Improvement in survival not demonstrated with adjuvant chemotherapy in locally advanced cervical cancer
The final analysis revealed that despite the additional cycles of chemotherapy, OS at 5 years was the same between the 2 groups. The OS at 5 years for chemotherapy alone was 71% and 72% for the chemotherapy plus adjuvant chemotherapy group. PFS told a similar story, with PFS for the control group being 61% and 63% for the experimental group. The disease recurrence patterns between the 2 groups were also similar.
In an interview with Targeted oncology, Bradley Monk, MD, FACCOG, FACS, Gynecologist Oncologist at Arizona Oncology and Medical Director of Gynecologic Oncology Research at the US Oncology Network, discusses the OUTBACK trial, including results, strengths and challenges.
Targeted Oncology ™: Can you give a brief overview of the OUTBACK trial?
MONK: I have a passion for trying to help women who develop cervical cancer. I understand that this is a disease that should be avoided with HPV vaccination, PAP test and HPV cervical virus test. I think we all know this is not going the way we would like and that there are still women, even in this country, who are struggling and even dying from cervical cancer. At the 2021 American Society of Clinical Oncology Annual Meeting Plenary Session, the OUTBACK trial was presented. This study examined adjuvant chemotherapy after chemoradiation as the primary treatment for locally advanced cervical cancer compared to chemoradiation alone. This was a collaborative trial between the Australian New Zealand Gynecologic Oncology Group, Radiation Therapy Oncology Group and NRG Oncology. At the time the study was developed, I was chair of the NRG’s Cervical Cancer Committee, a position I held for 11 years.
Can you explain the design of the study?
In 1999, the National Cancer Institute issued a clinical alert, saying that weekly chemotherapy of cisplatin should be added to radiation therapy in the treatment of locally advanced cervical cancer and in 1999, became the clinical standard. In the context of recurrence, cervical cancer was historically considered resistant to chemotherapy. Also through the Historical Group of Gynecological Oncology, which has become the NRG Oncology Group, we have shown that chemotherapy is very sensitive and on behalf of NRG Oncology, I published in 2009, in the Journal of Clinical Oncology a study called Protocol 204 (NCT03438396), which established comprehensive systemic therapy for cervical cancer in the setting of a recurrence as a cisplatin or carboplatin platinum taxane with paclitaxel.
With this new discovery, we decided to launch a very ambitious randomized phase 3 trial involving patients with locally advanced cervical cancer treated with radiotherapy and randomizing them on a 1: 1 to 4 basis. Additional cycles of carboplatin, paclitaxel, delivered in an area under the curve of 5, and paclitaxel at 155 milligrams per square meter. This was a bit unusual dose because these patients had all received previous radiation therapy, which increases the toxicity of the cytotoxic chemotherapy. It was a very ambitious trial. The study was originally scheduled to include 780 patients and was scaled up to 900 and had 80% power with 5% bilateral alpha for an 8% absolute improvement in OS.
While this trial was ongoing, in 2013 a study was presented to ASCO and we obtained FDA approval for the addition of bevacizumab (Avastin) to the use of taxane-based chemotherapy. platinum in recurrent cervical cancer. He changed the standard of care while the standard was in progress. Recently, we also had 2 Phase 3 trials of checkpoint inhibitors that advanced the standard of care.
That said, this trial reported to ASCO 2021 showed that there was no difference when 4 more cycles of carboplatin and paclitaxel were added to chemotherapy. There was no difference in OS at 5 years, which in the radiotherapy alone group was 71%.
When there were 4 additional cycles of carboplatin and paclitaxel after chemotherapy and radiotherapy, the 5-year survival was 1% greater with a relative risk of 0.90 and a confidence interval of 0.70 overlapping 1 with a cut-off greater than 1.17.
Interestingly, there was also no improvement in PFS. The 5-year PFS was 61% versus 63%. There has also been no improvement in local regional control. There has been a slight numerical improvement in local control, but not in a substantial way. If anything, as we looked at the subset analysis, which generated assumptions, patients over 60 did better without the chemotherapy additions. So, by looking at the important prognostic factors, not only were we unable to identify the subset where it was working, but we actually identified a subset where it appeared not to be working.
Can you explain the rationale behind adding these extra rounds of chemotherapy to this treatment plan?
The OUTBACK trial identified a group of patients at high risk of recurrence, meaning the tumors were too large for radical surgery, the hypothesis being that chemotherapy might improve OS and possibly the cure rate by cytotoxic destruction of micrometastatic disease.
What impact do you think these results will have on the clinical or community oncology environment?
We have seen the evolution that cervical cancer is indeed sensitive to chemotherapy. NRG Oncology and the Historical Gynecologic Oncology Group have played a very important role in defining the role of radiation in the systemic therapy and treatment of cervical cancer, especially locally advanced cervical cancer. This is a wonderful opportunity to improve on this result, especially with the discovery over the last decade or so that cervical cancer is in fact a disease sensitive to chemotherapy, rather than a disease resistant to chemotherapy. chemotherapy. For this reason, these dates had an impact because they show that this is not the case.
There are well-meaning providers who administer additional cycles of chemotherapy after chemotherapy and radiation therapy in locally advanced cervical cancer with no evidence. It must stop because it does not bring any benefit. This is the impact of this research.
There are 4 lessons to be learned from the OUTBACK trial. And we should use these lessons to improve the quality of our ongoing and future clinical trials and locally advanced cervical cancer. Number 1, when post-progression survival is long and crossbreeding is common, or switching as we call it, the endpoint should never be OS. It should be PFS. Turns out it probably wouldn’t have been positive anyway.
The second lesson is that you have to use the right agents at this time. The good agents back then were carboplatin / paclitaxel, but as I mentioned in 2014, bevacizumab and carboplatin / paclitaxel have become the global standard. And today we have 2 randomized phase 3 trials of checkpoint inhibitors.
Third, we need to register the right patients. These patients who were recruited were in fact not at high risk of recurrence, most of them were cured. So we need to identify the patients with the highest unmet medical need, register those patients with the right endpoint, and treat them with the right agents.
Finally, patients who receive radiotherapy and chemotherapy are quite rough at the end of their treatment. Twenty percent of patients, in fact, have not even completed their chemotherapy and radiation therapy. If you don’t complete it, you’re definitely not going to move into a maintenance phase. Even when they finished it, about 20% did not move on to a maintenance phase. So if we want to change the impact of chemotherapy and radiotherapy, this idea of a strategy of sustaining the change after chemotherapy and radiotherapy, is probably not a good idea. It may be best to start systemic therapy during radiation therapy, which after all is the start of systemic cisplatin therapy.