Adjuvant chemotherapy after chemoradiation fails to extend OS in cervical cancer subset
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Adjuvant chemotherapy following chemoradiation did not prolong OS or PFS compared with chemoradiation alone among women with locally advanced cervical cancer, according to results of the randomized phase 3 OUTBACK study.
In addition, women who received adjuvant chemotherapy experienced more grade 3 to grade 5 adverse events and worse quality of life up to 6 months after treatment, according to the findings, scheduled for presentation during the plenary session of the virtual ASCO Annual Meeting.
“With the success seen in systemic therapy in both the chemoradiation setting as well as in recurrent disease, the NRG Oncology Cooperative Group tested the addition of four additional maintenance cycles of carboplatin and paclitaxel following standard cisplatin and radiation in treating locally advanced cervical cancer with curative intent,” Bradley Monk, MD, FACOG, FACS, oncologist with Arizona Oncology and medical director of gynecologic oncology for US Oncology Network, told Healio. “This trial of ‘outback’ chemotherapy did not show any clinically meaningful benefit but did increase adverse reactions.”
The use of the now widely used biologics, including bevacizumab and checkpoint inhibitors, which are clearly active, was “conspicuously untested,” Monk added.
“Cervical cancer is a major global health problem, with more than half a million women diagnosed with the disease each year. Many of these women reside in low- and middle-income countries and more than 3,000 will die of this cancer annually, making it the fourth leading cause of cancer-associated death among women,” Linda R. Mileshkin, MD, oncologist at Peter McCallum Cancer Centre in Melbourne, Australia, said during a press conference. “Standard treatment for women with advanced cervical cancer since 1999 has been concurrent cisplatin chemotherapy along with radiation and brachytherapy. The addition of low-dose chemotherapy during radiation led to a 5-year OS benefit of 6%.”
However, a substantial proportion of women die due to the development of distant metastatic disease, Mileshkin added.
“Prior trials have suggested that giving more chemotherapy after chemoradiation may help with survival,” she said. “These findings changed practice across some centers; however, the international community felt that there were flaws in the research. It was therefore important to perform a confirmatory trial — hence the purpose of the current OUTBACK trial.”
Researchers assigned 919 women with locally advanced cervical cancer suitable for primary treatment with curative-intent chemoradiation to standard cisplatin-based chemoradiation with (n = 463) or without (n = 456) adjuvant chemotherapy with four cycles of carboplatin and paclitaxel. Overall, 361 women initiated adjuvant treatment.
OS at 5 years served as the primary endpoint. PFS, adverse events and patterns of disease recurrence served as secondary endpoints.
Median follow-up was 5 years.
Results showed 5-year OS of 72% with adjuvant treatment vs. 71% with standard chemoradiation alone (difference, 1 percentage point; 95% CI, 6 to 7), corresponding to an HR of 0.9 (95% CI, 0.7-1.17).
Five-year PFS also was similar between the adjuvant chemotherapy and control groups (63% vs. 61%; difference, 2 percentage points; 95% CI, 5 to 9), with an HR for PFS of 0.87 (95% CI, 0.7-1.08). Disease recurrence patterns were comparable between the two groups, Mileshkin added.
A greater proportion of women assigned adjuvant treatment experienced grade 3 to grade 5 adverse events (81% vs. 62%) up to 1 year after random assignment.
“Quality of life was also reportedly worse during adjuvant treatment and for the following 3 to 6 months after treatment but returned to similar between the two groups at 1 year and onward,” Mileshkin said. “The standard treatment for women with advanced cervical cancer should continue to be pelvic chemoradiation with concurrent weekly cisplatin.”
Monk said clinical trials are now focusing on the addition of targeted agents and checkpoint inhibitors to chemoradiation and as maintenance therapy with the hope of increasing local control, time to progression and OS.
“The results of these trials are imminent and eagerly awaited,” Monk said. “In second-line recurrent cervical cancer, checkpoint inhibitors are becoming increasingly common with pembrolizumab [Keytruda, Merck] receiving FDA accelerated approval in June 2018. Now, the exciting results of GOG-3016, EMPOWER-Cervical 1, were presented as a European Society of Medical Oncology Virtual Plenary in May, showing a survival advantage of cemiplimab [Libtayo; Regeneron, Sanofi Genzyme] compared with second-line physicians-choice chemotherapy. Global regulatory filings of second-line cemiplimab are underway.”
Perspective
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Lori J. Pierce, MD, FASTRO, FASCO
This is an important trial. The results clearly show that women with advanced cervical cancer do not benefit from adjuvant chemotherapy. Physicians who currently use adjuvant chemotherapy based upon preliminary data and who have been promised that it will work will clearly see that it does not work and that the practice needs to be discontinued. What adjuvant chemotherapy did do in this study was cause unnecessary side effects for the women who received it. This tells us that as clinical researchers, we need more trials for women with locally advanced cervical cancer using a different therapeutic approach. It also clearly shows the importance of the outcomes of clinical trials, whether positive or negative. Both clearly inform practice.
Michigan Medicine
Perspective
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Mehdi M. Kebria, MD
Cervical cancer continues to be one of the most common gynecologic cancers worldwide despite global vaccination efforts. Historically, locally advanced cervical cancer has been treated with concurrent chemoradiation therapy using a combination of external beam radiation therapy, intracavitary brachytherapy and concurrent weekly cisplatin. Unfortunately, a significant percentage of women develop distant recurrences.
The OUTBACK trial was an international collaborative study designed to address this issue. The outcome of this long-awaited study showed adjuvant chemotherapy in locally advanced cervical cancer was associated with lack of survival benefit and led to additional treatment-related toxicity.
There have been several previous attempts to improve the outcomes of this subgroup of patients. Various therapeutic strategies have been studied, including neoadjuvant chemotherapy followed by concomitant chemoradiation and neoadjuvant chemotherapy followed by surgery. However, so far, none of these approaches has been proven to improve the outcome of women with locally advanced cervical cancer beyond the results achieved with concomitant chemoradiation. More recently, novel therapeutic approaches such as immune checkpoint inhibitors and adjuvant therapeutic vaccines have been studied in ongoing clinical trials, including among women with locally advanced cervical cancer. In my opinion — for now and until future studies show survival benefit — concomitant chemoradiation using weekly cisplatin plus radiation therapy remains the standard of care for management of locally advanced cervical cancer.
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Mileshkin LR, et al. Abstract LBA3. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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