ORIGINAL ARTICLE
HPV-related oropharyngeal cancer: Risk factors for treatment failure in patients managed with primary transoral robotic surgery John M. Kaczmar, MD,1* Kay See Tan, PhD,2 Daniel F. Heitjan, PhD,2 Alexander Lin, MD,3 Peter H. Ahn, MD,3 Jason G. Newman, MD,4 Christopher H. Rassekh, MD,4 Ara A. Chalian, MD,4 Bert W. O’Malley, Jr, MD,4 Roger B. Cohen, MD,5 Gregory S. Weinstein, MD4 1
Department of Medical Oncology, Fox Chase Cancer Center/Temple University, Philadelphia, Pennsylvania, 2Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, 3Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, 4Department of Otorhinolaryngology/Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, 5Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Accepted 3 September 2014 Published online 6 April 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23850
ABSTRACT: Background. The purpose of this study was to determine clinical factors that predict locoregional recurrence or distant metastasis in patients with human papillomavirus (HPV)-positive oropharyngeal cancer treated with surgery and guideline-indicated adjuvant therapy. Methods. We identified all presumed HPV-positive patients with oropharyngeal cancer in our health system from January 2010 to August 2012 treated with surgery and guideline-indicated adjuvant therapy. Statistical analysis was performed to identify clinical predictors associated with treatment failure. Results. One hundred fourteen p161 oropharyngeal cancers managed with initial surgical resection were identified. Median follow-up was 17
INTRODUCTION Human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (SCC) is an increasingly common cancer diagnosis in the developed world, accounting for approximately 10% of all SCCs of the head and neck.1 In the developed world, greater than 50% of newly diagnosed oropharyngeal SCC will test positive for HPV or its surrogate biomarker p16, and the incidence is rising at approximately 5% per year2 with the greatest increase in patients under age 50.3 In the United States, more than 11,000 HPV-related oropharyngeal SCCs are now diagnosed annually.2,4 Of those tumors positive for HPV, 90% demonstrate HPV-16, an oncogenic HPV strain that is an established cause of cervical cancer.5–7 Management options for oropharyngeal SCC typically involve multiple treatment modalities, including chemotherapy, radiation, and surgery. As more intensive and effective treatment regimens have been developed, including concurrent chemotherapy and radiation, treatment morbidity has also increased substantially.8,9 An expanding literature shows that HPV-positive and HPV-negative
*Corresponding author: J. M. Kaczmar, Department of Medical Oncology, Fox Chase Cancer Center/Temple University, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail: [email protected]
months. Two-year locoregional failure was 3.3% and distant failure was 8.4%. Statistical analysis found that conventional poor prognostic features did not predict treatment failure. Conclusion. Locoregional recurrence and development of distant metastatic disease are uncommon in patients who are appropriately selected for surgical management of p161 oropharyngeal cancer regardless of the presence or absence of conventional poor prognostic features. C 2015 Wiley Periodicals, Inc. Head Neck 38: 59–65, 2016 V
KEY WORDS: human papillomavirus (HPV), oropharyngeal, p16, transoral robotic surgery (TORS), prognostic factors
oropharyngeal SCC behave very differently10; HPVrelated disease pursues a more benign course with a significantly improved overall survival.5,11–18 At this time, however, treatment regimens for oropharyngeal SCC do not differ significantly based on HPV status. Given the better outcomes seen in patients with HPVpositive disease, there is now a focus on identifying opportunities for deintensification of treatment. A recent landmark study describing a large series of patients managed with primary radiotherapy with or without chemotherapy found that patients with less than N2c nodal status may be appropriate for treatment deintensification as such patients seemed to have a low risk for distant metastasis.19 That study, however, did not include patients treated with a primary surgical approach. Transoral robotic surgery (TORS) has been shown to be highly effective in the management of oropharyngeal SCC independent of HPV status.20,21 Surgery in carefully selected cases may allow for more accurate risk stratification and possibly treatment deintensification by allowing full pathological tumor staging, including analysis of presence or absence of established risk factors for recurrence, such as extracapsular extension (ECE), and negative margins and relative risk factors, such as lymphovascular invasion and perineural invasion. Although HPV status generally seems to trump many traditionally accepted risk factors for high-risk disease, HEAD & NECK—DOI 10.1002/HED
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TABLE 1. Demographics and clinical characteristics of patients. Smoking 10 pack-years (n 5 75)
All surgical patients (n 5 114) Variables
No. of patients
Male Age, y Median Range Current smoker Smoking history, pack-years Median Range Alcohol use Location BOT Tonsil Other T classification (T3–4) N classification (N2b–3) Overall stage (stage IV) Tumor grade 1 2 2.5 3 Radiation (yes) Max. radiation dose received (full, >6996) ECE (present) Lymphovascular invasion (yes) Perineural invasion (yes) Nodes involved 0 1 2 2 Margin 10 pack-years (n 5 35)
%
%
p value
91
.677 .131
1
58 45–77 5
14
.012 < .001
25 11–95 19
54
.024 .379
95
No. of patients
32
5
55 41–91 1
3 0–95 80
70
0 0–10 58
77
43 6 65 10 72 86
38 5 57 9 63 75
27 3 45 5 45 56
36 4 60 7 60 75
15 3 17 5 24 27
43 9 48 14 69 77
1 29 18 66 89 8 38 40 16
1 25 16 58 78 10 33 35 14
0 16 16 43 58 6 23 24 6
0 21 21 58 77 12 31 32 8
1 11 2 21 28 2 12 12 8
3 31 6 60 80 9 35 34 23
18 29 24 42
16 26 21 37
12 20 12 30
16 27 16 41
5 9 11 10
14 26 31 29
26 79 9
23 69 8
19 49 7
25 65 10
6 27 2
17 77 6
26 88 54
23 77 43
19 56 34
25 75 45
6 29 17
17 83 49
0 52 3.3 0.1–8.6 8.4 2.5–18.9 3
0 100
.286 .407 1.000 .056
.810 1.000 .665 .830 .061 .319
.503
.465
3
0 34 1.4 0.1–6.9 8.7 1.7–23.3 2
0 100
3
0 15 7.9 1.3–22.9 8.3 1.2–24.4 1
.838 1.000
0 100 .173* .567* 3
1.000
Abbreviations: BOT, base of tongue; Max., maximum; ECE, extracapsular extension; CI, confidence interval. * Gray’s test p values. p values: Fisher’s exact test (both categorical factors) or 2-sample Wilcoxon rank-sum test (continuous factor given categorical groups). Significant p values (p < .05) are given in boldface.
