Low-Dose Radiation a Possible “Game Changer” for Treating HPV-Positive Throat Cancer

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MSK radiation oncologist Nancy Lee has pioneered an approach for treating selected head and neck cancers with a much lower radiation dose than the standard protocol.

The number of head and neck cancers related to human papillomavirus (HPV) infection has surged in recent years, especially in men. This type of cancer usually responds well to a combination of surgery, radiation, and chemotherapy. The cure rate for the disease is close to 90%. But the side effects of treatment can cause serious discomfort and long-term complications. This is particularly true of radiation.

The outlook for people with HPV-positive head and neck cancer could soon improve markedly. Memorial Sloan Kettering researchers report that many of these cancers might be successfully treated with a sharply reduced radiation dose that could eliminate nearly all radiation-associated side effects.

“This is an absolute game changer for treating HPV-positive cancer,” says MSK radiation oncologist Nancy Lee, who pioneered the approach. “The difference in toxicity is dramatic compared with standard radiation therapy.”

The researchers reported their findings on January 12 in the Journal of the National Cancer Institute.

A pilot study in July 2015 involving 19 MSK patients with HPV-positive oropharynx (throat) cancer showed that, in select patients, a low-dose radiation approach after surgery could control the cancer while avoiding side effects. The new technique reduces radiation by nearly 60%. The patients did not have their cancer return after being followed for a median period of nearly three years.

Building on these striking results, MSK completed a larger study in January 2021 that involved 158 new HPV-positive patients using the same approach as the pilot study. Given significant interest from patients and treating physicians, MSK has expanded the trial to enroll an additional 150 patients.

Dr. Lee expects that the expanded trial will provide definitive answers about the effectiveness of the technique in two to three years. Although the treatment lasts only a few weeks, the researchers are conducting meticulous follow-up visits to evaluate the long-term effects.

“We hope to use the results to gain approval of this technique from the US Food and Drug Administration for specific use in the de-escalation of HPV-positive cancer so we can bring this technique to the world,” she says.

She is working with Heiko Schöder, nuclear medicine physician and Chief of the Molecular Imaging and Therapy Service, to bring this about.

A Dramatic Dose Reduction

Radiation dosage is measured in units called grays (Gy). The standard approach for treating head and neck cancer has been 70 Gy given over seven weeks along with three cycles of chemotherapy. This level of radiation often causes mouth sores, difficulty swallowing, dry mouth, loss of taste, and nausea. The new regimen pioneered by Dr. Lee and other MSK doctors reduces the dosage to 30 Gy given over three weeks along with only two cycles of chemotherapy.

“Reducing the radiation dose to 30 Gy for HPV-positive head and neck cancer seemed feasible because HPV-positive anal cancer has been treated effectively with that dosage,” says Dr. Lee.

“It’s hard to describe the huge difference this makes,” MSK radiation oncologist Nadeem Riaz says. “With the seven-week treatment, patients typically lose 20 to 30 pounds and may have to go on work disability for several months. When receiving the smaller dose over just three weeks, they have almost no radiation side effects. It’s like you’re not even using the same treatment.”

The new approach has not shown any negative effect in cure rates. Patients have less throat pain, less fatigue, and less radiation burn. This results in a better quality of life not only during treatment but also afterward. Patients are also able to return to work sooner — or never miss any work at all.

“It is amazing to no longer see the late side effects of radiation that used to be common in my clinic, such as feeding tube dependence, inability to swallow normally, dry mouth, tooth decay, and very scarred necks,” says MSK head and neck surgeon Jay Boyle.

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Careful Selection of Tumors

Key to the success of the new technique is the careful selection of people who would benefit. Most HPV-positive tumors respond well to treatment with chemotherapy and radiation, but a fraction are more resistant and aggressive. Dr. Lee developed a method for detecting which tumors would respond to the lower dose.

The approach involves using PET imaging to see if there’s the presence of hypoxia (low oxygen concentration) in the head and neck tumors. Tumors with low oxygen concentration are less likely to respond to radiation and chemotherapy. In Dr. Lee’s method, patients are initially given radiation and chemotherapy. PET imaging is then used to determine whether the tumors are hypoxic (and could be resistant).

The difference in toxicity is dramatic compared with standard radiation therapy.
Nancy Y. Lee radiation oncologist

For people whose tumors are not hypoxic, the radiation dosage is lowered to 30 Gy, and the chemotherapy is reduced from three cycles to two. People whose tumors are revealed to be hypoxic go on to receive the standard 70 Gy radiation dose and three cycles of chemotherapy.

