Adding chemotherapy after standard chemoradiation treatment does not improve survival for women with locally advanced cervical cancer, and it also leads to additional side effects. The long-anticipated findings of a Phase III trial likely will change the minds of early adopters of this combination therapy, who had hoped the regimen would reduce distant disease recurrence.
"The study confirms that chemoradiotherapy alone is currently our best possible treatment for women with locally advanced cervical cancer. Not only is there no benefit with adjuvant chemotherapy, but severe side effects are also increased," said lead author Linda R. Mileshkin, MD, a medical oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia, during a presentation at the 2021 ASCO Annual Meeting (Abstract LBA3).
Cervical cancer is a major global health problem, with more than half a million women diagnosed each year, and a large percentage of them die of the disease. Concurrent cisplatin and radiation to the pelvis plus brachytherapy have been the standard of care since 1999. An individual patient data meta-analysis of 18 trials in 2008 confirmed the benefit of adding concurrent chemotherapy to radiation. This resulted in an absolute improvement in overall survival (OS) of 6 percent. However, a significant percentage of these women relapsed after this treatment and died due to the development of distant metastatic disease.
The meta-analysis also suggested more benefit in two trials that gave cycles of additional chemotherapy, and a subsequent randomized trial suggested additional benefit from the use of cisplatin-gemcitabine followed by 2 cycles of this combination chemotherapy. But this trial was criticized for having only a 1-year follow-up and significantly increased toxicity in the intervention arm.
About the Study
This led to the development of a confirmatory trial, the OUTBACK trial, a Phase III international trial that randomly assigned 926 patients with locally advanced cervical cancer to receive standard cisplatin-based chemoradiation (426 patients) or the same regimen with additional chemotherapy with carboplatin and paclitaxel (465 patients).
Standard chemoradiation in both groups consisted of 40-45 Gy of external beam radiation in 20-25 fractions, including a nodal boost plus brachytherapy. Patients received cisplatin 40 mg/m2 weekly during chemoradiation. Adjuvant chemotherapy after chemoradiation in the experimental group included carboplatin AUC 5 and paclitaxel 155 mg/m2 3 times a week for 4 cycles. The primary endpoint was OS at 5 years. The researchers also examined progression-free survival (PFS), adverse side effects, and patterns of disease recurrence.
Key Findings
Results show that chemotherapy following chemoradiation did not improve survival over standard chemoradiation alone for patients with locally advanced cervical cancer. At 5 years, OS was comparable for both groups, 72 percent for those receiving adjuvant chemotherapy and 71 percent for those receiving standard care. Similarly, at 5 years, disease had not progressed for 63 percent of patients who received the additional treatment as compared with 61 percent who did not.
Serious adverse events (Grade 3-5) were experienced by more patients up to 1 year after randomization (81%) in patients in the adjuvant chemotherapy group as compared with the standard treatment group (62%). "Beyond 1 year of randomization, the only differences between the two arms were increased peripheral neuropathy (7% vs. 2%, Grade 2). There was no sign of increased late radiation toxicity," said Mileshkin. Patterns of disease recurrence were similar in the two treatment groups. Global quality-of-life scores appeared to worsen during adjuvant chemotherapy and for 3-6 months afterward, but were similar for months 12-36.
Mileshkin noted some limitations of the study. Randomization occurred before chemoradiation, adjuvant chemotherapy was not started for 22 percent of patients, outcomes were better than expected, patients were confined to high-income countries, and sensitivity analyses for non-compliance are subject to bias.
The researchers plan to complete additional analyses to answer some of the secondary objectives, such as the impact of standard chemoradiation with or without additional chemotherapy on the psycho-sexual health of patients with advanced cervical cancer.
In conclusion, Mileshkin said: "Adjuvant chemotherapy given after standard cisplatin-based chemoradiation for women with locally advanced cervical cancer did not improve OS or PFS. Pelvic radiation with concurrent weekly cisplatin continues to be the standard of care for the treatment of locally advanced cervical cancer. These findings do not support the use of adjuvant chemotherapy with carboplatin and paclitaxel after chemoradiation after weekly cisplatin. Further research should focus on adjuvant therapies that may be more tolerable and effective when given after standard therapy."
ASCO President Lori J. Pierce, MD, radiation oncologist, professor, and Vice Provost for Academic and Faculty Affairs at the University of Michigan, commented: "This trial provides clear evidence that the addition of chemotherapy after chemoradiation does not extend survival. The results are immediately practice-changing, showing that this approach should not be used to treat locally advanced cervical cancer. We can now spare our patients the side effects and toxicity that comes with additional chemotherapy."
Mark L. Fuerst is a contributing writer.