we note that 5% to 10% of patients with HPV-positive oropharyngeal SCC will develop locoregional recurrence and/or distant metastatic disease after contemporary definitive treatment regimens.12,22,23 Distant metastatic disease, while treatable, is incurable and uniformly fatal. The purpose of our study was to examine a contemporary cohort of patients at a single institution with p161 oropharyngeal SCC treated with initial surgery. Our goal was to describe the outcomes in these patients and 60
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determine in a preliminary manner whether there are discrete, readily available clinical factors that might identify patients destined for an adverse outcome. As the field considers a variety of deintensification strategies for HPV-positive oropharyngeal SCC, some involving surgery and others not, it is vital to learn to stratify patients with respect to risk for poor outcomes. Accurate identification of the low and high risk patients is an essential step in designing future clinical trials.
HPV–RELATED
TABLE 2. Estimated cumulative incidence (%) of any recurrence and distant metastasis by various T and N categories using competing risk analysis. Surgery (n 5 114) Outcome and subgroup
Any recurrence T classification T1 T2 T3 T4 N classification N0 N1–N2a N2b N2c N3 Distant metastasis T classification T1 T2 T3 T4 N classification N0 N1–N2a N2b N2c N3
No. of patients
1-y incidence
2-y incidence
3 5 0 0
0.0 6.7 0.0 0.0
14.6 11.6 NA NA
1 2 5 0 0
0.0 6.6 3.6 0.0 0.0
20.0 6.6 12.4 NA 0.0
p value*
.792
.925
0.0 3.4 0.0 0.0
9.8 8.3 NA NA
0 1 4 0 0
0.0 3.2 1.8 0.0 0.0
0.0 3.2 10.6 NA 0.0
oropharyngeal SCC yielded 114 patients who had primary surgical management, including, when indicated, neck dissection. Primary analysis was performed on these primary surgery patients. Clinical, demographic, and social factors were abstracted from the electronic medical record. For the small number5 of patients who had portions of their adjuvant treatment performed outside our institution, we utilized available scanned reports in our electronic medical records to summarize their treatment course as fully as possible. Treatment consisted of a combination of TORS resection, radiation therapy, and chemotherapy, as per our institution’s standard practices. Local recurrence or distant metastasis was judged to have occurred on the date of the confirmatory biopsy and, in cases in which biopsy was not performed, by imaging and/ or clinical diagnosis of recurrence/metastasis.
Statistical analysis .851
2 3 0 0
OROPHARYNGEAL CANCER
.954
Abbreviation: NA, not applicable. * p values are Gray’s test and are 2-sided.
MATERIALS AND METHODS After approval by our Institutional Review Board, we performed a retrospective review of p161 patients with oropharyngeal SCC treated in the University of Pennsylvania Health system (treatment centers include the Hospital of the University of Pennsylvania and Pennsylvania Hospital). Immunohistochemical testing for the surrogate marker p16 began at our institution in 2009 and by 2010 was universally performed in patients newly diagnosed with oropharyngeal SCC. We restricted our search to patients pathologically diagnosed after January 1, 2010, to ensure that uniform p161 testing had been performed. We included consecutively treated patients through August 14, 2012. Only patients with oropharyngeal SCC who tested positive for p16 were included in this study. Patients were staged before surgery with positron emission tomography CT, chest CT, or chest X-ray at the surgeon’s discretion and all patients had a CT or MRI of the neck. All patients recommended for adjuvant radiation therapy had pretreatment positron emission tomography scans to rule out metastatic disease. All tumors were histologically confirmed and staged according to the American Joint Committee on Cancer/ Union Internationale Contre le Cancer sixth edition TNM criteria. Patients were identified through 3 separate patient databases maintained at our institution: the tumor registry, the radiation oncology treatment database, and the TORS calendar. A query of these databases for HPV-positive
Patient and clinical characteristics were summarized by descriptive statistics. They were then stratified by smoking status into >10 or 10 pack-years based on results of recursive-partitioning analysis described by Ang et al.22 The 2-sample Wilcoxon rank-sum test was used to compare continuous variables, and the Fisher’s exact test was used to compare categorical variables. The primary outcome was time to disease progression, defined as the number of months between the initial oropharyngeal SCC diagnosis to the first evidence of distant metastasis or locoregional recurrence. Death from any cause occurring before disease progression was treated as a competing risk event. We also evaluated the alternative endpoint of distant metastasis alone, in which locoregional recurrence was considered a competing event. All deaths occurred in patients who had a distant metastasis event, so death was not considered a competing risk. Cumulative incidence functions for each competing event (ie, the failure probabilities before experiencing any events), were calculated using competing risk methodology.24 We used Gray’s test to compare the risk of disease progression and distant metastasis between groups defined by the variables listed in Table 2 and Table 3. Potential covariates included age (continuous), sex, tumor (T) and node (N) category, grade, keratinization, smoking packyears (10 or >10 pack-years), alcohol consumption, treatment modality, presence of ECE, perineural invasion, lymphovascular invasion, and surgical margin status. Surgical margin status was broken down into 2 groups: close margins (60 Sex Female Male Currently smoking No Yes Smoking (pack-years) Smoking (pack-years) 10 >10 Alcohol history No Yes TNM stage I/II/III IVA/IVB T classification 1/2/3 4 N classification 0/1/2a 2b–3 Tumor grade 1 2 2.5 3 Margin Close Negative Radiation No Yes Radiation dose Adjuvant Definitive ECE Not present Present Lymphovascular invasion No Yes Perineural invasion No Yes Chemotherapy No Yes