In the United States, only 15% of HPV-positive head and neck tumors are hypoxic, which suggests that 85% of patients could get the reduced treatment.

“Previous attempts to minimize the chemotherapy portion of the treatment had not been successful, even for HPV-positive throat cancer patients who have a good prognosis,” says MSK medical oncologist Eric Sherman. “A key insight in our approach was to retain the synergy between chemotherapy and radiotherapy but shorten the radiation portion of the treatment, which has led to these amazing outcomes.”

The researchers also identified a possible cause for why certain HPV-positive  tumors are more sensitive than others, by analyzing the genetic makeup of tumors. They identified a “mutational signature” that suggested some HPV-positive tumors have a certain defect in the way DNA is repaired that make them especially sensitive to radiotherapy.

“The analysis of the entire genomes of these cancers has provided a path to identify those patients who will benefit the most from this groundbreaking treatment approach,” says Jorge Reis-Filho, an experimental pathologist and cancer geneticist who helped conduct the analysis. Work is ongoing to determine how to use this information to guide radiation de-escalation efforts in the future.

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A Possibility of No Surgery

The ongoing clinical trial will also include proton therapy as an option. Proton therapy is an advanced form of radiation therapy using protons rather than x-rays to treat cancer. Proton therapy enables doctors to direct cancer-fighting energy to precise locations within the body. MSK radiation oncologists now deliver proton therapy at a new state-of-the-art facility in upper Manhattan.

“There is a lot of interest in proton therapy — we recently had a patient come to MSK from Las Vegas for treatment because we are offering the 30 Gy dose that way,” Dr. Lee says.

MSK is enrolling patients in a clinical trial testing the low-dose radiation approach.

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The trial also is investigating whether surgery can be avoided altogether. The second group of 150 patients enrolled for the expanded trial will receive chemotherapy and the low-dose radiation, and surgery will be optional — a decision that will be made jointly by the patient and physician.

“We hope that in the future, many people with HPV-positive throat cancer will be able to receive an even less invasive, less intense, and more-precise treatment.” Dr. Lee says.

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A more personalized form of radiotherapy

The success of this study has led to the development of a Precision Radiotherapy Program at MSK, led by Drs. Riaz, Lee, Reis-Filho, and radiation oncologist Jeremy Setton. The application of using precise radiation techniques is enormous and not limited to HPV-positive throat cancer. Created by Simon Powell, Chair of MSK’s Radiation Oncology Department, this new program will develop similar studies aimed at making radiation treatments more personalized for each patient’s cancer — regardless of its location in the body.

“Radiation therapy has proven to be one of the most effective cancer treatments,” Dr. Powell says. “The ultimate goal of our initiative is to make radiation therapy a targeted treatment based on the biology of the tumor and the characteristics of the patients.”


This story was originally published in 2017 and has been updated with new information.


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This work was funded by NIH grant R01 CA157770-01A1, the Serra Family, the James and Judith K. Dimon Foundation, the Imaging and Radiation Sciences Program at MSK, and in part through the National Institutes of Health National Cancer Institute Cancer Center Support Grants P30 CA008748 and P30AQ23 CA016042. Dr. Reis-Filho is funded in part by the Breast Cancer Research Foundation.

Nancy Y. Lee discloses the following relationships and financial interests:

  • Merck & Co Inc.
    Provision of Services
  • Merck Serono
    Provision of Services
  • Pfizer, Inc.
    Provision of Services

Nadeem Riaz discloses the following relationships and financial interests:

  • Illumina
    Provision of Services
  • Mirati Therapeutics
    Provision of Services
  • Repare Therapeutics
    Provision of Services

Jorge S. Reis-Filho discloses the following relationships and financial interests:

  • Belgian Volition
    Provision of Services
  • Goldman Sachs
    Provision of Services
  • Oncoclinicas do Brasil Servicos Medicos S.A.
    Fiduciary Role/Position; Ownership / Equity Interests
  • Paige.AI, Inc.
    Ownership / Equity Interests; Provision of Services
  • Repare Therapeutics
    Provision of Services
  • prIME Oncology
    Provision of Services

Eric J. Sherman discloses the following relationships and financial interests:

