RTOG 0617 Trial: With Chest Radiation, More Is Not Better
RTOG 0617 Trial: With Chest Radiation, More Is Not Better
Bradley JD, Paulus R, Komaki R, et al
Lancet Oncol. 2015;16:187-199
Sometimes the most influential studies inform us with their negative results. The SWOG 0023 trial, which randomly assigned patients with stage III, unresectable non-small cell lung cancer (NSCLC) to maintenance gefitinib or placebo after initial chemotherapy/radiation followed by consolidation docetaxel, was conceived and conducted with a general presumption that the addition of gefitinib may or may not significantly improve survival in this molecularly unselected patient population, but nobody envisioned the final result.
In fact, maintenance gefitinib was associated with a significantly inferior overall survival (OS) compared with the placebo arm, the difference in median OS a remarkable 12 months. We have never seen such a dramatic difference in survival in a trial in locally advanced NSCLC, unfortunately in the wrong direction relative to our hypothesis and hopes of improving on prevailing standards of care.
The RTOG 0617 trial, just published (online first) in Lancet Oncology, echoes this same theme, this time clearly refuting a widespread presumption that a higher dose of chest radiation therapy (RT)—in this case 74 Gray (Gy)—would be superior to a historical standard of 60 Gy. The trial was developed as a two-by-two factorial phase 3 trial in which 544 patents with stage IIIA or IIIB NSCLC received weekly carboplatin and paclitaxel with chest RT followed by two additional cycles of carboplatin/paclitaxel every 3 weeks; patients were randomly assigned to an RT dose of either 60 or 74 Gy, and with or without the epidermal growth factor receptor (EGFR) antibody cetuximab administered weekly.
Comparisons were between RT doses of 60 and 74 Gy and arms receiving or not receiving cetuximab. The trial closed early because of an interim review of data by the data safety monitoring committee that found that the trial results crossed a futility boundary for high-dose radiation, after which patients continued to be randomly assigned to chemotherapy/radiation to 60 Gy with vs without cetuximab. The trial was then closed after a second interim analysis showed that results in regard to cetuximab also crossed a futility boundary.
There was no difference noted as a result of the addition of cetuximab: median progression-free survival (PFS) was 10.8 vs 10.7 months, median OS was 25.0 vs 24.0 months with vs without cetuximab, respectively.
In contrast, there was a highly significant difference favoring the 60 Gy arm vs 74 Gy: median PFS was 11.8 vs 9.8 months (hazard ratio [HR] 1.19; P = .12) and median OS was 28.7 vs 20.3 months (HR 1.38; P = .004).
There were also more treatment-related deaths in the high-dose radiation and cetuximab groups: 8 vs 3 deaths with high- vs low-dose RT, and 10 vs 5 patient deaths in the cetuximab vs no cetuximab arms. Severe esophagitis was also seen significantly more commonly in patients who received high-dose RT (21% vs 7%, P < .0001). Severe toxicity from a wide range of adverse events was significantly more common in recipients of cetuximab (86% vs 70%, P < .0001).
There was no significant interaction between cetuximab and RT dose, but an exploratory analysis of outcomes on cetuximab as a function of "H-score," a product of the percentage of tumor cells positive for EGFR protein expression by immunohistochemistry and the intensity (0-3+) of the staining, suggested a detrimental effect from cetuximab in the half of patients with a low H-score (< 200). Median OS was 19.5 months in such patients who received cetuximab, vs 29.6 months in low H-score patients who did not receive cetuximab (P = .056), another sobering indication that we may harm patients by administering additional treatments beyond current standards of care.
In a postmortem review of what went wrong, the authors speculate, and I agree, that this is likely multifactorial. First, we routinely see a 5%-7% treatment-related mortality (TRM) rate in trials of concurrent chemotherapy/radiation for stage III NSCLC, so it is reasonable to expect that increasing dose and/or additional agents may lead to an attendant increase in TRM that is not offset by improved efficacy. Increased RT dose was associated with a modestly reduced ability to complete intended therapy (70% vs 64%). RT planning was more likely to be noncompliant in the high-dose group (26% vs 17%, P = .02), and heart dose was also higher in the 74 Gy group.
Regardless of whether we can identify one or more leading causes, RTOG 0617 provides clear and practice-changing results. Unfortunately, these results show that neither RT dose escalation nor the addition of cetuximab to a standard chemotherapy/radiation approach improves outcomes, but rather that RT to 74 Gy is detrimental overall, while the addition of cetuximab may also be detrimental to a subset of patients with a low H-score.
Notably, accrual to this trial was challenging in part because some clinicians felt so confident that the higher RT dose was superior that it was unethical to randomly assign people to the 60 Gy dose. At the same time, chest RT dosing to 64-66 Gy, and sometimes higher, became commonly pursued outside of a protocol setting, due to the demonstrated feasibility and a prevailing presumption that more must be better.
It is sobering to recognize that our efforts to improve outcomes for patients with locally advanced NSCLC have failed to yield significant clinical benefits in the past several years, but definitive testing of new treatments and approaches is valuable even when a trial is negative. This is particularly true when negative results challenge an assumption made in the absence of data from prospective trials, even more so when clinical practice that is ahead of the evidence demonstrates a significant detrimental effect. As we see proton beam radiation marketed well outside of a proven role, or we become enthused about using targeted therapies outside of their evidence-based indications based on newly obtained results of genomic testing, we should beware of hubris and heed the warnings of trials like SWOG 0023 and RTOG 0617. We can do significant harm to patients by presuming to know more than the evidence demonstrates.
