Weekly Cisplatin New Standard in Postop Head and Neck Cancer

Liam Davenport

June 10, 2020

For the first time, weekly cisplatin plus radiotherapy (CDDP+RT) has been shown to be not only less toxic than dosing once every three weeks but also achieves better outcomes in patients with postoperative squamous cell carcinoma of the head and neck (SCCHN), say Japanese researchers.

Consequently, the results of the JCOG1008 trial suggest that the weekly schedule should become the new standard of care in these patients, potentially settling what has been a "contentious" issue.

The research was presented the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.

Lead author Naomi Kiyota, MD, PhD, Medical Oncology and Hematology, Cancer Center, Kobe University Hospital, Japan, said that the study involving more than 160 high-risk patients with SCCHN demonstrated comparable overall survival in the weekly and three-weekly CDDP+RT groups.

Moreover, it showed that the weekly schedule was associated with better relapse-free and local relapse-free survival, and, in line with previous studies, had a more favorable safety profile.

"This phase II/III study is the first to show that weekly CDDP+RT is non-inferior to three-weekly CDDP+RT [and] is a new standard treatment option for these patients," Kiyota said.

Study discussant Hisham M. Mehanna, MD, PhD, Warwickshire Head and Neck Clinic, University of Birmingham, UK, described the study as a "significant achievement" that answers "an important question that we’ve been asking for a very long time."

He said that, despite three-weekly CDDP+RT being the standard treatment in the postoperative setting for SCCHN, there have been "lingering concerns," as 40% of patients don’t get all three CDDP cycles "and it is toxic."

Weekly CDDP is, on the other hand, "widely used, although the evidence for it is not as strong," and has a number of advantages, including that it can be delivered in the outpatient setting and it may be less toxic.

Mehanna said that there was "a surprise" to the current study, in that it was terminated early because it crossed the boundary for non-inferiority because  weekly CDDP has better survival than the three-weekly dose; notably, however, superiority was not achieved.

Mehanna also expressed some reservations over imbalances in the treatment groups that could have meant the three-weekly cohort had an unfavorable prognosis, and said questions remain over longer-term toxicity.

"Contentious Issue"

In a highlights session, Nabil F. Saba, MD, director of the Head and Neck Onology Program at Emory University's Winship Cancer Institute in Atlanta, Georgia, said that the dosing of CDDP in these patients has been "a contentious issue."

One issue has been whether scheduling of CDDP or the cumulative dose achieved is the key determinant of clinical outcome, and he suggested that the superior results seen in the current study can be attributed to the high cumulative dose that the investigators achieved in their patients compared with previous investigations.

For Saba, the take-home message of the trial is that weekly cisplatin "is now, finally, an accepted standard of care in the postoperative high-risk setting, which is a major change at this ASCO meeting."

Presenting the trial, Kiyota said, in a recent study from the Tata Memorial Hospital, weekly CDDP at 30 mg/m2 plus radiotherapy failed to achieve non-inferiority to a three-weekly regimen, "albeit with fewer toxicities."

He suggested that this could be because it was a single center trial, the use of two different treatment strategies, the majority of primary sites being in the oral cavity, and the dose being insufficient.

His team, on the other hand, undertook a randomized trial in which patients with postoperative high-risk SCCHN were recruited from 28 institutions.

The participants, who were aged 20 to 75 years and had ECOG performance status 0 to 1, all had pathological stage III/IV disease and a microscopically positive margin and/or extranodal extension.

They were randomly assigned to 100 mg/m2 CDDP once every three weeks or weekly 40 mg/m2 CDDP, plus radiotherapy at 66 Gy over 33 fractions.

For the intention-to-treat efficacy analysis, 132 patients received three-weekly CDDP+RT and 129 had weekly CDDP+RT, while the per protocol safety analysis included 129 and 122 patients, respectively.

The median age of the patients was 61 to 62 years and 110 patients in both treatment groups were male. Although there was a similar distribution of primary sites and high-risk factors in the two groups, more patients in the weekly group had pathological stage T2 disease (40) than in the three-weekly group (26).

The dose targets were met in both treatment groups. In the 3-weekly group, the cumulative dose of CDDP achieved was 280 mg/m2 and in the weekly group it was 239 mg/m2.

The second planned interim analysis showed that, over a median follow-up of 2.2 years, three-year overall survival was estimated at 71.6% in the weekly group vs 59.1% in the three-weekly group (hazard ratio [HR], 0.69).

As this was below the one-sided P value for non-inferiority, the data and safety monitoring committee recommended terminating the trial early.

The researchers also found that the 3-year relapse-free survival was higher with weekly CDDP+RT, at 64.5% vs 53.0% with three-weekly dosing (HR, 0.71).

Local relapse-free survival was also better with weekly dosing, at a three-year rate of 69.6% vs 59.5% for patients in the three-weekly group (HR, 0.73).

On a planned subgroup analysis, weekly CDDP+RT was nonsignificantly superior to the three-weekly schedule on almost every measure, whether looking at patient age, ECOG performance status, and primary site.

There were also differences in the occurrence of hematologic toxicities between the two groups, with fewer patients given the weekly schedule experiencing grade 3/4 neutropenia than those on the three-weekly dosing; however, there were more cases of any grade thrombocytopenia for patients getting the weekly dosing.

The weekly CDDP+RT regimen demonstrated its lower toxicity when looking at acute nonhematologic adverse events, with fewer occurrences of any grade dysphagia, nausea, hyponatremia, renal impairment, and hearing impairment vs the three-weekly schedule.

The weekly dosing schedule was also associated with lower rates of grade 3/4 dysphagia, nausea, and infection.

The study was funded by the National Cancer Center Research and Development Fund, Japan Agency for Medical Research and Development Fund.

Kiyota reports honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb Japan, Chugai Pharma, Eisai, Merck Serono, MSD, and Ono Pharmaceutical; speakers bureau fees from AstraZeneca, Bayer, Bristol-Myers Squibb Japan; Eisai, Merck Serono, MSD, and Ono Pharmaceutical; and receiving research funding from AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), and Roche (Inst). Other study authors report potential conflicts of interest. The full list can be found here.

Mehanna reports stock and other ownership interests in Warwickshire Head and Neck Clinic; honoraria from AstraZeneca; speakers bureau fess from Merck, MSD, and Sanofi Pasteur; research funding from AstraZeneca, GlaxoSmithKline (Inst), MSD (Inst), Sanofi Pasteur (Inst), and Silence Therapeutics (Inst); and travel, accommodations, and expenses from Merck, MSD, and Sanofi Pasteur.

Saba reports honoraria from Aduro Biotech, Bristol-Myers Squibb, Cue Biopharma, Genentech/Roche, GSK, Kura, Lilly, Merck, and Pfizer; a consulting or advisory role with Biontech, Bluprint, Bristol-Myers Squibb, Lilly, Merck, and Pfizer; research funding from Bristol-Myers Squibb and Exelixis; travel, accommodations, and expenses from Bluprint, Bristol-Myers Squibb, Genentech/Roche, GSK, Lilly, Merck, and Pfizer.

American Society of Clinical Oncology 2020 Annual Meeting: Abstract 6502.

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