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 Table of Contents  
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 61-66

De-escalation Strategies in Human Papilloma Virus-Positive Oropharyngeal Cancer

Department of Head and Neck/Plastic Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

Date of Submission24-Jun-2020
Date of Acceptance30-Jun-2020
Date of Web Publication8-Dec-2020

Correspondence Address:
Vishal Gupta
Department of Head and Neck/Plastic Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Elm and Cartlon Streets, Buffalo, NY 14263
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhnps.jhnps_29_20

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Human papilloma virus (HPV) is now attributable to most of the oropharyngeal squamous cell cancers (OPSCCs) occurring in western world. The HPV-associated OPSCC effect younger, otherwise healthy population and is typically associated with better outcome. Traditional treatment strategies, while successful, are associated with significant long-term morbidity and poorer quality of life. This has led to various trials and investigations to de-escalate the treatment in this patient population while maintaining excellent outcome. The objective of this review is to discuss various de-escalation strategies and trials.

Keywords: De-escalation, Human papilloma virus, oropharyngeal squamous cell cancer

How to cite this article:
Gupta V. De-escalation Strategies in Human Papilloma Virus-Positive Oropharyngeal Cancer. J Head Neck Physicians Surg 2020;8:61-6

How to cite this URL:
Gupta V. De-escalation Strategies in Human Papilloma Virus-Positive Oropharyngeal Cancer. J Head Neck Physicians Surg [serial online] 2020 [cited 2021 Apr 21];8:61-6. Available from: https://www.jhnps.org/text.asp?2020/8/2/61/302625

  Introduction Top

Epidemiological trends in the USA and western world demonstrate decline in cases of squamous cell cancer involving oral cavity, hypopharynx, and larynx related to decline in tobacco and alcohol abuse. During the same time period, there has been increase in the incidence of squamous cell cancer of oropharynx caused by human papilloma virus (HPV) which now accounts for 70% of all newly diagnosed head and neck cancers in the United States.[1],[2] HPV virus is sexually transmitted with increased risk associated with higher number of sexual partners.[3] Chaturvedi et al.[4],[5] reviewed data from surveillance, epidemiology, and end results program registries and reported significant increase in the incidence of HPV-associated oral cancer in the United States. The incidence increased from 16% in 1984–1989 to about 70% in 2000–2004. HPV-associated squamous cell cancer is usually seen in younger and with higher incidence of lymph node involvement at presentation.[6]

  HPV and Survival Outcome Top

HPV-associated carcinogenesis involves integration of HPV DNA in host DNA allowing production of E6 and E7 proteins. These proteins inhibit the activation of certain tumor suppressor proteins such as p53 and Rb, respectively. In contrast to HPV-negative tumors, HPV-associated tumors have p53 wild type. Furthermore, inactivation of RB protein by E7 results in overexpression of p16 which is commonly used as surrogate marker for HPV-associated cases.

EGFR expression is noted to higher in HPV-negative cancer as compared to those associated with HPV positivity. Both, EGFR and p53 status are correlated to treatment outcome and survival.

Multiple trials have shown improved prognosis in patients with HPV-positive oropharyngeal cancers.[7],[8],[9] Ang et al.[9] performed retrospective analysis of association between HPV-associated tumors and survival among patients with Stage III or IV oropharyngeal squamous cell cancer (OPSCC). They reported better 3-year rates of overall survival in HPV-associated cases (82.4%) compared to HPV-negative tumors (57.1%) [Table 1]. HPV-associated OPSCC patients had about 58% reduction in the risk of death. However, with each additional pack-year of tobacco smoking, the risk of death increased by 1% regardless of HPV status. The findings of this study concluded that HPV status was the greatest predictor of overall survival, followed by tobacco use (≤10 pack-years vs. >10 pack-years), T stage (T2/3 vs. T4), and nodal status (N0/N2a) which was based on AJCC 7th ed.ition. Recursive partition analysis was used to stratify patient into three risk groups and corresponding 3-year overall survival rates:
Table 1: Risk categories based on Ang et al. RTOG 0129 study[9]

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Ragin and Taioli[10] in their meta-analysis reported that patients with HPV-positive HNSCC had a lower risk of dying and a lower risk of recurrence than HPV-negative HNSCC patients. Site-specific review showed HPV-positive OPSCC patients had 28% reduced risk of death when compared with patients with HPV-negative OPSCC. Similarly, HPV-associated OPSCC patients had better DFS than HPV negative.

The improved survival in HPV-associated OPSCC related to combination of multiple factors such as[11],[12]:

  1. Increased radiosensitivity
  2. Lack of field cancerization and less likelihood of second primary due to lower incidence of cigarette smoking
  3. And inverse correlation between survival and adverse tumor biomarkers such as epidermal growth factor receptor (EGFR) and p53 mutations.

