Pathologic response to neoadjuvant chemotherapy in HPV-associated oropharynx cancer

Sadeghi N, Khalife S, Mascarella MA, Ramanakumar AV, Richardson K, Joshi AS, Bouganim N, Taheri R, Fuson A, Siegel R.

From Head and Neck, March 2020;42(3):417-425.

Article Review by Joe Goodman, MD

Background / Hypothesis
According to the authors, a paradigm shift is underway leading to de-escalation trials for HPV-associated oropharynx cancer (OPC). Because of the excellent prognosis for most HPV OPC, efforts have been made to improve quality-of-life after treatment and reduce treatment-related morbidity. While most de-escalation trials have looked at reducing radiation dose or eliminating chemotherapy, this trial uses neoadjuvant chemo therapy plus transoral surgery (NAC+S) with the goal of avoiding post-op radiation based on surgical pathology.

Design
This is a prospective cohort of patients with p16+ OPC (stage III/IV AJCC 7th) treated with chemotherapy consisting of 3 cycles of cisplatin/docetaxel every 3 weeks followed by transoral surgery and neck dissection. N3 disease was excluded. All 54 patients demonstrated at least partial response to the chemotherapy regimen based on preoperative post-treatment imaging. Goal was to correlate reduction in tumor volume with likelihood of complete pathologic response pCR. Surgical pathology was assessed for presence of primary tumor and neck metastases to determine yTNM restaging and assess need for postoperative XRT. Partial response was defined as any residual tumor. MRI response of tumor was also correlated with pathological response, but not RECIST criteria because often pathological response was underpredicted by imaging response.

Summary of Results
Surgical pathology showed overall pCR of 44%, with 72% pCR at the primary and 57% pCR in the neck.

96% had negative margins. There were 3 mortalities. Preop imaging volume reduction of 90% or greater had predictive value for pCR (sensitivity 0.82 and specificity 0.73). More patients at all stages showed pCR than PR on surgical pathology although this was not specifically analyzed.

Strengths

• Building on several other small series to show efficacy of neoadjuvant chemotherapy regimen based on surgical pathology, justifying de-escalation strategies
• Since transoral robotic surgery involves en bloc resections of radical tonsil or base of tongue, as well as neck dissection, less likelihood of missing a small discontiguous positive margin vs endoscopic partial resection

 Weaknesses

• Mortality of 5.6% seems high, not well explained if they declined recommended post-op treatment
• Survival outcomes not analyzed but this data is forthcoming
• No real attempt at understanding cellular mechanisms for this phenomenon
• Not powered to analyze based on smoking status as possible contributor to biological response in p16+ OPC
• While toxicity seems acceptable, long-term studies will need to be done

Key Points

• There seems significant biological response of p16+ OPC to this particular neoadjuvant chemotherapy regimen of cisplatin and taxotere. Other regimens have been studied, for instance the Weiss article from UNC, as well as bioselection papers from UM for larynx cancer.
• Even the original VA study showed 30% CR.
• While the current treatment paradigm states that chemotherapy is never sufficient for primary treatment of squamous cell carcinoma, in many cases in this series there was no evidence of tumor at the primary site or in the neck as assessed on surgical pathology. This speaks to the possible for bioselection strategies using NAC+S for de-escalation in p16+ OPC.
• Also supports an increased role for transoral surgery with good functional outcomes after neoadjuvant chemotherapy, avoiding “triple-therapy”—unless dictated by adverse features on surgical pathology – Supports role of post-chemotherapy pre-operative imaging to predict likelihood of pathologic complete response to further refine the treatment algorithm
• Long term, multi-institutional studies of disease free survival and toxicity will need to be done

From the Basic Science/Translational Section
Jeffrey C. Liu MD Vice Chair
Richard Wong Md Chair

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Joseph Goodman

Dr. Goodman is currently Assistant Professor of Otolaryngology and Associate Residency Program Director at The George Washington University in Washington, DC. He serves as a member of the Basic and Translational Science Service of the AHNS and is a working group member of the Salivary Gland Section. His research interests include HPV-related oropharyngeal cancer and reconstructive surgery of the Head and Neck.