No. of patients
No. of patients with any recurrence
114
1-y any recurrence rate
p value*
SHR
95% CI
p value†
–
–
1.03
(0.95–1.13)
.382
1 1.65
(0.42–6.50)
.474
1 0.37
(0.04–2.38)
.370
1 0 1.02
– (0.99–1.05)
– .121
1 2.53
(0.66–9.76)
.176
1 0.42
(0.11–1.67)
.219
1 0.66
(0.13–3.28)
.616
1 0
–
–
1 0.74
(0.19–2.94)
.667
–
–
(.04–2.87) (.07–1.51)
.326 .154
(0.57–9.25)
.241
69 45
4 4
11 12
.476
7 107
1 7
14 11
.349
108 6 110
8 0
12 0 –
.450
75 35
4 4
10 16
.179
34 80
4 4
16 10
.213
28 86
2 6
11 11
.622
110 3
8 0
12 NA
.605
42 72
3 5
9 12
.681
1 29 18 66
0 4 1 3
– 26 9 5
.443
26 88
3 5
25 8
.245
2.30 1
25 89
4 4
26 8
.014
1 0.20
(0.05–0.77)
.020
69 8
2 0
8 0
.556
1 0
–
–
74 38
6 2
15 7
.569
1 0.63
(0.13–3.16)
.575
74 40
5 3
9 12
.965
1 0.97
(0.25–3.80)
.963
99 15
7 1
12 8
.921
1 0.90
(0.11–7.49)
.921
60 54
6 2
21 5
.119
1 0.42
(0.10–1.68)
.219
–
0 1 0.35 0.33
Abbreviations: SHR, subhazard ratio; CI, confidence interval; NA, not applicable; ECE, extracapsular extension. * p values are Gray’s test and are 2-sided. † p values are from univariate cumulative incidence function regressions and are 2-sided; significant p values are shown in boldface.
RESULTS One hundred fourteen patients with p161 oropharyngeal SCC were treated with primary surgery at our institution between January 1, 2010, and August 2012. Primary analysis was performed on this cohort of patients (see Table 1). 62
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At the close of data collection (December 2012), 8 patients had experienced recurrent disease. The 2-year locoregional failure rate was calculated to be 3.3% in these surgically managed patients, and the 2-year distant failure rate was calculated to be 8.4%. During the
HPV–RELATED
OROPHARYNGEAL CANCER
TABLE 3B. Competing risk univariate analysis of distant metastasis for 114 patients who underwent surgery with cumulative incidence rate of distant metastasis.
Variables
Age, (y, continuous) Age, y 60 >60 Sex Female Male Currently smoking No Yes Smoking (pack-years) Smoking (pack-years) 10 >10 Alcohol history No Yes TNM stage I/II/III IVA/IVB T classification 1/2/3 4 N classification 0/1/2a 2b–3 Tumor grade 1 2 2–3 3 Margin Close Negative Radiation No Yes Radiation dose Adjuvant Definitive ECE Not present Present Lymphovascular invasion No Yes Perineural invasion No Yes Chemotherapy No Yes
No. of patients
24-mo distant metastasis rate (%)
p value*
SHR
95% CI
p value†
114
–
–
0.97
(0.88–1.08)
.585
69 45
9 6
.935
1 1.08
(0.18–6.35)
.934
7 107
14 8
.131
1 0.20
(0.02–1.89)
.161
108 6 110
9 0 –
.548
1 0 1.02
– (0.99–1.06)
– .213
75 35
9 8
.567
1 1.67
(0.29–9.56)
.563
34 80
8 8
.640
1 0.65
(0.11–3.81)
.636
28 86
4 9
.828
1 0.80
(0.10–6.40)
.831
110 3
9 NA
.684
1 0
–
–
42 72
3 10
.649
1 1.69
(0.20–13.92)
.628
1 29 18 66
– 17 9 4
.886
–
–
(0.07–7.43) (0.07–3.22)
.786 .441
26 88
20 5
.312
2.49 1
(0.44–14.15)
.302
25 89
14 7
.162
1 0.30
(0.05–1.70)
.173
69 8
8 0
.556
1 0
–
–
74 38
10 7
.790
1 1.28
(0.20–8.02)
.793
74 40
7 6
.343
1 0.36
(0.06–2.32)
.282
99 15
9 8
.682
1 1.58
(0.17–14.89)
.689
60 54
15 5
.565
1 0.58
(0.09–3.86)
.588
–
0 1 0.72 0.47
Abbreviations: SHR, subhazard ratio; CI, confidence interval; NA, not applicable; ECE, extracapsular extension. * p values are Gray’s test and are 2-sided. † p values are from univariate cumulative incidence function regressions and are 2-sided.
follow-up period, 3 patients died (see Table 2). All 3 events were judged to have been related to their cancer. The median time of follow-up in our patient cohort was 17 months. Factors including T classification, nodal
classification, TNM stage, tumor grade, presence of ECE, lymphovascular invasion, perineural invasion, and surgical margin status were not associated with an increased risk of local or distant progression (Table 3). The use of HEAD & NECK—DOI 10.1002/HED
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radiation was associated with decreased hazard ratio (HR) of any recurrence (HR 5 0.20; p 5 .02), but not distant metastasis (HR 5 0.30; p 5 .162). One factor in our cohort that trended toward an increased risk of progression (HR 5 2.53; p 5 .17) was smoking history (>10 pack-years). Multivariate analysis demonstrated a significant decrease in the hazard ratio of death with the use of radiation (HR 5 0.18; p 5 .033). None of the other factors in the multivariate model were significant. Overall, our institution’s rate of distant control mirrors that found by O’Sullivan et al.19 In our cohort of surgically managed patients, the 2-year distant failure rate was 8.4% versus 3-year distant failure rate of 10% in their cohort. Two-year locoregional failure was 3.4% in our cohort versus 3-year locoregional failure of 5% in their cohort (Table 1). The 8 patients in our cohort who would be considered high-risk (T4 and/or N2c or greater), based on risk-profiling analysis by O’Sullivan et al,19 did not experience distant metastasis or locoregional recurrence in the follow-up period.
