Escalating Radiation Dose Shows Promise in Patients With Locally Advanced Pancreatic Cancer

Michael Chuong, MD

Administration of ablative radiation therapy in 5 fractions guided by MRIdian Linac online adaptive replanning or 15-25 fractions delivered with CT guidance appear to be viable options for the treatment of locally advanced pancreatic cancer.¹

According to results from a multi-institutional study conducted at Miami Cancer Institute [MCI] and Memorial Sloan Kettering Cancer Center [MSK], these ablative radiation therapy strategies should only be performed on appropriately selected patients. Moreover, the choice of either 5 fractions or 15-25 fractions should be based on anatomical considerations and the technology that is available.

Of the 183 patients treated in the 2-center study, 62 received radiation therapy at 50 Gy in 5 fractions, 23 patients received 67.5 Gy in 15 fractions, and 98 received 75 Gy in 25 fractions. Results showed that achievement of node-negative disease was more likely in the 5 fractions group compared with 15-25 fractions (69.3% vs 44.6%, P = .0219). However, there were no clinical differences between the 2 arms.

In an interview with Targeted Oncology™, Michael Chuong, MD, medical director of proton therapy and photon therapy, radiation, Baptist Health South Florida, discussed how 5 fractions of ablative radiation therapy compare with 15-25 fractions for the treatment of locally advanced pancreatic cancer.

TARGETED ONCOLOGY: Can you discuss standard radiation therapy used in locally advanced pancreatic cancer? What kind of results are being seen with that therapy?

Chuong: I would start by saying that the use of radiation therapy for locally advanced pancreas cancer really is not standard. In many regions of the world, patients are not offered radiation therapy. For those who are, a modest dose of radiation, what we call non-ablative, is a standard of care. It is a dose that can have some good local effects. At the end of the day, it's not a dose that we expect to have a high chance of eradicating the tumor or providing good tumor control beyond 1 year or so for most patients. That simply is because these tumors are many times surrounded by the intestine or stomach, so delivering high doses to those organs would increase the risk of causing severe [adverse events]. For that reason, a modest dose that can have some efficacy, but without major side effects is a standard of care.

What was the rationale for multi-institutional study of 5 vs 15-25 fractions of ablative radiation therapy in patients with pancreatic cancer?

The concept of escalating the radiation dose to an ablative range or a very high dose range is something that has been explored by several different institutions using different technological approaches. Individually, centers like Miami Cancer Institute and MSK have approached this differently but have reached similar conclusions in their own separate studies. The concept of this study was to see if collectively, there was benefit of ablative radiation therapy, combining our data together using these different approaches. That is, in fact, what we did in that our patients at Miami Cancer Institute who were all treated with a meridian device in 5 days, using what's called an online adaptive radiation therapy. The outcomes from these patients were combined with patients who were treated at 15 but more often 25 days using CT scans for guidance. We combined our data to see if collectively there was a still a consistent benefit to ablative radiation.

Can you give an overview of the results that were presented at the ASTRO Annual Meeting?

The study was conducted with just over 180 patients between our 2 institutions. In most of these patients who had chemotherapy before radiation therapy, we saw a very strong signal in the combined data that we each had individually seen at our institutions using our own individual approaches. That included excellent long-term results as measured by 2-year freedom from local progression. Also, what was especially exciting were the survival rates that we saw collectively. At 2 years, the survival percentage was right around 35%, which is substantially higher than what is expected from what is seen after non-ablative radiation therapy, as measured from the time of the radiation therapy delivery, and not from the time of diagnosis. Lastly, we saw that escalating the radiation dose using either approach did not cause major toxicity in most patients. Each of our advanced technological approaches seem to be highly effective but also very well tolerated.

How do you interpret these findings?

This is a strong signal that the concept of escalating the radiation dose for locally advanced unresectable pancreas cancers is a viable strategy. This also signals potentially a true improvement in long-term survival for patients with pancreas cancer. As I mentioned before, some patients throughout the world are not even offered radiation as a consideration. But if we can demonstrate in prospective trials that ablative radiation therapy not only improves local control but also substantially prolongs patient survival, that could change the paradigm of how this disease is managed.

What are the next steps for pushing these strategies forward in pancreatic cancer?

There are several prospective clinical trials either that are being designed or are planning to open in the near future. I’m the principal investigator of a phase 3, randomized trial called the LAP-ABLATE trial [NCT05585554], which is comparing chemotherapy alone vs chemotherapy plus 5 fraction ablative radiation therapy delivered on the MRIdian Linac. That is a trial that is primarily designed to evaluate to your overall survival, building on the data that we have published and including data from our combined analysis with MSK.

What other novel radiation strategies look promising for locally advanced pancreatic cancer?

We at MCI are especially excited about MRI-guided radiation therapy. There are other technologies that can be used for pancreatic cancer, including proton therapy, which we feature here at our institution. I think from a dose-escalation standpoint, there were very few technologies and approaches that have been shown to potentially prolong survival without increasing toxicity. That is why MRI-guided radiation therapy is so exciting to us.

_REFERENCES:

_{Reyngold M, O’Reilly E. Herrera R, et al. 297 Multi-institutional comparison of ablative radiation therapy in 5 versus 15-25 fractions for locally advanced pancreatic cancer. Presented at: ASTRO 2022 Annual Meeting; October 23-26, 2022; San Antonio, TX.}