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.

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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Eliminating Surgery or Radiation

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.

Other patients who do have surgery may be able to avoid radiation completely. A clinical trial  beginning in March 2022 is investigating whether some patients with HPV-positive tumors who appear disease-free after surgery can avoid radiation treatment. Doctors will assess each patient’s risk using a new blood-based biomarker that indicates whether cancer cells are circulating in the blood, combined with other pathologic information from the tumor. Patients considered low-risk will be closely monitored, with regular blood checks and imaging scans. If the biomarker starts to rise, the patient will begin radiation.

“We think selecting patients carefully for this approach will allow them to remain free of disease while being entirely spared from side effects of radiation,” says radiation oncologist Linda Chen, who is leading the trial along with surgeon Marc Cohen.

“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