De-intensification of adjuvant therapy in human papillomavirus-associated oropharyngeal cancer
© The Author(s) 2016
Received: 30 August 2016
Accepted: 23 October 2016
Published: 20 December 2016
Current adjuvant treatment guidelines for oropharyngeal squamous cell carcinoma treated with primary surgery are based on studies that predate the human papillomavirus (HPV) era. HPV-associated oropharynx carcinoma (HPV-OPC) has a much more favorable prognosis compared to HPV-unassociated cancer and is increasingly considered to be a distinct disease entity due to its unique etiology, presentation, and behavior. Currently, there is significant interest in adjuvant treatment de-intensification of HPV-OPC patients in order to reduce treatment-related toxicity while maintaining excellent clinical outcomes. Here, we review the evidence and rationale underlying the ongoing prospective trials of adjuvant treatment de-intensification for HPV-OPC patients.
KeywordsHuman Papilloma Virus (HPV) Oropharyngeal cancer De-intensification Adjuvant Therapy
The incidence of oropharyngeal cancer (OPC) has been increasing, in contrast to an overall decrease in all head and neck cancers rates [1, 2]. The rise in incidence of OPC has been attributed to the human-papillomavirus (HPV), and HPV-associated oropharyngeal carcinoma (HPV-OPC) is known to have distinct oncogenesis, clinical features, treatment response, and prognosis. Cigarette smoking is not thought to have a causative role in the development of HPV-OPC and this likely explains why its rising incidence differs from the overall trend of head and neck cancers . High-risk HPV strains, predominantly HPV-16 and HPV-18, cause carcinogenesis via viral proteins E6 and E7, which inactivate tumor suppressors p53 and Rb, respectively. HPV-OPC is more likely found in younger males in developed countries with a limited smoking history and now comprises about 70% of all new oropharynx cancers in the United States . Clinically, HPV-associated disease tends to present with smaller primary tumors, larger metastatic lymph nodes, and with histopathology more likely to have non-keratinizing, basaloid features and poor differentiation .
Select prospective trials that demonstrated improved outcomes for HPV-associated disease on unplanned retrospective subgroup analysis
Finding (HPV+ improved outcomes)
RTOG 0129 
70 Gy over 7 weeks vs 72 Gy over 6 weeks. Both arms included concurrent cisplatin
70.9% vs. 30.2%
RTOG 0522 
Concurrent radiation with cisplatin +/- cetuximab
85.6% vs. 60.1%
ECOG 2399 
Phase II trial: 2 cycles of induction paclitaxel/carboplatin followed by radiation with concurrent paclitaxel
95% vs. 62%
TROG 02.02 
Radiation with concurrent cisplatin vs. radiation with concurrent cisplatin and tirapazamine
91% vs. 74%
TAX 324 
Induction docetaxel/cisplatin/fluorouracil followed by radiation with concurrent carboplatin vs. induction cisplatin/fluorouracil followed by radiation with concurrent carboplatin
82% vs. 35%
Since HPV-OPC has a more favorable prognosis, treatment de-intensification for HPV-OPC has become a primary research objective, especially due to concern over long-term treatment toxicities. Long-term treatment-related morbidity may be even more impactful for HPV-OPC patients because of their potential for longer survival after therapy and younger age at diagnosis. Concerning treatment-related side effects include gastrostomy-tube requirement, with 1-year rates ranging from 4 to 18% after trans-oral surgery [9–11] and 5–10% after definitive chemoradiation with modern radiation techniques . And even for patients who are not feeding tube dependent, dysphagia or aspiration can significantly decrease quality of life [13, 14].
Oropharynx carcinoma surgery
Standard management of OPC includes either frontline surgery or frontline radiation therapy, with or without concurrent chemotherapy. Frontline surgery includes not only resection of the primary tumor but also neck dissection with adjuvant therapy reserved for adverse pathologic features.