  • Bristol Myers Squibb
    Provision of Services (uncompensated)
  • COTA, Inc.
    Provision of Services
  • Eisai
    Provision of Services
  • Goldilocks Therapeutics Inc.
    Ownership / Equity Interests
  • Loxo Oncology
    Provision of Services
  • Novartis
    Provision of Services
  • Regeneron Pharmaceuticals, Inc.
    Provision of Services

Simon N. Powell discloses the following relationships and financial interests:

  • Artios Pharam Limited
    Provision of Services (uncompensated)
  • Astra Zeneca
    Provision of Services (uncompensated)
  • Elekta
    Provision of Services
  • PharmaPier US LLC
    Provision of Services (uncompensated)
  • Varian Medical Systems
    Provision of Services

Comments

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I am 61 and healthy and have just been diagnosed with HPV cancer. Two nodes in my neck are involved and I am scheduled for surgery on the base of my tongue Feb. 16. I am very interested in reducing the amount of radiation, if the curative effect is the same. My treatment center is Vanderbilt Medical Center. I meet with an radiologist and oncologist Feb. 1.

Dear Betsy, we’re sorry to hear about your diagnosis. We recommend that you discuss your concerns with your medical team at Vanderbilt. Thank you for your comment and best wishes to you.

This is a very interesting article. I have recently been diagnosed with HPV positive neck cancer and the side effects from radiation really scare me. I am interested to know what institutions are partnering with this study and if it is still open. I am currently established with the University of Michigan with the pending start of therapy on the 22 of October, 2018.

Dear Mark, we’re very sorry to hear about your diagnosis. According to Dr. Lee, the protocol discussed in this story is currently available only at MSK, but we are looking to open it at other hospitals. If you are interested in coming here for a consultation, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

Dr. Lee and Dr. Riaz,
What test did you use to confirm your 19 subjects had HPV-related cancer?

Nicola, thank you for your question. We consulted with Dr. Riaz, who responds:

We confirm HPV status using two different tests.

(1) P16 immunohistochemistry testing which tests for a downstream effect of viral infection.
(2) RNA in-situ hybridization which looks for viral gene transcripts that are responsible for dysregulating cellular growth.

Is this reduced treatment protocol actively being offered to HPV positive tonsil with T4, N2, M0? Is the chemotherapy also reduced, or just the radiation? Is the survival rate the same as the standard treatment at 70g and Cisplatin? What is the treatment response if there are local failures from the reduced therapy protocol? Is this reduced treatment available now?

Ales, thank you for reaching out. We consulted with Dr. Nadeem Riaz, who responds: “Unfortunately patients with T4 disease are ineligible for the clinical trial. The chemotherapy is also reduced from a standard dose of 300 mg to 200 mg.The purpose of the study is to determine if the survival rate is similar to standard therapy, which we believe it will be, but the study will help demonstrate this. If a patient develops local failure, they will undergo a salvage neck dissection and then may receive additional radiotherapy.

I’m happy to talk with the patient more about the study if they would like. They can contact my office at 646-888-3495.”

On Nov.21. 2018 I had a modified radical neck dissection at UCLA, and a radical tonsillectomy. There was a 1.8 cm tumor in the right tonsil consistent with an HPV associated orophayngeal squamous cell carcinoma. It was also found in two of 20 lymph nodes. Recovery has been a nightmare. I am very frightened of the radiation treatment offered at UCLA. I would like to be considered for treatment at Sloan’s. Kettering.

Nice blog thanx for given me a specific information that is usefull about throat cancer

I WAS RECENTLY DIAGNOSED WITH HEAD AND NECK OROPHARNYX CANCER AND A RECENT PET SCAN SHOWED THAT IT IS ALSO IN MY NECK LYMPH NODES. I AM PLANNING TREATMENT AT JEFFERSON HOSPITAL IN PHILLY USING THE 7 WEEK 70 GY APPROACH AND I AM VERY INTERESTED IN YOUR TRIAL, DO YOU HAVE ANY LOCATIONS IN OR NEAR PHILLY PA THAT ARE USING THIS STUDY? IF NOT, IS IT POSSIBLE FOR JEFFERSON HOSPITAL TO PARTICIPATE IN THIS STUDY? THANK YOU.

Dear Pat, we’re sorry to hear about your diagnosis. The closest MSK location to Philadelphia is in Basking Ridge, New Jersey, If you are interested in making an appointment there, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Otherwise, we recommend you ask your current doctors about what clinical trials may be available where you are being treated. You can also go to clinicaltrials.gov to look for trials closer to where you live. Thank you for your comment and best wishes to you.

