ORIGINAL ARTICLE
Rising prevalence of human papillomavirus–related oropharyngeal cancer in Australia over the last 2 decades Angela Hong, PhD,1,2* C. Soon Lee, MD,1,3 Deanna Jones, BAppSci,4 Anne-Sophie Veillard, MS,5 Mei Zhang, MD,1,2 Xiaoying Zhang, PhD,1 Robert Smee, MBBS,6 June Corry, MBBS,7 Sandro Porceddu, MBBS,8 Christopher Milross, MD,1,2 Michael Elliott, MPhil,9 Jonathan Clark, MBBS,1,9 Barbara Rose, PhD4 1
Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia, 2Department of Radiation Oncology, Lifehouse, Sydney, New South Wales, Australia, 3Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia, 4Department of Infectious Diseases and Immunology, The University of Sydney, Sydney, New South Wales, Australia, 5NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia, 6Department of Radiation Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia, 7Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, 8Cancer Services, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia, 9Sydney Head and Neck Cancer Institute, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Accepted 10 December 2014 Published online 25 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23942
ABSTRACT: Background. This study provides Australian data on the characteristics of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) over the last 2 decades. Methods. The HPV status of 515 patients with oropharyngeal SCC diagnosed between 1987 and 2010 was determined by HPV E6-targeted multiplex real time polymerase chain reaction assay (PCR) and p16 immunohistochemistry. Results. The HPV positivity rate increased from 20.2% (1987–1995) to 63.5% (2006–2010). Among HPV-positive oropharyngeal SCC over the study period, the median age increased from 55.4 years to 59.8 years (p 5 .004) and there was a trend of an increasing proportion of never
INTRODUCTION Head and neck squamous cell carcinoma is the sixth most common cancer worldwide1 and the incidence of oropharyngeal squamous cell carcinoma (SCC) is increasing in Western countries despite declining tobacco use.2–6 We have previously reported that this increase in Australia is likely attributable to a rise in the proportion of oropharyngeal SCC caused by human papillomavirus (HPV); from 19% (1987– 1990) to 47% (2001–2005) to 66% (2005–2006).3 This trend is particularly apparent in the younger age group and parallels findings in other developed countries where HPV positivity rates as high as 72% have been reported.7 The biological characteristics of HPV-positive oropharyngeal SCC are distinct from those of HPV-negative oropharyngeal SCC with respect to expression of the p16INK4A (p16), and genetic profiles, including the frequency of mutations in the p53 gene.8,9 Epidemiologically,
smokers (19.2% to 34.0%). The use of radiation therapy (RT) in patients with HPV-positive oropharyngeal cancer increased from 26.9% to 68.1% (p 5 .007) and we also observed a trend of improved outcomes. Conclusion. Our data show a rising prevalence of HPV-positive oropharyngeal SCC in Australia over the last 2 decades. These patients with HPV-positive oropharyngeal SCC are now presenting at an older age and C 2015 Wiley Periodicals, Inc. Head about one third have never smoked. V Neck 38: 743–750, 2016
KEY WORDS: human papillomavirus (HPV), oropharyngeal cancer, head and neck cancer
it has been reported that patients with HPV-positive oropharyngeal SCC tend to be younger, less likely to have a history of tobacco and alcohol use, and tend to have a higher number of sexual partners, in particular oral sexual partners, than patients with HPV-negative oropharyngeal SCC.10 Furthermore, HPV-positive oropharyngeal SCC is associated with markedly better survival, despite a tendency for higher grade and more advanced nodal disease.11 This study extends our previous work3 by including patients treated for oropharyngeal SCC at 10 large teaching hospitals in Australia over the last 2 decades. We sought evidence of change in HPV status relative to tobacco exposure, personal characteristics, treatment patterns, and outcomes over the study period. The purpose of this study was to gain new insight into the changing epidemiology of oropharyngeal SCC in Australia.
MATERIALS AND METHODS Incidence of oropharyngeal cancer in Australia
*Corresponding author: A. Hong, Central Clinical School, The University of Sydney, Level 6, Blackburn Building, New South Wales, 2006 Australia. E-mail: [email protected] Contract grant sponsor: This study was supported by a grant from the Cure Cancer Australia.
Cancer incidence data were obtained from the National Cancer Statistics Clearing House database of the Australian Institute of Health and Welfare (AIHW; www.aihw. gov.au), which incorporates data from the 8 Australian HEAD & NECK—DOI 10.1002/HED
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TABLE 1. Patient characteristics by human papillomavirus status. Characteristic
HPV-positive (n 5 220)
HPV-negative (n 5 295)
p value for heterogeneity
55.8 (31–89)
61 (39–83)
< .0001 .6336
49 (22.3%) 171 (77.7%)
71 (24.1%) 224 (75.9%)
59 (26.8%) 86 (39.1%) 75 (34.1%)
14 (4.7%) 90 (30.5%) 191 (64.7%)
32 (17.4%) 15 (8.2%) 137 (74.5%)
21 (8.3%) 25 (9.8%) 208 (81.9%)
181 (82.3%) 29 (13.2%) 10 (4.5%)
222 (75.3%) 30 (10.2%) 43 (14.6%)
20 (9.1%) 76 (34.5%) 124 (56.4%)
60 (20.3%) 161 (54.6%) 74 (25.1%)
55 (25.1%) 77 (35.2%) 56 (25.6%) 31 (14.2%)
32 (10.9%) 107 (36.4%) 104 (35.4%) 51 (17.3%)
46 (20.9%) 38 (17.3%) 112 (50.9%) 24 (10.9%)
146 (50.2%) 61 (21.0%) 71 (24.4%) 13 (4.5%)
6 (2.7%) 18 (8.2%) 47 (21.4%) 149 (67.7%)
26 (8.8%) 63 (21.4%) 92 (31.3%) 113 (38.4%)
Age at diagnosis, y (mean, range) Sex Female Male Smoking status Nonsmoker Ex-smoker Current smoker Alcohol status (missing 5 77) Nondrinker Ex-drinker Drinker Primary tumor site Tonsil Base of tongue Other oropharyngeal Grade 1 2 3 T classification (missing 5 2) 1 2 3 4 N classification (missing 5 4) 0 1 2 3 TNM classification (missing 5 1) 1 2 3 4
< .0001
.0148
.0009
< .0001
.0002
< .0001
< .0001
Abbreviation: HPV, human papillomavirus.
state and territory cancer registries. We used the data for oropharyngeal SCC – incorporating the base of tongue (C01), tonsil (C09), and other sites within the oropharynx (C10) – and laryngeal cancer as a smoking-related head and neck cancer for comparison.
