Review Open Access
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Feb 10, 2016; 7(1): 15-26
Published online Feb 10, 2016. doi: 10.5306/wjco.v7.i1.15
Advanced oropharyngeal squamous cell carcinoma: Pathogenesis, treatment, and novel therapeutic approaches
Paul L Swiecicki, Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, United States
Kelly M Malloy, Department of Otolaryngology, University of Michigan Health System, Ann Arbor, MI 48109, United States
Francis P Worden, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, United States
Author contributions: Swiecicki PL, Malloy KM and Worden FP contributed equally drafting of the article, making critical revisions, and final approval of the final article.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Paul L Swiecicki, MD, Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Drive, SPC 5848, Ann Arbor, MI 48109, United States. pswiecic@med.umich.edu
Telephone: +1-734-6478921 Fax: +1-734-2329365
Received: July 24, 2015
Peer-review started: July 27, 2015
First decision: September 30, 2015
Revised: October 7, 2015
Accepted: November 24, 2015
Article in press: November 25, 2015
Published online: February 10, 2016

Abstract

Oropharyngeal cancer accounts for approximately 2.8% of newly cancer cases. Although classically a tobacco related disease, most cases today are related to infection with human papilloma virus (HPV) and present with locally advanced tumors. HPV related tumors have been recognized as a molecularly distinct entity with higher response rates to therapy, lower rates of relapse, and improved overall survival. Treatment of oropharyngeal cancer entails a multi-disciplinary approach with concomitant chemoradiation. The role of induction chemotherapy in locally advanced tumors continues to be controversial however large studies have demonstrated no difference in survival or time to treatment failure. Surgical approaches may be employed with low volume oropharyngeal cancers and with development new endoscopic tools, more tumors are able to be resected via an endoscopic approach. Given advances in the understanding of HPV related oropharyngeal cancer, ongoing research is looking at ways to minimize toxicities via de-intensification of therapy. Unfortunately, some patients develop recurrent or metastatic disease. Novel therapeutics are currently being investigated for this patient population including immunotherapeutics. This review discusses the current understanding of the pathogenesis of oropharyngeal cancer and treatment. We also discuss emerging areas of research as it pertains to de-intensification as well novel therapeutics for the management of metastatic disease.

Key Words: Oropharyngeal cancer, Human papilloma virus, Transoral robotic surgery, Immunotherapy, Metastatic head and neck squamous cell carcinoma

Core tip: Treatment of oropharyngeal cancer entails a multi-disciplinary approach with concomitant chemoradiation. Given advances in the understanding of human papilloma virus related oropharyngeal cancer, ongoing research is looking at ways to minimize toxicities via de-intensification of therapy. Unfortunately, some patients develop recurrent or metastatic disease. This review discusses the current understanding of the pathogenesis of oropharyngeal cancer and treatment. We also discuss emerging areas of research as it pertains to de-intensification as well novel therapeutics for the management of metastatic disease.



INTRODUCTION

Oropharyngeal cancer accounts for approximately 2.8% of newly diagnosed cancer cases and, in 2015, will result in 8650 estimated deaths[1]. Today, most cases are related to human papilloma virus (HPV) infections and many are curable with definitive combinations of surgery and radiation or chemoradiotherapy. Hence, HPV is a prognostic biomarker, but not yet predictive. As the field of clinical research continues to advance, methods for de-intensifying treatment for such patients are becoming more important. Here, we will review the epidemiology of oropharyngeal cancer as well as treatment strategies and areas of developing research for those afflicted with this disease.

EPIDEMIOLOGY, PATHOGENESIS, AND RISK STRATIFICATION

Classically, use of tobacco products has been the leading factor for development of oropharyngeal cancer, although this has been shifting with changes in societal trends in tobacco usage[2-4]. This increased risk pertains to use of cigarettes, cigars, and pipes and increases with the number of years an individual has smoked[5]. Smoking cessation resulted in a normalization of risk in casual smokers after approximately 15 years[6,7]. Additionally, tobacco usage during definitive therapy for head and neck cancer is associated with an increased rate of disease progression and death, particularly in those whose cancers are not related to HPV or are p16 negative[8]. Similarly, alcohol intake increases the risk of head and neck cancers in a dose dependent manner[7,9-11].

HPV, most notably genotype 16, has been identified as an increasing causative factor for oropharyngeal cancer and is chiefly seen in patients with minimal tobacco and alcohol use. This is especially important since the pathogenesis, presentation, and prognosis differ in HPV(+) vs HPV(-) oropharyngeal carcinomas. The molecular carcinogenesis of HPV associated oropharyngeal cancer has been explored in detail and is separate from that seen in HPV(-) cancer and relates to loss of cell cycle checkpoints[12,13]. In a subset of patients with chronic HPV infections, the viral oncoproteins E6 and E7 bind p53 and pRb/p21, respectively. The resultant effect is that E6 binding causes p53 degradation whereas E7 binding to pRb and p21 leads to an activation of transcription factors. These transcription factors cause malignant cells to progress into the G1 cell cycle phase which is unopposed due to the loss of p53. The latency from time of primary infection to development of malignancy is approximately 15-20 years. Over the last 20 years there has been an steady rise in the number of newly diagnosed HPV(+) oropharyngeal cancers, increasing from 16.3% to 71.7%, accompanied by a corresponding 50% decline in the incidence HPV(-) oropharyngeal carcinomas[3,14-16].

Clinically, HPV+ cancers are more likely to present in younger patients and involve the base of the tongue or tonsils[3,17,18]. Additionally, patients with HPV+ oropharyngeal cancers are much more likely to respond to therapy, have lower rates of disease relapse, and enjoy improved overall survivals. Furthermore, such tumors are less likely to develop second malignancies compared to matched HPV(-) patients[3,14-16,19]. Based on these studies, a model for risk stratification has been generated based on HPV status, smoking history, tumor stage, and nodal involvement. A classification of low, intermediate, or high risk disease has been generated, predicting 3 year overall survivals of 93%, 70.8%, and 46.2%, respectively[15]. Interestingly, a single center study analyzing survival and TNM staging in oropharyngeal cancers found that survival based on TNM status did not correlate with survival in those patients with HPV(+) disease, but it did correlate with survival in those with HPV(-) disease. A retrospective, multivariate analysis of the HPV+ patients, however, was able to generate an accurate prognostic model by including tumor stage, smoking status, and age by recursive partitioning analysis (RPA). Thus, the authors propose an RPA-based staging system in HPV-related oropharynx cancers, whereby stage I cancers would be classified by T1-3, N0-N2b tumors, stage II by T1-3, N2c, and stage III by T4 or N3 disease[20].