Primary surgery for OPC has experience a renaissance within the last decade . Traditionally, primary surgery required an open trans-cervical approach with potential for considerable morbidity. As such, organ-preservation with definitive chemoradiation gained popularity in the 1990s and early 2000s. More recently, transoral endoscopic head and neck surgery (eHNS) has emerged as a functional organ preservation approach. eHNS consists of a minimally-invasive procedure using miniaturized instrumentation that avoids mandibulotomy and external incisions. eHNS is performed with carbon dioxide laser microsurgery or robotic surgical system and has been associated with a resurgence of primary surgical treatment for T1-T2 OPC . Early reports have demonstrated that eHNS is associated with a lower complication rate and faster post-operative recovery [17, 18]. Moreover, oncologic outcomes from eHNS appear to be promising. A 2012 meta-analysis of over 500 OPSCC patients from 17 retrospective eHNS studies showed 1-year OS of over 90% and 2-year survival between 80 and 90% . Most patients in this meta-analysis with standard indications for adjuvant treatment received adjuvant radiation or chemoradiation. Additionally, the meta-analysis found generally lower rates of functional deficits after trans-oral surgery, including a gastrostomy-tube dependence at 1-year of 0–9.5%. Aside from T1-2 disease, eHNS has also been used for locally-advanced OPSCC with acceptable clinical outcomes, suggesting upfront eHNS for selected stage III/IV OPC may also be appropriate [9, 19]. Recently, the largest multi-institutional report thus far of 410 head and neck cancer patients treated with eHNS, 89% of which were oropharyngeal primaries, found 2-year and 3-year loco-regional control rates of 91.8 and 88.8% with only 1 surgery-related mortality .
Indications for adjuvant therapy
National Comprehensive Cancer Network (NCCN) guidelines recommend OPC patients after up-front surgery who have distinct adverse pathologic features receive either adjuvant radiation alone or chemoradiation . Chemoradiation is recommended for high risk adverse features: extranodal extension (+ENE) and/or positive surgical margin(s). Other adverse pathologic factors are typically treated with adjuvant radiation alone. These are perhaps best summarized by the inclusion criteria of RTOG 0920, a phase III study of adjuvant radiation +/- cetuximab for head and neck squamous cell carcinoma (HNSCC) patients with intermediate risk factors. These intermediate risk factors include: close margin (<5 mm), ≥ 2 metastatic lymph nodes (LN) or a single LN > 3 cm, perineural invasion (PNI), lymphovascular invasion (LVI), T3 or T4a primary, or patients with initially focally positive margins but undergo re-excision with final negative margins. While not an inclusion criterion of RTOG 0920, nodal involvement of levels IV or V in oropharynx primary was also included by NCCN as an “intermediate” risk factor.
Inclusion criteria for select randomized adjuvant treatment trials comparing chemoradiation versus radiation alone
EORTC 22931 
Sites: oral cavity, oropharynx, larynx, or hypopharynx
1 of the following:
• pT3-4 N0-3 except for T3N0 of the larynx with negative resection margins
• pT1-2 N2-3
• pT1-2 N0-1 and positive margins, PNI, or vascular embolism (lymphovascular invasion)
• oral cavity or oropharyngeal primaries with level IV or V lymph node involvement
RTOG 9501 
Sites: oral cavity, oropharynx, larynx, or hypopharynx
Status post complete macroscopic resection
1 of the following
• two or more metastatic regional lymph nodes
• extracapsular extension
• microscopically involved mucosal margins of resection
The prognosis of extranodal extension in HPV-OPC
Given the favorable prognosis of HPV-OPC, the question has been raised whether ENE carries the same adverse prognostic value in this favorable group of patients. Several concerns arise with applying findings from RTOG 9501 and EORTC 22931 to HPV-OPC patients. HPV status testing was not routinely performed in the two trials. Furthermore, oropharyngeal primaries made up only 42 and 30% of the RTOG 9501 and ECOG 22931, respectively, suggesting that HPV-OPC made up a minority of patients in those studies.
Several other issues arise when trying to understand the prognostic implications of ENE amongst HPV-OPC patients, not the least of which is there may be significant intra- and inter-observer variability in assessing ENE. In a study from Washington University with 152 patients, slides were re-examined by a single study-pathologist and the results were compared to the original pathology report. ENE was reported to be present in 124/152 cases or 82% of cases as read on the initial pathology reports but only present in 79/152, or only 52%, on re-review . It is troubling that even within a single high-volume center there can be a thirty percent discrepancy in pathologic assessment of ENE. In a later study, the same authors created digitally scanned nodal metastases slides, which were initially read by five different pathologists. These pathologists were instructed to perform a dichotomous assessment for ENE as either present or absent, and there was agreement in only 48% of cases. Subsequently, the pathologists were given a defined system which grades ENE into four categories, and agreement improved slightly to 64% .
Grading system for extranodal extension for metastatic lymph node established by Lewis et al .