Study population The study cohort comprised 520 consecutive patients with primary oropharyngeal SCC treated with curative intent at 10 hospitals in Australia between 1987 and 2010. The study was approved by Sydney Local Health Service Ethics committees (Protocol x12–0141). The oropharynx is defined as palatine tonsil (tonsillar fossa, tonsillar pillar), base of tongue, soft palate, and posterior walls of the oropharynx. Patient selection was based on the availability of tumor and clinicopathological data. The HPV status of the oropharyngeal SCC was not determined at the time of diagnosis and therefore treatment decisions were not based on HPV status.
mined on two to six 4 to 5 mm sections of formalin-fixed paraffin-embedded tumor using an HPV E6-based multiplex real time polymerase chain reaction assay (PCR) modified from Stanley and Szewczuk.13 This assay detects and identifies 21 HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73, 82, 53, 6, 11, and 26). Stringent precautions were taken to avoid cross-contamination and water blanks placed after every fifth tube to detect contamination. DNA was extracted using the QIAmp RNA viral mini kit (Qiagen, Germany). Measured amounts of equine herpesvirus were used to monitor DNA extraction efficiency and removal of PCR inhibitors. The presence of cancer cells was confirmed by pathologist C.S.L. in hematoxylin-eosin stained sections cut after those for HPV analysis. Expression of p16 was determined by semiquantitative immunohistochemistry using an autostainer (Dako, Australia), the JC2 clone (Neomarkers, USA) (1/200) and the EnVision Flex Dual Link horseradish peroxidase/DAB visualization system (Dako, Australia). Staining was evaluated by 2 investigators, including a pathologist, as per our established protocol.14
Laboratory studies An HPV-positive tumor was defined as one testing positive for both HPV DNA and p16 expression to ensure virus causality.12 Presence and type of HPV DNA were deter744
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Statistical analyses Associations between HPV status and clinicopathological characteristics were assessed using a 2-sample t test
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FIGURE 1. (A) Locoregional recurrence. (B) Event free survival (C) Overall survival. HPV, human papillomavirus.
for the continuous variable and chi-square tests for categorical variables. The time trend in the proportion of oropharyngeal cancers testing HPV-positive was analyzed using the binary test for trend. Times to locoregional failure, death from oropharyngeal cancer, and death from any cause were calculated from the date of diagnosis. Locoregional recurrence was defined as clinical, radiological, and/or pathological evidence of recurrence at the primary site or in the regional nodal area. The Kaplan– Meier method was used to construct time-to-event curves.
RESULTS Patient characteristics This 23-year study was divided into 4 periods (1995 and prior, 1996–2000, 2001–2005, and 2006–2010). Five patients with HPV DNA-positive but p16-negative oropharyngeal SCC were excluded from the analysis. The characteristics of the 515 patients included in the study are shown in Table 1. Overall 220 of the 515 patients (42.7%) had HPV-positive oropharyngeal SCC. There was a gradual increase in the prevalence of HPV-positive oropharyngeal SCC from 20.2% in the 1987 to 1995 period to 63.5% in the 2006 to 2010 period. At diagnosis, patients with HPV-positive oropharyngeal SCC were significantly younger, more likely to be never smokers and nondrinkers, and to have a tonsillar primary, lower T stage and higher N stage (hence, higher TNM stage;
FIGURE 2. (A) Incidence of oropharyngeal cancer in Australia from 1991 to 2009 (from Australian Institute of Health and Welfare [AIHW]). (B) Incidence of laryngeal cancer in Australia from 1991 to 2009 (from AIHW).
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TABLE 2. The baseline characteristics of patients with HPV-positive tumors by study period.
Mean age at diagnosis, y (range) Sex Female Male Smoking status Non smoker Ex-smoker Current smoker Alcohol status (missing 5 36) Non smoker Ex-drinker Drinker Primary tumor site Tonsil Base of tongue Other oropharyngeal Grade 1 2 3 T classification (missing 5 1) 1 2 3 4 N classification 0 1 2 3 TNM classification 1 2 3 4 Treatment RT (1/- CTX) Surgery 1/- adjuvant RT (1/- CTX)
All years (n 5 220)
Before 1995 (n 5 26)
1996–2000 (n 5 80)
2001–2005 (n 5 67)
2006–2010 (n 5 47)
55.8 (31–89)
55.4 (34–77)
52 (31–76)
57.0 (35–89)
59.8 (32–86)
49 (22.3%) 171 (77.7%)
6 (23.1%) 20 (76.9%)
19 (23.8%) 61 (76.3%)
13 (19.4%) 54 (80.6%)
11 (23.4%) 36 (76.6%)
59 (26.8%) 86 (39.1%) 75 (34.1%)
5 (19.2%) 12 (46.2%) 9 (34.6%)
18 (22.5%) 31 (38.8%) 31 (38.8%)
20 (29.9%) 28 (41.8%) 19 (28.4%)
16 (34.0%) 15 (31.9%) 16 (34.0%)
32 (17.4%) 15 (8.2%) 137 (74.5%)
6 (28.6%) 1 (4.8%) 14 (66.7%)
8 (13.8%) 4 (6.9%) 46 (79.3%)
13 (21.3%) 5 (8.2%) 43 (70.5%)
5 (11.4%) 5 (11.4%) 34 (77.3%)
181 (82.3%) 29 (13.2%) 10 (4.5%)
21 (80.8%) 4 (15.4%) 1 (3.8%)
70 (87.5%) 6 (7.5%) 4 (5.0%)
57 (85.1%) 5 (7.5%) 5 (7.5%)
33 (70.2%) 14 (29.8%) 0 (0.0%)
20 (9.1%) 76 (34.5%) 124 (56.4%)
3 (11.5%) 10 (38.5%) 13 (50.0%)
9 (11.3%) 29 (36.3%) 42 (52.5%)
4 (6.0%) 25 (37.3%) 38 (56.7%)
4 (8.5%) 12 (25.5%) 31 (66.0%)
55 (25.1%) 77 (35.2%) 56 (25.6%) 31 (14.2%)
5 (19.2%) 9 (34.6%) 8 (30.8%) 4 (15.4%)
13 (16.5%) 25 (31.6%) 24 (30.4%) 17 (21.5%)
20 (29.9%) 24 (35.8%) 18 (26.9%) 5 (7.5%)
17 (36.2%) 19 (40.4%) 6 (12.8%) 5 (10.6%)
46 (20.9%) 38 (17.3%) 112 (50.9%) 24 (10.9%)
5 (19.2%) 4 (15.4%) 13 (50.0%) 4 (15.4%)
21 (26.3%) 17 (21.3%) 32 (40.0%) 10 (12.5%)
11 (16.4%) 10 (14.9%) 39 (58.2%) 7 (10.4%)
9 (19.1%) 7 (14.9%) 28 (59.6%) 3 (6.4%)
6 (2.7%) 18 (8.2%) 47 (21.4%) 149 (67.7%)
2 (7.7%) 1 (3.8%) 6 (23.1%) 17 (65.4%)
2 (2.5%) 7 (8.8%) 23 (28.8%) 48 (60.0%)
1 (1.5%) 4 (6.0%) 12 (17.9%) 50 (74.6%)
1 (2.1%) 6 (12.8%) 6 (12.8%) 34 (72.3%)
112 (50.9%) 108 (49.1%)
7 (26.9%) 19 (73.1%)
42 (52.5%) 38 (47.5%)
31 (46.3%) 36 (53.7%)
32 (68.1%) 15 (31.9%)
p value for heterogeneity (p value for trend)
.0040 (.003) .9267 (.86) .6101 (.19) .5574 (.63) .0058
.6874 (.11) .0691 (.001)
.5520 (.67)
.3144 (.20)
.0068 (.007)
Abbreviations: RT, radiotherapy; CTX, chemotherapy.
Table 1). The median follow-up of the whole cohort was 48.5 months and 233 patients had died at the time of last follow-up. Patients with HPV-positive oropharyngeal SCC had significantly better outcomes in terms of locoregional recurrence, event-free survival, and overall survival (Figure 1A–1C).
