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DeCIDE: Addition of induction chemotherapy to chemoradiotherapy did not significantly improve OS
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CHICAGO — The addition of induction chemotherapy to chemoradiotherapy did not significantly improve OS for patients with advanced squamous cell carcinoma of the head and neck, according to results of the phase 3 DeCIDE trial.
Induction chemotherapy is associated with lower distant failure rates in squamous cell carcinoma of the head and neck.
Ezra E.W. Cohen, MD, an associate professor of medicine at the University of Chicago, and colleagues conducted the study to determine whether the addition of induction chemotherapy prior to chemoradiotherapy would improve survival compared with chemoradiotherapy alone.
The researchers enrolled 280 patients with squamous cell carcinoma of the head and neck in the open-label trial between 2004 and 2009. All patients had treatment-naïve N2/N3 disease without metastases.
The researchers randomized the patients to chemoradiotherapy alone, or two cycles of induction chemotherapy followed by the same chemoradiotherapy regimen.
Minimum follow-up was 36 months. The primary endpoint was OS.
Of the 142 patients assigned to induction chemotherapy, 91% received two cycles and 87% continued on to the chemoradiotherapy regimen.
Three-year OS was 75% for the induction chemotherapy arm vs. 73% for the chemoradiotherapy alone arm (HR=0.92; 95% CI, 0.59-1.42; P=.70). Patients in the induction chemotherapy arm experienced longer distant-free failure survival (69% vs. 64%; HR=0.84; 95% CI, 0.56-1.26; P=.39); longer relapse-free survival (67% vs. 59%; HR=0.76; 95% CI, 0.52-1.13; P=0.18); lower cumulative incidence of distant failure (10% vs. 19%; HR=0.46; 95% CI, 0.23-0.92; P=.025); and lower cumulative incidence of locoregional failure (9% vs. 12%; HR=0.79; 95% CI, 0.37-1.68; P=.55).
“Further analysis and follow-up may provide insight into why the significant decrease in distant failure did not translate to improved OS,” Cohen and colleagues wrote.
The most common grade-3/grade-4 toxicities reported during induction chemotherapy were febrile neutropenia (9%) and mucositis (8%). The most common grade-3/grade-4 toxicities reported by patients in both arms as they underwent chemoradiotherapy were mucositis (45%), dermatitis (19%) and leukopenia (17%). Only grade-3/grade-4 leukopenia (P=.002) and neutropenia (P=.02) rates were significantly higher among patients who underwent induction chemotherapy, the researchers said.
“I think what DeCIDE told us was that induction chemotherapy did what it was supposed to do — reduce distant failure,” Cohen told HemOnc Today. “However, in the selected group of patients with N2/N3 disease that was not enough to significantly improve overall survival. I believe the future direction for induction chemotherapy is to find parameters to select patients who are most likely to benefit from induction chemotherapy. For instance, our sub-group analyses hinted that in subjects with N2c/N3 disease, there was an improvement in overall survival with induction.”
For more information:
Cohen EEW. Abstract #5500. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: Dr. Cohen is a consultant for Acceleron Pharma, AstraZeneca, Boehringer Ingelheim and Eli Lilly.
Perspective
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Barbara Burtness, MD
Two trials of induction chemotherapy followed by chemoradiation vs. chemoradiation alone were reported at ASCO 2012.
Although both studies began with fairly ambitious statistical assumptions, each accrued more slowly than projected, each closed early and each was reported with a much smaller sample size than initially projected.
The DeCIDE trial as actually reported had only an 80% power to detect a HR of 0.5 for improved survival after use of induction therapy. The DeCIDE trial demonstrated no difference in OS for the use of two cycles of induction therapy in the entire study population, although there was a significant advantage in those with N2C-N3 disease. Because the main difference in events between the arms was a lower rate of distant-only failure on the induction arm, it seems possible that an adequately powered trial in only this high-risk subset might have demonstrated a modest benefit to the use of docetaxel/cisplatin/5FU induction prior to DFHX and radiation. However, this would still not establish the utility of induction, as the chemoradiation regimen used here was non-platinum containing and it is impossible to dissect whether the use of platinum or the use of systemic chemotherapy before radiation was the source of benefit from the induction regimen given here.
The second presentation concerned the Paradigm trial, in which patients received three cycles of induction chemotherapy followed by chemoradiation, or conventional chemoradiation alone. For patients who received induction therapy, the radiation sensitization was with carboplatin, except for patients with non-response to induction, who received docetaxel-radiation. This study also was quite underpowered; however, there was no suggestion of a benefit here that merely failed to achieve statistical significance. Rather, the hazard for progression was non-significantly worsened in the induction arm.
These two trials are the largest direct studies of chemoradiation vs. induction chemotherapy followed by chemoradiation, and they demonstrate no improvement in survival for the use of induction. Although joint analysis of the outcome across the two studies for patients with N2c/N3 disease might be informative, and future studies may still employ induction as a means to study less-invasive surgical approaches or lower-dose radiation regimens, these studies leave us with no justification for the routine use of induction chemotherapy followed by chemoradiation off study.
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