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PARADIGM: Sequential therapy did not extend survival
Results of the phase 3 PARADIGM trial showed no significant differences in OS among patients with locally advanced head and neck cancers who were treated with sequential therapy vs. concurrent chemoradiotherapy.
The multicenter study compared docetaxel, cisplatin and 5-fluorouracil (TPF)-based sequential therapy to upfront cisplatin chemoradiotherapy in patients with locally advanced head and neck cancers.
Robert I. Haddad, MD, disease center leader of the Head and Neck Oncology Program at Dana-Farber Cancer Institute, and colleagues enrolled 145 previously untreated patients who were randomly assigned to one of two arms.
Seventy patients assigned to Arm A underwent sequential therapy, which consisted of induction chemotherapy followed by chemoradiotherapy with either weekly carboplatin and once-daily radiotherapy, or weekly docetaxel and accelerated boost radiotherapy based on response to induction chemotherapy.
Seventy-five patients were assigned to Arm B, which consisted of accelerated boost chemoradiotherapy with bolus cisplatin.
Of the 145 patients, 127 were white and 127 were men. Disease sites included oropharynx (n=80), larynx (n=24), hypopharynx (n=15) and oral cavity (n=26).
The median age of patients was 55 years. The primary endpoint was survival.
After a median follow-up of 49 months, 41 patients died (20 in Arm A and 21 in Arm B).
Three-year survival was 73% in Arm A vs. 78% in Arm B (HR=1.09; 95% CI, 0.59-2.03; P=.77). Three-year PFS was 67% in Arm A vs. 73% in Arm B (HR=1.20; 95% CI, 0.65-2.22; P=.55), according to study results.
The results suggest “excellent survival” in both arms but they do not indicate a significant survival difference between sequential therapy and chemoradiotherapy, the researchers said. However, the researchers emphasized the study was terminated in December 2008 before planned accrual could be reached.
Reference:
- Haddad RI. Abstract #5501.
Disclosure:
- Dr. Haddad reports serving as a consultant/advisor to Boehringer Ingelheim. He received research funding from AstraZeneca.
Perspective
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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.