Extra Nodal Extension Grading System
Tumor is surrounded by lymphoid tissue
Tumor reaches the capsule (with no intervening lymphoid tissue) with thickening of overlying capsule
Tumor in perinodal tissue, extending ≤ 1 mm beyond capsule
Tumor in perinodal tissue and extending > 1 mm beyond capsule
Tumor mass without residual nodal tissue or architecture. No residual lymphoid architecture or germinal center.
Studies have also examined whether ENE in patients with HPV-OPC is a risk factor for disease-free survival following surgical resection. In the Washington University experience of p16+ OPC patients after eHNS, the rate of DFS was not significantly different amongst patients whose pathology reports described ENE versus those without, with 3-year disease-specific survival (DFS) estimates of 89% (95% CI 84–95%) and 94% (95% CI 83–100%), respectively . These results were corroborated by a study from the University of Pittsburgh that examined 76 patients with HPV-OPC, 45 of which had ENE. There was no difference in rates of DSS amongst patients with or without ENE (p = 0.936) . In a subsequent update, these patients were reported to have a 5-year DSS of 84.8% (95% CI 64.4–94.05%) in patients with ENE and 89.3% (95% CI 73.9–98.1%) in patient without ENE .
The most provocative evidence suggesting a lack of benefit from concurrent chemoradiation for patients with HPV-OPC comes from retrospective comparisons of patients with ENE that received either radiation therapy alone or chemoradiation. In the Washington University series, 113 patients had ENE graded on their pathology reports, and, of this group, 48 were treated with radiation alone while 65 were treated with chemoradiation. The 3-year DFS rates were similar at 94.5% in the radiation group and 91.8% in the chemoradiation group (p = .74) . These values should of course be taken with the caveats associated with a single institution retrospective study, and the results could of course be reflective of patient selection, but nonetheless it remains a notable finding.
Taken together, the benefit of chemoradiation in HPV-OPC patients with ENE remains a pivotal unanswered question in modern head and neck oncology. The underlying recommendation for chemoradiation for ENE positive patients came from a larger group of HNSCC most of which were likely not HPV-associated, and therefore carry a different biology, natural history, and a significantly worse prognosis. In addition, the historic dichotomization of ENE may actually be an oversimplification of the true risk of recurrence, and further efforts are needed to standardize the reporting of ENE across centers. The current data, limited to small single institution series at high volume centers, shows that ENE does not appear to be necessarily associated with worse disease specific survival, and that patients who received radiation seemed to do similarly to those who receive chemoradiation. Given the additional toxicity with chemoradiation, which is associated with more than double the rate of grade 3 or higher acute toxicity in comparison to radiation alone , answering the question of whether concurrent chemotherapy is necessary for patients with ENE is a critical priority for the head and neck oncology community.
Number of positive lymph nodes
Attention has recently been paid to whether patients with a higher number of pathologically involved lymph nodes represent a separate high-risk group. A study of HPV-OPC after eHNS from Washington University found the presence of five or more involved LN was associated with a recurrence rate of 24% on multivariable analysis (OR 3.12) . Additionally, a recent study from the SEER database demonstrated that oropharyngeal carcinoma patients with 5 or more involved lymph nodes had a worsened survival, although this study was limited in that information on HPV and p16 testing was unavailable . In contrast, the recently proposed staging system for HPV-OPC, the ICON-S group concluded that the number of positive lymph nodes was not predictive of OS, though this was in a group of patients that largely had clinically as opposed to pathologically staged nodal disease . ECOG 3311 includes patients with five or more involved nodes in its high-risk group to receive adjuvant chemoradiation, and results from this study should provide needed prospective data about nodal number and the risks of recurrence .
