In women with locally advanced cervical cancer, adjuvant chemotherapy adds no benefit to standard cisplatin-based chemoradiation, results of the international phase III OUTBACK study have shown,1 as reported at the 2021 ASCO Annual Meeting by Linda R. Mileshkin, MD, Professor of Medical Oncology at the Peter MacCallum Cancer Centre in Victoria, Australia.
“These findings do not support the use of adjuvant chemotherapy. Pelvic chemoradiation with concurrent weekly cisplatin continues to be the standard of care for the treatment of locally advanced cervical cancer,” Dr. Mileshkin announced.
Linda R. Mileshkin, MD
Bradley Monk, MD
“This trial of ‘outback’ chemotherapy did not show any clinically meaningful benefit but did increase adverse reactions,” said the study’s senior investigator, Bradley Monk, MD, Professor of Gynecologic Oncology at the University of Arizona, Phoenix.
For locally advanced cervical cancer, concurrent cisplatin and radiation with brachytherapy has been the standard of care since 1999. Many patients relapse, however, and die of distant metastatic disease. A number of influential studies have suggested that more chemotherapy after chemoradiation might convey additional benefits. Despite flaws in these studies—including short follow-up and treatment intolerability—“the studies changed practice in some centers,” Dr. Mileshkin said.
Based on the success with systemic therapy in both the chemoradiation setting and recurrent disease, the randomized OUTBACK trial tested the effect of four cycles of adjuvant chemotherapy after chemoradiation, the primary endpoint being overall survival at 5 years. The study enrolled 919 patients with cervical cancer suitable for chemoradiation with curative intent. Eligible women with locally advanced disease (FIGO 2008 stages IB1 and positive lymph nodes, IB2, II, IIIB, or IVA) were randomly assigned to concurrent chemoradiation, or the same followed by adjuvant chemotherapy:
Both arms: Standard chemoradiation with 40 to 45 Gy of external-beam radiation in 20 to 25 fractions, including a nodal boost plus brachytherapy, plus cisplatin at 40 mg/m2 weekly concurrently with radiation;
Adjuvant chemotherapy arm: Carboplatin at AUC 5 and paclitaxel at 155 mg/m2 every 3 weeks for four cycles, following chemoradiation.
Primary Endpoint Not Met
After a median follow-up of 5 years, the 5-year overall survival rates were 71% with chemoradiation alone and 72% with the addition of adjuvant chemotherapy (hazard ratio [HR] = 0.90; P = .8). Progression-free survival was also similar between the arms: 61% and 63%, respectively (HR = 0.86; P = .6).
Moreover, patterns of relapse were similar, with 11% and 9%, respectively, experiencing distant relapse (with or without locoregional disease) and 7% and 10%, respectively, having locoregional recurrence alone. There was no evidence of benefit in subsets of women with higher-risk disease, Dr. Mileshkin reported.
Lack of Initiation in 22%
In both arms, 77% of the subjects completed chemoradiation, and the vast majority of patients received full doses of treatments. Of note, 22% of women in the experimental arm never started adjuvant chemotherapy—an observation that was most common among women aged ≥ 60, non-White women, and women who did not complete chemoradiation.
A sensitivity analysis according to completion, or not, of chemoradiation confirmed the lack of benefit based on interaction P values of .11 and .12 for overall survival and progression-free survival, respectively, she added.
In the panel discussion, Dr. Mileshkin said she was surprised so many women failed to initiate adjuvant chemotherapy. “This was one reason we had to increase our sample size,” she said. The ongoing phase III INTERLACE trial is evaluating additional induction chemotherapy prior to chemoradiation, which might have better adherence, she said.
The typical side effects of chemotherapy were significantly increased with adjuvant chemotherapy. Grade 3 to 5 toxicities emerging within the first year of treatment occurred in 81% of the adjuvant chemotherapy arm and 62% of the chemoradiation arm. Quality of life was worse during adjuvant chemotherapy and for the following 3 to 6 months but was similar between the arms after 12 months.
“The use of the now widely used biologics, including bevacizumab, and checkpoint inhibitors, which are clearly active, was conspicuously untested,” Dr. Monk added. Current clinical trials are now evaluating the addition of checkpoint inhibitors and targeted agents to chemoradiation and during maintenance, he said.
Encouraging data have clearly emerged for checkpoint inhibitors as a second-line treatment of recurrent disease. Most recently, as reported during a European Society for Medical Oncology (ESMO) Virtual Plenary in May 2021, the newer agent cemiplimab-rwlc showed a survival advantage over chemotherapy (HR = 0.73; P = .00306) in the GOG-Partners protocol 3016 Cervical Empower-1 trial.2 Global regulatory filings are underway, said Dr. Monk, an investigator in that study.
DISCLOSURE: Dr. Mileshkin reported no conflicts of interest. Dr. Monk reported a leadership role with US Oncology; has received honoraria from and served as a consultant for Advaxis, Agenus, Akeso Biopharma, AstraZeneca, EMD Serono, Genmab/Seattle Genetics, GOG Foundation, GSK, Iovance Biotherapeutics, Merck, Oncosec, Puma Biotechnology, Regeneron, and Roche/Genentech.
1. Mileshkin L, Moore KN, Barnes EH, et al: Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase 3 OUTBACK trial (ANZGOG 0902, RTOG 1174, NRG 0274). 2021 ASCO Annual Meeting. Abstract LBA3. Presented June 8, 2021.
2. Tewari KS, Monk BJ, Vergote I, et al: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: Interim analysis of phase III trial of cemiplimab vs. investigator’s choice chemotherapy in recurrent/metastatic cervical carcinoma. ESMO Virtual Plenary. Abstract VP4-2021. Presented May 12, 2021.
Comments on the OUTBACK trial were provided by invited discussant Kunle Odunsi, MD, PhD, Professor of Obstetrics and Gynecology, Dean for Oncology, and Director of the University of Chicago Medicine Comprehensive Cancer Center. Lilian T. Gien, MD, MSc, Associate Professor of Oncology at the...