TREATMENT STRATEGIES
Surgical approaches

Surgical approaches are currently one of the primary modalities in the treatment of low volume oropharyngeal cancers. Early stage squamous cell carcinomas of the oropharynx can be managed with either surgery or radiation therapy. Given the significant acute and long term side effects of radiation therapy, minimally invasive surgical approaches [including transoral robotic surgery (TORS) and transoral laser microsurgery (TLM)] have been increasingly employed for the management of early stage tumors. This increased utilization has been further driven by development of new endoscopic tools including the da Vinci Robot, enabling better visualization and surgical manipulation in the oropharynx. These technologies have allowed tumors only previously resectable via external and highly morbid approaches (mandibular split and pharyngotomy approaches) to now be treatable via the transoral route with significantly less morbidity. One report of TLM demonstrated the promise of this modality in patients with early stage oropharyngeal cancer (T1-4a, N0). In this study, sixty-nine patients in two centers underwent TLM and neck dissection, of which no patients were treated with adjuvant radiation. Excellent patient outcomes were reported, including a five year overall survival of 86%. Similarly, locoregional recurrences were quite low, with a 90% locoregional control rate in patients with T1 disease, and a 94% control rate in patients with T2 disease[21].

Although treatments with TORS and TLM are increasingly becoming employed in early stage oropharyngeal carcinomas, the bulk of the evidence supporting their use stems from the surgical management of patients with locally advanced (stage III/IV) disease. The utilization of TORS was first reported in 2005[22], and since then has been described in numerous publications as an effective treatment for oropharyngeal cancers[23-25]. In one large case series of patients with locally advanced oropharyngeal cancers (T2-4a, N0-2c), treatment with TORS and selective neck dissections resulted in excellent outcomes, notably with a 98% 1-year disease specific survival. Regarding the need for further multimodality therapy, only 39% required radiation and 39% received chemoradiation. Based on these results, the use of TORS accompanied by selective neck dissection may be a method to de-intensify therapy, sparing patients from the toxic effects of adjuvant chemotherapy, and in some select cases, adjuvant radiation as well[26]. Further matched retrospective patient studies, directly comparing TORS to chemoradiation, have demonstrated that patients treated with TORS have less acute toxicities and a higher rate of recovery to baseline swallowing function at 12 mo[27]. Although these studies support the use of transoral surgery in select patient populations for both early and locally advanced, low volume oropharyngeal cancers, further multi-center, randomized studies comparing transoral surgery-based approaches to definitive chemoradiotherapy are needed in order to establish the role of primary surgery in standard of care practice.

Chemoradiotherapy

The management of locoregionally advanced oropharyngeal cancer (stage III-IVB) is complex and emphasizes the need for a multidisciplinary approach as treatment for each patient is individualized based on the clinical setting. Currently, the treatment of locally advanced disease focuses around definitive chemoradiotherapy.

Organ preservation with chemoradiation has been studied exhaustively over the last 20 years. The relative benefit of concomitant chemotherapy and radiation has been established through numerous trials; however, the MACH-NC meta-analysis, which combined 93 randomized trials and more than 17000 patients, offers the most comprehensive perspective to date. In this study, concomitant chemotherapy and radiation was found to offer a significant improvement in 5-year overall survival compared to radiation therapy alone (33.7% vs 27.2%, absolute difference of 6.5% ± 1%). In an exploratory multivariate analysis, the observed effect of chemotherapy on improved survival decreased as a function of age; in the group of patients 70 and older, no improvement in survival was observed[28]. A similar analysis, presented at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, also noted lower survival rates in patients 70 years or older collectively from three previously published Radiation Thoracic Oncology Group (RTOG) studies[29]. A subsequent analysis, based on tumor site, also noted improvement of the 5-year overall survival rate in patients with oropharyngeal cancers, whereby the absolute benefit in 5-year overall survival was 8.1%[30].

A number of chemotherapeutic agents have been utilized as radiation sensitizers during concomitant therapy. However, the most commonly used regimens include high-dose cisplatin (100 mg/m2 every 21 d for two or three doses), weekly cisplatin (30-40 mg/m2), weekly carboplatin (AUC = 2) plus paclitaxel (45 mg/m2), and weekly cetuximab. Landmark studies defining non-surgical approaches established high-dose bolus cisplatin as the original, standard concomitant agent[31-33]. Given the proven efficacy of bolus cisplatin, several phase II studies and retrospective case series have sought to establish if weekly cisplatin is an effective and well-tolerated alternative[34,35]. Sharma et al[34] demonstrated that the addition of weekly cisplatin (40 mg/m2) to radiotherapy improved overall survival when compared to radiation alone, though 40% of patients experienced Grade 3 or 4 toxicities in the concomitant arm as compared to 20% treated with radiation alone. Similarly, 29% of patients receiving cisplatin required treatment interruptions, compared to 9% in the radiation alone arm[34]. One meta-analysis found that increased cumulative cisplatin dose, regardless of schedule (bolus vs weekly), was associated with improvement in survival[36]. To date, there still are still no prospective, randomized published trials comparing weekly cisplatin and radiation with bolus cisplatin and radiation. Several retrospective reviews presented as abstracts suggest that survival may not be compromised with weekly platinum vs high-dose platinum-radiation regimens. Furthermore, patients with low risk disease (i.e., p16+, low tumor volume, < 10 pack smoking histories) will inherently enjoy longer survival times regardless of the chemoradiotherapy regimen administered. Patients with poor prognosis tumors (T4, N2c, N3 tumors, > 10 pack year smoking histories), on the other hand, may benefit from high-dose cisplatin combined with radiation[37].