Increasing incidence of oropharyngeal squamous cell carcinoma in Australia Data from AIHW showed that the incidence of oropharyngeal SCC in Australia doubled from 322 cases per year in 1991 to 665 cases per year in 2009 (Figure 2A). This increase was seen in both sexes but was more apparent in men (from 235 cases in 1991 to 530 cases in 2009). In comparison, the incidence of laryngeal SCC (a smoking-related head and neck cancer) was stable in both men and women during the same period (Figure 2B). 746
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Time trends by human papillomavirus status Among patients with HPV-positive oropharyngeal SCC, the median age increased from 55.4 years in the 1987 to 1995 period to 59.8 years in the 2006 to 2010 period (p 5 .004; Table 2). The proportion that was never smokers at the time of diagnosis increased from 19.2% (1995 and prior) to 34.0% (2006–2010; p value for trend 5 .19 for never smokers vs ex-smokers vs current smokers and p value for trend 5 .08 for never smokers vs smokers). Over time, patients with HPV-positive oropharyngeal SCC were also more likely to have base of tongue primary sites (15.4% vs 29.8%; p 5 .006) and lower T classification (in the more recent study period [19.2% vs 36.2%; p 5 .069]). In patients with HPV-negative oropharyngeal SCC, there was no significant difference in the median age at diagnosis, the proportion of nonsmokers (4.7%), the location of the primary site, or T classification over the study period (Table 3).
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TABLE 3. The baseline characteristics of patients with HPV-negative tumors by study period.
Characteristic
Mean age at diagnosis, y Gender Female Male Smoking status Non smoker Ex-smoker Current smoker Alcohol status (missing 5 41) Non drinker Ex-drinker Drinker Primary tumor site Tonsil Base of tongue Other oropharyngeal Grade 1 2 3 T classification (missing 5 1) 1 2 3 4 N classification (missing 5 4) 0 1 2 3 TNM classification (missing 5 1) 1 2 3 4 Treatment RT (1/- CTX) Surgery 1/- adjuvant RT (1/- CTX)
All years (n 5 295)
Before 1995 (n 5 103)
1996–2000 (n 5 94)
2001–2005 (n 5 71)
2006–2010 (n 5 27)
61.0 (39–83)
59.5 (42–77)
61.7 (39–82)
61.2 (41–83)
63.3 (45–82)
71 (24.1%) 224 (75.9%)
32 (31.1%) 71 (68.9%)
20 (21.3%) 74 (78.7%)
13 (18.3%) 58 (81.7%)
6 (22.2%) 21 (77.8%)
14 (4.7%) 90 (30.5%) 191 (64.7%)
5 (4.9%) 28 (27.2%) 70 (68.0%)
2 (2.1%) 32 (34.0%) 60 (63.8%)
5 (7.0%) 22 (31.0%) 44 (62.0%)
2 (7.4%) 8 (29.6%) 17 (63.0%)
21 (8.3%) 25 (9.8%) 208 (81.9%)
9 (10.3%) 6 (6.9%) 72 (82.8%)
3 (3.8%) 9 (11.4%) 67 (84.8%)
7 (11.1%) 3 (4.8%) 53 (84.1%)
2 (8.0%) 7 (28.0%) 16 (64.0%)
222 (75.3%) 30 (10.2%) 43 (14.6%)
78 (75.7%) 11 (10.7%) 14 (13.6%)
75 (79.8%) 10 (10.6%) 9 (9.6%)
51 (71.8%) 7 (9.9%) 13 (18.3%)
18 (66.7%) 2 (7.4%) 7 (25.9%)
60 (20.3%) 161 (54.6%) 74 (25.1%)
26 (25.2%) 54 (52.4%) 23 (22.3%)
18 (19.1%) 54 (57.4%) 22 (23.4%)
11 (15.5%) 41 (57.7%) 19 (26.8%)
5 (18.5%) 12 (44.4%) 10 (37.0%)
32 (10.9%) 107 (36.4%) 104 (35.4%) 51 (17.3%)
15 (14.6%) 38 (36.9%) 39 (37.9%) 11 (10.7%)
8 (8.6%) 29 (31.2%) 39 (41.9%) 17 (18.3%)
4 (5.6%) 30 (42.3%) 19 (26.8%) 18 (25.4%)
5 (18.5%) 10 (37.0%) 7 (25.9%) 5 (18.5%)
146 (50.2%) 61 (21.0%) 71 (24.4%) 13 (4.5%)
60 (58.3%) 20 (19.4%) 19 (18.4%) 4 (3.9%)
45 (48.4%) 18 (19.4%) 22 (23.7%) 8 (8.6%)
30 (43.5%) 16 (23.2%) 23 (33.3%) 0 (0.0%)
11 (42.3%) 7 (26.9%) 7 (26.9%) 1 (3.8%)
26 (8.8%) 63 (21.4%) 92 (31.3%) 113 (38.4%)
14 (13.6%) 24 (23.3%) 36 (35.0%) 29 (28.2%)
6 (6.5%) 18 (19.4%) 29 (31.2%) 40 (43.0%)
2 (2.8%) 16 (22.5%) 19 (26.8%) 34 (47.9%)
4 (14.8%) 5 (18.5%) 8 (29.6%) 10 (37.0%)
126 (42.7%) 169 (57.3%)
42 (40.8%) 61 (59.2%)
41 (43.6%) 53 (56.4%)
30 (42.3%) 41 (57.7%)
13 (48.1%) 14 (51.9%)
p value for heterogeneity (p value for trend)
.1748 (.059) .2122 (.088) .7311 (.38) .0197 (.22) .4650
.5375 (.071) .0867 (.37)
.1312 (.073)
.1346 (.048)
.9142 (.58)
Abbreviations: RT, radiotherapy; CTX, chemotherapy.
Treatment over the study period There was an increase in the use of definitive radiation therapy (RT; with or without chemotherapy) and a decrease in the use of surgery (with or without adjuvant therapy) over the study period (p 5 .0001). Overall, RT was used in 27.6% of patients in the earliest period (1995 and prior), but the rate had more than doubled (58.6%) by the latest period (2006–2010). This increase was seen only in patients with HPV-positive oropharyngeal SCC, 26.9% in the 1987 to 1995 period to 68.1% in the 2006 to 2010 period (p 5 .007). In contrast, there was no significant change in the treatment approach in patients with HPV-negative oropharyngeal SCC (p 5 .914).
Outcomes over the study period During the 23-year study period, there was a trend toward better locoregional control in patients with HPV-
positive oropharyngeal SCC (p 5 .075; Figure 3A). Similarly, the event-free survival and overall survival also improved in the more recent study periods (Figure 3B and 3C). However, the outcomes of patients with HPVnegative oropharyngeal SCC did not change during the study period (Figure 4).
