The Radiation Therapy Oncology Group (RTOG) has been working on a large randomized trial in patients with stage III, locally advanced, unresectable NSCLC that asked two key questions:
1) is the best dose of radiation the "old" standard of 60 Gray (Gy), over about 6 weeks, or a higher dose of 74 Gy that has been found to be feasible?
2) Is there a value in adding weekly Erbitux (cetuximab), the antibody to the epidermal growth factor receptor (EGFR), along with weekly carboplatin/Taxol (paclitaxel) and concurrent chest radiation therapy (RT)?
This study was done in a "2 x 2" design, in which patients were randomized to four groups:
1) 60 Gy, carbo/Taxol/RT, no Erbitux
2) 75 Gy, carbo/Taxol/RT, no Erbitux
3) 60 Gy, carbo/Taxol/RT, with Erbitux
4) 75 Gy, carbo/Taxol/RT, with Erbitux
This way, it's possible to test two different questions in one trial. And at this point, we have gotten a clear answer to one of those questions of high vs. lower dose, and yes vs. no Erbitux. We now know that, counter to what many would have anticipated, the higher dose is NOT better, and in fact, it's significantly WORSE than the lower dose.
This trial was actually challenging to study because many people thought it was unethical to do a study in which people might be randomized to the lower dose, when they felt we could safely presume that a higher dose of radiation MUST be more effective. Others noted that the higher dose of 74 Gy hadn't been studied in combination with chemo and Erbitux previously, so there could be an unanticipated danger in treating the 4th arm with Erbitux and the higher dose of radiation.
We received some initial word about the trial two years ago, when the RTOG performed and interim analysis of the trial and closed the two arms receiving the higher dose of radiation based on a "futility analysis", meaning that the early results indicated that there was no way that the higher dose RT would be significantly better than the standard dose RT. The trial continued to enroll patients, who were randomized between standard dose RT with chemo and Erbitux or standard dose RT with chemo alone. We hadn't seen actual results from this work until ASCO 2013.
Though the question of the value of Erbitux is still being studied, the actual results presented thus far show a striking and highly significant improvement in progression-free survival (PFS) and overall survival (OS) for the lower dose RT arm, as well as a less surprising significantly higher rate of serious side effects in the recipients of the higher dose of radiation. Specifically, among 419 patients analyzed thus far by receiving 60 vs. 74 Gy of RT, we saw that the PFS was 36.6% vs. 26.3% at 18 months from randomization, favoring (HR 1.3, p = 0.0116). The OS at 18 months was 66.9% vs. 53.9%, median OS 28.7 vs. 19.5 months (HR 1.56, p = 0.0007), which represents a remarkable difference favoring the lower dose of radiation.
Interestingly, the higher dose of radiation was associated with a significantly higher risk of progression in the area of the cancer being treated ("local failure" rate): 34.3% vs. 25.1% (HR = 1.37, p = 0.0319), and a trend toward a higher risk of progression distantly as well. Not surprisingly, the higher dose of radiation was associated with a higher rate of serious (grade 3) esophagitis (21% vs. 7%, p = 0.0003) and more treatment-related deaths (10 vs. 2; not statistically significantly different).
Why did this happen? The short answer, and probably the best answer, is that we don't know. It may be related to the higher rate of treatment-related deaths, a higher dose of radiation to the heart, unreported side effects, perhaps the higher dose requiring more compromise of treatment dose and schedule, but the best answer is that we just don't know, but it was a remarkably worse outcome. Along with findings like Iressa after chemo/radiation or surgery being associated with significantly worse outcomes (at least in molecularly unselected patients), it ranks among the more humbling, unexpected findings that should remind us that we shouldn't make leaps without the evidence from clinical trials. If this trial hadn't been done, many more people would have received higher dose radiation and potentially been harmed in the future.
The one silver lining that I see based on the results that have been presented was the excellent results seen in the lower dose arm. Perhaps it's related to Erbitux -- we don't know if Erbitux helped, hurt, or is having no effect -- but the median survival of 28.7 months with weekly carbo/Taxol and concurrent chest RT (and Erbitux in half of the patients) is better than the results we've seen in other large trials of chemo/RT. It's possible that this result stems from unusually fit patients being enrolled on this trial, given the potentially of being randomized to a high dose radiation arm with chemo and Erbitux, and this isn't as valuable as a direct comparison of carbo/Taxol to another commonly used regimen like cisplatin/etoposide. But at least in this early report of the data, the results with carbo/Taxol are very impressive and lead me to be far more inclined to favor this regimen with concurrent chest RT than I have been up to this point (I've generally favored cisplatin/etoposide based on the results with trials with this regimen seeming modestly superior to some trials with carboplatin/Taxol).
We'll need to learn more from this trial, especially about the value of Erbitux here, but this trial provided some valuable information for the third of NSCLC patients with locally advanced, unresectable stage III disease.
What do you think?
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