Given the persistent toxicities with weekly cisplatin and issues with renal failure, carboplatin has been explored alone or in combination with 5-fluorouracil or paclitaxel for use with radiation therapy[38,39]. In a pilot study of 60 patients, the combination of carboplatin and paclitaxel given concomitantly with radiation was well tolerated. Eighty-two percent of patients achieved a complete response and the 2 year overall survival rate was 62%. Fifty nine of the patients completed treatment, with the most common grade 3 toxicities being mucositis, dysphagia, leukopenia, and skin desquamation[38]. In another multicenter phase III study, weekly carboplatin and 5-flurouracil given with radia–tion was compared to radiation alone in patients with locally advanced oropharyngeal carcinomas. Although this study demonstrated increased rates of grade 3 or 4 toxicities in patients receiving chemoradiation vs radiation alone (71% vs 29%), the three year overall survival rates favoring the chemoradiotherapy arm were impressive (51% vs 31%)[39].

Randomized, prospective studies comparing weekly platinum regimens to high-dose cisplatin with radiation have yet to be conducted. Investigators at the University of Michigan compared their institutional studies, utilizing weekly carboplatin and paclitaxel with intense modulated radiation therapy (IMRT) and bolus cisplatin with IMRT, in stage III/IV oropharyngeal cancer patients via a matched, paired, retrospective analysis. This evaluation demonstrated that patients treated with high dose cisplatin had higher numbers of grade 3 or 4 toxicities (54% vs 40%). After accounting for HPV status, there was no significant difference noted in overall or progression-free survival between the two treatment arms[40].

The anti-EGFR monoclonal IgG1 antibody Cetuximab has been established as an effective agent for use with radiation therapy. In a large Phase III trial, the median overall survival and 5-year overall survivals were both significantly improved with the addition of Cetuximab to radiation therapy over radiotherapy alone (49 mo vs 29.3 mo and 45.6% vs 36.4%, respectively). Of note, on exploratory multivariate analysis it was noted that the greatest benefit was seen in patients with oropharyngeal cancers but a benefit was not seen in those > 65 years old. In addition, it was noted that the development of a prominent acneiform rash (grade 2 or greater) was associated with a significantly improved overall survival[41,42]. Analysis of the effect of cetuximab on overall survival based on pre-treatment characteristics demonstrated that the addition was most beneficial in non-elderly men with oropharyngeal tumors, grade 1-3 tumors, node positive (N1-3), with good performance status[42]. A biomarker analysis evaluating outcomes related to HPV status was recently conducted on this study, and the results were presented at the 2014 ASCO annual meeting in Chicago. This investigation demonstrated improvement in OS with the addition of cetuximab to radiation in both HPV+ vs HPV- tumors, though a greater degree of improvement was seen in those tumors which were p16+. This study was exploratory in nature and not powered to make definitive conclusions; however, it does confirm that HPV is a prognostic biomarker, not yet predictive[43].

Given the improvement in clinical outcomes seen with cetuximab, several large trials have sought to answer whether the addition of anti-EGFR monoclonal antibodies (cetuximab or panitumumab) to conventional platinum based chemoradiation results in clinical improvement. Each of these studies has failed to demonstrate improvement in clinical outcomes with the addition of EGFR inhibition[44,45]. One of these studies did demonstrate that although EGFR expression did not distinguish outcome in patients treated with cetuximab, patients with p16 positive oropharyngeal carcinomas had a better 3 year progression free survival (72.8% vs 49.2%) and overall survival (85% vs 60.1%)[44]. Unplanned post-hoc analysis of RTOG 0522 (reviewing the role of cisplatin based chemoradiotherapy plus cetuximab) demonstrated that patients with high baseline metabolic tumor volumes on PET/CT had an inferior response to chemoradiotherapy in terms of progression-free survival and locoregional control. Interestingly, this remained an independent prognostic factor on multivariate analysis even after factoring for T stage[46].

Based on the evidence of efficacy with the use of Cetuximab as a radio-sensitizing agent, the question has arisen regarding the comparative efficacy vs a platinum based regimen. A published single center retrospective study was recently published describing the outcomes of patients with locally advanced head and neck squamous cell carcinoma treated with concurrent chemoradiation stratified by chemotherapeutic agent. It was noted that patients treated with platinum based chemotherapy had significantly superior relapse free and overall survival compared to those treated with cetuximab monotherapy or in combination with chemotherapy[47]. One meta-analysis including 15 trials and 1808 patients which was presented in a preliminary form demonstrates that studies to date support a greater improvement in both locoregional recurrence and overall survival with the use of cisplatin. However, this study had significant heterogeneity and did not account for p16 status[48]. Other studies comparing panitumumab and radiation with cisplatin and radiation have also failed to demonstrate the improvements of this fully human monoclonal antibody against EGFR to the standard of care[49,50]. Ongoing studies are still seeking to answer this question in select populations, including RTOG 1016.

The role of induction chemotherapy in oropharyngeal cancer has been debated extensively and there continues to be some controversy regarding its role. In general, the use of induction chemotherapy has been intended to decrease the rate of distant metastases, to cause rapid cytoreduction, to offer high doses of chemotherapy to tumor prior to disruption of vasculature by radiation, and to decrease tissue volume requiring exposure to radiation[51]. Three large, randomized phase III studies have been performed to date evaluating the role of induction vs concurrent chemoradiation, all of which demonstrated no difference in survival or time to treatment failure[52-54]. In the recently published DeCIDE trial, evaluating induction chemotherapy primarily in oropharyngeal cancer, enrollment was difficult and the study was closed after enrollment of 285 of the planned 400 patients. Although overall survival was no different between the arms at three years, one should note that (albeit not statistically significant) the difference in the rate of distant failure was 10% in the induction chemotherapy group vs 19% in the concurrent chemoradiation group. HPV status was available for only 49 patients and on subgroup analysis is was noted that there was no statistically significant difference in overall survival between HPV(+) and HPV(-) patients[54]. Early results of a phase III trial from Italy, comparing induction chemotherapy followed by definitive chemoradiotherapy vs concomitant chemoradiation with cetuximab vs cisplatin and 5-flourouracil (5-FU) via 2 × 2 factorial design, were presented at the 2014 ASCO annual meeting in Chicago. This trial had a primary endpoint of 3 year overall survival between the induction vs no induction groups. Preliminary results demonstrated a statistically significant improvement with induction chemotherapy in both median progression-free (29.7 mo vs 18.5 mo, P = 0.12) and overall survival (57.6 mo vs 45.7 mo, P = 0.03). On unplanned subgroup analysis, these improvements were not seen in patients with oropharyngeal cancers. Additionally, when compared with similar previously published trials as historical controls[41,44,54], both progression-free survival and overall survival appear to be lower across the board, for which the etiology is unclear. Reporting of HPV status amongst the treatment groups is pending and will be important in fully interpreting the results of this study[55].