DISCUSSION Ours is one of the first reports of outcomes in a series of prospectively diagnosed p161 (presumed HPV-related) patients with oropharyngeal SCC managed with primary surgery. Our results and favorable outcomes support the utility of primary surgery in appropriately selected patients. Several factors considered to expose patients at higher risk for disease progression, such as ECE, lymphovascular invasion, margin status, and perineural invasion, did not demonstrate significant effects in our analysis. Unlike O’Sullivan et al,19 we did not find a significant interaction between nodal status and risk of recurrence. Possible reasons for this latter observation may be that it is standard practice at our institution to offer sensitizing chemotherapy, usually cisplatin, in addition to adjuvant radiation in instances in which clinicians deem the patient to be at high risk for disease recurrence owing to the presence or absence of adverse nodal findings. In fact, only 1 patient with N2c nodal status did not receive systemic chemotherapy. Our finding that adjuvant radiation improved the risk of any recurrence, irrespective of stage, may be mediated by enhanced local control as it did not have a significant effect on the risk of distant metastasis. This finding is likely mediated by improved local control from radiation therapy. This means that there may be a subset of the 25 patients in our cohort who did not receive radiation (based on absence of any pathologic features that would lead to a guideline-based recommendation of adjuvant radiation), who might have benefited from it. We note that within our cohort there is a relatively low proportion of T4 and N2c or greater disease. Fewer high T classification patients are present as they would have a higher likelihood to be poor surgical candidates based on anatomic considerations. Additionally, within our own institutional data, surgical patients had a lower prevalence of continued smoking and lower median pack-years of smoking than patients who were not managed with primary surgery. Given concerns for inferior wound healing in patients who continue to smoke, such patients are less likely to be offered surgery. This patient selection 64
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undoubtedly influences the recurrence rates in our cohort. Nevertheless, our results do confirm that patients who are carefully selected for primary surgery and treated according to published guidelines for postsurgical adjuvant therapy have generally excellent outcomes. Limitations of our study include its retrospective nature, the relatively low number of events, and the biases inherent to patient selection for surgical management. Relatively short median follow-up is another limitation, especially given recent findings suggesting that HPVpositive disease may recur distantly at later time points than HPV-negative oropharyngeal SCC.26 Finally, ours is a single-institution study in which we follow a series of uniform policies to mitigate recurrence risk in high-risk patients. Through uniform application of adjuvant therapy guidelines, thereby systematically eliminating heterogeneity in patient management, we probably eliminated some of the chances to identify opportunities for treatment deintensification. A series of prospective randomized studies are planned to assist in defining the HPV-positive oropharyngeal SCC populations who might be appropriate for treatment deintensification.27 Eastern Cooperative Oncology Group 3311, for example, will enroll patients with HPV-positive tumors who are treated with primary TORS and stratify them into low-risk, intermediate-risk, and high-risk groups, which will receive adjuvant therapy tailored to their level of recurrence risk. In conclusion, our results demonstrate that locoregional failure and the development of distant metastatic disease are uncommon in patients who are appropriately selected for primary surgical management of HPV-positive oropharyngeal SCC, regardless of the presence or absence of traditionally described poor prognostic features. Importantly, we did not find any clinical or tumor features that predicted a worse outcome with upfront surgical management. Prospective investigation focused on HPV-positive patient cohorts will be needed to further determine how HPV positivity modifies the accepted risk factors for treatment failure, given our study findings suggesting that accepted risk factors for treatment failure may not hold in HPV-positive disease managed with primary surgery. Finally, our patient cohort, which has enjoyed a very high overall survival, further validates the premise underlying the design of Eastern Cooperative Oncology Group 3311, namely that surgical management can help to more accurately risk-stratify patients and assist in more refined and potentially less morbid selection of appropriate adjuvant therapy for these patients.
REFERENCES 1. Ramqvist T, Dalianis T. Oropharyngeal cancer epidemic and human papillomavirus. Emerg Infect Dis 2010;16:1671–1677. 2. 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;9:665–673. 3. Nguyen NP, Ly BH, Betz M, Vinh–Hung V. Importance of age as a prognostic factor for tonsillar carcinoma. Ann Surg Oncol 2010;17:2570–2577. 4. Panwar A, Batra R, Lydiatt WM, Ganti AK. Human papilloma virus positive oropharyngeal squamous cell carcinoma: a growing epidemic. Cancer Treat Rev 2014;40:215–219. 5. 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;92:709–720. 6. Gillison ML, Shah KV. Human papillomavirus-associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for
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7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol 2001;13:183–188. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143–1154. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–1944. Park G, Lee SW, Kim SY, et al. Can concurrent chemoradiotherapy replace surgery and postoperative radiation for locally advanced stage III/IV tonsillar squamous cell carcinoma? Anticancer Res 2013;33:1237–1243. Smith EM, Wang D, Rubenstein LM, Morris WA, Turek LP, Haugen TH. Association between p53 and human papillomavirus in head and neck cancer survival. Cancer Epidemiol Biomarkers Prev 2008;17:421–427. Ang KK, Sturgis EM. Human papillomavirus as a marker of the natural history and response to therapy of head and neck squamous cell carcinoma. Semin Radiat Oncol 2012;22:128–142. Granata R, Miceli R, Orlandi E, et al. Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study. Ann Oncol 2012;23:1832–1837. Fischer CA, Kampmann M, Zlobec I, et al. p16 expression in oropharyngeal cancer: its impact on staging and prognosis compared with the conventional clinical staging parameters. Ann Oncol 2010;21:1961–1966. 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. Haughey BH, Sinha P. Prognostic factors and survival unique to surgically treated p161 oropharyngeal cancer. Laryngoscope 2012;122 Suppl 2:S13–S33. Lewis JS Jr, Carpenter DH, Thorstad WL, Zhang Q, Haughey BH. Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. Mod Pathol 2011;24: 1413–1420.