DISCUSSION This study has provided new insight into the changing epidemiology of oropharyngeal SCC in Australia. Data collected from more than 500 patients treated at 10 teaching hospitals in Australia over the last 2 decades showed a steady increase in the proportion of HPV-positive oropharyngeal SCC (from 20.2% to 63.5% over the study period). This is consistent with our earlier smaller series3 and parallels findings from other developed countries.2,15–18 Overall results strongly support the concept HEAD & NECK—DOI 10.1002/HED
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FIGURE 3. Outcomes of patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) over the 4 study periods (1 5 1995 and prior; 2 5 1996–2000; 3 5 2001–2005; and 4 5 2006–2010). (A) Locoregional recurrence. (B) Event-free survival. (C) Overall survival. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
that HPV accounts for the increasing incidence of oropharyngeal SCC seen in Australia and in other developed countries.18,19 The effect of declining tobacco use in our community on the epidemiology of oropharyngeal SCC was a major focus of this study. Many studies have shown that patients with HPV-positive oropharyngeal SCC are less likely to have a history of tobacco use than those with HPV-negative oropharyngeal SCC.20,21 In our cohort, patients with HPV-positive oropharyngeal SCC were increasingly likely to be never smokers at diagnosis (from 19.2% to 34.0% over the study period). Our current rate of never smokers with HPV-positive oropharyngeal SCC is similar to that reported from other Western countries.20,22 The role of mutagens in tobacco as a co-factor to HPV in the development of oropharyngeal SCC, and the interaction between HPV and smoking in prognosis and response to treatment are not fully understood. Previous studies have shown that among patients with HPVpositive oropharyngeal SCC, smokers had poorer outcomes than never smokers.21,23 Our findings have important research and public health implications. However, 748
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smoking remains a major risk factor for oropharyngeal SCC worldwide, underscoring the need for prevention strategies targeted toward tobacco and alcohol use. Interestingly, the median age at diagnosis for our patients with HPV-positive oropharyngeal SCC increased over time. We speculate that this could be related to the declining proportion of smokers in this cohort, therefore less exposure to the potential co-carcinogen tobacco. Overall, the median age of patients with HPV-positive oropharyngeal SCC was still less than that of patients with HPV-negative oropharyngeal SCC. HPV-negative oropharyngeal SCC has traditionally been associated with tobacco use (and alcohol abuse), and smoking patterns among this group did not change over time, with only about 5% being never smokers, 30% ex-smokers, and 60% current smokers at the time of diagnosis. In line with our previous studies24,25 and other published data,26 the tonsil was the predominant primary site for HPV-positive oropharyngeal SCC. Interestingly, the proportion of base of tongue primaries increased over time and there was also a trend for lower T stage at presentation. Further longitudinal studies will be needed to
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FIGURE 4. Outcomes of patients with human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (SCC) over the 4 study periods (1 5 1995 and prior; 2 5 1996–2000; 3 5 2001–2005; and 4 5 2006–2010). (A) Locoregional recurrence. (B) Event-free survival. (C) Overall survival. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
confirm these trends and to identify underlying factors. This study found no evidence of changes in the epidemiology of HPV-negative oropharyngeal SCC over the study period. It is unlikely that the difference in HPV prevalence in the different periods is due to a different analytical sensitivity of our HPV DNA PCR in different periods as the cycle threshold values did not differ between the years. We also tested for p16 expression with immunohistochemistry, which our controls have shown is unaffected by sample DNA quality. P16 is a cyclin-dependent kinase inhibitor and is induced as a consequence of inhibition of retinoblastoma protein activity by the HPV E7 oncoprotein. The reason for the rapid increase in prevalence of HPV-positive oropharyngeal SCCs remains elusive. One explanation may be a change in sexual behavior (ie, the increasing practice of oral sex and increasing numbers of lifetime sex partners). Data from Europe and the United States suggest that the number of lifetime sexual partners has increased over recent decades.27,28 As the HPV infection usually takes more than 10 years to progress from infection to malignancy, a temporal change in sexual
behavior could explain the increased incidence observed in HPV-positive oropharyngeal SCC. There is a geographic variation in terms of incidence rates of oropharyngeal SCC.10 This likely reflects wide variability in the prevalence of established risk behaviors and modifiers. Our study lacks details of sexual activity, drug use, and socioeconomic status to show any change in these risk factors during the study period. Although HPV vaccination offers the potential to stem this trend, it will not have an impact on the incidence of HPV-positive oropharyngeal SCC for decades. Given the rising trends and the approximately 40-year lag time between infection and manifestation of the disease, HPVpositive oropharyngeal SCC will be a problem for the foreseeable future. In the interim, the HPV-positive oropharyngeal SCC epidemic will have tremendous implications for health care resources; these typically younger, healthier patients have a high chance of surviving their disease,23 and they will have to live with the late effects of treatment for many decades. Our results showed a trend in improved outcomes in patients with HPV-positive oropharyngeal SCC over the HEAD & NECK—DOI 10.1002/HED
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study period but not in patients with HPV-negative oropharyngeal SCC. This could be the result of the increasing use of combined chemotherapy and RT, but our data do not allow us to draw definitive conclusions on the best treatment for patients with HPV-positive oropharyngeal SCC. The choice of treatment in our study cohort was not based on the HPV status (the HPV status was not available in the majority) and the increasing use of RT was only seen in the patients with HPV-positive oropharyngeal SCC. This is likely because of their younger age and higher nodal stage at diagnosis. Given the favorable prognosis in this cohort, assessment of the HPV status of oropharyngeal SCC should be routine in clinical practice. However, the best treatment regimen for HPV-positive oropharyngeal SCC has not been defined and tremendous interest has been expressed in deescalating therapy to decrease toxicity. Potential deescalation strategies include the use of transoral robotic surgery, reduced doses of radiation or chemotherapy (or both), or avoidance of chemotherapy entirely for low-risk patients. One such trial is the TROG 12.01 study, which aims to compare the treatment-related side effects of RT with concurrent cisplatin or cetuximab regimens in HPV-positive oropharyngeal SCC. In conclusion, our data show a rising prevalence of HPV-positive oropharyngeal SCC in Australia over the last 2 decades, from 20.2% (1995 and prior) to 63.5% (2006–2010). These patients with HPV-positive oropharyngeal SCC are now presenting at an older age and about one-third have never smoked.
Acknowledgments The authors thank the clinicians at all the participating hospitals.
