In a multicentre, randomised phase III INTERLACE study, short-course of six, once-a-week, induction dose-dense carboplatin and paclitaxel delivered immediately before standard cisplatin-based chemoradiotherapy for five weeks resulted in significantly improved progression-free survival (PFS) and overall survival (OS) rates at 5 years in patients with locally advanced cervical cancer. This is the first randomised phase III study to show a significant survival advantage with the addition of induction chemotherapy before chemoradiotherapy in locally advanced cervical cancer. The drugs are cheap and widely available.
Haematological toxicity (mainly neutropenia) was more common with induction chemotherapy followed by chemoradiotherapy, particularly during chemoradiotherapy. The findings are published by Dr. Mary McCormack of the University College Hospital NHS Trust in London, UK and colleagues on 19 October 2024 in The Lancet.
The authors wrote in the background that the incidence of cervical cancer has decreased in high-income countries due to the implementation of successful screening and HPV vaccination programmes. However, even in high-income countries health inequalities exist. Patients often present with locally advanced disease for which chemoradiotherapy has been the standard treatment for nearly 25 years. Improvements in local control have been driven by the delivery of high-quality radiotherapy, but still up to 30% of patients will relapse and die within 5 years.
Adjuvant carboplatin and paclitaxel chemotherapy after chemoradiotherapy did not improve PFS or OS in the international phase III OUTBACK study. A single arm multicentre phase II CXII study was conducted to investigate neoadjuvant short-course weekly carboplatin and paclitaxel before chemoradiotherapy and showed a high tumour response rate. The CXII results led to the INTERLACE study which took 10 years to recruit; this was partly due to strict radiotherapy quality assurance requirements, and clinician and patient-related factors such as concern about delaying definitive treatment and hair loss. The INTERLACE was conducted at 32 medical centres in Brazil, India, Italy, Mexico, and the UK.
Adults (aged ≥18 years) with locally advanced cervical cancer (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, IIA, IIB, IIIB, or IVA disease) were randomly assigned 1:1 to standard cisplatin-based chemoradiotherapy (once-a-week intravenous cisplatin 40 mg/m2 for five 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 or induction chemotherapy (once-a-week intravenous carboplatin area under the receiver operator curve 2 and paclitaxel 80 mg/m2 for six weeks) followed by standard cisplatin-based chemoradiotherapy.
Stratification factors were recruiting site, stage, nodal status, three-dimensional conformal radiotherapy or intensity modulated radiation therapy (IMRT), age, tumour size, and histology (squamous versus non-squamous). Primary endpoints were PFS and OS in the intention-to-treat population. Between 8 November 2012 and 17 November 2022, 500 eligible patients were enrolled and randomly assigned to the chemoradiotherapy alone group or the induction chemotherapy with chemoradiotherapy group (250 patients in each group).
Of 500 patients, 354 (70%) had stage IIB disease and 56 (11%) stage IIIB disease. Pelvic lymph nodes were positive in 215 patients (43%). A total of 230 patients (92%) 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 212 patients (85%) in the induction chemotherapy with chemoradiotherapy group and to 224 patients (90%) in the chemoradiotherapy alone group. In total, 462 patients (92%) received external beam radiotherapy and brachytherapy with a median overall treatment time of 45 days.
After a median follow-up of 67 months, 5-year PFS rates were 72% in the induction chemotherapy with chemoradiotherapy group and 64% in the chemoradiotherapy alone group with a hazard ratio (HR) of 0.65 (95% confidence interval [CI] 0.46–0.91; p = 0.013); 5-year OS rates were 80% in the induction chemotherapy with chemoradiotherapy group and 72% in the chemoradiotherapy alone group, with an HR of 0.60 (95% CI 0.40–0.91; p = 0.015).
Distant only relapses were more frequent in the chemoradiotherapy alone group suggesting that induction chemotherapy with chemoradiotherapy was more effective in controlling distant micrometastatic disease.