Post-operative radiation dose
There is considerable variation among studies in terms of radiation dose used in the adjuvant setting, and whether this should be affected by high risk factors such as ENE or positive margins. Fortunately, there is randomized data to help provide guidance. Peters et al. performed a Phase III study investigating the optimal adjuvant radiation dose required based on postoperative risk stratification. The study included 240 patients, and nearly all were stage III/IV oral cavity, oropharynx, hypopharynx, or larynx primaries after initial resection. Patients were assigned into low-risk or high-risk groups for both primary site and nodal disease based on a point system incorporating T-stage, margins status, and nerve involvement for primary site and nodal number, and nodal groups for nodal disease. Low risk patients were randomized to a dose of 57.6 Gy (initially < 54 Gy) vs. 63 Gy, and high-risk patients were randomized to 68.4 Gy vs. 63 Gy. The 2-years loco-regional control rate for the low risk primary site group was 92% for 57.6 Gy, 89% for 63 Gy, but only 63% for <54 Gy. This led the authors to conclude 57.6 Gy in 1.8 Gy fractions was the recommended dose for postoperative patients with intermediate risk factors. In the high-risk group, 2-year local control was 89% with 63 Gy and 81% with 68.4 Gy. There was a noticeable local control dose-response in the subgroup of ENE+ cases, as among ENE+ cases, the 2-years control rate was 52% for 57.6 Gy, 74% for 63 Gy, and 72% for 68.4 Gy . With these findings, the recommended postoperative radiation dose for ENE+ patients was 63 Gy in 1.8 Gy fractions. Interestingly a similar dose response was not seen for patients with positive margins. Despite this level 1 evidence, these doses were never widely adopted. Practitioners have largely moved to using a daily dose of at least 2 Gy per day, given data that showed a benefit to shorter treatment courses [35, 36]. Using the linear quadratic equation, 57.6 Gy in 1.8 Gy fractions translates to approximately 56–58 Gy in 2 Gy fractions, and 63 Gy in 1.8 Gy fractions translates to approximately 62 Gy in 2 Gy fractions. Perhaps for reasons more logistical than scientific, this has often translated to a dose of 60 Gy to areas of potential microscopic disease, with some pushing for a boost to areas of ENE or positive margins to 66 Gy. This variation is seen even among large cooperative group trials. Current studies of intermediate risk patients, such as RTOG 0920, and the standard arm of ECOG 3311 use a dose of 60Gy. For high-risk patients, RTOG 9501 mainly used 60 Gy though 13% received an optional 6 Gy boost while EORTC 22931 mainly used 66 Gy. The current high-risk study for p16(-) cancers, RTOG 1216, calls for 60 Gy with an optional 6 Gy boost given concurrently. ECOG 3311, which is limited to p16 positive patients, uses 66 Gy in its high-risk arm. This variation is reflected in national practice guidelines which call for a dose to high-risk sites (positive margins and/or + ENE) of 60–66 Gy in 2 Gy fractions and a dose to intermediate risk sites of 54–63 Gy using simultaneous dosing techniques . Recent evidence, however, suggests a lack of benefit for higher doses in HPV-associated oropharyngeal cancer. Investigators at Washington University compared outcomes for patients with HPV-associated OPSCC and the risk factors of close or positive margins and/or ECE, but treated to different radiation doses . The institutional standard dose for such patients was 66 Gy from 1998 to 2009 but was changed to 60 Gy in 2009. Researchers found no significant differences in 2-year loco-regional recurrence-free survival, cause-specific survival or overall survival between 60 Gy and 66 Gy groups, suggesting 60Gy may be a reasonable adjuvant radiation dose in HPV-associated OPSCC.
Omitting adjuvant radiation to the primary tumor bed
Another potential de-intensification approach is consideration of omitting adjuvant radiation to the primary tumor bed. The rationale here is that given the improved margin control of eHNS and low rates of tumor bed recurrence seen in early stage patients who are observed after eHNS, primary site irradiation may not be necessary. The indication for irradiation in many early stage patients ends up being the presence of multiple involved lymph nodes, and thus it is hypothesized that perhaps, the neck alone can be irradiated, translating to smaller radiation volumes and potentially less morbidity.
A recently published study of p16+ oropharyngeal SCC patients after eHNS found a local recurrence rate of only 3% (3/92) in pT1-T2 patients who did not receive adjuvant radiation to the primary tumor bed, although approximately half did receive neck directed irradiation . Those spared adjuvant RT to the primary bed were also found to have lower gastrostomy tube rates (10% vs 2% 1-year rate for pT1-T2). The authors concluded their findings suggest that omitting primary tumor adjuvant radiation in low-risk, early T-stage, HPV-associated oropharyngeal carcinoma patients appears safe and may be associated with less functional morbidity.
Of note, while in theory eliminating the primary tumor bed as a target would theoretically lead to a substantial decrease in radiation to normal tissues, dosimetric studies comparing primary plus neck irradiation with neck-only irradiation suggest only a modest potential benefit with this approach [39, 40]. This may be due to the fact that the level II lymph nodes, which represent the first echelon nodal drainage for oropharyngeal cancers, and are thus always in the neck radiation volume, sit adjacent to the tonsil and base of tongue. An dosimetric analysis of radiation for tonsillar cancer patients compared tonsil/post-operative bed doses for patients treated to the unilateral neck only, and found that the primary site still received a mean dose of 53.9 Gy . Additionally, the radiation dose to bilateral parotid glands, larynx or mandible was not significantly lower in the neck-only radiation treatment plans. There was however a slight benefit in dose to the oral cavity (34.0 Gy vs. 29.8 Gy p = 0.002) and superior pharyngeal constrictors (46.1 Gy vs. 42.9 Gy p = 0.01). A separate study of base of tongue tumors compared radiation plans of patients receiving adjuvant radiation to the bilateral neck and primary tumor to those same patients replanned to receive only bilateral neck radiation and found a decrease in oral cavity dose (47.4 Gy vs. 22.3 Gy) but no significant benefit for contralateral parotid or pharyngeal constrictor muscles . Of note, the primary tumor bed still received a mean dose of 40.2 Gy, which could complicate consideration of future re-irradiation for any patients who may recur.
