Induction chemotherapy prior to chemoradiotherapy improves the survival of patients with locally advanced cervical cancer
Results of the GCIG INTERLACE trial presented in a Presidential Symposium at ESMO 2023 show that 6 weeks of induction chemotherapy with paclitaxel and carboplatin prior to chemoradiotherapy (CRT) significantly boosts the progression-free (PFS) and overall survival (OS) of women with locally advanced cervical cancer. As could be expected, the induction chemotherapy did lead to a higher rate of hematological toxicity, but this did not compromise the delivery of radiotherapy.
Background
Cervical cancer continues to be a global threat accounting for more than 320,000 deaths in 2020. For more than 2 decades the standard of care for patients with local-advanced cervical cancer consisted of CRT. Over the years, advances in the radiotherapy techniques and an optimization of the radiation dose gradually improved the local control rate in these patients, but still 30% of patients suffer a distant relapse and die from their disease. Several clinical trials evaluating the potential of induction chemotherapy in this setting generated conflicting results. However, a meta-analysis pooling the data from all these studies failed to show an OS benefit with this approach, but indicated an association between outcome and a short course of induction chemotherapy. Based on these results, a short induction chemotherapy protocol was developed using weekly paclitaxel and carboplatin followed by CRT within 7 days, which proved to be feasible and active in a small study (objective response rate [ORR]: 70%). These results formed the rationale to evaluate this regimen in a randomized phase III setting.
Study design
The phase III INTERLACE study enrolled 500 newly diagnosed patients with histologically confirmed FIGO stage IB1 (node positive), IB2, II, IIIB, or IVA squamous, adeno, or adenosquamous cervical cancer. In order to be eligible for the study, patients had to to be fit for chemotherapy and radical radiotherapy and have an adequate renal, liver, and bone marrow function. Furthermore, patients were not allowed to have nodes above the aortic bifurcation on imaging, and prior pelvic radiation was not permitted. Patients in the trial were randomly assigned patients (1:1) to receive induction chemotherapy followed by CRT or CRT alone. This induction chemotherapy consisted of carboplatin at an area under the curve of 2 in combination with paclitaxel at a dose of 80 mg/m2 once a week for 6 cycles prior to the start of CRT. In both arms, the CRT regimen consisted of 40 mg/m2 of cisplatin once every week for 5 weeks plus external beam radiation (EBRT) ranging from 40 Gy to 50.4 Gy given in 20 to 28 fractions. Patients also received brachytherapy at a minimum total of biologically equivalent doses of 78 Gy. PFS and OS served as the trial’s co-primary endpoints, with secondary objectives including adverse effects (AEs), pattern of relapse, quality of life (QoL), and time to subsequent treatment (TTST).
Results
The median age of patients in the study was 46 years and almost 9 out of 10 had an ECOG performance status of 0. Furthermore, ~75% of patients in the study had FIGO stage IIA-B disease and 82% had a squamous histology. Finally, 57% of patients in the trial were node negative at baseline. In the experimental arm, 84% of patients completed 6 cycles of induction chemotherapy. The median interval between induction chemotherapy and radiotherapy was 7 days, ranging from 5-53 days. During CRT, 68% of patients in the experimental arm completed all 5 cycles of cisplatin, while this was the case for 79% in the control arm. Overall, 97% of patients in the experimental arm and 92% of patients in the control arm received EBRT. The corresponding rates for IMRT and 3D-conformal radiation were 42% vs. 40% and 58% vs. 60%, respectively. Furthermore, the majority of patients in both the experimental (98%) and control arm (97%) received brachytherapy.
Interestingly, induction chemotherapy followed by CRT reduced the risk of disease progression or death by 35% compared to CRT alone (HR[95%CI]: 0.65[0.46-0.91]; p= 0.013). At the 3- and 5-year landmark, PFS rates in the experimental arm were reported at 75% and 73%, respectively, while corresponding rates for patients who only received CRT were 72% and 64%. Induction chemotherapy prior to CRT also led to a significant reduction in the risk of death, with a HR for OS of 0.61 (95%CI: 0.40-0.91; p= 0.04). In the experimental arm, 86% and 80% of patients were alive after 3- and 5-years, while this was the case for 80% and 72% of patients in the control arm.
Any-grade AEs occurred in 99% of patients in the experimental arm as compared to 95% in the control arm (59% vs. 48% grade ≥3). Any-grade hematologic AEs were reported in 30% of patients in the experimental arm and 13% of patients in the control arm. The incidence of non-hematologic AEs was similar in both arms at 44% and 43%, respectively. The most common of these AEs were abdominal/pelvic pain (5% vs. 7%), diarrhea (8% vs. 12%) and fatigue, muscle weakness, or joint pain (11% vs. 6%).
Conclusions
Six weeks of induction chemotherapy with paclitaxel-carboplatin prior to CRT results in a significant benefit in PFS and OS for patients with locally advanced cervical cancer. While induction chemotherapy did increase the rate of hematological toxicity, this did not compromise the delivery of radiotherapy. Of note, 58% of patients in the trial had node-negative disease at baseline, which could raise some questions on the risk profile of the study population. In this respect, further analyses in function of nodal status of patients are eagerly awaited.
Reference
McCormack M, et al. A randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: The GCIG INTERLACE trial. Presented at ESMO 2023; Abstract LBA8.
