.

“Staging helps clinicians answer two questions,” said Allen Ho, MD, professor of Surgery, director of the Head and Neck Cancer Program at Cedars-Sinai and lead author of the study. “The first: How serious is the cancer? The second: What is the best treatment?”

Previous staging guidelines for HPV-positive throat cancer were so broad that as many as 80% of patients were classified as stage 1, with three different possible treatment strategies. Some stage 1 patients were treated with surgery alone, some with surgery plus radiation therapy, and some with surgery and radiation plus chemotherapy.

“The new staging will better inform clinicians and patients about a patient’s prognosis and will minimize inconsistencies in the treatments patients are offered,” Ho said. “Currently, a patient diagnosed as stage 1 might be offered surgery plus radiation and chemotherapy, while another stage 1 patient may be offered surgery alone. The new guidelines will help ensure each patient receives the most appropriate treatment.”

Investigators divided the huge group of stage 1 patients into three separate groups, Ho said. They created new subdivisions of nodal staging, which consider whether cancer has spread to lymph nodes, and paired a more cohesive treatment recommendation with each.

“Perhaps the biggest change in the new staging system is that it takes into account something called extranodal extension, where the cancer has not only spread to the lymph nodes, but has progressed further to destroy the lymph node capsule and spill into the surrounding tissue. Inclusion of this factor is important, because it often changes both prognosis and the recommended treatment following surgery,” said Zachary Zumsteg, MD, professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai and senior author of the paper. 

Ho noted that cases of HPV-positive throat cancer, caused by the same virus that causes cervical cancer, have outpaced cervical cancer because women are routinely screened for cervical cancer. They are also more likely than men to receive the HPV vaccine, which can prevent both cancer types.

The new guidelines were developed by an international committee led by Ho that analyzed data on more than 14,000 patients from 984 healthcare facilities. They are set to become the official worldwide staging guidance in the coming year.

“These findings represent compelling evidence for staging modification,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer and the Steven Spielberg Family Chair in Hematology Oncology. “It is a challenging endeavor, but it improves the information and care that we are able to offer our patients; Cedars-Sinai Cancer is honored to be part of this international effort.”

Ho suggested that patients with newly diagnosed HPV-positive throat cancer ask their care team how these new guidelines have shaped their staging and treatment options.

“Patients should ask their caregivers how these new guidelines impact the clinician’s thinking about the patient’s staging, prognosis and which treatment to offer,” Ho said.

Additional Cedars-Sinai authors include Brian O’Sullivan.

Additional authors include Shao Hui Huang, Michael Luu, Mererid Evans, Robert L. Ferris, James S. Lewis Jr., Raja R. Seethala, Sue S. Yom, Hisham Mehanna, Barton F. Branstetter, Nabil F. Saba, Snehal G. Patel, and William M. Lydiatt.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

The research was published in the peer-reviewed journal The Lancet Diabetes & Endocrinology.

“Many studies have established that the incidence of thyroid cancer has dramatically increased for at least four decades, but the probability of dying of thyroid cancer has remained exactly the same,” said Zachary Zumsteg, MD, associate professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai Cancer and senior author of the study. “This means we are diagnosing and treating many cancers that would do no harm despite recent efforts to reduce overdiagnosis.”

Cancer of the thyroid, a hormone-secreting gland at the front of the neck, is treated surgically. All surgeries have risk, and removing the thyroid often requires patients to take hormone supplements for life, Zumsteg said.

Investigators analyzed data from more than 91,000 thyroid cancer patients registered in public databases from 1975 to 2019 to determine trends in thyroid cancer incidence according to year of birth and year of diagnosis.

A plateau: Zumsteg said efforts have been made to curb overdiagnosis of thyroid cancer over the past several decades, and previous research suggested that rates of thyroid cancer were finally beginning to decline in recent years.

“When we looked at a broader range of data, we found there has been no decline in thyroid cancer diagnoses,” Zumsteg said. “Rates have hit a plateau, with no further increases over the past decade or so. However, the plateau is at peak levels. We continue to diagnose many patients who will not benefit from surgery, and we have essentially made no progress in reducing unnecessary treatments.”