Currently, a University of Pennsylvania phase-II trial is underway that will further elucidate the benefits of neck only irradiation in HPV-associated OPSCC patients after eHNS (NCT02159703). The ADEPT adjuvant trial will also allow omission of primary bed radiation in pT1-2 patients with a negative surgical margin who still have an indication for neck irradiation (NCT01687413).
Current treatment de-intensification trials with primary surgery in HPV-OPC
Active Phase II/III Trials of Surgically-treated HPV-OPC
ECOG 3311 
Post trans-oral surgery
Stage III, IVA, IVB
+ENE (≤1 mm)
Randomized: 50 in 25 fx Gy vs 60 Gy in 30 fx
+ENE (>1 mm)
66 Gy with weekly cisplatin (40 mg/m2 weekly)
Post trans-oral surgery
Stage III, IV
Randomized: 60 Gy +/- cisplatin (40 mg/m2 weekly)
Post trans-oral surgery
• Close margins (1–5 mm)
Randomized: 50 Gy in 25 fx vs 60 Gy in 30 fx
Positive margin (<1 mm)
Negative marginal biopsy
Randomized: 60 Gy +/- cisplatin (40 mg/m2 weekly)
T1N1-2b or T2N0-2b
-LVI, -PNI, no LN+
ENE (<1 mm)
ENE (≥1 mm)
Matted or SCV nodes
56 Gy with cisplatin (40 mg/m2 weekly)
Mayo Clinic 
At least one of following:
• LN > 3 cm
• >1 LN+
• T3 or microscopic T4a
Accelerated/hyperfractionated: 36 Gy in 20 fractions
• BID 5 days/week, days 1-12
• Concurrent docetaxel
University of Pennsylvania 
Post-TORS and Selective Neck Dissection
Notable exclusion criteria:
• Positive or microscopically positive surgical margins (negative or close (<2 mm) margins of primary cancer
• PNI of primary cancer
All trial patients forgo adjuvant radiotherapy to the primary cancer
The PATHOS trial, funded by Cancer Research UK, is similar to ECOG 3311 since it also calls for post-eHNS stratification into low, intermediate, and high-risk groups. However, the PATHOS trial employs different criteria for intermediate and high-risk groups. Intermediate-risk inclusion criteria are: negative margin, at least pT3 disease or pT1-2 disease with pN2a/b, PNI, LVI, or close margin (defined as 1–5 mm). Intermediate risk patients are randomized to standard arm of 60 Gy in 30 fractions or dose-de-escalated to 50 Gy in 25 fractions. The high-risk group requires positive margins or + ENE, and these patients are randomized to 60 Gy with cisplatin or without concurrent chemotherapy.
Similar to the PATHOS high-risk arm, the ADEPT phase III trial will also elucidate if adjuvant chemotherapy is needed for HPV-OPC patients with + ENE. Closed to accrual, the ADEPT trial includes post-eHNS patients with + ENE but negative surgical margins. Patients are randomized to the standard 60 Gy with concurrent cisplatin or de-intensified to 60 Gy without chemotherapy.
Additionally, a single-arm Mayo Clinic phase II trial underway is studying the use of an accelerated hyperfractionated twice daily (BID) radiation in post-operative cases . The radiation schedule consists of 36 Gy in 20 fractions in 1.8 Gy BID dosing and delivered 5 days a week within the first 12 days with concurrent docetaxel. This reduced radiation dosing is inspired by studies showing lower doses were able to control disease in anal cancer, another HPV-associated squamous cell carcinoma . Eligible patients must have at least one of the following risk factors: LN > 3 cm, two or more metastatic LN, perineural invasion, LVSI, pT3, or microscopic pT4a stage.