HPV-associated tumors usually present as small primary with early nodal metastasis as compared to HPV-negative tumors. Preceding the implementation of AJCC current 8th ed.ition for staging, HPV-associated tumors were staged same as HPV-negative tumors leading to advanced stage notwithstanding much better prognosis. Reflecting these differences in tumor pathology, tumor biology, response to treatment and prognosis, AJCC instituted different staging system for HPV-positive OPSCC.[13] With the implantation of new staging, distribution of cases in stage I increased from 3.7% to 80.2%.[14] The individual presenting with HPV associated OPSCC are typically younger than HPV-negative patients, with median age difference of about 5 years. The incidence of HPV-associated OPSCC is about four time higher in men than women.[15] The proportion of OPSCC that is HPV-positive has increased in recent decades for both the sexes and is approximately 70% for both men and women.[16]

  De-Escaltion Strategies in HPV-Positive Oropharyngeal Squamous Cell Cancer Top

Nonsurgical standard of the treatment for advanced staged OPSCC has been radiotherapy to a dose of 70 Gy with concurrent cisplatin irrespective of HPV status. While this regimen provided better overall and disease-free survival, it is also found to lead to many acute and chronic toxicities. There is dose dependent relationship between chronic toxicities such as dysphagia, and dysarthria and other speech-related issues. Esophageal strictures rate and PEG dependence as radiation dose increases to pharyngeal constrictors. The severity of dysphagia increases with every 10 Gy above 50 Gy increase in radiation dose to superior and middle constrictors muscles.[17],[18]

With better survival outcome noted with HPV-associated OPSCC, the current therapy maybe more intensive than need for the purpose of optimal treatment outcome. Logically, there has been trend toward de-escalating the treatment protocol for HPV-associated OPSCC and hence improve QOL posttreatment. These toxicities can be reduced either by decreasing the radiation dose or reducing the volume of normal tissue irradiated.

De-escalation of definitive chemoradiotherapy

Cetuximab is an IgG1 monoclonal antibody that inhibits ligand binding to the EGFR and stimulates antibody-dependent cell-mediated cytotoxicity. The EGFRs are a member of the ErbB family of receptor tyrosine kinases. EGFRs are abnormally activated in head and neck epithelial cancer and are associated with poor clinical outcome. Cetuximab as an IgG1 monoclonal antibody against the ligand binding domain of EGFR sensitizes the cell to the effects of radiation.[19]

In RTOG 1016 study reported by Gillison et al.,[20] 987 patients with HPV + oropharyngeal SCC were enrolled. Eight hundred and forty-nine were randomly assigned to receive radiotherapy plus cetuximab (n = 425) or radiotherapy plus cisplatin (n = 424). They reported estimated 5-year overall survival of 77.9% in cetuximab group as compared 84.6% in cisplatin group. Progression-free survival was noted to be significantly lower in cetuximab group. The cetuximab group was also noted to have significantly higher locoregional failure rates. Both cohorts noted similar proportions of acute moderate-to-severe toxicity and late moderate-to-severe toxicity. Based on these findings, authors concluded that in patients with HPV + OPSCC, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin.

De-ESCALaTE open-label phase III trial[21] was conducted at 32 head and neck treatment centers across the UK, Ireland, and the Netherlands. Three hundred and thirty-four patients were randomized to receive definitive standard-dose radiotherapy (70 Gy) given concurrently with either cisplatin (100 mg/m2 on days 1, 22, and 43) or cetuximab (400 mg/m2 loading dose followed by 7 weekly 250 mg/m2 doses). Acute and later severe toxicity did not differ significantly between the two groups at 24 months. At 2 years, there was significantly inferior overall survival (89.4% vs. 97.5%) and recurrence rate (16.1% vs. 6.0%) in cetuximab group as compared to cisplatin group, respectively.

De-escalation of radiation dose after induction chemo regimen

Marur et al.[22],[23] in phase II, ECOG trial evaluated whether complete clinical response to induction chemotherapy (IC) could help select patients with HPV + OPSCC for decreased radiation dose as a way to spare the radiation toxicity. The trial enrolled 90 patients, 80 were evaluable and completed three cycles of IC with cisplatin, paclitaxel, and cetuximab. Seventy percent (56 patients) had a complete clinical response and 51 patients continued to IMRT 54 Gy with cetuximab. Two-year progression-free and overall survival after median follow-up on 35.4 months was reported to be 80% and 94%, respectively, for patients with primary-site clinical complete response treated with 54 Gy. Acute toxicity was reported to be tolerable with all patients recovering within 14 days. Ninety-six percent patients were able to go through radiotherapy without delay. At 12 months, significantly lower number of patients treated with radiotherapy dose of ≤54 Gy had difficulty swallowing solids or had impaired nutrition.