Abstract
Standard-Dose vs. High-Dose Conformal Radiotherapy With Concurrent and Consolidation Carboplatin Plus Paclitaxel With or Without Cetuximab for Patients With Stage IIIA or IIIB Non-small-cell Lung Cancer (RTOG 0617): A Randomized, Two-by-Two Factorial Phase 3 Study
Bradley JD, Paulus R, Komaki R, et al
Lancet Oncol. 2015;16:187-199
Sometimes the most influential studies inform us with their negative results. The SWOG 0023 trial, which randomly assigned patients with stage III, unresectable non-small cell lung cancer (NSCLC) to maintenance gefitinib or placebo after initial chemotherapy/radiation followed by consolidation docetaxel, was conceived and conducted with a general presumption that the addition of gefitinib may or may not significantly improve survival in this molecularly unselected patient population, but nobody envisioned the final result.
In fact, maintenance gefitinib was associated with a significantly inferior overall survival (OS) compared with the placebo arm, the difference in median OS a remarkable 12 months. We have never seen such a dramatic difference in survival in a trial in locally advanced NSCLC, unfortunately in the wrong direction relative to our hypothesis and hopes of improving on prevailing standards of care.
The RTOG 0617 trial, just published (online first) in Lancet Oncology, echoes this same theme, this time clearly refuting a widespread presumption that a higher dose of chest radiation therapy (RT)—in this case 74 Gray (Gy)—would be superior to a historical standard of 60 Gy. The trial was developed as a two-by-two factorial phase 3 trial in which 544 patents with stage IIIA or IIIB NSCLC received weekly carboplatin and paclitaxel with chest RT followed by two additional cycles of carboplatin/paclitaxel every 3 weeks; patients were randomly assigned to an RT dose of either 60 or 74 Gy, and with or without the epidermal growth factor receptor (EGFR) antibody cetuximab administered weekly.
Comparisons were between RT doses of 60 and 74 Gy and arms receiving or not receiving cetuximab. The trial closed early because of an interim review of data by the data safety monitoring committee that found that the trial results crossed a futility boundary for high-dose radiation, after which patients continued to be randomly assigned to chemotherapy/radiation to 60 Gy with vs without cetuximab. The trial was then closed after a second interim analysis showed that results in regard to cetuximab also crossed a futility boundary.
There was no difference noted as a result of the addition of cetuximab: median progression-free survival (PFS) was 10.8 vs 10.7 months, median OS was 25.0 vs 24.0 months with vs without cetuximab, respectively.
In contrast, there was a highly significant difference favoring the 60 Gy arm vs 74 Gy: median PFS was 11.8 vs 9.8 months (hazard ratio [HR] 1.19; P = .12) and median OS was 28.7 vs 20.3 months (HR 1.38; P = .004).
There were also more treatment-related deaths in the high-dose radiation and cetuximab groups: 8 vs 3 deaths with high- vs low-dose RT, and 10 vs 5 patient deaths in the cetuximab vs no cetuximab arms. Severe esophagitis was also seen significantly more commonly in patients who received high-dose RT (21% vs 7%, P < .0001). Severe toxicity from a wide range of adverse events was significantly more common in recipients of cetuximab (86% vs 70%, P < .0001).
There was no significant interaction between cetuximab and RT dose, but an exploratory analysis of outcomes on cetuximab as a function of "H-score," a product of the percentage of tumor cells positive for EGFR protein expression by immunohistochemistry and the intensity (0-3+) of the staining, suggested a detrimental effect from cetuximab in the half of patients with a low H-score (< 200). Median OS was 19.5 months in such patients who received cetuximab, vs 29.6 months in low H-score patients who did not receive cetuximab (P = .056), another sobering indication that we may harm patients by administering additional treatments beyond current standards of care.
In a postmortem review of what went wrong, the authors speculate, and I agree, that this is likely multifactorial. First, we routinely see a 5%-7% treatment-related mortality (TRM) rate in trials of concurrent chemotherapy/radiation for stage III NSCLC, so it is reasonable to expect that increasing dose and/or additional agents may lead to an attendant increase in TRM that is not offset by improved efficacy. Increased RT dose was associated with a modestly reduced ability to complete intended therapy (70% vs 64%). RT planning was more likely to be noncompliant in the high-dose group (26% vs 17%, P = .02), and heart dose was also higher in the 74 Gy group.
Regardless of whether we can identify one or more leading causes, RTOG 0617 provides clear and practice-changing results. Unfortunately, these results show that neither RT dose escalation nor the addition of cetuximab to a standard chemotherapy/radiation approach improves outcomes, but rather that RT to 74 Gy is detrimental overall, while the addition of cetuximab may also be detrimental to a subset of patients with a low H-score.
Notably, accrual to this trial was challenging in part because some clinicians felt so confident that the higher RT dose was superior that it was unethical to randomly assign people to the 60 Gy dose. At the same time, chest RT dosing to 64-66 Gy, and sometimes higher, became commonly pursued outside of a protocol setting, due to the demonstrated feasibility and a prevailing presumption that more must be better.
It is sobering to recognize that our efforts to improve outcomes for patients with locally advanced NSCLC have failed to yield significant clinical benefits in the past several years, but definitive testing of new treatments and approaches is valuable even when a trial is negative. This is particularly true when negative results challenge an assumption made in the absence of data from prospective trials, even more so when clinical practice that is ahead of the evidence demonstrates a significant detrimental effect. As we see proton beam radiation marketed well outside of a proven role, or we become enthused about using targeted therapies outside of their evidence-based indications based on newly obtained results of genomic testing, we should beware of hubris and heed the warnings of trials like SWOG 0023 and RTOG 0617. We can do significant harm to patients by presuming to know more than the evidence demonstrates.
Abstract
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