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7. Vidal L, Gillison ML. Human papillomavirus in HNSCC: recognition of a distinct disease type. Hematol Oncol Clin North Am 2008;22:1125–1142. 8. Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 2010;11: 781–789. 9. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006;24:736–747. 10. Gillison ML, Castellsague X, Chaturvedi A, et al. Eurogin roadmap: comparative epidemiology of HPV infection and associated cancers of the head and neck and cervix. Int J Cancer 2014;134:497–507. 11. Hong AM, Martin A, Armstrong BK, et al. Human papillomavirus modifies the prognostic significance of T stage and possibly N stage in tonsillar cancer. Ann Oncol 2013;24:215–219. 12. Smeets SJ, Hesselink AT, Speel EJ, et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer 2007;121:2465–2472. 13. Stanley KK, Szewczuk E. Multiplexed tandem PCR: gene profiling from small amounts of RNA using SYBR Green detection. Nucleic Acids Res 2005;33:e180. 14. Hong A, Jones D, Chatfield M, et al. HPV status of oropharyngeal cancer by combination HPV DNA/p16 testing: biological relevance of discordant results. Ann Surg Oncol 2013;20 Suppl 3:S450–S458. 15. N€asman 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;125:362–366. 16. Nichols AC, Palma DA, Dhaliwal SS, et al. The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population. Curr Oncol 2013;20:212–219. 17. Rietbergen MM, Leemans CR, Bloemena E, et al. Increasing prevalence rates of HPV attributable oropharyngeal squamous cell carcinomas in the Netherlands as assessed by a validated test algorithm. Int J Cancer 2013; 132:1565–1571. 18. Evans M, Newcombe R, Fiander A, et al. Human papillomavirusassociated oropharyngeal cancer: an observational study of diagnosis, prevalence and prognosis in a UK population. BMC Cancer 2013;13:220. 19. Chaturvedi AK, Anderson WF, Lortet–Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol 2013;31:4550–4559. 20. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35. 21. Maxwell JH, Kumar B, Feng FY, et al. Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res 2010;16:1226–1235. 22. Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16negative head and neck cancers. J Natl Cancer Inst 2008;100:407–420. 23. Hong AM, Martin A, Chatfield M, et al. Human papillomavirus, smoking status and outcomes in tonsillar squamous cell carcinoma. Int J Cancer 2013;132:2748–2754. 24. Hong A, Zhang M, Veillard AS, et al. The prognostic significance of hypoxia inducing factor 1-A in oropharyngeal cancer in relation to human papillomavirus status. Oral Oncol 2013;49:354–359. 25. Hong AM, Dobbins TA, Lee CS, et al. Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. Br J Cancer 2010;103:1510–1517. 26. Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16negative oropharyngeal cancer. J Clin Oncol 2012;30:2102–2111. 27. Agius PA, Pitts MK, Smith AM, Mitchell A. Sexual behaviour and related knowledge among a representative sample of secondary school students between 1997 and 2008. Aust N Z J Public Health 2010;34:476–481. 28. Bajos N, Bozon M, Beltzer N, et al. Changes in sexual behaviours: from secular trends to public health policies. AIDS 2010;24:1185–1191.
Rising prevalence of human papillomavirus–related oropharyngeal cancer in Australia over the last 2 decades Angela Hong, PhD,1,2* C. Soon Lee, MD,1,3 Deanna Jones, BAppSci,4 Anne-Sophie Veillard, MS,5 Mei Zhang, MD,1,2 Xiaoying Zhang, PhD,1 Robert Smee, MBBS,6 June Corry, MBBS,7 Sandro Porceddu, MBBS,8 Christopher Milross, MD,1,2 Michael Elliott, MPhil,9 Jonathan Clark, MBBS,1,9 Barbara Rose, PhD4 1
Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia, 2Department of Radiation Oncology, Lifehouse, Sydney, New South Wales, Australia, 3Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia, 4Department of Infectious Diseases and Immunology, The University of Sydney, Sydney, New South Wales, Australia, 5NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia, 6Department of Radiation Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia, 7Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, 8Cancer Services, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia, 9Sydney Head and Neck Cancer Institute, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Accepted 10 December 2014 Published online 25 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23942
ABSTRACT: Background. This study provides Australian data on the characteristics of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) over the last 2 decades. Methods. The HPV status of 515 patients with oropharyngeal SCC diagnosed between 1987 and 2010 was determined by HPV E6-targeted multiplex real time polymerase chain reaction assay (PCR) and p16 immunohistochemistry. Results. The HPV positivity rate increased from 20.2% (1987–1995) to 63.5% (2006–2010). Among HPV-positive oropharyngeal SCC over the study period, the median age increased from 55.4 years to 59.8 years (p 5 .004) and there was a trend of an increasing proportion of never
INTRODUCTION Head and neck squamous cell carcinoma is the sixth most common cancer worldwide1 and the incidence of oropharyngeal squamous cell carcinoma (SCC) is increasing in Western countries despite declining tobacco use.2–6 We have previously reported that this increase in Australia is likely attributable to a rise in the proportion of oropharyngeal SCC caused by human papillomavirus (HPV); from 19% (1987– 1990) to 47% (2001–2005) to 66% (2005–2006).3 This trend is particularly apparent in the younger age group and parallels findings in other developed countries where HPV positivity rates as high as 72% have been reported.7 The biological characteristics of HPV-positive oropharyngeal SCC are distinct from those of HPV-negative oropharyngeal SCC with respect to expression of the p16INK4A (p16), and genetic profiles, including the frequency of mutations in the p53 gene.8,9 Epidemiologically,
smokers (19.2% to 34.0%). The use of radiation therapy (RT) in patients with HPV-positive oropharyngeal cancer increased from 26.9% to 68.1% (p 5 .007) and we also observed a trend of improved outcomes. Conclusion. Our data show a rising prevalence of HPV-positive oropharyngeal SCC in Australia over the last 2 decades. These patients with HPV-positive oropharyngeal SCC are now presenting at an older age and C 2015 Wiley Periodicals, Inc. Head about one third have never smoked. V Neck 38: 743–750, 2016
KEY WORDS: human papillomavirus (HPV), oropharyngeal cancer, head and neck cancer
it has been reported that patients with HPV-positive oropharyngeal SCC tend to be younger, less likely to have a history of tobacco and alcohol use, and tend to have a higher number of sexual partners, in particular oral sexual partners, than patients with HPV-negative oropharyngeal SCC.10 Furthermore, HPV-positive oropharyngeal SCC is associated with markedly better survival, despite a tendency for higher grade and more advanced nodal disease.11 This study extends our previous work3 by including patients treated for oropharyngeal SCC at 10 large teaching hospitals in Australia over the last 2 decades. We sought evidence of change in HPV status relative to tobacco exposure, personal characteristics, treatment patterns, and outcomes over the study period. The purpose of this study was to gain new insight into the changing epidemiology of oropharyngeal SCC in Australia.
MATERIALS AND METHODS Incidence of oropharyngeal cancer in Australia
*Corresponding author: A. Hong, Central Clinical School, The University of Sydney, Level 6, Blackburn Building, New South Wales, 2006 Australia. E-mail: [email protected] Contract grant sponsor: This study was supported by a grant from the Cure Cancer Australia.
Cancer incidence data were obtained from the National Cancer Statistics Clearing House database of the Australian Institute of Health and Welfare (AIHW; www.aihw. gov.au), which incorporates data from the 8 Australian HEAD & NECK—DOI 10.1002/HED
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TABLE 1. Patient characteristics by human papillomavirus status. Characteristic
HPV-positive (n 5 220)
HPV-negative (n 5 295)
p value for heterogeneity
55.8 (31–89)
61 (39–83)
< .0001 .6336
49 (22.3%) 171 (77.7%)
71 (24.1%) 224 (75.9%)
59 (26.8%) 86 (39.1%) 75 (34.1%)
14 (4.7%) 90 (30.5%) 191 (64.7%)
32 (17.4%) 15 (8.2%) 137 (74.5%)
21 (8.3%) 25 (9.8%) 208 (81.9%)
181 (82.3%) 29 (13.2%) 10 (4.5%)
222 (75.3%) 30 (10.2%) 43 (14.6%)
20 (9.1%) 76 (34.5%) 124 (56.4%)
60 (20.3%) 161 (54.6%) 74 (25.1%)
55 (25.1%) 77 (35.2%) 56 (25.6%) 31 (14.2%)
32 (10.9%) 107 (36.4%) 104 (35.4%) 51 (17.3%)
46 (20.9%) 38 (17.3%) 112 (50.9%) 24 (10.9%)
146 (50.2%) 61 (21.0%) 71 (24.4%) 13 (4.5%)
6 (2.7%) 18 (8.2%) 47 (21.4%) 149 (67.7%)
26 (8.8%) 63 (21.4%) 92 (31.3%) 113 (38.4%)
Age at diagnosis, y (mean, range) Sex Female Male Smoking status Nonsmoker Ex-smoker Current smoker Alcohol status (missing 5 77) Nondrinker Ex-drinker Drinker Primary tumor site Tonsil Base of tongue Other oropharyngeal Grade 1 2 3 T classification (missing 5 2) 1 2 3 4 N classification (missing 5 4) 0 1 2 3 TNM classification (missing 5 1) 1 2 3 4
< .0001
.0148
.0009
< .0001
.0002
< .0001
< .0001
Abbreviation: HPV, human papillomavirus.
state and territory cancer registries. We used the data for oropharyngeal SCC – incorporating the base of tongue (C01), tonsil (C09), and other sites within the oropharynx (C10) – and laryngeal cancer as a smoking-related head and neck cancer for comparison.