Investigators at the University of Michigan have studied the use of induction chemotherapy as a means of chemoselection, whereby patients with oropharyngeal cancers who had a response to one cycle of induction chemotherapy were treated with definitive chemoradiation, whereas those patients without evidence of response proceeded to salvage surgery. In this study, induction therapy failed to successfully select patients for surgical salvage, but a subgroup analysis demonstrated that higher HPV titers were associated with a significant reduction in tumor burden following the administration of a single cycle of chemotherapy, demonstrating the robust response of p16 positive oropharyngeal tumors to cytotoxic agents[56]. In the companion paper published with this article, correlative analysis noted that EGFR expression was inversely associated with response to chemoselection as well as patient outcomes including disease specific survival and overall survival. Moreover, when biomarkers were combined low EGFR and high p16 expression were associated with a good response to chemoselection however the combination of high EGFR expression, low p53 expression, and high Bcl-xL expression was associate with a poor response to chemoselection and overall survival[57].

DE-INTENSIFICATION OF THERAPY

Although chemoradiotherapy has improved survival outcomes in patients with loco-regionally advanced oropharyngeal cancers, this has come at the expense of both acute and late treatment related toxicities. These toxicities substantially impair patients’ quality of life, potentially for the remainder of their lives, and include long-term swallowing dysfunction as a result of radiation. HPV+ oropharyngeal cancer is now being increasingly recognized as a biologically distinct malignancy with a distinct disease course and response to therapy. Moreover, HPV+ tumors have higher response rates to multimodality therapies, lower rates of disease relapse, and improved overall survivals compared with HPV- tumors. In an attempt to mitigate acute and late toxicities, an area of research looking to define patients with low risk oropharyngeal cancer who may be candidates for de-intensification of therapy is actively underway. Proposed methods of de-intensification include decreasing doses of radiation (so called de-escalation) or switching from cisplatin based radio-sensitization to targeted therapy with cetuximab.

To date, few published trials provide insight into this matter, and hopefully with the maturity of several ongoing prospective trials, there will be a body of literature as to guide the field. One retrospective study sought to define the pattern of recurrence in HPV + low risk patients (< 10 pack-year smoking and T1-T3 disease) based on treatment with radiation alone vs concomitant chemoradiation. It was shown that low risk patients, those with N0-N2a nodal involvement, had no difference in disease control rates with the introduction of chemo-sensitization as compared to those receiving only radiotherapy[58]. Given the retrospective nature of this study and the fact that the majority of patients not receiving chemotherapy were those with advanced age or restricting medical co-morbidities, it is difficult to draw definitive conclusions. However, this research certainly supports the consideration for de-escalation of therapy in a subset of low risk patients. Currently, RTOG 1333 is assessing such an approach with the primary endpoint of 2 year progression free survival. In this study low, risk patients (HPV+ with a ≤ 10 pack-year smoking history) with oropharyngeal cancer are being randomized to either radiation (60 Gy, 2.0 Gy/fraction in 6 wk) with concurrent weekly cisplatin (40 mg/m2× 6 doses) or radiation alone (60 Gy of radiation, 2.0 Gy/fraction over 5 wk)[59]. As a chief aim of de-escalation is improving treatment related toxicities, one of the main secondary endpoints being followed in this trial includes quality life, most notably swallowing function. ECOG 3311 is an ongoing risk stratified randomized phase II study evaluating an approach of TORS followed by a risk adapted approach in patients with HPV(+) stage III/IV oropharyngeal carcinoma. In this study, based on post-operative findings low risk patients will be observed, intermediate risk patients will be treated with radiation alone, and high risk patients will be treated with chemoradiation.

ECOG 1308 is a prospective, phase II study that also examined the role of de-escalation. In this trial, patients were treated with 3 cycles of induction chemotherapy, and if they were found to have a complete response, they were treated with weekly cetuximab and low dose intensity IMRT (54 Gy/27 fractions). If, on the other hand, patients had less than complete response, they received weekly cetuximab with full dose IMRT (68.3 Gy/33 fractions). Preliminary analyses demonstrated that patients with complete responses, treated with low dose IMRT, had an improved 2 years progression free and overall survival compared to those patients in the standard-dose IMRT arm. Additional insights from the analysis of the patient cohort receiving low dose radiotherapy demonstrate that progression-free survival and overall survival were better in patients with a ≤ 10 pack-year smoking histories and low volume (< T4, T1-N2b) disease. This favorable risk cohort had a significantly improved 2 year progression-free survival compared to other enrolled patients (96% vs 64%)[60]. Although this data yields valuable insights into the potential for reducing intensity of treatment for a select population of oropharyngeal cancer patients, a larger, multi-center phase III is needed study to verify the results of this de-escalation trial, comparing this concept to standard cisplatin and radiotherapy.

Finally, RTOG 1016 is an ongoing non-inferiority phase III trial that is seeking to identify the role of substituting Cetuximab for high dose bolus Cisplatin (100 mg/m2 q 21 d × 2 doses) in combination with accelerated IMRT. This protocol exclusively enrolled 1000 patients with p16+ locoregionally advanced oropharyngeal cancer (clinical stage T1-2 N2a-N3 or T3-4 any N) with any smoking status. In addition to defining whether the substitution of cisplatin is non-inferior to standard therapy, this study will assess the effect of tobacco exposure and molecular profiles on patient outcomes. This study is now closed to accrual and the results are eagerly awaited.