Finally, there is also an ongoing University of Pennsylvania single-arm phase II trial of pT1-T2, N2a-c patients after eHNS who receive adjuvant radiation only to the neck and not the primary tumor bed . This study addresses the question can the primary tumor bed forgo adjuvant radiation and potentially reduce toxicity if the only indication for adjuvant irradiation is multiple involved neck nodes (without risk factors at the primary site) .
The superior prognosis of HPV-OPC has catalyzed clinical investigation of treatment de-intensification. Ongoing phase II and phase III trials will provide novel risk-adjusted adjuvant treatment schemes and provide answers regarding the appropriateness of radiation dose reduction or reduction of systemic therapy in HPV-OPC. These studies will also answer if traditional adverse post-operative risk factors, such as + ENE or positive margins, have the same prognostic value as in HPV-associated cohort. It should be noted, however, that therapeutic de-escalation is a hypothesis requiring clinical study - at this time HPV-OPC patients should continue to receive standard of care adjuvant treatment according to national guidelines unless on a clinical trial.
transoral endoscopic head and neck surgery
head and neck squamous cell carcinoma
HPV-associated oropharynx carcinoma
metastatic lymph nodes
soft tissue metastasis
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
YA and ZH were responsible for the conception, design, and draft of the manuscript. CH made substantial contributions to conception and design. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
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- Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer. 2005;103:1843–9.View ArticlePubMedGoogle Scholar
- Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, Moller B, Pukkala E, Schiller JT, Youngman L, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med. 2001;344:1125–31.View ArticlePubMedGoogle Scholar
- D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–56.View ArticlePubMedGoogle Scholar
- Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26:612–9.View ArticlePubMedGoogle Scholar
- Adelstein DJ, Ridge JA, Gillison ML, Chaturvedi AK, D’Souza G, Gravitt PE, Westra W, Psyrri A, Kast WM, Koutsky LA, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008, Washington, D.C. Head Neck. 2009;31:1393–422.View ArticlePubMedGoogle Scholar
- Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, Oggionni M, Rossini C, Cantu G, Squadrelli M, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol. 2006;24:5630–6.View ArticlePubMedGoogle Scholar
- Harari PM, Harris J, Kies MS, Myers JN, Jordan RC, Gillison ML, Foote RL, Machtay M, Rotman M, Khuntia D, et al. Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol. 2014;32:2486–95.View ArticlePubMedPubMed CentralGoogle Scholar
- Lohaus F, Linge A, Tinhofer I, Budach V, Gkika E, Stuschke M, Balermpas P, Rodel C, Avlar M, Grosu AL, et al. HPV16 DNA status is a strong prognosticator of loco-regional control after postoperative radiochemotherapy of locally advanced oropharyngeal carcinoma: results from a multicentre explorative study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Radiother Oncol. 2014;113:317–23.View ArticlePubMedGoogle Scholar
- Haughey BH, Hinni ML, Salassa JR, Hayden RE, Grant DG, Rich JT, Milov S, Lewis Jr JS, Krishna M. Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. Head Neck. 2011;33:1683–94.View ArticlePubMedGoogle Scholar
- Moore EJ, Olsen SM, Laborde RR, Garcia JJ, Walsh FJ, Price DL, Janus JR, Kasperbauer JL, Olsen KD. Long-term functional and oncologic results of transoral robotic surgery for oropharyngeal squamous cell carcinoma. Mayo Clin Proc. 2012;87:219–25.View ArticlePubMedPubMed CentralGoogle Scholar
- Bhayani MK, Hutcheson KA, Barringer DA, Lisec A, Alvarez CP, Roberts DB, Lai SY, Lewin JS. Gastrostomy tube placement in patients with oropharyngeal carcinoma treated with radiotherapy or chemoradiotherapy: factors affecting placement and dependence. Head Neck. 2013;35:1634–40.View ArticlePubMedGoogle Scholar
- Setton J, Lee NY, Riaz N, Huang SH, Waldron J, O’Sullivan B, Zhang Z, Shi W, Rosenthal DI, Hutcheson KA, Garden AS. A multi-institution pooled analysis of gastrostomy tube dependence in patients with oropharyngeal cancer treated with definitive intensity-modulated radiotherapy. Cancer. 2015;121:294–301.View ArticlePubMedGoogle Scholar
- Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer. J Clin Oncol. 2006;24:2636–43.View ArticlePubMedGoogle Scholar
- Rich JT, Milov S, Lewis Jr JS, Thorstad WL, Adkins DR, Haughey BH. Transoral laser microsurgery (TLM) +/- adjuvant therapy for advanced stage oropharyngeal cancer: outcomes and prognostic factors. Laryngoscope. 2009;119:1709–19.View ArticlePubMedGoogle Scholar
- Liederbach E, Lewis CM, Yao K, Brockstein BE, Wang CH, Lutfi W, Bhayani MK. A contemporary analysis of surgical trends in the treatment of squamous cell carcinoma of the oropharynx from 1998 to 2012: a report from the national cancer database. Ann Surg Oncol. 1998;2015(22):4422–31.Google Scholar
- Cracchiolo JR, Baxi SS, Morris LG, Ganly I, Patel SG, Cohen MA, Roman BR. Increase in primary surgical treatment of T1 and T2 oropharyngeal squamous cell carcinoma and rates of adverse pathologic features: National Cancer Data Base. Cancer. 2016;122:1523–1532.