Grade 3 or greater adverse events were reported in 147 of 250 patients (59%) in the induction chemotherapy with chemoradiotherapy group versus 120 of 250 patients (48%) in the chemoradiotherapy alone group. Haematological toxicity (mainly neutropenia) was more common with induction chemotherapy with chemoradiotherapy, particularly during chemoradiotherapy. The frequency of low-grade thrombocytopenia in the induction chemotherapy treatment period was low.
No differences in vaginal symptoms or bleeding in the two groups were reported. Hair loss was reported as grade 1 in 39 patients (16%) and grade 2 in 106 patients (42%). Grade 1-2 peripheral neuropathy, fatigue, constipation, and dyspnoea were more common in the induction chemotherapy with chemoradiotherapy group, but they were all transient.
In the induction chemotherapy with chemoradiotherapy group, quality-of-life (QoL) slightly worsened during the induction chemotherapy treatment, with mean change from baseline generally of less than 5 units, which is not a clinically relevant effect. QoL will be reported in more detail separately.
The authors commented that during the past decade IMRT and image-guided adaptive brachytherapy (IGABT) were adopted as standard of care, but only 40% of both groups were treated with IMRT and 30% had IGABT within the INTERLACE study. However, the techniques applied and dose delivered were well balanced across both treatment groups.
They concluded that the data in favour of immune checkpoint inhibitors, as well as the positive results for induction chemotherapy presented in this article, support the need for further investigation of a combination approach in patients with locally advanced cervical cancer. Although chemoradiotherapy is curative treatment for about 75% of patients with locally advanced cervical cancer, increasing this by 7-10% at 3-5 years represents a clinically meaningful improvement and at a relatively low cost according to the study team.
In an accompanied comment, Drs. Linda R Duska of the Division of the Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia School of Medicine in Charlottesville, VA, US and Leslie M Randall of the Inova Schar Cancer Institute in Fairfax, VA, US wrote that the KEYNOTE-A18 study, the first published definitively positive trial since 1999, showed improved PFS and OS with the addition of pembrolizumab during and after chemoradiotherapy for patients with FIGO 2014 stage IB2–IIB with any pelvic nodal metastases and III–IVA regardless of nodal status. The investigator-initiated, INTERLACE is a second practice-changing study in locally advanced cervical cancer.
When compared to KEYNOTE-A18, the INTERLACE addresses the relatively lower risk locally advanced cervical cancer group (no patients with positive para-aortic nodes, 43% with pelvic node involvement) and suggests that chemical cytoreduction is feasible, tolerated, and effective. The patterns of failure data from the INTERLACE indicate a role for induction chemotherapy in reducing the rate of distant metastases; these data are awaited from the KEYNOTE-A18. The KEYNOTE-A18 regimen was tolerable and effective in the higher risk group, although questions remain regarding best sequencing of immunotherapy, as well as the need for and length of maintenance immunotherapy.
Both trials also present barriers in the real-world setting. Despite controlled transition, 22% of patients in the INTERLACE did not begin chemoradiotherapy within the 7-day mandated time interval after induction chemotherapy, a timeframe that is theoretically critical to the optimal success of subsequent radiation due to accelerated repopulation. The KEYNOTE-A18 study also presents challenges, particularly in areas of the world where immunotherapy is not available; therefore, induction chemotherapy with chemoradiotherapy could be a cost-effective alternative. Additionally, in parts of the world where radiotherapy is delayed, care could be bridged with the INTERLACE regimen, as long as this is done with the plan to begin radiation within 7 days of chemotherapy completion.
According to the commentators, further studies are needed to determine the best regimen for patients with locally advanced cervical cancer, which might include novel combinations and sequencing of modalities. In the interim, a focus on screening and prevention across the world would go a long way in improving outcomes.
The study was funded by Cancer Research UK with additional support from the University College London–University College London Hospitals Biomedical Research Centre.
References
- McCormack M, Eminowicz G, Gallardo D, et al. on behalf of the INTERLACE investigators. Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): an international, multicentre, randomised phase 3 trial. The Lancet 2024;404(10462):P1525-1525.
- Duska LR, Randall LM. Progress in the treatment paradigms for locally advanced cervical cancer. The Lancet 2024;404(10462):p1494-1496.