Even so, they and other independent experts interpret the negative results from PARADIGM and DeCIDE cautiously, however, arguing that there might yet be reason to suspect clinical benefits for induction chemotherapy.
Both trials suffered from poor accrual of study participants, which is a longstanding and widespread problem for clinical cancer trials; this reduced the statistical power to detect potentially clinically important survival advantages associated with induction chemotherapy. Furthermore, the surprisingly high survival rates among patients in control groups reduced the percent differences that were even possible between induction and no-induction treatment arms. 1,4
Continue Reading
PARADIGM and DeCIDE were designed based on data available a decade ago, that had suggested 55% 3-year survival rates were a reasonable expectation.2 But as noted above, the 3-year overall survival rates for both studies were much higher than expected, for all treatment arms, exceeding 70% (78% in PARADIGM study participants assigned to the no-induction control group and 73% in the DeCIDE trial’s control group).1-3 Together with poor accrual, these higher-than-expected survival rates among patients assigned to the studies’ control groups rendered it “almost impossible to detect any benefit of induction chemotherapy”—even if one exists, noted Sandrine Faivre, MD (Beaujon University Hospital, Clichy, France) and coauthors, in a commentary accompanying PARADIGM’s publication in The Lancet Oncology.4
Nor were patients in the trials stratified by human papillomavirus (HPV) status, which is now widely recognized to be associated with superior treatment responses and patient prognoses.2
“We have effectively entered a new era in head and neck cancer wherein, for the first time, we have an important prognostic marker such that, stage-for stage, significant differences in outcome and different biology exist with different potential therapeutic pathways,” the PARADIGM coauthors noted.2
But the importance of HPV in head and neck cancer prognosis was not fully recognized in 2004, when the PARADGIM trial started, its authors note—and so HPV testing was not considered in the study’s design.2
“It is quite conceivable that, because of the epidemic of HPV-related oropharynx cancer we are currently witnessing, it will be very hard to see a survival advantage with any modality in studies that include HPV-related oropharyngeal cancer or fail to stratify for this entity,” the PARADIGM authors acknowledged.2 “In this context, PARADIGM with its original design, including both HPV-related and unrelated cancers, would very probably still be a negative trial, had it completed its original accrual target.”
Stratifying—or separately studying—HPV-associated oropharyngeal cancer treatment outcomes is an “imperative,” the PARADIGM authors emphasized.2 HPV-specific treatment studies are already under way in the United States and Europe.
Despite the negative results for induction TPF, observers seem reluctant to conclude at this stage that induction chemotherapy cannot benefit patients with head and neck cancers.
“Apparent failure in this trial does not justify the conclusion that induction chemotherapy cannot provide benefit,” concluded Dr. Faivre and colleagues, citing “novel combinations” of other agents, such as preclinical investigational work with another induction regimen of everolimus, carboplatin and paclitaxel.4
“Writing an obituary on induction chemotherapy at this stage may seem premature,” concluded Dr. Loo and coauthors. “However, in an era of evidence-based medicine, DeCIDE and PARADIGM may yet turn out to be nails in the coffin of the routine use of induction chemotherapy in locoregionally advanced SCCHN.”1
References
1. Loo SW, Geropantas K, Roques TW. DeCIDE and PARADIGM: nails in the coffin of induction chemotherapy in head and neck squamous cell carcinoma? Clin Transl Oncol. 2013;15:248-251.
2. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomized phase 3 trial. Lancet Oncol. 2013 Mar;14(3):257-64. doi: 10.1016/S1470-2045(13)70011-1. Epub 2013 Feb 13.
3. Cohen EEW, Karrison T, Kocherginsky M, et al. DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol. 2012 ASCO Annual Meeting Proceedings (Post-Meeting Edition); 30(15, suppl.): abstract 5500.
4. Faivre S, Albert S, Raymond E. Induction chemotherapy challenges for head and neck cancer. Lancet Oncol. 2013 Mar;14(3):188-9. doi: 10.1016/S1470-2045(13)70023-8. Epub 2013 Feb 13.
