New Classification System Reflects Improved Prognosis for HPV+ Oropharyngeal Cancer

Brian O'Sullivan, MD

Researchers at the University of Toronto have created a new classification system specific to HPV-positive oropharyngeal cancer. The system, known as ICON-S, is adjusted for the improved prognosis for patients with HPV-positive disease versus negative.

One of the most significant difference between the standard 7th edition TNM stage criteria and this HPV-positive specific system is the classification of stage IV or advanced disease, said Brian O'Sullivan, MD, the lead author on the study supporting the proposed new system.

“When we see patients with so-called advanced disease based on what we used to use as a classification, it is just not true, said O'Sullivan. “These so-called stage IV patients have a real chance to be cured and have been reclassified as stage II or stage I.”

Of the 1907 patients with HPV-positive oropharyngeal cancer enrolled in the study, the 5-year overall survival rate was similar for 7th edition TNM stage I, II, III, and IVA, with 88% 82%, 84%, and 81%, respectively.

To understand more about the impact of this new classification, OncLive spoke with O'Sullivan, a professor in the department of Radiation Oncology at the University of Toronto.

OncLive: How has the understanding of HPV-related oropharynx cancer evolved in recent years?

O'Sullivan: The start of this whole story was when we began to recognize the existence of this disease. I guess we were a little asleep at the switch up until about 10 years ago. Those of us who have been practicing for a long time can all remember patients who had cancer of the lymph nodes and then were cured and we didn’t really understand how we cured them. Now we know that these were the early cases related to the HPV virus, usually subtype 16 and sometimes subtype 18 and a few others.

The difficulty with our normal approach to managing cancer is that we have no way of describing the extent of disease, which is the very important part of surveillance, cancer control, guidance of treatment, research, maintenance, and the design of clinical trials. This new disease completely confounded everything we knew about normal head and neck cancer.

A number of papers began to emerge and we learned that lymph nodes probably didn’t even matter toward the prognosis, except for very advanced disease. Last year, we presented data showing that the normal TNM, which was designed for HPV-negative cancers, still worked very well for them, but was completely hopeless for this new group of patients. In particular, we felt that patients with stage IV disease, which everybody thinks is very bad, were doing extremely well. After that study last year, we felt that we had to validate it with another study.

Were you able to validate these findings?

Our previous findings were validated in a large cohort with about 2000 patients coming from 7 centers across North America and Europe using our own data as a training cohort. I think we showed fairly well that we had a good concordance between the validate cohort, which had about 1200 patients, and our own cohort. Using a number of different parameters and a number of different statistical tools that are recognized for comparing staging systems, this new staging system turned out to be way better than anything we had before. It was consistent across all 6 additional centers.

What are the most significant differences between the previous classification system and this one?

Another interesting aspect is a lot of which used to be stage IV in the TNM system, gets moved up to stage II or I. Stage I is now defined as T1 or T2, N0, or N1 in the new category.

It is a very dramatic difference. Many of these patients were N2s before; they were N2a or N2b stage IV and they are now stage I. That is the way they behave and they have a very favorable prognosis.

We then took what used to be N2c disease, and made it N2. That group of patients also does extremely well, just a bit lower than stage I. And finally T4 and N3 becomes stage III. They still do well though, but not as well as the earlier group.

Stage IV would be patients who have advanced to distance metastasis. This is an interesting group as well because some of those patients, if they have solidary disease, may even be able to be controlled in the long term with surgery, stereotactic radiotherapy, or even chemotherapy. We had never seen that before in HPV-negative patients. There is a group of indolent metastasis patients who would be considered stage IV that could be cured. It’s a small number, but we shouldn’t forget them.

What can the community oncologist take away from these findings?

Many, many of these patients will be cured and that is something we need to remind these patients when they first come in. Patients come in after they find out they have stage IV disease and think they have a death sentence. But it is not a death sentence, these patients do have a chance to be cured.

O'Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 2016;17(4):440-451.

A couple of things were of interest. One is the fact that all of the nodal disease that is less than what we would traditionally call N2c disease, contralateral disease or bilateral disease, collapses into just N1. There is no separation between traditional N1, which is a small lymph node and N2a, which is a node bigger than 3 cm but less than 6 cm solitary on one side of the neck, or multiple lymph nodes on one side of the neck provided they are not greater than 6 cm. They all behave exactly the same and don’t even do worse than N0, which is no lymph nodes.