Written By Kevin Kerfoot / Reviewed By Ray Spotts
Previous research has suggested that patients with metastatic oral cancer - cancer that spreads beyond the mouth - experience more pain than those whose cancer has not spread. A new study - published in Scientific Reports - helps researchers understand why. The findings may ultimately be used to alleviate oral cancer pain and refine surgical decision making when treating oral cancer.
Oral cancer can cause severe pain during everyday activities, including talking and eating, and is more likely to spread in patients experiencing high levels of pain, according to researchers at New York University (NYU) College of Dentistry that found genetic and cellular clues as to why metastatic oral cancers are so painful.
While most oral cancer surgeries include a prophylactic neck dissection, research shows that up to 70 percent are unnecessary. When oral cancer metastasizes and spreads to lymph nodes in the neck, a patient’s chance of survival is cut by half.
However, it’s often unclear through imaging and physical assessment if oral cancer has spread, leaving surgeons struggling with whether to preemptively remove lymph nodes - an invasive procedure termed prophylactic neck dissection - during surgery to remove the oral cancer.
“Clinicians and researchers are keen to define a biomarker that accurately predicts metastasis,” says the study’s lead author Aditi Bhattacharya, Ph.D., an assistant professor in the Department of Oral and Maxillofacial Surgery at NYU College of Dentistry, an investigator at NYU Bluestone Center for Clinical Research.
“Given that patients with metastatic oral cancer experience more pain, we thought that a patient’s level of pain might help predict metastasis. A surgeon could then use this knowledge to only remove lymph nodes in patients with cancers that are most likely to metastasize.”
Oral cancer pain questions
The researchers first documented the pain experienced by 72 oral cancer patients before surgery using an oral cancer pain questionnaire developed by the investigators. While most patients reported some pain, those who suffered with the most pain were more likely to have cancer that spread to lymph nodes in the neck.
This observation suggested that patients with less pain are at low risk of metastasis, and will rarely benefit from a neck dissection. The investigators looked for differences in gene expression between metastatic cancers from patients with high levels of pain compared to non-metastatic cancers from patients not experiencing pain.
Cancer pain is attributed to the release of mediators from cancers that sensitize nerves near the cancer. Forty genes were identified that were more highly expressed in painful metastatic cancers, suggesting that they promote metastasis and mediate cancer pain.
Many of these genes are found in exosomes, small vesicles that break away from a cell and can be taken up by other cells - revealing a potential mechanism for how cancers communicate with nerves.
“This is the first time that we have demonstrated a correlation between a patient’s pain and the clinical behavior of the cancer,” says Brian L. Schmidt, DDS, MD, Ph.D., director of the NYU Bluestone Center for Clinical Research and professor in the Department of Oral and Maxillofacial Surgery at NYU College of Dentistry.
The researchers undertook laboratory experiments to study exosomes found in the extracellular fluid of oral cancer cells grown in the lab. When this extracellular fluid was injected into animal models, it produced pain, but when the cancer-derived exosomes in the fluid were removed, it did not cause pain, suggesting that exosomes from cancer may be responsible for oral cancer pain.
With a deeper understanding of why metastatic oral cancers are painful, the researchers point to several potential clinical applications for their research, including a biomarker for oral cancer metastasis to help with surgical decision making and future testing options.
“The identified genes are targets for therapy aimed at stopping pain and cancer. In addition, exosomes shed from cancers can be detected in saliva, blood, and urine, offering the potential for an objective molecular test to diagnose risk of metastasis,” added Donna Albertson, Ph.D., professor in the Department of Oral and Maxillofacial Surgery at NYU College of Dentistry, an investigator at NYU Bluestone Center for Clinical Research, and the study’s corresponding author.
Pre-operative immunotherapy and oral cancers
A recent clinical trial suggests that immunotherapy given before other treatments for oral cavity cancers can elicit an immune response that shrinks tumors, which could provide long-term benefit for patients.
In the randomized phase II trial, two neoadjuvant doses of nivolumab given with or without ipilimumab led to complete or partial tumor shrinkage in most cases and did not delay any patients from continuing on to standard treatment. These promising responses could translate into improved outcomes for patients with an especially difficult and painful type of cancer.
"With roughly three weeks of treatment, we were able to trigger significant tumor regression,” says lead author Jonathan D. Schoenfeld, MD, MPH, senior physician at the Dana-Farber/Brigham and Women's Cancer Center and associate professor of radiation oncology at Harvard Medical School.
“In a couple cases, there were complete pathological responses, and in other cases, there was very little tumor left. Both the single drug and the two-drug combination led to visible tumor shrinkage, and, albeit with relatively early follow-up, the majority of these patients have no evidence of disease recurrence. Our hope is that even a couple doses of immunotherapy can stimulate an immune response that continues to prevent the cancer from coming back after patients have surgery and other therapy."
Thirty adults newly diagnosed with tumors in their tongue, gums or other parts of the mouth were enrolled in the trial. All tumors were stage T2 or higher, and over half of the patients' cancers had spread to their lymph nodes.
After receiving two doses of the PD-1 blocker nivolumab either alone or in combination with a single dose of the CTLA-4 blocker ipilimumab over the course of three weeks, no patients were delayed from surgery, the first component of standard treatment for this disease.
Fifty-two percent of the patients experienced clinical reduction of their primary tumor after immunotherapy, and four patients had more than 90 percent pathologic response. While these exploratory results are promising, direct comparisons with the current standard of care are needed to determine whether the single-agent or combination therapy can lead to durable responses and improve patient survival.
The researchers also want to understand why immunotherapy worked better with some patients than others and identify additional immune targets that could further enhance the treatment.
Twenty-one of the 30 patients experienced side effects possibly related to treatment, and grade three to four toxicities for five patients in the combination group and two patients in the single-drug group. The researchers were encouraged by these results; by comparison, more than half of patients experienced serious adverse events with the same combination in trials for high-risk resectable melanoma.
Immunotherapy drugs for oral cancer
While immunotherapy drugs generally are used after other treatments have failed and a patient's cancer has spread, this study adds to a growing body of research on immunotherapy given prior to surgery for patients with newly diagnosed, curable disease.
"The preoperative setting is interesting because patients' immune systems haven't been affected by prior treatment,” Schoenfeld added. “The tumor is actually in place to serve as a focal point for an immune response, so it may be easier for the body's immune system to recognize and target the tumor."
"Oral cavity cancer is a notoriously difficult cancer with high rates of disease recurrence and death, and the side effects from standard treatment tend to be particularly challenging because the treated area is essential for speaking, swallowing and breathing. We're excited about moving immunotherapy earlier to treat more of these curative patients and, in the future, possibly reduce how aggressive their other treatments need to be."
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With over 30 years of writing and editing experience for newspapers, magazines and corporate communications, Kevin Kerfoot writes about natural health, nutrition, skincare and oral hygiene for Trusted Health Products’ natural health blog and newsletters.
Founder Ray Spotts has a passion for all things natural and has made a life study of nature as it relates to health and well-being. Ray became a forerunner bringing products to market that are extraordinarily effective and free from potentially harmful chemicals and additives. For this reason Ray formed Trusted Health Products, a company you can trust for clean, effective, and healthy products. Ray is an organic gardener, likes fishing, hiking, and teaching and mentoring people to start new businesses. You can get his book for free, “How To Succeed In Business Based On God’s Word,” at www.rayspotts.com.