Study population The study cohort comprised 520 consecutive patients with primary oropharyngeal SCC treated with curative intent at 10 hospitals in Australia between 1987 and 2010. The study was approved by Sydney Local Health Service Ethics committees (Protocol x12–0141). The oropharynx is defined as palatine tonsil (tonsillar fossa, tonsillar pillar), base of tongue, soft palate, and posterior walls of the oropharynx. Patient selection was based on the availability of tumor and clinicopathological data. The HPV status of the oropharyngeal SCC was not determined at the time of diagnosis and therefore treatment decisions were not based on HPV status.
mined on two to six 4 to 5 mm sections of formalin-fixed paraffin-embedded tumor using an HPV E6-based multiplex real time polymerase chain reaction assay (PCR) modified from Stanley and Szewczuk.13 This assay detects and identifies 21 HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73, 82, 53, 6, 11, and 26). Stringent precautions were taken to avoid cross-contamination and water blanks placed after every fifth tube to detect contamination. DNA was extracted using the QIAmp RNA viral mini kit (Qiagen, Germany). Measured amounts of equine herpesvirus were used to monitor DNA extraction efficiency and removal of PCR inhibitors. The presence of cancer cells was confirmed by pathologist C.S.L. in hematoxylin-eosin stained sections cut after those for HPV analysis. Expression of p16 was determined by semiquantitative immunohistochemistry using an autostainer (Dako, Australia), the JC2 clone (Neomarkers, USA) (1/200) and the EnVision Flex Dual Link horseradish peroxidase/DAB visualization system (Dako, Australia). Staining was evaluated by 2 investigators, including a pathologist, as per our established protocol.14
Laboratory studies An HPV-positive tumor was defined as one testing positive for both HPV DNA and p16 expression to ensure virus causality.12 Presence and type of HPV DNA were deter744
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Statistical analyses Associations between HPV status and clinicopathological characteristics were assessed using a 2-sample t test
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FIGURE 1. (A) Locoregional recurrence. (B) Event free survival (C) Overall survival. HPV, human papillomavirus.
for the continuous variable and chi-square tests for categorical variables. The time trend in the proportion of oropharyngeal cancers testing HPV-positive was analyzed using the binary test for trend. Times to locoregional failure, death from oropharyngeal cancer, and death from any cause were calculated from the date of diagnosis. Locoregional recurrence was defined as clinical, radiological, and/or pathological evidence of recurrence at the primary site or in the regional nodal area. The Kaplan– Meier method was used to construct time-to-event curves.
RESULTS Patient characteristics This 23-year study was divided into 4 periods (1995 and prior, 1996–2000, 2001–2005, and 2006–2010). Five patients with HPV DNA-positive but p16-negative oropharyngeal SCC were excluded from the analysis. The characteristics of the 515 patients included in the study are shown in Table 1. Overall 220 of the 515 patients (42.7%) had HPV-positive oropharyngeal SCC. There was a gradual increase in the prevalence of HPV-positive oropharyngeal SCC from 20.2% in the 1987 to 1995 period to 63.5% in the 2006 to 2010 period. At diagnosis, patients with HPV-positive oropharyngeal SCC were significantly younger, more likely to be never smokers and nondrinkers, and to have a tonsillar primary, lower T stage and higher N stage (hence, higher TNM stage;
FIGURE 2. (A) Incidence of oropharyngeal cancer in Australia from 1991 to 2009 (from Australian Institute of Health and Welfare [AIHW]). (B) Incidence of laryngeal cancer in Australia from 1991 to 2009 (from AIHW).
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TABLE 2. The baseline characteristics of patients with HPV-positive tumors by study period.
Mean age at diagnosis, y (range) Sex Female Male Smoking status Non smoker Ex-smoker Current smoker Alcohol status (missing 5 36) Non smoker Ex-drinker Drinker Primary tumor site Tonsil Base of tongue Other oropharyngeal Grade 1 2 3 T classification (missing 5 1) 1 2 3 4 N classification 0 1 2 3 TNM classification 1 2 3 4 Treatment RT (1/- CTX) Surgery 1/- adjuvant RT (1/- CTX)
All years (n 5 220)
Before 1995 (n 5 26)
1996–2000 (n 5 80)
2001–2005 (n 5 67)
2006–2010 (n 5 47)
55.8 (31–89)
55.4 (34–77)
52 (31–76)
57.0 (35–89)
59.8 (32–86)
49 (22.3%) 171 (77.7%)
6 (23.1%) 20 (76.9%)
19 (23.8%) 61 (76.3%)
13 (19.4%) 54 (80.6%)
11 (23.4%) 36 (76.6%)
59 (26.8%) 86 (39.1%) 75 (34.1%)
5 (19.2%) 12 (46.2%) 9 (34.6%)
18 (22.5%) 31 (38.8%) 31 (38.8%)
20 (29.9%) 28 (41.8%) 19 (28.4%)
16 (34.0%) 15 (31.9%) 16 (34.0%)
32 (17.4%) 15 (8.2%) 137 (74.5%)
6 (28.6%) 1 (4.8%) 14 (66.7%)
8 (13.8%) 4 (6.9%) 46 (79.3%)
13 (21.3%) 5 (8.2%) 43 (70.5%)
5 (11.4%) 5 (11.4%) 34 (77.3%)
181 (82.3%) 29 (13.2%) 10 (4.5%)
21 (80.8%) 4 (15.4%) 1 (3.8%)
70 (87.5%) 6 (7.5%) 4 (5.0%)
57 (85.1%) 5 (7.5%) 5 (7.5%)
33 (70.2%) 14 (29.8%) 0 (0.0%)
20 (9.1%) 76 (34.5%) 124 (56.4%)
3 (11.5%) 10 (38.5%) 13 (50.0%)
9 (11.3%) 29 (36.3%) 42 (52.5%)
4 (6.0%) 25 (37.3%) 38 (56.7%)
4 (8.5%) 12 (25.5%) 31 (66.0%)
55 (25.1%) 77 (35.2%) 56 (25.6%) 31 (14.2%)
5 (19.2%) 9 (34.6%) 8 (30.8%) 4 (15.4%)
13 (16.5%) 25 (31.6%) 24 (30.4%) 17 (21.5%)
20 (29.9%) 24 (35.8%) 18 (26.9%) 5 (7.5%)
17 (36.2%) 19 (40.4%) 6 (12.8%) 5 (10.6%)
46 (20.9%) 38 (17.3%) 112 (50.9%) 24 (10.9%)
5 (19.2%) 4 (15.4%) 13 (50.0%) 4 (15.4%)
21 (26.3%) 17 (21.3%) 32 (40.0%) 10 (12.5%)
11 (16.4%) 10 (14.9%) 39 (58.2%) 7 (10.4%)
9 (19.1%) 7 (14.9%) 28 (59.6%) 3 (6.4%)
6 (2.7%) 18 (8.2%) 47 (21.4%) 149 (67.7%)
2 (7.7%) 1 (3.8%) 6 (23.1%) 17 (65.4%)
2 (2.5%) 7 (8.8%) 23 (28.8%) 48 (60.0%)
1 (1.5%) 4 (6.0%) 12 (17.9%) 50 (74.6%)
1 (2.1%) 6 (12.8%) 6 (12.8%) 34 (72.3%)
112 (50.9%) 108 (49.1%)
7 (26.9%) 19 (73.1%)
42 (52.5%) 38 (47.5%)
31 (46.3%) 36 (53.7%)
32 (68.1%) 15 (31.9%)
p value for heterogeneity (p value for trend)
.0040 (.003) .9267 (.86) .6101 (.19) .5574 (.63) .0058
.6874 (.11) .0691 (.001)
.5520 (.67)
.3144 (.20)
.0068 (.007)
Abbreviations: RT, radiotherapy; CTX, chemotherapy.