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• AHNS Basic Science/Translational Newsletter Vol 1 - April 17, 2020

In light of the recent concerns about COVID-19 and the growing number of travel bans placed on both international and domestic colleagues, the AHNS Leadership has elected to postpone the AHNS 10th International Conference until July 22nd-25th 2021. This decision was made to preserve the health and safety of our attendees and patients.

Abstract Submissions

We will release all submitted oral and poster submissions and re-open abstract submissions in the Summer of 2020 if you would like to re-submit your abstract with our without updates or new research for consideration at the 2021 International Meeting.

We realize you’ve worked hard on your research and don’t want to delay disseminating the information for another year; therefore we encourage you to submit your manuscripts to JAMA Otolaryngology – Head & Neck Surgery.

Faculty Assignments

If you have been invited as faculty for the July 2020 Conference, look for your invitation over the next several months!  We anticipate that the vast majority of program will be the same.  The Program Committee will review the revised 2021 scientific program and re-assign and schedule faculty soon.

Hotel Reservations

If you have made your hotel reservations, please contact the Hyatt Regency Chicago directly to cancel.  You may contact them at (877) 803-7534 or use the Passkey link provided below.

https://www.hyatt.com/en-US/group-booking/CHIRC/G-GAHN

Registration Fees

For those who Have paid your registration to attend the July 2020 Conference, your fees will be refunded to the payment option you provided when registering.

We apologize for any inconvenience to our members and attendees.

Thank you for your understanding and continued support.

Robert Ferris, MD, PhD – AHNS 2021 Conference Chair
Eben Rosenthal, MD – AHNS 2021 Program Chair
Cherie-Ann Nathan, MD, FACS – AHNS President

How COVID-19 is Affecting our Head and Neck Community: AHNS COVID-19 Bulletin

By the AHNS Leadership and Patient Care Division

The American Head and Neck Society (AHNS) wishes to recognize and laude the actions of membership in the face of the COVID-19 pandemic. While abiding by our mission, “Advance Education, Research and Quality of Care for the head and neck oncology patient,” we must acknowledge that we, as head and neck physicians, are at “the tip of the spear” in the battle to control this pandemic. The evolving experiences worldwide demonstrate the serious impact of this virus on patients and the physicians who care for them. Similarly, the unique roles and risks of the head and neck physician are becoming more defined. Clearly, as our experience with this novel virus expands, more data will be available to assist in the best practices around clinical and caregiving trends. Until that accrues, we, as The American Head and Neck Society, will work to provide leadership and guidance based on current information.

We reinforce the critical importance of appropriate personal protective equipment (PPE) in the safe management of patients with COVID-19, but must also acknowledge the worldwide shortage of PPE. Judicious stewardship of PPE is a responsibility of all providers and we must reserve the use of any limited-availability PPE for patients and procedures deemed high risk. As the head and neck exam places the caregiver at heightened risk for potential COVID-19 infection from asymptomatic carriers, we recommend gloves, masks and eye protection be worn in the examination of the upper aerodigestive tract as PPE availability allows. In accordance with recommendations from the AAO-HNSF, https://www.entnet.org/content/otolaryngologists-and-covid-19-pandemic, special consideration should be made with endoscopic examinations as the nose and nasopharynx have been suggested to be high density reservoirs of this virus. Endoscopic exams should be clearly necessitated by the patient’s disease process and avoided if not necessary. It is suggested that these should be done with the most highly protective mask and eye protection available. Because of concern for aerosolized particles, nebulizers and atomizers are strongly discouraged if possible due to the increased risk of spreading the virus.