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17. Kumar B, Cordell KG, Lee JS, et al. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008;26:3128–3137. 18. Klozar J, Koslabova E, Kratochvil V, Salakova M, Tachezy R. Nodal status is not a prognostic factor in patients with HPV-positive oral/oropharyngeal tumors. J Surg Oncol 2013;107:625–633. 19. O’Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 2013;31:543–550. 20. Cohen MA, Weinstein GS, O’Malley BW Jr, Feldman M, Quon H. Transoral robotic surgery and human papillomavirus status: oncologic results. Head Neck 2011;33:573–580. 21. Weinstein GS, O’Malley BW Jr, Cohen MA, Quon H. Transoral robotic surgery for advanced oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 2010;136:1079–1085. 22. 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. 23. Rietbergen MM, Brakenhoff RH, Bloemena E, et al. Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment de-escalation trials. Ann Oncol 2013; 24:2740–2745. 24. Fine JP. Regression modeling of competing crude failure probabilities. Biostatistics 2001;2:85–97. 25. Fine J, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496–509. 26. Huang SH, Perez–Ordonez B, Weinreb I, et al. Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer. Oral Oncol 2013;49:79–85. 27. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol 2014;50: 565–574.
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HPV-related oropharyngeal cancer: Risk factors for treatment failure in patients managed with primary transoral robotic surgery John M. Kaczmar, MD,1* Kay See Tan, PhD,2 Daniel F. Heitjan, PhD,2 Alexander Lin, MD,3 Peter H. Ahn, MD,3 Jason G. Newman, MD,4 Christopher H. Rassekh, MD,4 Ara A. Chalian, MD,4 Bert W. O’Malley, Jr, MD,4 Roger B. Cohen, MD,5 Gregory S. Weinstein, MD4 1
Department of Medical Oncology, Fox Chase Cancer Center/Temple University, Philadelphia, Pennsylvania, 2Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, 3Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, 4Department of Otorhinolaryngology/Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, 5Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Accepted 3 September 2014 Published online 6 April 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23850
ABSTRACT: Background. The purpose of this study was to determine clinical factors that predict locoregional recurrence or distant metastasis in patients with human papillomavirus (HPV)-positive oropharyngeal cancer treated with surgery and guideline-indicated adjuvant therapy. Methods. We identified all presumed HPV-positive patients with oropharyngeal cancer in our health system from January 2010 to August 2012 treated with surgery and guideline-indicated adjuvant therapy. Statistical analysis was performed to identify clinical predictors associated with treatment failure. Results. One hundred fourteen p161 oropharyngeal cancers managed with initial surgical resection were identified. Median follow-up was 17
INTRODUCTION Human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (SCC) is an increasingly common cancer diagnosis in the developed world, accounting for approximately 10% of all SCCs of the head and neck.1 In the developed world, greater than 50% of newly diagnosed oropharyngeal SCC will test positive for HPV or its surrogate biomarker p16, and the incidence is rising at approximately 5% per year2 with the greatest increase in patients under age 50.3 In the United States, more than 11,000 HPV-related oropharyngeal SCCs are now diagnosed annually.2,4 Of those tumors positive for HPV, 90% demonstrate HPV-16, an oncogenic HPV strain that is an established cause of cervical cancer.5–7 Management options for oropharyngeal SCC typically involve multiple treatment modalities, including chemotherapy, radiation, and surgery. As more intensive and effective treatment regimens have been developed, including concurrent chemotherapy and radiation, treatment morbidity has also increased substantially.8,9 An expanding literature shows that HPV-positive and HPV-negative
*Corresponding author: J. M. Kaczmar, Department of Medical Oncology, Fox Chase Cancer Center/Temple University, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail: [email protected]
months. Two-year locoregional failure was 3.3% and distant failure was 8.4%. Statistical analysis found that conventional poor prognostic features did not predict treatment failure. Conclusion. Locoregional recurrence and development of distant metastatic disease are uncommon in patients who are appropriately selected for surgical management of p161 oropharyngeal cancer regardless of the presence or absence of conventional poor prognostic features. C 2015 Wiley Periodicals, Inc. Head Neck 38: 59–65, 2016 V
KEY WORDS: human papillomavirus (HPV), oropharyngeal, p16, transoral robotic surgery (TORS), prognostic factors