Table 1). The median follow-up of the whole cohort was 48.5 months and 233 patients had died at the time of last follow-up. Patients with HPV-positive oropharyngeal SCC had significantly better outcomes in terms of locoregional recurrence, event-free survival, and overall survival (Figure 1A–1C).
Increasing incidence of oropharyngeal squamous cell carcinoma in Australia Data from AIHW showed that the incidence of oropharyngeal SCC in Australia doubled from 322 cases per year in 1991 to 665 cases per year in 2009 (Figure 2A). This increase was seen in both sexes but was more apparent in men (from 235 cases in 1991 to 530 cases in 2009). In comparison, the incidence of laryngeal SCC (a smoking-related head and neck cancer) was stable in both men and women during the same period (Figure 2B). 746
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Time trends by human papillomavirus status Among patients with HPV-positive oropharyngeal SCC, the median age increased from 55.4 years in the 1987 to 1995 period to 59.8 years in the 2006 to 2010 period (p 5 .004; Table 2). The proportion that was never smokers at the time of diagnosis increased from 19.2% (1995 and prior) to 34.0% (2006–2010; p value for trend 5 .19 for never smokers vs ex-smokers vs current smokers and p value for trend 5 .08 for never smokers vs smokers). Over time, patients with HPV-positive oropharyngeal SCC were also more likely to have base of tongue primary sites (15.4% vs 29.8%; p 5 .006) and lower T classification (in the more recent study period [19.2% vs 36.2%; p 5 .069]). In patients with HPV-negative oropharyngeal SCC, there was no significant difference in the median age at diagnosis, the proportion of nonsmokers (4.7%), the location of the primary site, or T classification over the study period (Table 3).
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TABLE 3. The baseline characteristics of patients with HPV-negative tumors by study period.
Characteristic
Mean age at diagnosis, y Gender Female Male Smoking status Non smoker Ex-smoker Current smoker Alcohol status (missing 5 41) Non drinker Ex-drinker Drinker Primary tumor site Tonsil Base of tongue Other oropharyngeal Grade 1 2 3 T classification (missing 5 1) 1 2 3 4 N classification (missing 5 4) 0 1 2 3 TNM classification (missing 5 1) 1 2 3 4 Treatment RT (1/- CTX) Surgery 1/- adjuvant RT (1/- CTX)
All years (n 5 295)
Before 1995 (n 5 103)
1996–2000 (n 5 94)
2001–2005 (n 5 71)
2006–2010 (n 5 27)
61.0 (39–83)
59.5 (42–77)
61.7 (39–82)
61.2 (41–83)
63.3 (45–82)
71 (24.1%) 224 (75.9%)
32 (31.1%) 71 (68.9%)
20 (21.3%) 74 (78.7%)
13 (18.3%) 58 (81.7%)
6 (22.2%) 21 (77.8%)
14 (4.7%) 90 (30.5%) 191 (64.7%)
5 (4.9%) 28 (27.2%) 70 (68.0%)
2 (2.1%) 32 (34.0%) 60 (63.8%)
5 (7.0%) 22 (31.0%) 44 (62.0%)
2 (7.4%) 8 (29.6%) 17 (63.0%)
21 (8.3%) 25 (9.8%) 208 (81.9%)
9 (10.3%) 6 (6.9%) 72 (82.8%)
3 (3.8%) 9 (11.4%) 67 (84.8%)
7 (11.1%) 3 (4.8%) 53 (84.1%)
2 (8.0%) 7 (28.0%) 16 (64.0%)
222 (75.3%) 30 (10.2%) 43 (14.6%)
78 (75.7%) 11 (10.7%) 14 (13.6%)
75 (79.8%) 10 (10.6%) 9 (9.6%)
51 (71.8%) 7 (9.9%) 13 (18.3%)
18 (66.7%) 2 (7.4%) 7 (25.9%)
60 (20.3%) 161 (54.6%) 74 (25.1%)
26 (25.2%) 54 (52.4%) 23 (22.3%)
18 (19.1%) 54 (57.4%) 22 (23.4%)
11 (15.5%) 41 (57.7%) 19 (26.8%)
5 (18.5%) 12 (44.4%) 10 (37.0%)
32 (10.9%) 107 (36.4%) 104 (35.4%) 51 (17.3%)
15 (14.6%) 38 (36.9%) 39 (37.9%) 11 (10.7%)
8 (8.6%) 29 (31.2%) 39 (41.9%) 17 (18.3%)
4 (5.6%) 30 (42.3%) 19 (26.8%) 18 (25.4%)
5 (18.5%) 10 (37.0%) 7 (25.9%) 5 (18.5%)
146 (50.2%) 61 (21.0%) 71 (24.4%) 13 (4.5%)
60 (58.3%) 20 (19.4%) 19 (18.4%) 4 (3.9%)
45 (48.4%) 18 (19.4%) 22 (23.7%) 8 (8.6%)
30 (43.5%) 16 (23.2%) 23 (33.3%) 0 (0.0%)
11 (42.3%) 7 (26.9%) 7 (26.9%) 1 (3.8%)
26 (8.8%) 63 (21.4%) 92 (31.3%) 113 (38.4%)
14 (13.6%) 24 (23.3%) 36 (35.0%) 29 (28.2%)
6 (6.5%) 18 (19.4%) 29 (31.2%) 40 (43.0%)
2 (2.8%) 16 (22.5%) 19 (26.8%) 34 (47.9%)
4 (14.8%) 5 (18.5%) 8 (29.6%) 10 (37.0%)
126 (42.7%) 169 (57.3%)
42 (40.8%) 61 (59.2%)
41 (43.6%) 53 (56.4%)
30 (42.3%) 41 (57.7%)
13 (48.1%) 14 (51.9%)
p value for heterogeneity (p value for trend)
.1748 (.059) .2122 (.088) .7311 (.38) .0197 (.22) .4650
.5375 (.071) .0867 (.37)
.1312 (.073)
.1346 (.048)
.9142 (.58)
Abbreviations: RT, radiotherapy; CTX, chemotherapy.