- Holsinger FC, Ferris RL. Transoral endoscopic head and neck surgery and its role within the multidisciplinary treatment paradigm of oropharynx cancer: robotics, lasers, and clinical trials. J Clin Oncol. 2015;33:3285–92.View ArticlePubMedPubMed CentralGoogle Scholar
- Dowthwaite SA, Franklin JH, Palma DA, Fung K, Yoo J, Nichols AC. The role of transoral robotic surgery in the management of oropharyngeal cancer: a review of the literature. ISRN Oncol. 2012;2012:945162.PubMedPubMed CentralGoogle Scholar
- Grant DG, Salassa JR, Hinni ML, Pearson BW, Perry WC. Carcinoma of the tongue base treated by transoral laser microsurgery, part one: Untreated tumors, a prospective analysis of oncologic and functional outcomes. Laryngoscope. 2006;116:2150–5.View ArticlePubMedGoogle Scholar
- de Almeida JR, Li R, Magnuson JS, Smith RV, Moore E, Lawson G, Remacle M, Ganly I, Kraus DH, Teng MS, et al. Oncologic outcomes after transoral robotic surgery: a multi-institutional study. JAMA Otolaryngol Head Neck Surg. 2015;141:1043–51.View ArticlePubMedPubMed CentralGoogle Scholar
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Head and Neck Cancers (version 1.2015). [http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf]. Accessed 15 June 2016.
- Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937–44.View ArticlePubMedGoogle Scholar
- Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–52.View ArticlePubMedGoogle Scholar
- Cooper JS, Zhang Q, Pajak TF, Forastiere AA, Jacobs J, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;84:1198–205.View ArticlePubMedPubMed CentralGoogle Scholar
- Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefebvre JL. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27:843–50.View ArticlePubMedGoogle Scholar
- Sinha P, Lewis Jr JS, Piccirillo JF, Kallogjeri D, Haughey BH. Extracapsular spread and adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer. 2012;118:3519–30.View ArticlePubMedGoogle Scholar
- Lewis Jr JS, Tarabishy Y, Luo J, Mani H, Bishop JA, Leon ME, Prasad ML, Xu H, Di Palma S. Inter- and intra-observer variability in the classification of extracapsular extension in p16 positive oropharyngeal squamous cell carcinoma nodal metastases. Oral Oncol. 2015;51:985–90.View ArticlePubMedPubMed CentralGoogle Scholar
- Maxwell JH, Ferris RL, Gooding W, Cunningham D, Mehta V, Kim S, Myers EN, Johnson J, Chiosea S. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer. 2013;119:3302–8.View ArticlePubMedGoogle Scholar
- Transoral Surgery Followed By Low-Dose or Standard-Dose Radiation Therapy With or Without Chemotherapy in Treating Patients With HPV Positive Stage III-IVA Oropharyngeal Cancer. [https://clinicaltrials.gov/ct2/show/NCT01898494]. Accessed 14 Aug 2016.
- Sinha P, Kallogjeri D, Gay H, Thorstad WL, Lewis Jr JS, Chernock R, Nussenbaum B, Haughey BH. High metastatic node number, not extracapsular spread or N-classification is a node-related prognosticator in transorally-resected, neck-dissected p16-positive oropharynx cancer. Oral Oncol. 2015;51:514–20.View ArticlePubMedGoogle Scholar
- Roberts TJ, Colevas AD, Hara W, Holsinger FC, Oakley-Girvan I, Divi V. Number of positive nodes is superior to the lymph node ratio and American Joint Committee on Cancer N staging for the prognosis of surgically treated head and neck squamous cell carcinomas. Cancer. 2016;122:1388–1397.
