Researchers Identify Predictors for Distant Metastases in HPV+ Oropharyngeal Cancer

Shlomo Koyfman, MD

Although HPV-positive oropharyngeal cancer is associated with more favorable outcomes, there is a heterogeneous group of patients who have higher disease failure rates and a greater likelihood of distant metastases.

A recent study sought to identify predictors of distant metastases in patients with HPV-positive oropharyngeal cancer treated with cisplatin-based chemoradiotherapy or cetuximab-based bioradiotherapy.

Increased distant metastases rates were noted in active smokers versus never/former smokers (22% vs 5%, respectively), T4 versus T1-T3 (15% vs 6%, respectively), and cetuximab-based bioradiotherapy versus cisplatin-based chemoradiotherapy (23% vs 5%, respectively).

OncLive: Can you start by giving an overview of this study?

In an interview with OncLive, lead investigator Shlomo Koyfman, MD, associate staff, radiation oncology, Cleveland Clinic, discussed the study findings and the implication going forward for the treatment of patients with HPV-positive oropharyngeal cancer.Koyfman: Head and neck cancer was historically found in older men with a lot of smoking and alcohol exposure. In the last 10 to 15 years, we’ve seen an explosion of head and neck cancer—usually in the base of the tongue and tonsil, and mostly in young, healthy, white males who smoke or drink minimally. The discovery is there is a different kind of head and neck cancer in the oropharynx caused by HPV.

The reason this is important is because we found that it’s increasing and is going to be the most common virally associated cancer in the United States by 2020. Fascinatingly, while we're seeing this more, these patients are generally incredibly responsive to treatment and tend to have much fewer side effects to therapy.

Overall, the cure rate with these patients is about 90%, even though most of them present with stage IV disease. We noticed there is a small amount, roughly 15% to 20%, of patients with HPV-positive associated cancer whose cancer returned. Historically, if head and neck cancer returned, it would most commonly be where it started or occasionally come back in the lungs or elsewhere. In this study, 95% of patients with HPV-positive associated cancer whose cancer returned, never had it come back in the head and neck—it returned elsewhere.

What were the results of this study?

We tried to figure out why the cancers are coming back in the lungs and other places in the body instead of in the head and neck. In the study, we attempted to identify the predictors of distant metastasis.The predictors for distant metastasis were T4 tumors and heavy smoking. If you have a virus cancer that is associated with smoking, it causes the cancer to behave differently.

The most significant finding was we had patients treated with the standard radiation chemotherapy, which is cisplatin-based chemotherapy, and then we had patients treated with cetuximab. Most patients received cisplatin, whereas maybe 15% received cetuximab.

Are there any next steps following these results?

The chances of patients developing distant metastasis were doubled in the patients who were treated with cetuximab compared to those treated with cisplatin, which is traumatic because the chances of it coming back in head and neck is only 5%. Since, overwhelmingly, it either comes back in the rest of the body or you’re cured, the cure rates for these people were cut in half if they were treated with cetuximab as opposed to cisplatin. It's important to also recognize that cisplatin is a traditional chemotherapy, whereas cetuximab is more of an antibody medicine that is thought to help the cancer cells be more sensitive to radiation.

What this led us to understand is that this gives us important learning points. The pattern of failure is changing in these patients. Before, we primarily worried about a patient’s cancer coming back where it started, now we must start realizing that it’s much more likely for it to come back elsewhere in the body.

If a patient receives cetuximab, which in certain ways has fewer adverse events, we may be compromising our ability to eradicate micrometastatic disease and sterilize any cancer that has gotten into the bloodstream, putting these patients at a higher risk of having incurable disease. The reason that's important is because the next step would be to test this in a prospective trial to test radiation with cisplatin compared to radiation with cetuximab.

The good news is this trial has been done; it’s called the RTOG-1016 trial, which accrued 1000 patients in record time. We are awaiting the results which will determine whether our findings bear out in a larger, randomized fashion whether cetuximab is associated with a higher risk of cancer coming back elsewhere in the body. It’s still going to be a couple years to get that result.

What are some other challenges that are facing this space that you would like to see answered in the next 5 to 10 years?

While we’re waiting for those results, there are many doctors that use the cetuximab-based chemotherapy instead of regular cisplatin-based chemotherapy since there are fewer adverse events, it’s better tolerated by patients, and these virus patients have great cure rates. The whole purpose of our publishing this paper is as a cautionary note to providers, saying until we have high-level evidence that suggests that they are equivalent, we have concerns that cetuximab is not treating cancer elsewhere in the body. We want doctors to consider other more standard chemotherapy regimens rather than cetuximab, because we are concerned about the risk of it coming back elsewhere in the body. Between big tumors and heavy smokers, the real challenge is that HPV-positive oropharyngeal cancer is not 1 disease. There are different groups of patients within this disease. The next generation of trials would like to sort out who are the favorable patients that are going to have a 95% to 98% cure rate and don’t need to be treated as heavily.

Are there any other ongoing trials in this space that you are particularly excited to see the results of?

The next question is who are that 10% or 20% of patients who aren’t going to do as well and who need to intensify therapy. One of the exciting areas of research is induction chemotherapy, which is doing more intensive, whole-body chemotherapy to reduce the risk of it spreading elsewhere, as well as immunotherapy, which is a whole new class of medicines which has been approved in head and neck cancer and combining those regimens to chemoradiation. That's being tested in several trials, the most notable being the RTOG-3504 trial. HPV-positive cancers have become the best biomarker available in head and neck cancer. It is because of that we are now looking at virus associated cancer differently than non-associated virus cancer.

In these favorable HPV-positive settings, we just completed a trial with lower radiation doses and lower chemotherapy with some patients receiving no chemotherapy. The next step is to reduce the intensity of treatment further. These are young, healthy people trying to reduce adverse events and the burden of treatment, which is a very high priority for these people with high cure rates.

What are the main takeaways you would like community oncologists to take from this study?

The addition of immunotherapy might improve outcomes in the patients who don’t do as well.The main takeaways are even though patients with HPV-positive cancers have very high cure rates, there is a group of patients that don’t do well and are more likely to fail distantly elsewhere in the body as opposed to the head and neck. Therefore, avoiding systemic therapy should be done with great care in these patients, specifically traditional chemotherapies. We much prefer traditional chemotherapies as opposed to cetuximab. Cetuximab should be avoided in higher-risk patients until the trials have been reported.

Weller, M. A., Ward, M. C., Berriochoa, C., et al. Predictors of distant metastasis in human papillomavirus—associated oropharyngeal cancer [published online February 11, 2017]. Head Neck. doi: 10.1002/hed.24711