Weekly Dose-Dense Chemotherapy Not Superior to Standard of Care in Epithelial Ovarian Cancer

Andrew Clamp, BMBCh

Incorporation of weekly dose-dense chemotherapy is not superior to standard 3-weekly chemotherapy for patients with epithelial ovarian cancer. Both progression-free survival (PFS) and overall survival (OS) data failed to show improvement over the standard of care. However, results from the ICON8 presented at the European Society for Medical Oncology Virtual Annual Congress 2020 showed that the dose-dense regimen is safe and effective.1

“[For] the most of the past 3 decades, platinum paclitaxel doublet chemotherapy administered on a once-every-3-weeks schedule for 6 to 8 cycles has been cornerstone in the first-line modality management of epithelial ovarian cancer,” said Andrew Clamp, BMBCh, MSc Oncology, MRCP, PhD, chief investigator of the ICON8 study and senior lecturer and honorary consultant in medical oncology at The Christie NHS Foundation Trust. “There’s a strong rationale for the evaluation of weekly dose paclitaxel after settling into the first line of treatment,” Clamp said, adding that preclinical animal evidence demonstrated improved drug delivery, increased tumor cell apoptosis, and reduced angiogenesis with metronomic taxane treatment.

ICON8 (NCT01654146) included 1566 patients with epithelial ovarian cancer who had FIGO stage IcG3-IV disease. Participants were randomized 1:1:1 to 3 arms:

• Arm 1, standard chemotherapy: carboplatin AUC5/6 plus paclitaxel 175 mg/m2 every 3 weeks (n = 522),
• Arm 2, weekly paclitaxel: carboplatin AUC5/6 every 3 weeks plus paclitaxel 80mg/m2 once weekly (n = 523), or
• Arm 3, weekly carboplatin-paclitaxel: carboplatin AUC2 plus paclitaxel 80 mg/m2 once weekly (n = 521).

In updated PFS analysis, the median PFS was 17.4 months in arm 1, 20.1 months in arm 2, and 20.1 months in arm 3. No statistically significant difference was observed in either arm 2 versus arm 1 (HR, 0.94; 97.5% CI 0.80-1.10; P = .37) or arm 3 versus arm 1 (HR, 0.95; 97.5% CI, 0.81-1.11; P = .48).

The restricted mean time to progression was 25, 25.5, and 25.9 months in arms 1, 2, and 3, respectively. “As with the primary analysis, there was evidence of nonproportional hazards in the survival curves, so the restricted mean survival time is the most appropriate primary estimate of treatment,” Clamp said. “In fact, consistent with the primary analysis, there was no difference in restricted mean survival time across all 3 treatment arms.”

At the time of the final database lock on April 3, 2020, there were 319 deaths in arm 1 (61%), 300 deaths in arm 2 (57%), and 304 deaths in arm 3 (58%). The median OS was 47.4, 54.1, and 53.4 months in arms 1, 2, and 3, respectively. No significant improvement in OS was observed in arm 2 versus arm 1 (HR, 0.88; 97.5% CI, 0.74-1.06; P = .14) or arm 3 versus arm 1 (HR, 0.91; 97.5% CI, 0.76-1.09; P = .27).

“[Although] the hazard ratio in arm 2 of 0.88 is in favor of 3-weekly carboplatin and weekly paclitaxel compared [with] standard treatment and the [hazard ratio of] 0.91 [favors] weekly carboplatin and weekly paclitaxel…the confidence intervals cross unity, and so there is no statistically significant improvement in overall survival,” Clamp explained.

Baseline characteristics were well balanced among the arms. The median age of study participants was 62; 72% had serous histology; 10.5% had stage IC-IIA disease; 18% had stage IIA-IIIB disease; and 71% had stage IIIC-IV disease.

Half (50%) of patients planned delayed primary surgery (DPS) or were considered inoperable and 48% had immediate primary surgery (IPS). In a subgroup analysis, patients in the DPS cohort treated in arms 2 and 3 experienced a longer median overall survival (39 and 37 months, respectively) compared with those in arm 1 (32 months). However, no statistically significant improvement in overall survival was observed with the dose-dense regimen in either setting. “Further hypothesis-generating analyses are underway in our DPS cohort to determine if there is a subgroup of patients who may benefit [from] the [denser] approach,” Clamp said.

No changes in the toxicity profiles of the weekly regiments were observed when compared with results presented at prior meetings. Any grade 3/4 adverse events (AEs) were reported in 42% of patients treated in arm 1 compared with 62% and 53% inn arms 2 and 3, respectively. Predefined notable AEs included grade 2 or higher sensory neuropathy (28% vs 24% vs 23%), grade 2 anemia (26% vs 52% vs 36%), grade 3/4 anemia (5% vs 13% vs 5%), and grade 3/4 febrile neutropenia (4% vs 6% vs 3%).

“[Arms 2 and 3] were associated with an increased incidence of any grade 3 or 4 events during treatment, but this was predominantly driven by uncomplicated grade 3 or 4 neutropenia,” Clamp said. “Reassuringly, incidence of febrile neutropenia was low in all 3 treatment arms, and we did not see any increase in the incidence of grade 2 neuropathy in the 2 dose-dense paclitaxel-containing regimen.”

These data showed that the dose-dense regimen did not show improved survival results, and therefore 3-weekly carboplatin-paclitaxel regimen remains the standard of care chemotherapy component for the first-line treatment of patients with ovarian cancer, Clamp concluded.

Reference

Clamp AR, James EC, McNeish I, et. al. ICON8: overall survival results in a GCIC phase III randomised controlled trial of weekly dose-dense chemotherapy in first line epithelial ovarian, fallopian tube or primary peritoneal carcinoma treatment. Ann Oncol. 2020;31(suppl 4):S610. doi:10.1016/j.annonc.2020.08.944