oropharyngeal SCC behave very differently10; HPVrelated disease pursues a more benign course with a significantly improved overall survival.5,11–18 At this time, however, treatment regimens for oropharyngeal SCC do not differ significantly based on HPV status. Given the better outcomes seen in patients with HPVpositive disease, there is now a focus on identifying opportunities for deintensification of treatment. A recent landmark study describing a large series of patients managed with primary radiotherapy with or without chemotherapy found that patients with less than N2c nodal status may be appropriate for treatment deintensification as such patients seemed to have a low risk for distant metastasis.19 That study, however, did not include patients treated with a primary surgical approach. Transoral robotic surgery (TORS) has been shown to be highly effective in the management of oropharyngeal SCC independent of HPV status.20,21 Surgery in carefully selected cases may allow for more accurate risk stratification and possibly treatment deintensification by allowing full pathological tumor staging, including analysis of presence or absence of established risk factors for recurrence, such as extracapsular extension (ECE), and negative margins and relative risk factors, such as lymphovascular invasion and perineural invasion. Although HPV status generally seems to trump many traditionally accepted risk factors for high-risk disease, HEAD & NECK—DOI 10.1002/HED
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TABLE 1. Demographics and clinical characteristics of patients. Smoking 10 pack-years (n 5 75)
All surgical patients (n 5 114) Variables
No. of patients
Male Age, y Median Range Current smoker Smoking history, pack-years Median Range Alcohol use Location BOT Tonsil Other T classification (T3–4) N classification (N2b–3) Overall stage (stage IV) Tumor grade 1 2 2.5 3 Radiation (yes) Max. radiation dose received (full, >6996) ECE (present) Lymphovascular invasion (yes) Perineural invasion (yes) Nodes involved 0 1 2 2 Margin 10 pack-years (n 5 35)
%
%
p value
91
.677 .131
1
58 45–77 5
14
.012 < .001
25 11–95 19
54
.024 .379
95
No. of patients
32
5
55 41–91 1
3 0–95 80
70
0 0–10 58
77
43 6 65 10 72 86
38 5 57 9 63 75
27 3 45 5 45 56
36 4 60 7 60 75
15 3 17 5 24 27
43 9 48 14 69 77
1 29 18 66 89 8 38 40 16
1 25 16 58 78 10 33 35 14
0 16 16 43 58 6 23 24 6
0 21 21 58 77 12 31 32 8
1 11 2 21 28 2 12 12 8
3 31 6 60 80 9 35 34 23
18 29 24 42
16 26 21 37
12 20 12 30
16 27 16 41
5 9 11 10
14 26 31 29
26 79 9
23 69 8
19 49 7
25 65 10
6 27 2
17 77 6
26 88 54
23 77 43
19 56 34
25 75 45
6 29 17
17 83 49
0 52 3.3 0.1–8.6 8.4 2.5–18.9 3
0 100
.286 .407 1.000 .056
.810 1.000 .665 .830 .061 .319
.503
.465
3
0 34 1.4 0.1–6.9 8.7 1.7–23.3 2
0 100
3
0 15 7.9 1.3–22.9 8.3 1.2–24.4 1
.838 1.000
0 100 .173* .567* 3
1.000
Abbreviations: BOT, base of tongue; Max., maximum; ECE, extracapsular extension; CI, confidence interval. * Gray’s test p values. p values: Fisher’s exact test (both categorical factors) or 2-sample Wilcoxon rank-sum test (continuous factor given categorical groups). Significant p values (p < .05) are given in boldface.
we note that 5% to 10% of patients with HPV-positive oropharyngeal SCC will develop locoregional recurrence and/or distant metastatic disease after contemporary definitive treatment regimens.12,22,23 Distant metastatic disease, while treatable, is incurable and uniformly fatal. The purpose of our study was to examine a contemporary cohort of patients at a single institution with p161 oropharyngeal SCC treated with initial surgery. Our goal was to describe the outcomes in these patients and 60
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determine in a preliminary manner whether there are discrete, readily available clinical factors that might identify patients destined for an adverse outcome. As the field considers a variety of deintensification strategies for HPV-positive oropharyngeal SCC, some involving surgery and others not, it is vital to learn to stratify patients with respect to risk for poor outcomes. Accurate identification of the low and high risk patients is an essential step in designing future clinical trials.
HPV–RELATED
TABLE 2. Estimated cumulative incidence (%) of any recurrence and distant metastasis by various T and N categories using competing risk analysis. Surgery (n 5 114) Outcome and subgroup
Any recurrence T classification T1 T2 T3 T4 N classification N0 N1–N2a N2b N2c N3 Distant metastasis T classification T1 T2 T3 T4 N classification N0 N1–N2a N2b N2c N3
No. of patients
1-y incidence
2-y incidence
3 5 0 0
0.0 6.7 0.0 0.0
14.6 11.6 NA NA
1 2 5 0 0
0.0 6.6 3.6 0.0 0.0
20.0 6.6 12.4 NA 0.0
p value*
.792
.925
0.0 3.4 0.0 0.0
9.8 8.3 NA NA
0 1 4 0 0
0.0 3.2 1.8 0.0 0.0
0.0 3.2 10.6 NA 0.0
oropharyngeal SCC yielded 114 patients who had primary surgical management, including, when indicated, neck dissection. Primary analysis was performed on these primary surgery patients. Clinical, demographic, and social factors were abstracted from the electronic medical record. For the small number5 of patients who had portions of their adjuvant treatment performed outside our institution, we utilized available scanned reports in our electronic medical records to summarize their treatment course as fully as possible. Treatment consisted of a combination of TORS resection, radiation therapy, and chemotherapy, as per our institution’s standard practices. Local recurrence or distant metastasis was judged to have occurred on the date of the confirmatory biopsy and, in cases in which biopsy was not performed, by imaging and/ or clinical diagnosis of recurrence/metastasis.
Statistical analysis .851
2 3 0 0
OROPHARYNGEAL CANCER
.954
Abbreviation: NA, not applicable. * p values are Gray’s test and are 2-sided.