LOCALLY RECURRENT AND METASTATIC DISEASE

Despite increased understanding of oropharyngeal cancer and advances in treatment of both early stage and loco-regionally advanced disease, a number of patients still develop locally recurrent and metastatic disease. Evidence now supports that HPV(+) oropharyngeal cancer patients who develop progression have a better median overall survival than those cancers which are HPV(-) (2.6 years vs 0.8 years). Fakhry et al[61] noted a worse survival upon progression in patients with distant metastases or those who initially presented with T4 lesions. Patterns of recurrence are also related to HPV status in oropharyngeal cancers. HPV(+) status markedly reduces the risk for loco-regional recurrence (HR = 0.09, P = 0.03)[62] and in one study was associated with a longer time to distant failure (16.4 mo vs 7.2 mo)[63].

The goal of therapy in patients with locally recurrent or metastatic oropharyngeal cancer who are treated with chemotherapy is palliative. As prognosis is poor and effective treatment options are limited, enrollment onto clinical trials offers the best possible care, especially for those who have failed a front-line platinum containing regimens. If trial involvement is not possible, numerous treatment modalities with standard agents may be considered.

Surgical salvage should be entertained in select situations as a treatment for locally recurrent or metastatic oropharyngeal cancer. Recent studies have demonstrated that surgery is an effective treatment option, often improving survival. One large study of 181 patients demonstrated that even when factoring in T/N stage, progression type (distant vs locoregional), smoking history, and p16 status to a multivariate analysis, salvage surgery still remained a significant predictor of overall survival (HR = 0.56, P = 0.02)[61]. Another similar retrospective study attempted to gain similar insight; however, this evaluation also considered whether salvage treatment with nonsurgical methods or with surgical methods offered superior overall survival. The investigators found that surgical salvage offered an improvement in overall survival compared to those treated with salvage radiation or chemotherapy. Similar to previous studies, this finding remained significant even on multivariate analysis when p16 status, T/N stage, smoking history, site of disease recurrence, and number of sites with disease recurrence were factored in[64].

If surgical salvage is not an option, there are numerous classes of cytotoxic chemotherapy drugs including platinum agents, taxanes, methotrexate, 5-FU as well as the anti-EGFR targeted therapy, cetuximab, which have proven efficacy in metastatic head and neck cancer. Response rates to chemotherapy range between 10%-30% with single agent regimens and 20%-40% for multi-drug regimens[65-67]. It is important to appreciate that although conventional cytotoxic agents may be combined as doublet therapies (traditionally platinum based), these combinations increase response rates but not overall survival, and they have notable increases in toxicities[66]. There have been no studies showing superiority of one cytotoxic regimen over the other, median overall survivals ranging from 6.6-8.7 mo[65-68]. Incorporation of cetuximab into a 5-FU and platinum containing regimens is associated with an increased objective response rate (36% vs 20%), progression free survival (5.6 mo vs 3.3 mo), and overall survival (10.1 mo vs 7.4 mo) relative to platinum-5 FU doublet therapy in patients with metastatic head and neck cancer[69]. Although underpowered to draw conclusions, a post-hoc analysis of p16+ oropharyngeal cancers seemed to have a greater degree of benefit with the incorporation of cetuximab compared to those that were p16-[70].

FUTURE DIRECTIONS

There are currently numerous ongoing trials involving the treatment of oropharyngeal cancer. Among the current research avenues are novel predictive factors for recurrence and the development of immunotherapeutics. Although the prognosis of HPV+ advanced oropharyngeal cancer is impressive with 3 year survival rates of 62%-83%[71,72], there is an increasing rate of distant treatment failure, not accounting for 45% of long term deaths in the population[15,73]. Numerous prognostic factors have been explored as methods to better tailor therapy for those at increased risk, including micro-RNA, advanced T and N classification, and smoking status[58,74,75]. One novel finding, identified as prognostic as well as predictive, is the presence of matted nodes on pre-treatment imaging (CT or PET/CT). Matted nodes are defined as the presence of three lymph nodes abutting one another with loss of the intervening fat plane which is thought to represent radiologic evidence of extracapsular spread. Matted nodes have been identified in 20% of patients presenting with advanced oropharyngeal cancer. In one analysis, patients presenting with matted nodes had a three year disease specific survival of 58% vs 97% in those without. This bore out as a predictive marker on a further analysis and on a multivariate analysis whereby the presence of matted nodes remained an independent predictor of poor prognosis even when controlling for age, tumor classification, HPV status, and smoking status[76,77].

There has also been interest in searching for novel biomarkers as to guide patients at risk for reoccurrence. Retrospective analysis of patients with locally advanced HPV+ oropharyngeal cancer has demonstrated that patients who recurred were noted to have a significantly lower rate of E7 antibody clearance[78]. Prospective analyses are needed to determine the utility of E6 and E7 antibody clearance perhaps in combination with plasma HPV DNA levels. Two abstracts presented at the 2015 ASCO annual meeting may also aid in identifying patients at high risk for recurrence. In one study, loss of function tumor suppressor gene mutations appears to decrease the efficacy of treatments for locally advanced squamous cell carcinomas of the head and neck. Activating driver gene mutations, on the other hand, may define poor risk patients, in particular those with HPV(+) oropharyngeal carcinomas[79]. A second study evaluated the implication of persistent HPV-16 DNA detection in oral rinses in patients with p16 positive oropharyngeal carcinomas, treated for locally advanced disease. Data from this evaluation suggests that persistent oral HPV DNA in post-treatment rinses is strongly associated with poorer outcomes[80]. These findings may help to tailor intensification of therapy in high risk populations as to improve patient outcomes.

Immunotherapy [namely Programmed Death-1 (PD-1) inhibition] is currently one of the most exciting and rapidly changing areas of oncology with impressive response rates and improvements in overall survival seen in melanoma and lung cancer[81-83]. PD-1 targeting in head and neck cancer has been of interest as these malignancies [especially HPV(+) tumors] are thought to be quite antigenic[84]. In addition, pathologic samples in both HPV(+) and negative tumors have demonstrated a high frequency of PD-1 and PD-L1 expression, suggestive of a potential role for checkpoint inhibitors[85,86]. Preliminary results of the KEYNOTE-012 study, a phase 1b multisite study evaluating the activity of Pembrolizumab in patients with recurrent or metastatic HNSCC regardless of PD-L1 or HPV status, were reported at the ASCO Annual Meeting in 2015. An overall response rate of 24.8% and stable disease rate of 24.8% was reported with activity observed in both HPV(+) and HPV(-) patients. Although follow up was limited as only preliminary results were available, it was intriguing that the median duration of response was not reached[87]. An accompanying study analyzed this population as to try and identify predictors of response as both HPV and PD-L1 status have been non-discriminatory. It was demonstrated that an inflamed-phenotype gene expression, chiefly interferon gamma, was able to predict 6 mo progression free survival with a 95% negative predictive value and 40% positive predictive value[88]. Similar findings have been reported in melanoma where inflamed-phenotype gene expression signatures appear to predict benefit from pembrolizumab[89]. There are multiple ongoing phase II/III clinical trials investigating the role for Pembolizumab and Nivolumab in the setting of metastatic disease for head and neck cancer, which include the evaluation of markers to potentially identify responders[87]. Results of these studies will offer new insights and may drastically alter the treatment of metastatic oropharyngeal cancer.

