Keeping it Old School: Escalation of Chest RT Dose Fails

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Keeping it Old School: Escalation of Chest RT Dose Fails to Help More than Established Lower Dose for Stage III NSCLC

http://blog.lungevity.org/2011/10/09/rtog-0617/

October 9th, 2011 - by Dr. Jack West

An important result came out of the recent annual meeting of the American Society for Therapeutic Radiation and Oncology (ASTRO) in Miami. At this conference, researchers from the Radiation Therapy Oncology Group (RTOG) reported on a preliminary result from a study, known as RTOG 0617, that will likely alter the way that many patients with stage III (locally advanced) NSCLC are managed today.

It’s important to recognize that our older standards for what is the “standard” dose of chest radiation, about 60-61 Gray (Gy) range (Gy being the units of radiation dose) over 6-6.5 weeks, was historically based on this being about the highest dose that was regularly able to be safely delivered. However, it wasn’t that this is clearly the best dose for killing cancer most effectively: in fact, higher doses lead to more effective cancer cell killing, but at a cost of greater side effects that have limited the feasibility of higher dosing. However, over the past 10-15 years, certain centers have done research using more refined radiation techniques to deliver chest radiation up to doses in the range of 74 Gy or even higher, with concurrent chemotherapy. Following these limited studies that have proven feasibility, there has been a drift in routine practice to often higher doses, to 63-66 Gy pretty routinely and even up to 70-74 Gy in some places, and not just in clinical trials. More and more radiation oncologists are now using conformal radiation techniques to routinely push what is perceived as a “standard dose” of chest radiation with concurrent chemotherapy, and many of us in the field came to view radiation to 60-61 Gy as potential under-dosing of treatment for concurrent chemoradiation today.

In the setting of patients being treated for stage III unresectable NSCLC, the RTOG 0617 study was developed to test high dose vs. lower dose (best standard) radiation with concurrent weekly carbo/Taxol (paclitaxel), all followed by additional carbo/Taxol administered every three weeks. Using a so-called “2 x 2″ randomized design, the study was also designed to determine whether addition of the monoclonal antibody Erbitux (cetuximab) when given to patients getting either the higher radiation dose or lower radiation dose plan could also improve patients outcomes.

Interestingly, the study has been beset by challenges with enrollment over the past few years, because some participating oncologists felt it was problematic to randomize patients locally advanced NSCLC to 60 vs. 74 Gy with concurrent weekly carboplatin/paclitaxel. While these people felt convinced that one or the other dose was clearly superior, it was especially interesting that some people had a problem with the lower dose, which they felt was under-dosing radiation, while others were concerned that treating to 74 Gy wasn’t well tested enough to have this be incorporated into a large trial, particularly if it also included Erbitux, since no trial had tested carbo/Taxol/Erbitux with radiation to 74 Gy.

What we learned from ASTRO is that RTOG has now closed the high dose arm in the wake of analysis by the Data Safety Monitoring Board (DSMB), after 423 patients of just over 500 planned to be enrolled. The DSMB reviewed the results thus far and concluded that there was no way for the higher dose arm to appear superior. This isn’t the same thing as proving that the higher dose radiation is harmful; however, when we see a DSMB closing a trial or an arm of a trial due to futility analysis before enrollment is complete, that often proves to be case. I expect to see that there is actually a worse result with the higher radiation dose, though it may not be statistically significant. It’s also possible that there may be a particular problem to add Erbitux, especially with higher dose RT. At this point, we haven’t seen any actual concrete results.

For now, we can safely conclude that lower dose radiation remains the standard, and that increasing the dose of radiation isn’t clearly beneficial and a good idea simply because it’s feasible to do so. We may also learn that a higher intensity of treatment may be more feasible in more specialized centers, which also tend to attract and treat unusually fit patients, but that this approach runs aground when this is done in a wider experience in a broad population of patients and treating centers is.

We will learn more about this trial in the next couple of years, when the actual results are presented. For now, however, this trial provides another reminder that it’s a mistake to presume that the newer approach is always an improvement and that more is definitely better.