MATERIALS AND METHODS After approval by our Institutional Review Board, we performed a retrospective review of p161 patients with oropharyngeal SCC treated in the University of Pennsylvania Health system (treatment centers include the Hospital of the University of Pennsylvania and Pennsylvania Hospital). Immunohistochemical testing for the surrogate marker p16 began at our institution in 2009 and by 2010 was universally performed in patients newly diagnosed with oropharyngeal SCC. We restricted our search to patients pathologically diagnosed after January 1, 2010, to ensure that uniform p161 testing had been performed. We included consecutively treated patients through August 14, 2012. Only patients with oropharyngeal SCC who tested positive for p16 were included in this study. Patients were staged before surgery with positron emission tomography CT, chest CT, or chest X-ray at the surgeon’s discretion and all patients had a CT or MRI of the neck. All patients recommended for adjuvant radiation therapy had pretreatment positron emission tomography scans to rule out metastatic disease. All tumors were histologically confirmed and staged according to the American Joint Committee on Cancer/ Union Internationale Contre le Cancer sixth edition TNM criteria. Patients were identified through 3 separate patient databases maintained at our institution: the tumor registry, the radiation oncology treatment database, and the TORS calendar. A query of these databases for HPV-positive
Patient and clinical characteristics were summarized by descriptive statistics. They were then stratified by smoking status into >10 or 10 pack-years based on results of recursive-partitioning analysis described by Ang et al.22 The 2-sample Wilcoxon rank-sum test was used to compare continuous variables, and the Fisher’s exact test was used to compare categorical variables. The primary outcome was time to disease progression, defined as the number of months between the initial oropharyngeal SCC diagnosis to the first evidence of distant metastasis or locoregional recurrence. Death from any cause occurring before disease progression was treated as a competing risk event. We also evaluated the alternative endpoint of distant metastasis alone, in which locoregional recurrence was considered a competing event. All deaths occurred in patients who had a distant metastasis event, so death was not considered a competing risk. Cumulative incidence functions for each competing event (ie, the failure probabilities before experiencing any events), were calculated using competing risk methodology.24 We used Gray’s test to compare the risk of disease progression and distant metastasis between groups defined by the variables listed in Table 2 and Table 3. Potential covariates included age (continuous), sex, tumor (T) and node (N) category, grade, keratinization, smoking packyears (10 or >10 pack-years), alcohol consumption, treatment modality, presence of ECE, perineural invasion, lymphovascular invasion, and surgical margin status. Surgical margin status was broken down into 2 groups: close margins (60 Sex Female Male Currently smoking No Yes Smoking (pack-years) Smoking (pack-years) 10 >10 Alcohol history No Yes TNM stage I/II/III IVA/IVB T classification 1/2/3 4 N classification 0/1/2a 2b–3 Tumor grade 1 2 2.5 3 Margin Close Negative Radiation No Yes Radiation dose Adjuvant Definitive ECE Not present Present Lymphovascular invasion No Yes Perineural invasion No Yes Chemotherapy No Yes
No. of patients
No. of patients with any recurrence
114
1-y any recurrence rate
p value*
SHR
95% CI
p value†
–
–
1.03
(0.95–1.13)
.382
1 1.65
(0.42–6.50)
.474
1 0.37
(0.04–2.38)
.370
1 0 1.02
– (0.99–1.05)
– .121
1 2.53
(0.66–9.76)
.176
1 0.42
(0.11–1.67)
.219
1 0.66
(0.13–3.28)
.616
1 0
–
–
1 0.74
(0.19–2.94)
.667
–
–
(.04–2.87) (.07–1.51)
.326 .154
(0.57–9.25)
.241
69 45
4 4
11 12
.476
7 107
1 7
14 11
.349
108 6 110
8 0
12 0 –
.450
75 35
4 4
10 16
.179
34 80
4 4
16 10
.213
28 86
2 6
11 11
.622
110 3
8 0
12 NA
.605
42 72
3 5
9 12
.681
1 29 18 66
0 4 1 3
– 26 9 5
.443
26 88
3 5
25 8
.245
2.30 1
25 89
4 4
26 8
.014
1 0.20
(0.05–0.77)
.020
69 8
2 0
8 0
.556
1 0
–
–
74 38
6 2
15 7
.569
1 0.63
(0.13–3.16)
.575
74 40
5 3
9 12
.965
1 0.97
(0.25–3.80)
.963
99 15
7 1
12 8
.921
1 0.90
(0.11–7.49)
.921
60 54
6 2
21 5
.119
1 0.42
(0.10–1.68)
.219
–
0 1 0.35 0.33
Abbreviations: SHR, subhazard ratio; CI, confidence interval; NA, not applicable; ECE, extracapsular extension. * p values are Gray’s test and are 2-sided. † p values are from univariate cumulative incidence function regressions and are 2-sided; significant p values are shown in boldface.
RESULTS One hundred fourteen patients with p161 oropharyngeal SCC were treated with primary surgery at our institution between January 1, 2010, and August 2012. Primary analysis was performed on this cohort of patients (see Table 1). 62
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At the close of data collection (December 2012), 8 patients had experienced recurrent disease. The 2-year locoregional failure rate was calculated to be 3.3% in these surgically managed patients, and the 2-year distant failure rate was calculated to be 8.4%. During the
HPV–RELATED
OROPHARYNGEAL CANCER
TABLE 3B. Competing risk univariate analysis of distant metastasis for 114 patients who underwent surgery with cumulative incidence rate of distant metastasis.
Variables
Age, (y, continuous) Age, y 60 >60 Sex Female Male Currently smoking No Yes Smoking (pack-years) Smoking (pack-years) 10 >10 Alcohol history No Yes TNM stage I/II/III IVA/IVB T classification 1/2/3 4 N classification 0/1/2a 2b–3 Tumor grade 1 2 2–3 3 Margin Close Negative Radiation No Yes Radiation dose Adjuvant Definitive ECE Not present Present Lymphovascular invasion No Yes Perineural invasion No Yes Chemotherapy No Yes
No. of patients
24-mo distant metastasis rate (%)
p value*
SHR
95% CI
p value†
114
–
–
0.97
(0.88–1.08)
.585
69 45
9 6
.935
1 1.08
(0.18–6.35)
.934
7 107
14 8
.131
1 0.20
(0.02–1.89)
.161
108 6 110
9 0 –
.548
1 0 1.02
– (0.99–1.06)
– .213
75 35
9 8
.567
1 1.67
(0.29–9.56)
.563
34 80
8 8
.640
1 0.65
(0.11–3.81)
.636
28 86
4 9
.828
1 0.80
(0.10–6.40)
.831
110 3
9 NA
.684
1 0
–
–
42 72
3 10
.649
1 1.69
(0.20–13.92)
.628
1 29 18 66
– 17 9 4
.886
–
–
(0.07–7.43) (0.07–3.22)
.786 .441
26 88
20 5
.312
2.49 1
(0.44–14.15)
.302
25 89
14 7
.162
1 0.30
(0.05–1.70)
.173
69 8
8 0
.556
1 0
–
–
74 38
10 7
.790
1 1.28
(0.20–8.02)
.793
74 40
7 6
.343
1 0.36
(0.06–2.32)
.282
99 15
9 8
.682
1 1.58
(0.17–14.89)
.689
60 54
15 5
.565
1 0.58
(0.09–3.86)
.588
–
0 1 0.72 0.47
Abbreviations: SHR, subhazard ratio; CI, confidence interval; NA, not applicable; ECE, extracapsular extension. * p values are Gray’s test and are 2-sided. † p values are from univariate cumulative incidence function regressions and are 2-sided.