CONCLUSION

The management of oropharyngeal cancer is complex and depends on a multidisciplinary team including otolaryngologists, medical oncologists, and radiation oncologists. Although great strides have been made in the last 20 years in approaches to organ preservation and risk stratification, improvements are needed in delineating the role of treatment de-intensification and development of novel therapeutics for the treatment of metastatic disease. We eagerly await final publications of the data from the recent ASCO annual meetings to further validate the use of several novel agents and treatment approaches.

Footnotes

P- Reviewer: Deganello A, Rapidis AD S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK

References
1.  Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.  [PubMed]  [DOI]  [Cited in This Article: ]
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.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-4301.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamines. IARC Working Group. Lyon, 23-30 October 1984. IARC Monogr Eval Carcinog Risk Chem Hum. 1985;37:1-268.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Wyss A, Hashibe M, Chuang SC, Lee YC, Zhang ZF, Yu GP, Winn DM, Wei Q, Talamini R, Szeszenia-Dabrowska N. Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Am J Epidemiol. 2013;178:679-690.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Andre K, Schraub S, Mercier M, Bontemps P. Role of alcohol and tobacco in the aetiology of head and neck cancer: a case-control study in the Doubs region of France. Eur J Cancer B Oral Oncol. 1995;31B:301-309.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S, Bernstein L, Schoenberg JB, Stemhagen A, Fraumeni JF. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48:3282-3287.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Gillison ML, Zhang Q, Jordan R, Xiao W, Westra WH, Trotti A, Spencer S, Harris J, Chung CH, Ang KK. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol. 2012;30:2102-2111.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Fernandez L. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99:777-789.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  De Stefani E, Boffetta P, Oreggia F, Fierro L, Mendilaharsu M. Hard liquor drinking is associated with higher risk of cancer of the oral cavity and pharynx than wine drinking. A case-control study in Uruguay. Oral Oncol. 1998;34:99-104.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Kato I, Nomura AM. Alcohol in the aetiology of upper aerodigestive tract cancer. Eur J Cancer B Oral Oncol. 1994;30B:75-81.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000;92:690-698.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576-582.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  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;100:261-269.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Huang SH, Perez-Ordonez B, Liu FF, Waldron J, Ringash J, Irish J, Cummings B, Siu LL, Kim J, Weinreb I. Atypical clinical behavior of p16-confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 2012;82:276-283.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100:407-420.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Näsman A, Attner P, Hammarstedt L, Du J, Eriksson M, Giraud G, Ahrlund-Richter S, Marklund L, Romanitan M, Lindquist D. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer. 2009;125:362-366.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27:1992-1998.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, Ringash J, Bayley A, Kim J, Hope A. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol. 2015;33:836-845.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Grant DG, Hinni ML, Salassa JR, Perry WC, Hayden RE, Casler JD. Oropharyngeal cancer: a case for single modality treatment with transoral laser microsurgery. Arch Otolaryngol Head Neck Surg. 2009;135:1225-1230.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Hockstein NG, Nolan JP, O’Malley BW, Woo YJ. Robot-assisted pharyngeal and laryngeal microsurgery: results of robotic cadaver dissections. Laryngoscope. 2005;115:1003-1008.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Genden EM, Desai S, Sung CK. Transoral robotic surgery for the management of head and neck cancer: a preliminary experience. Head Neck. 2009;31:283-289.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Dean NR, Rosenthal EL, Carroll WR, Kostrzewa JP, Jones VL, Desmond RA, Clemons L, Magnuson JS. Robotic-assisted surgery for primary or recurrent oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136:380-384.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Weinstein GS, O’Malley BW, Cohen MA, Quon H. Transoral robotic surgery for advanced oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136:1079-1085.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Weinstein GS, Quon H, O’Malley BW, Kim GG, Cohen MA. Selective neck dissection and deintensified postoperative radiation and chemotherapy for oropharyngeal cancer: a subset analysis of the University of Pennsylvania transoral robotic surgery trial. Laryngoscope. 2010;120:1749-1755.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Genden EM, Park R, Smith C, Kotz T. The role of reconstruction for transoral robotic pharyngectomy and concomitant neck dissection. Arch Otolaryngol Head Neck Surg. 2011;137:151-156.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Pignon JP, le Maître A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92:4-14.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Kish JA, Zhang Q, Langer CJ, Nguyen-Tan F, Rosenthal DI, Weber RS, List MA, Wong SJ, Garden AS, Cooper JS. The effect of age on outcome in prospective, phase iii nrg oncology/rtog trials of radiotherapy (xrt) /- chemotherapy in locally advanced (la) head and neck cancer (hnc). J Clin Oncol. 2015;33 suppl:abstr 2003 Available from: http://meetinglibrary.asco.org/content/146059-156.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, Pignon JP. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011;100:33-40.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Marcial VA, Pajak TF, Mohiuddin M, Cooper JS, al Sarraf M, Mowry PA, Curran W, Crissman J, Rodríguez M, Vélez-García E. Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group study 81-17. Cancer. 1990;66:1861-1868.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Adelstein DJ, Li Y, Adams GL, Wagner H, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21:92-98.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31:845-852.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Sharma A, Mohanti BK, Thakar A, Bahadur S, Bhasker S. Concomitant chemoradiation versus radical radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: a phase II randomized trial. Ann Oncol. 2010;21:2272-2277.