome SE, Savva A, Brissett AE, et al. Squamous cell carcinoma of the tonsils: A molecular analysis of HPV associations. Clin Cancer Res. 2002;8(4):1093–1100. [PubMed] [Google Scholar]
- 21.Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int J Cancer. 2007;121(8):1813–1820. doi: 10.1002/ijc.22851. [DOI] [PubMed] [Google Scholar]
- 22.Mehta V, Yu GP, Schantz SP. Population-based analysis of oral and oropharyngeal carcinoma: Changing trends of histopathologic differentiation, survival and patient demographics. Laryngoscope. 2010;120(11):2203–2212. doi: 10.1002/lary.21129. [DOI] [PubMed] [Google Scholar]
- 23.Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261–269. doi: 10.1093/jnci/djn011. [DOI] [PubMed] [Google Scholar]
- 24.Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. doi: 10.1056/NEJMoa0912217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28(27):4142–4148. doi: 10.1200/JCO.2010.29.2904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27(12):1992–1998. doi: 10.1200/JCO.2008.20.2853. [DOI] [PubMed] [Google Scholar]
- 27.Posner MR, Lorch JH, Goloubeva O, et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: A subset analysis from an international phase III trial. Ann Oncol. 2011;22(5):1071–1077. doi: 10.1093/annonc/mdr006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Cuzick J. A wilcoxon-type test for trend. Stat Med. 1985;4(1):87–90. doi: 10.1002/sim.4780040112. [DOI] [PubMed] [Google Scholar]
- 29.Zhang H, Singer B. Recursive Partitioning in the Health Sciences. New York: Springer-Verlag; 1999. Analysis of censored data: Survival trees; pp. 93–104. [Google Scholar]
- 30.Davies L, Welch HG. Epidemiology of head and neck cancer in the United States. Otolaryngol Head Neck Surg. 2006;135(3):451–457. doi: 10.1016/j.otohns.2006.01.029. [DOI] [PubMed] [Google Scholar]
- 31.Pytynia KB, Grant JR, Etzel CJ, Roberts DB, Wei Q, Sturgis EM. Matched-pair analysis of survival of never smokers and ever smokers with squamous cell carcinoma of the head and neck. J Clin Oncol. 2004;22(19):3981–3988. doi: 10.1200/JCO.2004.02.133. [DOI] [PubMed] [Google Scholar]
- 32.Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: Response and survival positively associated with HPV16 copy number. J Clin Oncol. 2008;26(19):3138–3146. doi: 10.1200/JCO.2007.12.7597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467–475. doi: 10.1158/1055-9965.EPI-04-0551. [DOI] [PubMed] [Google Scholar]