follow-up period, 3 patients died (see Table 2). All 3 events were judged to have been related to their cancer. The median time of follow-up in our patient cohort was 17 months. Factors including T classification, nodal
classification, TNM stage, tumor grade, presence of ECE, lymphovascular invasion, perineural invasion, and surgical margin status were not associated with an increased risk of local or distant progression (Table 3). The use of HEAD & NECK—DOI 10.1002/HED
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radiation was associated with decreased hazard ratio (HR) of any recurrence (HR 5 0.20; p 5 .02), but not distant metastasis (HR 5 0.30; p 5 .162). One factor in our cohort that trended toward an increased risk of progression (HR 5 2.53; p 5 .17) was smoking history (>10 pack-years). Multivariate analysis demonstrated a significant decrease in the hazard ratio of death with the use of radiation (HR 5 0.18; p 5 .033). None of the other factors in the multivariate model were significant. Overall, our institution’s rate of distant control mirrors that found by O’Sullivan et al.19 In our cohort of surgically managed patients, the 2-year distant failure rate was 8.4% versus 3-year distant failure rate of 10% in their cohort. Two-year locoregional failure was 3.4% in our cohort versus 3-year locoregional failure of 5% in their cohort (Table 1). The 8 patients in our cohort who would be considered high-risk (T4 and/or N2c or greater), based on risk-profiling analysis by O’Sullivan et al,19 did not experience distant metastasis or locoregional recurrence in the follow-up period.
DISCUSSION Ours is one of the first reports of outcomes in a series of prospectively diagnosed p161 (presumed HPV-related) patients with oropharyngeal SCC managed with primary surgery. Our results and favorable outcomes support the utility of primary surgery in appropriately selected patients. Several factors considered to expose patients at higher risk for disease progression, such as ECE, lymphovascular invasion, margin status, and perineural invasion, did not demonstrate significant effects in our analysis. Unlike O’Sullivan et al,19 we did not find a significant interaction between nodal status and risk of recurrence. Possible reasons for this latter observation may be that it is standard practice at our institution to offer sensitizing chemotherapy, usually cisplatin, in addition to adjuvant radiation in instances in which clinicians deem the patient to be at high risk for disease recurrence owing to the presence or absence of adverse nodal findings. In fact, only 1 patient with N2c nodal status did not receive systemic chemotherapy. Our finding that adjuvant radiation improved the risk of any recurrence, irrespective of stage, may be mediated by enhanced local control as it did not have a significant effect on the risk of distant metastasis. This finding is likely mediated by improved local control from radiation therapy. This means that there may be a subset of the 25 patients in our cohort who did not receive radiation (based on absence of any pathologic features that would lead to a guideline-based recommendation of adjuvant radiation), who might have benefited from it. We note that within our cohort there is a relatively low proportion of T4 and N2c or greater disease. Fewer high T classification patients are present as they would have a higher likelihood to be poor surgical candidates based on anatomic considerations. Additionally, within our own institutional data, surgical patients had a lower prevalence of continued smoking and lower median pack-years of smoking than patients who were not managed with primary surgery. Given concerns for inferior wound healing in patients who continue to smoke, such patients are less likely to be offered surgery. This patient selection 64
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undoubtedly influences the recurrence rates in our cohort. Nevertheless, our results do confirm that patients who are carefully selected for primary surgery and treated according to published guidelines for postsurgical adjuvant therapy have generally excellent outcomes. Limitations of our study include its retrospective nature, the relatively low number of events, and the biases inherent to patient selection for surgical management. Relatively short median follow-up is another limitation, especially given recent findings suggesting that HPVpositive disease may recur distantly at later time points than HPV-negative oropharyngeal SCC.26 Finally, ours is a single-institution study in which we follow a series of uniform policies to mitigate recurrence risk in high-risk patients. Through uniform application of adjuvant therapy guidelines, thereby systematically eliminating heterogeneity in patient management, we probably eliminated some of the chances to identify opportunities for treatment deintensification. A series of prospective randomized studies are planned to assist in defining the HPV-positive oropharyngeal SCC populations who might be appropriate for treatment deintensification.27 Eastern Cooperative Oncology Group 3311, for example, will enroll patients with HPV-positive tumors who are treated with primary TORS and stratify them into low-risk, intermediate-risk, and high-risk groups, which will receive adjuvant therapy tailored to their level of recurrence risk. In conclusion, our results demonstrate that locoregional failure and the development of distant metastatic disease are uncommon in patients who are appropriately selected for primary surgical management of HPV-positive oropharyngeal SCC, regardless of the presence or absence of traditionally described poor prognostic features. Importantly, we did not find any clinical or tumor features that predicted a worse outcome with upfront surgical management. Prospective investigation focused on HPV-positive patient cohorts will be needed to further determine how HPV positivity modifies the accepted risk factors for treatment failure, given our study findings suggesting that accepted risk factors for treatment failure may not hold in HPV-positive disease managed with primary surgery. Finally, our patient cohort, which has enjoyed a very high overall survival, further validates the premise underlying the design of Eastern Cooperative Oncology Group 3311, namely that surgical management can help to more accurately risk-stratify patients and assist in more refined and potentially less morbid selection of appropriate adjuvant therapy for these patients.
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