1. Nalley, Catlin

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A radiation dose that is less than half of the standard treatment is a promising option for some patients with HPV-positive throat cancer, according to findings from a recent study. The research team at Memorial Sloan Kettering Cancer Center (MSK) determined that de-escalation of radiotherapy to 30 Gy from standard 70 Gy on the basis of intratreatment hypoxia response on imaging is feasible and safe (J Natl Cancer Inst 2021; doi:10.1093/jnci/djaa184).

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The path to this discovery began with Nancy Y. Lee, MD, FASTRO, a radiation oncologist at MSKCC, who sought to improve the quality of life for these patients while maintaining their response to treatment.


Head and neck cancers related to HPV typically respond well to a combination treatment of surgery, radiation, and chemotherapy; however, the side effects-especially related to radiation-can be serious and long-lasting.


"How can we help our patients? How can we give them a better quality of life while not jeopardizing their local control?" With these questions in mind, Lee initiated a pilot study in 2015, which included 19 HPV-positive oropharynx cancer patients from MSK. The study showed that low-dose radiation could control disease in selected patients. After a median follow-up of 3 years, the cancer had not returned.


Building off these findings, the researchers initiated a larger study to explore this new approach in a cohort of 158 patients. MSK has since expanded the trial to enroll an additional 150 patients, according to Lee, who is Vice Chair of the Department of Radiation Oncology.


A Unique Approach

While most patients will respond to the combination of chemotherapy and radiation, some have tumors that are more resistant. Lee developed a method to detect which patients will respond to a lower dose of radiation.


Working with Heiko Schoder, MD, from Nuclear Medicine at MSK, this new technique uses PET imaging to look for evidence of hypoxia in the tumors. "Tumors with hypoxia are less likely to respond to radiation and chemotherapy," Lee noted. "On the other hand, patients with tumors who do not have hypoxia are very sensitive to radiation. Trusting the biology, we could then de-escalate radiation for this group."


In the study, patients initially underwent radiation and chemotherapy. PET imaging was then used to determine if the tumors were hypoxic. Fifteen of 19 patients had no signs of hypoxia on their baseline PET or resolution on intratreatment PET 2 weeks into chemotherapy and radiation. They were de-escalated to 30 Gy over 3 weeks in combination with 2 cycles of chemotherapy instead of the standard 3 cycles. Patients with persistent hypoxia received the standard dose of 70 Gy with 3 cycles of chemotherapy. De-escalated patients underwent neck dissection at 4 months to assess pathologic response.


"The reason we chose to keep the chemotherapy at 2 cycles is because we know that HPV-positive tumors need at least this much," said Lee and her medical oncology colleague, Eric Sherman, MD. "These tumors can spread, and chemotherapy is the only weapon we have that can mitigate any micro-metastases that are not detected upfront."


Of these 15 patients, the study authors reported that 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4 percent and 94.7 percent, respectively. The researchers observed no acute grade 3 radiation-related toxicities.


With efforts led by Lee and her colleague, Nadeem Riaz, MD, the researchers also analyzed the genetic makeup of the tumors and found a possible reason behind why some HPV-positive tumors are more sensitive to radiation than others. According to Lee, they identified a "mutational signature" that suggests certain tumors have a defect in the way DNA is repaired.


"Using a lower dose of radiation has significant benefits for both patients and the health care system as a whole," Lee told Oncology Times. "There is less toxicity, providing patients with a better quality of life. It is also valuable from a health care cost standpoint. The burden is less because patients are not experiencing the same level of side effects and will not need additional medical intervention to address treatment-related toxicities.


"This is a new paradigm," she continued. "We always talk about precision medicine; this is precision radiation. This approach results in positive outcomes while improving the overall quality of life for our patients."


Practice-Changing Implications

The expanded trial will offer more insights into the effectiveness of this approach. Lee and colleagues hope these results will facilitate FDA approval. "We want every patient and provider to have access to this new technique," she noted.


The ongoing trial will also explore whether or not surgery is needed. The additional 150 patients enrolled in the study will undergo chemotherapy and low-dose radiation, but surgery will be optional-based on a joint decision between both the patient and their physician.


"We are also going to look at the immune signature to gain further insights," Lee said. "We envision a day where we can personalize medicine even further by using all the information available to us.


"We will no longer be boxed in, where everyone has to get the same dose of radiation," she added. "Some patients may only need 3 weeks; others might need 4 weeks. This will take time, but we are one step closer."


Lee noted that this approach could have ramifications for other cancer patients as well. Her team is currently starting a pilot that will explore HPV-negative tumors and if they could benefit from lower dose radiation.


"Ultimately, this study tells us that there is a way to personalize our approach," she concluded. "This new method has the potential to be practice-changing in the future and affect outcomes for many patients."


Catlin Nalley is a contributing writer.