In accordance with national recommendations, elective and non-urgent outpatient visits should be postponed and innovative care approaches utilizing telemedicine should be explored and optimized. In support of the CMS recommendations, all elective and non-urgent surgery should be postponed. Click here for the CMS recommendations: (https://www.cms.gov/files/document/31820-cms-adult-elective-surgery-and-procedures-recommendations.pdf). As the management of head and neck cancer patients remains core to our mission as physicians and a society, head and neck surgery will still be indicated and imperative in the care of patients with head and neck cancers. The CMS guidelines allow for the continued, appropriate use of surgical interventions when indicated. Yet, thoughtful consideration will be required in deciding which patients will benefit in this complex evolving context. As physicians we need to acknowledge the constraints of time, disease progression and the idiosyncratic strains placed upon each individual health system by the progressing COVID -19 pandemic. We must work with our oncologic caregivers to creatively navigate our patients through these unchartered waters with care and skill, while similarly partnering with all our health care colleagues in this COVID-19 era. Our effective care of the head and neck patient should complement the system, never constrain it.

Much attention has been given in recent days to the safety of invasive procedures in COVID-19 patients and potential asymptomatic carriers, from bronchoscopy and intubation to advanced aerodigestive tract and sinonasal surgery. Again, we emphasize that maximized PPE, including the use of powered, air purifying respirator (PARP), be used per the recommendation of each institution for proven COVID-19 patients. The infectivity of potential asymptomatic carriers has yet to be defined, but is felt in early anecdotal reports to be high. Although COVID-19 testing prior to surgery would offer potential benefit in further defining at risk procedures, testing capacity is currently insufficient to test symptomatic patients, much less screen asymptomatic surgical candidates. It is anticipated that this will change in coming days and preoperative testing may be a reasonable adjunct to decision making around surgical candidacy. The decision to proceed with interventions, surgical or otherwise will rest with the clinical decision-making of the health care provider and their personal comfort with such engagement in this pandemic. This will require daily re-evaluation as new information presents and the pandemic unfolds. We have trained and gained expertise throughout our careers, not preparing for this specific day, but to care for head and neck patients in need. In this time of need, we are here, uniquely prepared and empowered to be the caregivers and difference-makers the world and our patients need.

Our colleagues, the world over, are our greatest resource. We will need to actively leverage each other’s experiences during this time of crisis: our successes, our failures, our plans, our algorithms, our innovations, our challenges, our thoughts, our queries, our concerns. To this end, the AHNS will sponsor the COVID-19 BULLETIN BOARD on the AHNS website. We will solicit informative submissions related to specific issues in the management of head and neck patients and in the COVID-19 era, as well as, the role of the head and neck caregiver in the evolving pandemic. Specific policies enacted at given institutions, use of PPE, COVID testing policies, patient triage algorithms, management strategies for tracheotomy use, etc. are all example topics. Submissions will be rapidly evaluated by leadership members of the Patient Care Division of the AHNS and posted in an expeditious fashion. It is recognized that many of these approaches will be local, influenced by epidemiologic and resource factors and that all our early experiences will be anecdotal, lacking the usual robust data on which we typically make decisions.

The leadership of the AHNS will be evaluating the rapidly evolving pandemic and strive to be the responsive, effective, innovative and compassionate force this society and our patients deserve.

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Cherie-Ann Nathan

Dr. Cherie-Ann Nathan is a leading head and neck cancer surgeon. She is Prof. & Chair of the Dept. of Oto/HNS &the Director of Head and Neck Surgical Oncology and Cancer Research, Feist-Weiller Cancer Center Louisiana State University Health - Shreveport (LSU Health Shreveport). The National Cancer Institute has funded her translational research since 2000 and her focus is on targeted therapy for head and neck patients. Dr. Nathan is recognized nationally and internationally for her seminal work on molecular analysis of surgical margins. She has pioneered multi-institutional clinical trials using mTOR inhibitors in HNSCC patients. She has also received NIH funding for chemoprevention of cancer with curcumin and has a patent for a curcumin chewing gum. More recently she also received an NCI grant on cutaneous Squamous cell cancer.  She serves on the NCI head and neck steering committee and the American Cancer Society HPV steering committee. Dr. Nathan has published extensively, has over 180 publications in peer-reviewed journals, and has authored multiple textbooks and encyclopedia chapters. She is married to Dr. Raghu Nathan, a pulmonary and critical eye care specialist with whom she has two boys.

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• AHNS Leadership - July 24, 2020
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