Increased medical imaging over time: Investigators found that the main factor linked with increased thyroid cancer incidence appears to be the passage of time. They theorized that this is mainly due to increased detection of thyroid nodules in modern medical practice.

“People visiting the doctor in 1975 were less likely to receive imaging than those visiting the doctor in 2019,” Zumsteg said. “So today doctors are finding thyroid nodules that would not have been detected in previous decades, leading to more biopsies and diagnoses of small, slow-growing thyroid cancers that might not require treatment.”

A bump in middle age: The study also found that thyroid cancer incidence has increased disproportionately in middle-aged individuals, who are more likely to interact with the medical system.

“Our analysis found that in 1975, the probability of being diagnosed with thyroid cancer was basically the same in people of all ages,” Zumsteg said. “Over time, the increase has been concentrated in women ages 40-69 and men ages 50-79. This especially affected women, who tend to interface with the medical system more often than men.”

Zumsteg said that thyroid cancer overdiagnosis could be addressed with a two-pronged approach. Raising the threshold for both imaging and biopsy of thyroid nodules would reduce overdiagnosis. Less aggressive management would further reduce thyroid cancer overtreatment.

A practice called “active surveillance,” where doctors monitor thyroid cancer patients with regular imaging and perform surgery only if the cancer appears to be growing, could help. There are several ongoing clinical trials of active surveillance, including one at Cedars-Sinai.

“The hope is that these trials will make clinicians and patients more comfortable with active surveillance and that updated clinical guidelines will bring the practice into widespread use,” said study co-author Allen Ho, MD, co-director of the Thyroid Cancer Program and professor of Surgery at Cedars-Sinai, and leader of the Cedars-Sinai clinical trial. “If current trends continue, we will continue to overdiagnose thyroid cancer and to needlessly treat patients—doing more harm than good.”

Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair, said that research such as this is an important part of a community-based approach to cancer prevention and treatment.

“Through our office of Community Outreach and Engagement we promote preventive screening throughout the communities that we serve,” Theodorescu said. “And through our research, we are working to ensure that when we offer treatment, it will yield the best possible outcomes for patients.”

Additional Cedars-Sinai authors: Michael Luu, MPH; Wendy L. Sacks, MD; Jon Mallen-St. Clair, MD, PhD

Additional authors: Michelle M. Chen, MD, MHS; Lisa Orloff, MD; Lauren P. Wallner, PhD, MPH; Susan C. Pitt, MD, MPHS

Read more on the Cedars-Sinai Blog: Active Surveillance for Thyroid Cancer

Numerous laboratory studies have shown that drug-radiotherapy combinations increase the effectiveness of cancer therapy, but clinical trials in humans have been less successful. Only one new non-chemotherapeutic drug has been approved by the Food and Drug Administration for concurrent treatment with radiation.

“One of the biggest reasons for this is that early-phase clinical trials investigating these combinations are challenging to design and implement,” said Zachary Zumsteg, MD, associate professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai and first author of the paper. “Since many side effects of radiotherapy occur after treatment is completed, it can take longer to determine the appropriate dose of treatment. Testing of drug-radiation therapy combinations often occurs in patients receiving first-line therapy, leading to less tolerance of unexpected side effects. And because radiotherapy affects each organ differently, new drug-radiotherapy combinations must be tested separately for cancers arising in different parts of the body.”

To address these challenges, investigators suggest designing trials that use mathematical models with real-time toxicity data to calculate appropriate doses for each patient, allowing for continuous patient enrollment and making trials more efficient. They also advocate testing multiple drug-radiotherapy combinations simultaneously to limit the number of patients receiving any specific drug-radiotherapy combination at a given time. They note that these trial designs require substantial infrastructure and expertise, making them best suited for implementation in large cooperative group clinical trial networks.

The authors suggest that if these clinical trial designs are widely adopted, they are more likely to lead to the development of additional safe and effective cancer treatments.

Additional authors: Siddharth Sheth, Salma K Jabbour, Krishnan R Patel, Randall J Kimple, Terence M Williams, Meng Xu-Welliver, Pedro A Torres-Saavedra, Arta M Monjazeb, Jyoti Mayadev, Steven E Finkelstein, John M Buatti, Sandip P Patel, Steven H Lin.

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