Treatment over the study period There was an increase in the use of definitive radiation therapy (RT; with or without chemotherapy) and a decrease in the use of surgery (with or without adjuvant therapy) over the study period (p 5 .0001). Overall, RT was used in 27.6% of patients in the earliest period (1995 and prior), but the rate had more than doubled (58.6%) by the latest period (2006–2010). This increase was seen only in patients with HPV-positive oropharyngeal SCC, 26.9% in the 1987 to 1995 period to 68.1% in the 2006 to 2010 period (p 5 .007). In contrast, there was no significant change in the treatment approach in patients with HPV-negative oropharyngeal SCC (p 5 .914).
Outcomes over the study period During the 23-year study period, there was a trend toward better locoregional control in patients with HPV-
positive oropharyngeal SCC (p 5 .075; Figure 3A). Similarly, the event-free survival and overall survival also improved in the more recent study periods (Figure 3B and 3C). However, the outcomes of patients with HPVnegative oropharyngeal SCC did not change during the study period (Figure 4).
DISCUSSION This study has provided new insight into the changing epidemiology of oropharyngeal SCC in Australia. Data collected from more than 500 patients treated at 10 teaching hospitals in Australia over the last 2 decades showed a steady increase in the proportion of HPV-positive oropharyngeal SCC (from 20.2% to 63.5% over the study period). This is consistent with our earlier smaller series3 and parallels findings from other developed countries.2,15–18 Overall results strongly support the concept HEAD & NECK—DOI 10.1002/HED
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FIGURE 3. Outcomes of patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) over the 4 study periods (1 5 1995 and prior; 2 5 1996–2000; 3 5 2001–2005; and 4 5 2006–2010). (A) Locoregional recurrence. (B) Event-free survival. (C) Overall survival. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
that HPV accounts for the increasing incidence of oropharyngeal SCC seen in Australia and in other developed countries.18,19 The effect of declining tobacco use in our community on the epidemiology of oropharyngeal SCC was a major focus of this study. Many studies have shown that patients with HPV-positive oropharyngeal SCC are less likely to have a history of tobacco use than those with HPV-negative oropharyngeal SCC.20,21 In our cohort, patients with HPV-positive oropharyngeal SCC were increasingly likely to be never smokers at diagnosis (from 19.2% to 34.0% over the study period). Our current rate of never smokers with HPV-positive oropharyngeal SCC is similar to that reported from other Western countries.20,22 The role of mutagens in tobacco as a co-factor to HPV in the development of oropharyngeal SCC, and the interaction between HPV and smoking in prognosis and response to treatment are not fully understood. Previous studies have shown that among patients with HPVpositive oropharyngeal SCC, smokers had poorer outcomes than never smokers.21,23 Our findings have important research and public health implications. However, 748
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smoking remains a major risk factor for oropharyngeal SCC worldwide, underscoring the need for prevention strategies targeted toward tobacco and alcohol use. Interestingly, the median age at diagnosis for our patients with HPV-positive oropharyngeal SCC increased over time. We speculate that this could be related to the declining proportion of smokers in this cohort, therefore less exposure to the potential co-carcinogen tobacco. Overall, the median age of patients with HPV-positive oropharyngeal SCC was still less than that of patients with HPV-negative oropharyngeal SCC. HPV-negative oropharyngeal SCC has traditionally been associated with tobacco use (and alcohol abuse), and smoking patterns among this group did not change over time, with only about 5% being never smokers, 30% ex-smokers, and 60% current smokers at the time of diagnosis. In line with our previous studies24,25 and other published data,26 the tonsil was the predominant primary site for HPV-positive oropharyngeal SCC. Interestingly, the proportion of base of tongue primaries increased over time and there was also a trend for lower T stage at presentation. Further longitudinal studies will be needed to
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FIGURE 4. Outcomes of patients with human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (SCC) over the 4 study periods (1 5 1995 and prior; 2 5 1996–2000; 3 5 2001–2005; and 4 5 2006–2010). (A) Locoregional recurrence. (B) Event-free survival. (C) Overall survival. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
confirm these trends and to identify underlying factors. This study found no evidence of changes in the epidemiology of HPV-negative oropharyngeal SCC over the study period. It is unlikely that the difference in HPV prevalence in the different periods is due to a different analytical sensitivity of our HPV DNA PCR in different periods as the cycle threshold values did not differ between the years. We also tested for p16 expression with immunohistochemistry, which our controls have shown is unaffected by sample DNA quality. P16 is a cyclin-dependent kinase inhibitor and is induced as a consequence of inhibition of retinoblastoma protein activity by the HPV E7 oncoprotein. The reason for the rapid increase in prevalence of HPV-positive oropharyngeal SCCs remains elusive. One explanation may be a change in sexual behavior (ie, the increasing practice of oral sex and increasing numbers of lifetime sex partners). Data from Europe and the United States suggest that the number of lifetime sexual partners has increased over recent decades.27,28 As the HPV infection usually takes more than 10 years to progress from infection to malignancy, a temporal change in sexual
behavior could explain the increased incidence observed in HPV-positive oropharyngeal SCC. There is a geographic variation in terms of incidence rates of oropharyngeal SCC.10 This likely reflects wide variability in the prevalence of established risk behaviors and modifiers. Our study lacks details of sexual activity, drug use, and socioeconomic status to show any change in these risk factors during the study period. Although HPV vaccination offers the potential to stem this trend, it will not have an impact on the incidence of HPV-positive oropharyngeal SCC for decades. Given the rising trends and the approximately 40-year lag time between infection and manifestation of the disease, HPVpositive oropharyngeal SCC will be a problem for the foreseeable future. In the interim, the HPV-positive oropharyngeal SCC epidemic will have tremendous implications for health care resources; these typically younger, healthier patients have a high chance of surviving their disease,23 and they will have to live with the late effects of treatment for many decades. Our results showed a trend in improved outcomes in patients with HPV-positive oropharyngeal SCC over the HEAD & NECK—DOI 10.1002/HED
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study period but not in patients with HPV-negative oropharyngeal SCC. This could be the result of the increasing use of combined chemotherapy and RT, but our data do not allow us to draw definitive conclusions on the best treatment for patients with HPV-positive oropharyngeal SCC. The choice of treatment in our study cohort was not based on the HPV status (the HPV status was not available in the majority) and the increasing use of RT was only seen in the patients with HPV-positive oropharyngeal SCC. This is likely because of their younger age and higher nodal stage at diagnosis. Given the favorable prognosis in this cohort, assessment of the HPV status of oropharyngeal SCC should be routine in clinical practice. However, the best treatment regimen for HPV-positive oropharyngeal SCC has not been defined and tremendous interest has been expressed in deescalating therapy to decrease toxicity. Potential deescalation strategies include the use of transoral robotic surgery, reduced doses of radiation or chemotherapy (or both), or avoidance of chemotherapy entirely for low-risk patients. One such trial is the TROG 12.01 study, which aims to compare the treatment-related side effects of RT with concurrent cisplatin or cetuximab regimens in HPV-positive oropharyngeal SCC. In conclusion, our data show a rising prevalence of HPV-positive oropharyngeal SCC in Australia over the last 2 decades, from 20.2% (1995 and prior) to 63.5% (2006–2010). These patients with HPV-positive oropharyngeal SCC are now presenting at an older age and about one-third have never smoked.
Acknowledgments The authors thank the clinicians at all the participating hospitals.
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