Chen et al.[24] reported on single-arm, phase 2 trial in patients with newly diagnosed, biopsy-proven Stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing. Patients received two cycles of paclitaxel 175 mg/m2 and cisplatin given 21 days apart. Patients with complete or partial response (24 patients) received 54 Gy in 27 fractions, and those with less than partial or no responses (20 patients) were given 60 Gy in 30 fractions. Both the groups received weekly paclitaxel. Two-year progression-free survival was reported to be 92% for both groups. Twenty-six of 44 patients had grade 3 adverse event but no grade 4 were reported. The trial concluded that with 15-20% reduction in radiation dose associated with CCRT, there is improvement in toxicity profile with high rate of progression-free survival.

In phase II Quarterback trial, Misiukiewicz et al.[25] enrolled 23 patients with HPV + OPSCC, previously untreated, locally advanced disease and ≤20 pack years smoking history. Twenty-two were evaluable for toxicity associated with three cycles of IC with docetaxel, cisplatin, and fluorouracil. Twenty patients with partial clinical response (pCR) or complete clinical response (cCR) to IC were randomized 2:1. Twelve patients received reduced-dose (56 Gy) and 8 patients received standard-dose (70 Gy) radiation treatments, both cohorts received weekly carboplatin. At 3 years, there was statistically equivalent progression free and overall survival at 87.5% and 83.3% for the standard-dose and reduced dose cohorts, respectively. Functional outcome was not reported in this study.

OPTIMA[26] was a phase II dose and volume de-escalation trial that enrolled 62 patients with HPV + OPSCC and categorized 28 patients into low risk (≤T3, ≤N2B, ≤10 pack-year history) and 34 patients into high risk groups (T4 or ≥N2C or >10 pack-year history). Both the groups received three cycles of IC with carboplatin/nab-paclitaxel. Low-risk group with ≥50% response received 50 Gy RT (RT50) while low-risk patients with 30%–50% response or high-risk patients with ≥50% response received 45 Gy concurrent chemoradiotherapy (CRT45). Patients with lesser response received concurrent chemoradiotherapy with 75 Gy dose. Chemoradiotherapy/Respiratory Therapists was given to first echelon of uninvolved nodes. Two years’ overall and progression-free survival was reported to be 100% and 95% among the low risk group, respectively. For high-risk group, OS and PFS was 97% and 95%, respectively. The trial reported significantly decreased rates of acute toxicity and gastrostomy use in patients with lower doses of radiation.

De-escalation of adjuvant treatment following surgery

With recent advances in surgically technology and technique, it is now possible to utilize minimally invasive transoral technique for surgical removal of oropharyngeal cancers. On November 6–7, 2011, The National Cancer Institute Head and Neck Cancer Steering Committee proposed additional vigorous investigation into transoral surgery for OPSCC, both as a way to reduce toxicity in HPV-positive OPSCC and also to intensify treatment in HPV-negative OPSCC.[27]

Ma et al.[28] conducted a phase II trial to determine the feasibility of aggressive adjuvant radiation dose de-escalation from 60 to 66 Gy to 30–36 Gy in patients with HPV-associated OPSCC to reduce toxicity and preserve swallow and quality of life while maintaining historical disease control rates. Eligibility criteria included patients with p16 positive OPSCC, smoking history of 10 pack-years or less, and negative margins. Intermediate risk cohort A received 30 Gy delivered in 1.5 Gy fractions twice per day over 2 weeks along with 15 mg/m[2] docetaxel once a week. Cohort B included patients with extranodal extension and received same treatment as cohort A plus a simultaneous boost of 36 Gy in 1.8-Gy fractions twice per day to nodal levels with extranodal extension. The primary end point was locoregional tumor control at 2 years. Secondary end points included 2-year progression-free survival, overall survival, toxicity, swallow function, and patient-reported QOL. The study reported 2-year locoregional control rate of 100% and 93% in cohort A and B, respectively. The overall 96.2%, progression-free survival of 91.1% and overall survival of 98.7%

Nichols et al.[29] reported on ORATOR phase II trial conducted in Canada and Australia. Sixty-eight patients with the Eastern Cooperative Oncology Group scores of 0-2, and with T1-T2, N0-2 (≤4 cm) OPSCC tumor types were randomly assigned (1:1) to receive radiotherapy (70 Gy, with chemotherapy if N1-2) or transoral robotic surgery (TORS) plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). MD Anderson Dysphagia Inventory (MDADI) score at 1 year was reported to be mean 86.9 in the radiotherapy group versus 80.1 in the TORS plus neck dissection group. There were a greater number of patients with neutropenia, hearing loss, and tinnitus in radiotherapy group versus TORS plus neck dissection group. Trismus was more common in TORS and neck dissection group. The most common adverse outcome in radiotherapy group was dysphagia, hearing loss, and mucositis. The most common adverse effect in TORS group was dysphagia and one death from bleeding. The 1-year follow-up results showed superior swallow related QOL in radiotherapy group. Overall survival and progression-free survival were reported to be excellent in both the groups, with no significant differences between groups.

