Radiation therapy for chordoma: More personalized decisions may be possible through tumor genetics

After having surgery to remove their tumor, most skull base chordoma patients also undergo radiation therapy. However, even in experienced centers, radiation can be associated with some long-term side effects. Thus, patients sometimes wonder if they could forgo radiation – particularly if no tumor remains after surgery. Now, new data could make the choice a little clearer for most patients with skull base chordoma. Researchers discovered that patients whose tumors have certain genetic markers might be able to refrain from radiation if surgery is successful in removing the entire tumor.

The project was carried out at the University of Pittsburgh Medical Center by Dr. Georgios Zenonos, Hussein Abdallah, and colleagues including Dr. Paul Gardner, a member of the Chordoma Foundation’s Medical Advisory Board. Their work was presented at this year’s North American Skull Base Society Virtual Symposium, where it won the best basic science award.

Using a kind of genetic test called FISH (fluorescence in situ hybridization) on the removed tumors, the team analyzed samples from 152 adult patients with skull base chordoma for the presence or absence of certain stretches of DNA (chromosomes 1p36 and 9p21), which had previously been reported to be lost in some chordomas. Interestingly, they found that the proportion of tumor cells missing these two genetic markers varied significantly across individuals. Further, when patients were grouped based on the proportion of cells in their tumor (low, intermediate, or high) that lost the 1p36 and 9p21 markers, there was a strong correlation with prognosis: lower levels of loss corresponded to a significantly longer time without disease progression following initial surgery.

The researchers then linked the FISH testing results and duration of progression-free survival to data on whether patients’ surgeries resulted in total removal of the tumor and whether they underwent radiation.

As expected, the data suggested that surgery with complete tumor removal (gross total resection, GTR) improves outcomes compared to surgery without GTR. In addition, radiation showed clear benefit for most patients. However, whether patients benefited from radiation was found to depend on the proportion of cells in their tumors with loss of the two genetic markers:

• Patients with a low level of loss were unlikely to derive further benefit from radiation therapy if GTR is achieved – which it almost always is for these patients, as the tumors in this group tend to be smaller and less invasive. There wasn’t a large enough number of patients in this group for researchers to accurately determine whether radiation is beneficial when GTR isn’t possible.
• For patients with an intermediate level of loss, radiation seems to make a difference mainly when GTR isn’t possible. These data suggest that it could be withheld when GTR is achieved.
• Patients with a high level of loss benefit from radiation therapy regardless of whether GTR is achieved.

Overall, these findings suggest that FISH testing may be a useful tool for guiding decisions about radiation following surgery for skull base chordomas. This work also adds to strong evidence that not all chordomas are the same, and underscores the need to better understand tumor differences in order to offer more personalized clinical care. Critical next steps include conducting similar analyses on spinal and sacral chordoma tumors, and validating the findings in a greater number of patients from a range of medical centers. Doing so will continue to clarify which chordoma patients stand to gain the most from radiation therapy.