As you mentioned above, you perform p16 immunohistochemistry and ISH to confirm HPV status of a tumour. Are these tests carried out at diagnosis/staging? Is it possible that p16 immunohistochemistry can be used alone as a surrogate marker for HPV status? I am looking into a study about this and would be interested to know your thoughts.

Dear Emily, we sent your questions to Chrisann Kyi, an expert in HPV-related cancers. This is her response:

HPV DNA testing and p16 IHC testing is done in both cervical and head and neck cancers. These tests are carried out at both diagnosis and staging to confirm diagnosis. If the person has metastatic disease, test is performed on tissue biopsied at metastatic sites to confirm spread from primary cancer.
 
p16 is often used as surrogate marker as correlation exists between HPV viral detection and p16 protein overexpression in cancer cells. The p16 test is simple, low cost, and very feasible with immunohistohemical (IHC) analysis. It should be noted that p16 is a surrogate and HPV DNA testing cannot be used interchangeably with p16 in all circumstances. For example, in some head and neck orogpharyngeal cancers, a small fraction of oropharyngeal tumors are not etiologically driven by HPV yet overexpress p16. 
 
Thank you for your comment and best wishes to you.

Hello, my father was diagnosed with HPV-positive tonsil cancer a few weeks ago, it has spread to both the left and right lymph nodes (two on one side and one on the other). the initial recommendation for treatment does not include surgery but 35 sessions of radiation at 70 GY dose and cisplatin weekly for the duration of the radiation. His cancer is deemed to be stage IVA, would he qualify for this radiation de-escalation clinical trial?

Dear Annie, we’re sorry to hear about your father’s diagnosis. If he would like to learn about participating in a trial or receiving other treatment at MSK, he can make an appointment online or call 800-525-2225. Thank you for your comment and best wishes to you and your family.

Can this lower radiation possibly be done if the HPV squamous cell cancer is in the larynx?

Dear Renee, we are not able to answer individual medical questions on our blog. If you’re interested in arranging a consultation with a doctor at MSK, you can make an appointment online or call 800-525-2225. Thank you for your comment and best wishes to you.

My wife 47 years old is now likely being diagnosed with Hpv throat cancer. I truly do not want her to go through the full treatment regimen. We are out of state but willing to travel if she is a candidate for the de-escilation. Can the hypoxia testing be done here locally to determine if she could receive the lower dose? Also, is there any data showing that such a large dosage reduction can be successful long term? Avoiding side effects would be great but ultimately cure is the most important to her. Will Pencil Beam Proton be used or Imrt? What are the requirements from a tumor size and node involvement? What is the protocol for treatment if it recurred locally, near by or distant? If it’s just more radiation then is there any concern over trying this first since you can go back in and remove anything that might come back? Thank you in advance.

Dear Alex, we’re sorry to hear that your wife is going through this. If she would like to arrange a consultation with an expert at MSK to discuss her treatment options, you can make an appointment online or call 800-525-2225. Thank you for your comment and best wishes to both of you.

Hello colleagues, I am a General Surgeon from Venezuela.

Currently, my nephew who is 48yo and diagnosed with SCCOC (Uvula) T1N2bM0 in Jan 2018, ( an incisional Bx of the cervical lymph node was performed in Panama) had a recurrence (re-recurrence I would say).
He received Chemo Rad at standards doses with CISPLATIN and Rad until April 2018. In October 2018 he had a Neck Dissection (don't have info about level) because of a Positive BX for SCC on the scar of the biopsied lymph node. 5 Lymph nodes were negative for SCC but Ki67 and cytokeratin were +. After Oct 2018 he developed Left Vocal Cord Paralysis, left facial paralysis and has dysphagia to solids (has been drinking liquids for the last 6 months).
He went to Miami (Jackson mémorial last week) and apparently, there is not much to be done. A direct extension is reaching the Clivus and Corpus Petros. He has been offered ChemoRad as a palliative treatment.

I would like to hear from your thoughts, please.

Thank you in advance,

Respectfully

Daniel Salas, MD

Dear Daniel, we’re sorry to hear about your nephew. We are not able to offer medical advice on our blog, but if you’d like to arrange for one of our experts to conduct a records review you can contact our International Center at [email protected]. Thank you for your comment and best wishes to you and your family.