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Newlin HE, Amdur RJ, Riggs CE, Morris CG, Kirwan JM, Mendenhall WM. Concomitant weekly cisplatin and altered fractionation radiotherapy in locally advanced head and neck cancer. Cancer. 2010;116:4533-4540.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Strojan P, Vermorken JB, Beitler JJ, Saba NF, Haigentz M, Bossi P, Worden FP, Langendijk JA, Eisbruch A, Mendenhall WM. Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: A systematic review. Head Neck. 2015;.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Wong SJ, Li L, Hess LM, Chen AY, Curran WJ, Harari PM, Kimple RJ, Murphy BA, Opincar LLM, Garden AS. Utilization and outcomes of low dose versus high dose cisplatin in head and neck cancer patients receiving concurrent radiation. J Clin Oncol. 2015;33 suppl:abstr 6019 Available from: http://meetinglibrary.asco.org/content/144716-156.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Suntharalingam M, Haas ML, Conley BA, Egorin MJ, Levy S, Sivasailam S, Herman JM, Jacobs MC, Gray WC, Ord RA. The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys. 2000;47:49-56.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Oudinot P, Bertrand P. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91:2081-2086.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Dobrosotskaya IY, Bellile E, Spector ME, Kumar B, Feng F, Eisbruch A, Wolf GT, Prince ME, Moyer JS, Teknos T. Weekly chemotherapy with radiation versus high-dose cisplatin with radiation as organ preservation for patients with HPV-positive and HPV-negative locally advanced squamous cell carcinoma of the oropharynx. Head Neck. 2014;36:617-623.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567-578.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21-28.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA. Impact of p16 status on the results of the phase iii cetuximab (cet)/radiotherapy (rt). J Clin Oncol. 2014;32 suppl:abstr 6001 Available from: http://www.csco.org.cn/temp/2014BOAzy.pdf.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK. 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;32:2940-2950.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Mesía R, Henke M, Fortin A, Minn H, Yunes Ancona AC, Cmelak A, Markowitz AB, Hotte SJ, Singh S, Chan AT. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015;16:208-220.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Schwartz DL, Harris J, Yao M, Rosenthal DI, Opanowski A, Levering A, Ang KK, Trotti AM, Garden AS, Jones CU. Metabolic tumor volume as a prognostic imaging-based biomarker for head-and-neck cancer: pilot results from Radiation Therapy Oncology Group protocol 0522. Int J Radiat Oncol Biol Phys. 2015;91:721-729.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Tang C, Chan C, Jiang W, Murphy JD, von Eyben R, Colevas AD, Pinto H, Lee-Enriquez N, Kong C, Le QT. Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer. Head Neck. 2015;37:386-392.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Barni S, Coinu A, Borgonovo K, Cabiddu M, Cremonesi M, Petrelli F. Cisplatin versus cetuximab plus concomitant radiotherapy in locally advanced head and neck cancer: A meta-analysis of published trials. J Clin Oncol. 2014;32 suppl:abstr 6014 Available from: http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/6014.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Giralt J, Trigo J, Nuyts S, Ozsahin M, Skladowski K, Hatoum G, Daisne JF, Yunes Ancona AC, Cmelak A, Mesía R. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015;16:221-232.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Siu LL, Waldron JN, Chen BE, Winquist E, Wright JR, Nabid A, Hay JH, Ringash G, Liu J, Johnson A. Phase iii randomized trial of standard fractionation radiotherapy (sfx) with concurrent cisplatin (cis) versus accelerated fractionation radiotherapy (afx) with panitumumab (pmab) in patients (pts) with locoregionally advanced squamous cell carcinoma of the head and neck (la-scchn): Ncic clinical trials group hn.6 trial. J Clin Oncol. 2015;33 suppl:abstr 6000 Available from: http://meetinglibrary.asco.org/content/149178-156.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Busch CJ, Tribius S, Schafhausen P, Knecht R. The current role of systemic chemotherapy in the primary treatment of head and neck cancer. Cancer Treat Rev. 2015;41:217-221.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, Irigoyen A, Sastre J, Martínez-Trufero J, Brandariz Castelo JA, Verger E. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol. 2014;25:216-225.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Haddad R, O’Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, Clark J, Sarlis N, Lorch J, Beitler JJ. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013;14:257-264.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, Brockstein BE, Agulnik MB, Mittal BB, Yunus F. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. 2014;32:2735-2743.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Ghi MG, Paccagnella A, Ferrari D, Fao P, Rocca MC, Verri E, Morelli F, Azzarello G, D’Ambrosio C, Cruciani G, Guaraldi M, Massa E, Rossetto C, Bonetti A, Siena S, Minotti V, Koussis H, Pieri G, Baggio V, Floriani I, and for the GSTTC Italian Study Group. Concomitant chemoradiation (crt) or cetuximab/rt (cet/rt) versus induction docetaxel/ cisplatin/5-fluorouracil (tpf) followed by crt or cet/rt in patients with locally advanced squamous cell carcinoma of head and neck (lascchn). A randomized phase iii factorial study (nct01086826). J Clin Oncol. 2014;32 suppl:abstr 6004 Available from: http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/6004.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Worden FP, Kumar B, Lee JS, Wolf GT, Cordell KG, Taylor JM, Urba SG, Eisbruch A, Teknos TN, Chepeha DB. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol. 2008;26:3138-3146.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Kumar B, Cordell KG, Lee JS, Worden FP, Prince ME, Tran HH, Wolf GT, Urba SG, Chepeha DB, Teknos TN. 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.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  O’Sullivan B, Huang SH, Siu LL, Waldron J, Zhao H, Perez-Ordonez B, Weinreb I, Kim J, Ringash J, Bayley A. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol. 2013;31:543-550.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Radiation Therapy Oncology Group. Radiation Therapy in Treating Patients With Stage II or Stage III Oropharyngeal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT00006360 NLM Identifier: NCT00006360.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Cmelak A, Li S, Marur S, Zhao W, Westra WH, Chung CH, Gillison ML, Gilbert J, Bauman JE, Wagner LI. E1308: Reduced-dose imrt in human papilloma virus (hpv)-associated resectable oropharyngeal squamous carcinomas (opscc) after clinical complete response (ccr) to induction chemotherapy (ic). J Clin Oncol. 