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 University of Toronto and a gynecologic oncologist at Sunnybrook Odette Cancer Centre, Toronto, also shared her thoughts with The ASCO Post.
“The OUTBACK trial results were long-awaited for this patient population,” stated Dr. Gien, who noted that the benefit of adjuvant therapy in locally advanced cancer of the cervix has been unclear for some time. “The OUTBACK trial puts this question to rest,” she added.
Kunle Odunsi, MD, PhD
Lilian T. Gien, MD, MSc
Benefit of Adjuvant Chemotherapy Under Study
Ten years ago, Dueñas-González et al reported that the addition of adjuvant gemcitabine plus cisplatin to concurrent cisplatin and radiation improved 3-year progression-free survival (hazard ratio [HR] = 0.68) and overall survival (HR = 0.69) over chemoradiation alone but led to an almost doubling in toxicity.1 More recently, in 2019, a similar but smaller trial showed no benefit of adjuvant chemotherapy.2
The larger Dueñas-González study “showed promise” with adjuvant chemotherapy, but “criticism in the study design led to uncertainty of the reported results,” Dr. Gien said. A Cochrane review in 2014 found the available evidence to be insufficient to support the use of adjuvant chemotherapy after chemoradiation3; therefore, this approach was never recommended in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Dr. Odunsi added.
Clinicians and researchers have, however, continued to wonder whether adjuvant chemotherapy might yet prove capable of improving outcomes in locally advanced cervical cancer, leading to studies such as OUTBACK. “The current study is timely and important,” Dr. Odunsi commented.
Long-Awaited Answers
With its results now in, the conclusion can be drawn that adjuvant chemotherapy with current cytotoxics does not work, they agreed. “With no statistically significant difference between the two arms and its increased toxicity, adjuvant chemotherapy should not be used post-chemoradiation for this population with cervical cancer. There was also no benefit in subsets of higher-risk patients, and therefore the hypothesis of those who are at higher risk of developing distant metastasis benefiting from additional chemotherapy does not hold,” Dr. Gien commented.
With 919 patients enrolled, she added, “the global research community should be congratulated on the successful recruitment of this large number of patients to answer this important question. There is also deep appreciation to the large number of women who participated in this trial.”
Dr. Odunsi applauded the researchers for successfully completing the study and for modifying the design “based on reality” (ie, enlarging the sample when poor adherence to adjuvant chemotherapy became clear). He also was impressed at the high completion rates for chemoradiation, the efficient application of external-beam radiation, and the support given to patients experiencing toxicity.
Future Directions
Researchers are continuing the search for regimens that reduce distant metastasis in women with locally advanced disease. “Further research should focus on adjuvant therapies that may be more tolerable and effective when given after standard therapy,” Dr. Odunsi said. To this end, worthy aims are to prevent the mesenchymal state of the primary tumor, disturb circulating tumor cell survival pathways, and repress the epithelial state in metastasis, he said, “so that tumors are not able to survive in their new [metastatic] environment.” Phylogenetic analysis of the tumor could help elucidate the mechanisms of disease progression and yield targeted approaches, he said, suggesting a dozen or so potential strategies to combat dormant disseminated tumor cells.
Dr. Gien agreed that standard cytotoxic regimens have likely been “maximized,” and newer modalities are needed to enhance the effect of concurrent chemoradiation. “Immunotherapy checkpoint inhibitors continue to provide promising early data, and we await studies evaluating the combination of a checkpoint inhibitor with concurrent chemoradiation and adjuvant immunotherapy,” she said.
Moreover, she cited a randomized trial evaluating the use of a ribonucleotide reductase inhibitor in combination with chemoradiation (ClinicalTrials.gov identifier NCT02466971), noting promising activity in the metastatic setting of antibody-drug conjugates against tissue factor.4 Such exciting agents may eventually prove beneficial in the adjuvant setting, Dr. Gien hopes.
“Although these combination therapies are exciting and provide a new direction,” Dr. Gien cautioned, “one must also keep in mind whether these agents will be available and affordable by the countries where locally advanced cervical cancer is most prevalent and where innovative therapies to improve survival are needed the most.”
DISCLOSURE: Dr. Odunsi reported stock or other ownership interests in Tactiva Therapeutics; has received honoraria from KIYATEC; has served as a consultant or advisor to Regeneron; has received research funding from AstraZeneca and Tesaro; has patents, royalties, or other intellectual property with Roswell; and has received travel, accommodations, or expenses from Immunovaccine. Dr. Gien has served on advisory boards for Clovis Oncology, Leap Therapeutics, Myriad Genetics, and Toray; and has received honoraria from Merck.
REFERENCES
1. Dueñas-González A, Zarbá JJ, Patel F, et al: Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 29:1678-1685, 2011.
2. Tangjitgamol S, Tharavichitkul E, Tovanabutra C, et al: A randomized controlled trial comparing concurrent chemoradiation versus concurrent chemoradiation followed by adjuvant chemotherapy in locally advanced cervical cancer patients. J Gynecol Oncol 30:e8, 2019.
3. Tangjitgamol S, Katanyoo K, Laopaiboon M, et al: Adjuvant chemotherapy after concurrent chemoradiation for locally advanced cervical cancer. Cochrane Database Syst Rev 2014:CD010401, 2014.
4. Coleman RL, Lorusso D, Gennigens C, et al: Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 22:609-619, 2021.
