Results from 2 meta-analyses including 52 prospective trials involving patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) showed that weekly low-dose schedules of chemoradiotherapy produce comparable survival outcomes and response rates as the standard 3-weekly schedule.
Investigators observed no difference in overall survival (OS) between the 2 chemoradiation dosing regimens in either the postoperative or definitive settings. The results, published online by The Oncologist also showed that the overall (89% vs 80%) and complete (58% vs 60%) response rates were similar between the 2 treatment schedules.
“Neither a meaningful difference nor a favoring trend in overall survival could be demonstrated between the 2 chemoradiation protocols,” wrote lead author Petr Szturz, PhD, Department of Internal Medicine, Hematology, and Oncology, University Hospital Brno, Czech Republic, and coauthors. “Keeping in mind the lack of support for low-dose weekly cisplatin in controlled trials, we are concerned about its indiscriminate and premature adoption in routine clinical practice.”
There is minimal level 1 evidence showing that 3-weekly 100 mg/m2
IV cisplatin given concurrently with conventional external beam radiotherapy is associated with significant improvement in locoregional control and OS. However, that schedule is also associated with significant rates of severe acute and late AEs.
As a result, weekly low-dose cisplatin regimens, defined as a ≤50 mg/m2
administered for at least 6 treatment cycles, have gained popularity, despite the lack of phase III evidence supporting that schedule.
Investigators at institutions in Europe and the United States reviewed data from trials involving 4209 patients with LA-SCCHN treated with radiation and single-agent concurrent cisplatin to explore survival and toxicity outcomes associated with the 2 dosing schedules.
The analyses consisted of 34 randomized trials, including 11 that compared chemoradiotherapy with radiotherapy, 5 that analyzed targeted agents combined with either cisplatin-based chemoradiotherapy or radiotherapy alone, 4 that explored other cytotoxic drugs combined with either chemoradiotherapy or radiotherapy alone, 7 that explored supportive care drugs, measures, or radiosensitizers plus chemoradiotherapy; and 4 that compared different chemoradiation schedules (concurrent vs sequential, conventional vs altered fractionation) and routes of cisplatin administration (IV vs intra-arterial). Induction chemotherapy was tested prior to chemoradiation in 2 studies.
The meta-analyses also included results from just 1 small, randomized trial comparing weekly versus 3-weekly chemoradiation for postoperative LA-SCCHN.
The weekly schedule produced fewer adverse events (AEs) in the definitive setting. However, in the postoperative setting, that schedule was associated with significantly more grade 3/4 dysphagia (54% vs 20%) and weight loss (21% vs 3%) than the 3-weekly schedule.
There was a disproportionate number of oropharyngeal cancer cases (36% vs 49%) in the weekly dosing schedule group, but researchers noted no differences in OS, and adding this factor to the model of survival analysis did not affect results.
Patients undergoing weekly cisplatin in the definitive setting were significantly more likely to receive all planned cycles of chemotherapy (88% vs 71%; P
= .0017). Compared with 3-weekly dosing, investigators determined that patients on this regimen were statistically less likely to experience grade 3/4 leukopenia (1% vs 19%; P
= .0083), neutropenia (5% vs 18%; P
= .0024), nausea and/or vomiting (3% vs 16%; P
<.0001), and nephrotoxicity (1% vs 5%; P
Ezra Cohen, MD, associate director with Moores Cancer Center at UC San Diego, reviewed that data for OncLive
and said that anywhere from two-thirds to three-quarters of practitioners have adopted the weekly regimen despite the lack of high-level data supporting the practice. He said these results don’t provide strong evidence to switch regimens one way or the other, but they “add some reassurance” that the weekly regimen is at least noninferior to 3-weekly and may have better toxicity. However, he added that upcoming data may favor the conventional schedule.
“We are going to see in a couple of weeks at [the 2017 ASCO Annual Meeting] some head-to-head comparisons that may not be as friendly to the weekly as this meta-analysis,” he added. “The abstracts seem to show that although there may not be a survival difference, there also does not appear to be a toxicity difference. In fact, one of the studies demonstrates that the weekly may even be more toxic in some regards.
“This paper [Szturz et al] is nice because it brings all the data together, but still doesn’t substitute for prospective, randomized studies. When we see those data, it doesn’t look like the weekly is the better way to go and there’s some indicators it may be the worse way to go.”
Szturz P, Wouters K, Kiyota N, et al. Weekly low-dose versus three-weekly high-dose cisplatin for concurrent chemoradiation in locoregionally advanced non- nasopharyngeal head and neck cancer: a systematic review and meta-analysis of aggregate data [published online May 22, 2017]. Oncologist. doi: 10.1634/theoncologist.2016-0414.