2014;32 suppl:abstr LBA6006 Available from: http://meeting.ascopubs.org/cgi/content/short/32/15_suppl/LBA6006?rss=1.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Fakhry C, Zhang Q, Nguyen-Tan PF, Rosenthal D, El-Naggar A, Garden AS, Soulieres D, Trotti A, Avizonis V, Ridge JA. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol. 2014;32:3365-3373.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Lohaus F, Linge A, Tinhofer I, Budach V, Gkika E, Stuschke M, Balermpas P, Rödel C, Avlar M, Grosu 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;113:317-323.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Trosman SJ, Koyfman SA, Ward MC, Al-Khudari S, Nwizu T, Greskovich JF, Lamarre ED, Scharpf J, Khan MJ, Lorenz RR. Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy. JAMA Otolaryngol Head Neck Surg. 2015;141:457-462.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Guo T, Qualliotine JR, Ha PK, Califano JA, Kim Y, Saunders JR, Blanco RG, D’Souza G, Zhang Z, Chung CH. Surgical salvage improves overall survival for patients with HPV-positive and HPV-negative recurrent locoregional and distant metastatic oropharyngeal cancer. Cancer. 2015;121:1977-1984.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, Tueni EA, Verweij J, Wildiers J, Clerico M. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol. 1994;5:521-526.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992;10:1245-1251.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Jacobs C, Lyman G, Velez-García E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257-263.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2005;23:3562-3567.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116-1127.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Vermorken JB, Psyrri A, Mesía R, Peyrade F, Beier F, de Blas B, Celik I, Licitra L. Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial. Ann Oncol. 2014;25:801-807.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Vlacich G, Diaz R, Thorpe SW, Murphy BA, Kirby W, Sinard RJ, Shakhtour B, Shyr Y, Murphy P, Netterville JL. Intensity-modulated radiation therapy with concurrent carboplatin and paclitaxel for locally advanced head and neck cancer: toxicities and efficacy. Oncologist. 2012;17:673-681.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, Tan M, Fasciano J, Sammartino DE, Posner MR. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011;12:153-159.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Daly ME, Le QT, Maxim PG, Loo BW, Kaplan MJ, Fischbein NJ, Pinto H, Chang DT. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys. 2010;76:1339-1346.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Hui AB, Lin A, Xu W, Waldron L, Perez-Ordonez B, Weinreb I, Shi W, Bruce J, Huang SH, O’Sullivan B. Potentially prognostic miRNAs in HPV-associated oropharyngeal carcinoma. Clin Cancer Res. 2013;19:2154-2162.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  McBride SM, Ali NN, Margalit DN, Chan AW. Active tobacco smoking and distant metastasis in patients with oropharyngeal cancer. Int J Radiat Oncol Biol Phys. 2012;84:183-188.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Spector ME, Chinn SB, Bellile E, Gallagher KK, Ibrahim M, Vainshtein J, Chanowski EJ, Walline HM, Moyer JS, Prince ME. Matted nodes as a predictor of distant metastasis in advanced-stage III/IV oropharyngeal squamous cell carcinoma. Head Neck. 2016;38:184-190.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Vainshtein JM, Spector ME, Ibrahim M, Bradford CR, Wolf GT, Stenmark MH, Worden FP, McHugh JB, Prince ME, Carey T. Matted nodes: High distant-metastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer. Head Neck. 2015;.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Sacco AG, Bellile EL, Rozek LS, Chepeha DB, Spector ME, Jones T, Sun K, Bradford CR, Wolf GT, Prince ME. A retrospective study to determine the utility of measuring e6 and e7 antibody (ab) levels in sera as a biomarker of recurrence in patients (pts) with locally advanced (la), human papillomavirus-positive (hpv) oropharyngeal squamous cell carcinoma (opscc). J Clin Oncol. 2014;32 suppl:abstr 6096 Available from: http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/6096.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Tinhofer I, Budach V, Endris V, Stenzinger A, Weichert W. Genomic profiling using targeted ultra-deep next-generation sequencing for prediction of treatment outcome after concurrent chemoradiation: Results from the german aro-0401 trial. J Clin Oncol. 2014;32 suppl:abstr 6002.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Rettig EM, Wentz A, Posner MR, Gross ND, Haddad RI, Gillison ML, Quon H, Sikora AG, Stott W, Lorch JH. Prognostic implication of persistent hpv16 DNA detection in oral rinses for hpv-positive oropharyngeal carcinoma. J Clin Oncol. 2015;33 suppl:abstr 6005.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-2028.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521-2532.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257-265.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Gildener-Leapman N, Ferris RL, Bauman JE. Promising systemic immunotherapies in head and neck squamous cell carcinoma. Oral Oncol. 2013;49:1089-1096.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA. Evidence for a role of the PD-1: PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73:1733-1741.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Malm IJ, Bruno TC, Fu J, Zeng Q, Taube JM, Westra W, Pardoll D, Drake CG, Kim YJ. Expression profile and in vitro blockade of programmed death-1 in human papillomavirus-negative head and neck squamous cell carcinoma. Head Neck. 2015;37:1088-1095.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Seiwert TY, Haddad RI, Gupta S, Mehra R, Tahara M, Berger R, Lee SH, Burtness B, Le DT, Heath K. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (scchn): Preliminary results from keynote-012 expansion cohort. J Clin Oncol. 2015;33 suppl:abstr LBA6008.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Seiwert TY, Burtness B, Weiss J, Eder JP, Yearley J, Murphy E, Nebozhyn M, McClanahan T, Ayers M, Lunceford JK. Inflamed-phenotype gene expression signatures to predict benefit from the anti-pd-1 antibody pembrolizumab in pd-l1 head and neck cancer patients. J Clin Oncol. 2015;33 suppl:abstr 6017.  [PubMed]  [DOI]  [Cited in This Article: ]
89.  Ribas A, Robert C, Hodi S, Wolchok JD, Joshua AM, Hwu WJ, Weber JS, Zarour HM, Kefford R, Loboda A. Association of response to programmed death receptor 1 (pd-1) blockade with pembrolizumab (mk-3475) with an interferon-inflammatory immune gene signature. J Clin Oncol. 2015;33 suppl:abstr 3001.  [PubMed]  [DOI]  [Cited in This Article: ]