Induction Chemotherapy Prior to Chemoradiation Represents Potential New SOC in Locally Advanced Cervical Cancer

Treatment with platinum-based chemotherapy prior to the administration of chemoradiation led to statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared with chemoradiation alone in patients with locally advanced cervical cancer, according to data from the phase 3 INTERLACE trial (NCT01566240) presented at the 2023 ESMO Congress.

Findings showed that induction chemotherapy followed by chemoradiation reduced the risk of progression or death by 35% vs chemoradiation alone (HR, 0.65; 95% CI, 0.46-0.91; P = .013). Patients treated in the experimental arm (n = 250) experienced 3- and 5-year PFS rates of 75% and 73%, respectively. Those rates were 72% and 64%, respectively, for patients given chemoradiation alone (n = 250).

Additionally, induction chemotherapy prior to chemoradiation reduced the risk of death by 39% vs chemoradiation alone (HR, 0.61; 95% CI, 0.40-0.91; P = .04). Patients in the experimental arm achieved 3- and 5-year OS rates of 86% and 80%, respectively, vs 80% and 72%, respectively, for those given chemoradiation alone.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiation should be considered the new standard in locally advanced cervical cancer and is feasible across diverse health care settings,” lead study author Mary McCormack, MBBS, PhD, MSc, BSc, FRCR, a clinical oncologist at University College London Hospital in the United Kingdom, said in a presentation of the data.

For more than 20 years, chemoradiation has served as the standard of care for patients with locally advanced cervical cancer; however, up to 30% of patients still relapse and die from metastatic disease.

INTERLACE Trial Design

Patients enrolled had newly diagnosed, histologically confirmed International Federation of Gynaecology and Obstetrics (FIGO) 2008 stage IB1 (node-positive), IB2, II, IIIB, or IVA squamous, adeno, or adenosquamous cervical cancer. Patients needed to be fit for chemotherapy and radical radiotherapy and have adequate renal, liver, and bone marrow function. Prior pelvic radiation was not permitted, and patients were not allowed to have nodes above aortic bifurcation on imaging.

Investigators randomly assigned patients 1:1 to receive induction chemotherapy followed by chemoradiation or chemoradiation alone. In the experimental arm, patients received induction therapy with carboplatin at area under the curve 2 plus paclitaxel at 80 mg/m² once weekly for 6 weeks before beginning chemoradiation in week 7. In both arms, chemoradiation consisted of 40 mg/m² of cisplatin once weekly for 5 weeks plus external beam radiation (EBRT) ranging from 40 Gy to 50.4 Gy given in 20 to 28 fractions and brachytherapy to give a minimum total biologically equivalent dose of 78 Gy to point A. It was recommended that patients receive 3D image–guided adaptive brachytherapy.

The overall treatment time of chemoradiation was not to exceed 50 days, and all participating centers were required to undergo radiotherapy quality assurance.

Patients were stratified by site, stage, nodal status, 3D-conformal vs intensity-modulated radiotherapy (IMRT) EBRT, 2D vs 3D brachytherapy, tumor size, and squamous cell carcinoma vs other.

PFS and OS served as the trial’s coprimary end points. Key secondary end points included adverse effects (AEs), pattern of relapse, quality of life, and time to subsequent treatment. The study’s protocol included a hierarchical testing approach that required PFS data to reach statistical significance (P < .05) prior to formal testing of OS.

Baseline characteristics showed that the median age was 46 years (range, 26-78) in the experimental arm and 46 years (range, 24-78) in the control arm. Most patients had an ECOG performance status of 0 (86% and 88% for the experimental and control arms, respectively), were from the United Kingdom (76% and 76%), had FIGO 2008 stage IIB disease (71% and 70%), had squamous histology (82% and 82%), and had node-negative disease (58% and 57%). The median longest tumor diameter was 4.8 cm (range, 1.3-13.5) and 4.9 cm (range, 1.8-12.8), respectively.

Chemotherapy and Chemoradiation Received

In the experimental arm, 84% of patients completed 6 cycles of induction chemotherapy and 92% completed at least 5 cycles. The primary reasons for receiving less than 6 cycles were AEs (11%; n = 29), including hematologic AEs (n = 9), nonhematologic AEs (n = 17), both these AEs (n = 3), and patient withdrawal or other reason (4%; n = 10). The median interval between induction chemotherapy and radiotherapy was 7 days (range, 5-53).

During chemoradiation, 68% of patients in the experimental arm completed all 5 cycles of cisplatin and 85% completed at least 4 cycles. Those rates were 79% and 90%, respectively, in the control arm. In the experimental arm, the primary reasons for receiving less than 5 cycles of cisplatin were AEs leading to discontinuation (27%; n = 68), including hematologic AEs (n = 34), nonhematologic AEs (n = 20), both these AEs (n = 14), and other reason (5%). For the chemoradiation alone arm, the main reasons for not completing 5 cycles of cisplatin were AEs leading to discontinuation (13%; n = 33), including hematologic AEs (n = 4), nonhematologic AEs (n = 25), both these AEs (n = 4), and other reason (8%).

Ninety-seven percent of patients in the experimental arm and 92% of patients in the control arm received EBRT. In the experimental arm, the rates of IMRT and 3D-conformal radiation were 42% and 58%, respectively; those rates were 40% and 60%, respectively, for the control arm. Most patients in the experimental arm (98%) and control arm (97%) received brachytherapy, consisting of 2D point A (19% and 22% for the experimental and control arms, respectively), 3D point A (51% and 48%), and 3D high-risk clinical target volume D90 (30% and 30%).

“Adherence to standard chemoradiation was high in both arms and reflected best clinical practice,” McCormack said. The median overall treatment time was 45 days (range, 36-70) in the experimental arm and 45 days (range, 37-88) in the control arm.

In the induction chemotherapy/chemoradiation arm, the rates of total local/pelvic relapses and total distant relapses were 16% and 12%, respectively; 10% of patients had local/pelvic relapses, 6% had distant relapses, and 6% had both local/pelvic and distant relapses. In the chemoradiation alone arm, the rates of total local/pelvic relapses and total distant relapses were 16% and 20%, respectively; 8% of patients had local/pelvic relapses, 12% had distant relapses, and 8% had both.

Toxicity Profile As Expected

Regarding safety, any-grade AEs occurred in 99% of patients in the induction chemotherapy/chemoradiation arm and 95% of patients in the chemoradiation alone arm. The rates of grade 3/4 AEs were 59% and 48%, respectively.

Any-grade hematologic AEs were reported in 30% of patients in the experimental arm and 13% of patients in the control arm. The most common any-grade hematologic AEs included neutropenia (19% and 5% for the experimental and control arms, respectively), anemia (5% and 4%), and thrombocytopenia (5% and 2%).

The rates of any-grade nonhematologic AEs were 44% and 43%, respectively, and the most common included abdominal/pelvic pain (5% and 7%); diarrhea (8% and 12%); fatigue, muscle weakness, or joint pain (11% and 6%); and infection (6% and 5%). “As anticipated, hematologic toxicity was greater in the experimental arm, but this did not compromise the delivery of chemotherapy,” McCormack concluded.

Editor’s Note: Dr McCormack cited she is on the consultancy/advisory board for AstraZeneca, Eisai, and GSK; has received honoraria/meeting expenses from Daiichi Sankyo, Roche, and Medscape; and has received institutional funding from Roche, MSD, and GSK.

Reference

McCormack M, Gallardo Rincón D, Eminowicz G, et al. LBA8 a randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: the GCIG INTERLACE trial. Ann Oncol. 2023;34(suppl 2):S1276. doi:10.1016/j.annonc.2023.10.028