- O'Sullivan B, Huang SH, Su J, Garden AS, Sturgis EM, Dahlstrom K, Lee N, Riaz N, Pei X, Koyfman SA, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 2016;17:440–451.
- ClinicalTrials.gov. Transoral surgery followed by low-dose or standard-dose radiation therapy with or without chemotherapy in treating patients with HPV positive Stage III-IVA oropharyngeal cancer. 2015.Google Scholar
- Peters LJ, Goepfert H, Ang KK, Byers RM, Maor MH, Guillamondegui O, Morrison WH, Weber RS, Garden AS, Frankenthaler RA, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys. 1993;26:3–11.View ArticlePubMedGoogle Scholar
- Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J, Horiot JC, Le Maitre A, Pajak TF, Poulsen MG, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet. 2006;368:843–54.View ArticlePubMedGoogle Scholar
- Yamazaki H, Nishiyama K, Tanaka E, Koizumi M, Chatani M. Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time. Int J Radiat Oncol Biol Phys. 2006;64:77–82.View ArticlePubMedGoogle Scholar
- Chin RI, Spencer CR, DeWees T, Hwang MY, Patel P, Sinha P, Gay HA, Haughey BH, Nussenbaum B, Adkins DR, et al: Reevaluation of postoperative radiation dose in the management of human papillomavirus-positive oropharyngeal cancer. Head Neck. 2016;38:1643–1649.
- Sinha P, Patrik P, Thorstad WL, Gay HA, Haughey BH. Does elimination of planned postoperative radiation to the primary bed in p16-positive, transorally-resected oropharyngeal carcinoma associate with poorer outcomes? Oral Oncol. 2016;61:127–34.View ArticlePubMedGoogle Scholar
- Lazarev S, Todorov B, Tam J, Gupta V, Miles BA, Lee N, Bakst RL. Adjuvant Radiation in the TORS Era - Is There a Benefit to Omitting the Tumor Bed?. Pract Radiat Oncol. 2016. doi: 10.1016/j.prro.2016.08.002
- Fried D, Lehman-Davis M, Willson A, Kostich M, Hackman T, Lian J, Burkhardt K, Chera B. Dosimetric feasibility of sparing the primary site for oropharyngeal squamous cell carcinoma after transoral laser microsurgery in patients with unilateral positive neck nodes. Pract Radiat Oncol. 2013;3:282–6.View ArticlePubMedGoogle Scholar
- ClinicalTrials.gov. Radiation therapy and docetaxel in treating patients with HPV-related oropharyngeal cancer. 2016.Google Scholar
- Charnley N, Choudhury A, Chesser P, Cooper RA, Sebag-Montefiore D. Effective treatment of anal cancer in the elderly with low-dose chemoradiotherapy. Br J Cancer. 2005;92:1221–5.View ArticlePubMedPubMed CentralGoogle Scholar
- ClinicalTrials.gov: A Single-arm Phase II Study of Post-Transoral Robotic Surgery (TORS) Alone to the Primary Tumor Site and Selective Neck Dissection (SND) Followed by Adjuvant Radiation Therapy (+/- Chemotherapy) to the Regional Nodes for Advanced Stage, Human Papilloma Virus (HPV) Positive, Oropharyngeal Cancer; 2016.
- Nguyen-Tan PF, Zhang Q, Ang KK, Weber RS, Rosenthal DI, Soulieres D, Kim H, Silverman C, Raben A, Galloway TJ, et al. Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity. J Clin Oncol. 2014;32:3858–66.View ArticlePubMedPubMed CentralGoogle Scholar
- Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014;32:2940–50.View ArticlePubMedPubMed CentralGoogle Scholar
- Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261–9.View ArticlePubMedGoogle Scholar
- Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, Solomon B, Choi J, O’Sullivan B, Kenny LM, McArthur GA. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28:4142–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Posner MR, Lorch JH, Goloubeva O, Tan M, Schumaker LM, Sarlis NJ, Haddad RI, Cullen KJ. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol. 2011;22:1071–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Lewis Jr JS, 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;24:1413–20.View ArticlePubMedPubMed CentralGoogle Scholar
- ClinicalTrials.gov. Post operative adjuvant therapy de-intensification trial for human papillomavirus-related, p16+ Oropharynx Cancer (ADEPT). 2016.Google Scholar
- ClinicalTrials.gov. Post-operative adjuvant treatment for HPV-positive Tumours (PATHOS). 2014.Google Scholar
- ClinicalTrials.gov. The Sinai robotic surgery trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma (SCCA) (SIRS TRIAL). 2016.Google Scholar