Induction chemo followed by chemoradiotherapy bumps up survival in advanced cervical cancer

A short-course induction chemotherapy conducted prior to chemoradiotherapy appears to deliver significant survival boost in locally advanced cervical cancer, according to the phase III GCIG INTERLACE trial.

In the intention-to-treat analysis, “short-course once-a-week induction dose-dense carboplatin and paclitaxel delivered immediately before chemoradiotherapy resulted in an 11-percentage point improvement in the progression-free survival (PFS) rate and a 10-percentage point improvement in the overall survival (OS) rate at 5 years, which were clinically meaningful and statistically significant,” the investigators reported.

Compared with chemoradiotherapy alone, the administration of short-course induction chemo with chemoradiotherapy was associated with a 35-percent reduction in the risk of progression or death (hazard ratio [HR] for PFS, 0.65, 95 percent CI, 0.46–0.91; p=0.013) and a 40-percent reduction in the risk of dying (HR for OS, 0.60, 95 percent CI, 0.40–0.91; p=0.015). [Lancet 2024;doi:10.1016/S0140-6736(24)01438-7]

The 3-year PFS rates were 75 percent in the induction chemotherapy with chemoradiotherapy group and 72 percent in the chemoradiotherapy alone group (absolute risk difference, 8.7 percentage points). The corresponding 5-year rates were 72 percent and 64 percent (absolute risk difference, 10.8 percentage points).

The respective OS rates in the induction chemotherapy with chemoradiotherapy group and the chemoradiotherapy alone group were 85 percent and 80 percent at 3 years (absolute risk difference, 7.4 percentage points) and 80 percent and 72 percent at 5 years (absolute risk difference, 10.2 percentage points).

“This represents the first published substantial OS improvement among patients with locally advanced cervical cancer since concomitant cisplatin over 2 decades ago,” the investigators noted.

Safety

Grade 3 or higher adverse events (AEs) occurred in 59 percent of patients in the induction chemotherapy with chemoradiotherapy group and in 48 percent in the chemoradiotherapy alone group.

“As expected, haematological toxicity (mainly neutropenia) was more common with induction chemotherapy with chemoradiotherapy, particularly during chemoradiotherapy [19 percent vs 5 percent],” the investigators said.

“The frequency of low-grade thrombocytopenia in the induction chemotherapy treatment period was low, and no differences in vaginal symptoms or bleeding in the two groups were reported. We therefore do not believe vaginal bleeding should be a contraindication for this treatment approach,” they said.

In the induction chemotherapy with chemoradiotherapy group, grade 1 and grade 2 hair loss rates were 16 percent and 42 percent, respectively. Grade 1–2 peripheral neuropathy, fatigue, constipation, and dyspnoea were also documented, but these events were all transient. No grade 3 thrombocytopenia occurred during induction chemotherapy, and grade 1–2 thrombocytopenia was reported in only 4 percent of patients.

Within 30 days of treatment completion, one death in the induction chemotherapy with chemoradiotherapy group and two in the chemoradiotherapy alone group were recorded, but none were considered treatment-related.

GCIG INTERLACE

“One long-standing concern with the use of induction chemotherapy in locally advanced cervical cancer is the delay in the delivery of definitive chemoradiotherapy, with historical data suggesting a detrimental effect on outcome. The results presented should allay these concerns when using this specific weekly platinum dense regimen, especially as they are in keeping with findings of the first systematic review of neoadjuvant chemotherapy in locally advanced cervical cancer and a subsequent updated review,” the investigators said. [Eur J Cancer 2003;39:2470-2486; Cancers (Basel) 2022;14:842]

The intention-to-treat population included 500 patients (median age 46 years) with locally advanced cervical cancer. These patients were randomly assigned to receive standard cisplatin-based chemoradiotherapy (once-a-week intravenous cisplatin 40 mg/m² for 5 weeks with 45.0–50.4 Gy external beam radiotherapy delivered in 20–28 fractions plus brachytherapy to achieve a minimum total 2 Gy equivalent dose of 78–86 Gy) alone (n=250) or induction chemotherapy (once-a-week intravenous carboplatin area under the receiver operator curve 2 and paclitaxel 80 mg/m² for 6 weeks) followed by standard cisplatin-based chemoradiotherapy (n=250).

Of the patients, 70 percent had stage IIB disease and 43 percent had pelvic lymph node involvement. Most patients (92 percent) who received induction chemotherapy had at least five cycles. Median interval between induction chemotherapy and chemoradiotherapy was 7 days. Four or more cycles of cisplatin were given to 85 percent of patients in the induction chemotherapy with chemoradiotherapy group and in 90 percent of those in the chemoradiotherapy alone group. The median follow-up was 67 months.

The findings suggest that “induction chemotherapy delivered according to the INTERLACE protocol should be included in clinical guidelines as an option to improve outcomes in patients with locally advanced cervical cancer. This approach could be included in the design of future clinical trials of immunotherapy or other targeted drugs in the front-line setting,” the investigators concluded.