PATHOS is a randomized prospective trial[30] being done to determine the feasibility of reducing the intensity of adjuvant treatment after minimally invasive surgery in HPV-associated OPSCC to improve the long-term swallowing function while maintaining excellent prognosis. Patients with HPV OPSCC stage T1-T3 N0-N2b is resectable through transoral approach. Following surgery, patients are allocated into three groups based on pathological risk factors. Low risk pathology group will receive no adjuvant treatment, and intermediate group will be randomized to receive either standard dose postoperative radiotherapy (control) or reduced dose radiotherapy. Patients with high risk pathology will be randomized to receive either postoperative chemoradiotherapy (control) or radiotherapy alone. The outcome of phase II study will be reported as swallowing function measured using the MDADI score at 12 months’ posttreatment. If the phase II study is successful, PATHOS will advance to a phase III non-inferiority trail with overall survival as the endpoint.

EORTC 1420-HNCG-ROG is a randomized phase III European trial that began accrual in 2016.[31] The purpose of the study is to evaluate and compare the patient-reported swallowing function over the 1st year after randomization to either transoral surgery or IMRT with early stage OPSCC. The estimated primary completion date for the trial is November 2020 and estimated duty completion date is May 2026.

De-escalation using immunotherapy

Immunotherapy activates the immune system against tumor cells and has recently emerged as a promising strategy to a wide variety of tumors which are either refractory or sensitive to platinum-based chemotherapy. Numerous trials have shown encouraging effectiveness of anti-PD-1 monoclonal antibodies in a subset of patients with recurrent/metastatic head and neck cancer.[32],[33]

NCT03799445[34] is a phase II clinical trial currently underway to evaluate the side effects and dose of ipilimumab, nivolumab, and radiation therapy. This trial will also evaluate the efficacy of these drugs in the management of patients with advanced HPV-positive OPSCC. Enrolled patients will receive nivolumab intravenous (IV) over 30 min on days 1, 15, and 29 and ipilimumab IV over 30 min on day 1. In the absence of disease progression or unacceptable toxicity, the treatment will repeat every for 6 weeks for two cycles. Starting on day 1 of cycle 2, patients also undergo IMRT 5 days a week for 6 weeks in the absence of disease progression or intolerable toxicity. The study is estimated to be completed on August 1, 2022.

In another phase Ib/II clinical trial NCT03618134,[35] stereotactic body radiotherapy (SBRT) in combination with immunotherapy is being utilized prior to TORS for HPV-associated squamous cell cancers of head and neck. The study is estimated to be completed in October 23, 2023.

  Conclusion Top

Various studies, as discussed in above review, have shown better prognosis in terms overall and disease-free survival in patients with HPV-positive squamous cell cancers of head and neck region. De-escalation of treatment in this young population is a right step forward in reducing the morbidity associated with standard treatment. However, we have to tread de-escalation strategies carefully. Treatments such as radiation and minimally invasive surgery can only be utilized once. Failure of treatment will require more aggressive salvage with consequent worse quality of life and quite possibly, poorer survival. Currently, the de-escalation should only be utilized in the setting of clinical trial pending results of various prospective studies.

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This material has never been published and is not currently under evaluation in any other peer reviewed publication.

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Phase 2 Study (With Safety Lead in) of the Safety, Tolerability and Efficacy of Anti-CTLA4 (Ipilimumab) and Anti-PD-1 (Nivolumab) in Combination With Radiation Therapy to 50-66 Gy in Low-Intermediate Volume, Local-Regionally Advanced HPV-Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC). Available from: https://clinicaltrialsgov/ct2/show/NCT03799445 2019-2022. [Last assessed on 2020 Jun 20].  Back to cited text no. 34
Phase Ib/II Trial of Stereotactic Body Radiotherapy (SBRT) in Cominbation With Immunotherapy Prior to Transoral Robotic Surgery (TORS) for Human Papillomavirus Positive (HPV+) Squamous Cell Carcinoma of the Head and Neck (SCCHN). Available from: https://clinicaltrialsgov/ct2/show/NCT03618134 2018-2023. [Last assessed on 2020 Jun 20].  Back to cited text no. 35


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