Survival Improvement Not Shown With Adjuvant Chemotherapy in Locally Adnvaced Cervical Cancer

Despite being highly preventable with human papillomavirus (HPV) vaccines and testing, cervical cancer remains a leading cause of cancer-related death in women ,. Concurrent chemotherapy has proven to be effective in this patient population, but in the case of distant metastatic diseases, high death rates continue.

The OUTBACK trial (NCT01414608), which began in 1999, aimed to determine if additional cycles of chemotherapy would further improve survival in this patient population. The end points of the study were overall survival (OS), PFS, acute and long-term toxicities, patterns of disease recurrence, and quality of life. 

The final analysis found that despite the additional cycles of chemotherapy, the 5-year OS was similar same between the 2 groups. The 5-year OS for the chemotherapy alone was 71% and 72% for the chemotherapy plus adjuvant chemotherapy group. PFS told a similar story, with the PFS for the control group being 61% and 63% for the experimental group. Disease recurrence patterns between the 2 groupa were also similar.

In an interview with Targeted Oncology, Bradley Monk, MD, FACCOG, FACS, a gynecologic oncologist at Arizona Oncology and the medical director of gynecologic oncology research at the US Oncology Network, discusses the OUTBACK trial, including the results, strengths, and challenges.

Targeted Oncology™: Can you provide a brief overview of the OUTBACK Trial?

MONK: I have a passion for trying to help those women who develop cervical cancer. I get it's a disease that should be prevented with HPV vaccination, PAP testing, and testing for the HPV virus from the cervix. I think we all know that's not happening how we would like and there's still women even in this country, battling, and even dying from cervical cancer. At the 2021 American Society of Clinical Oncology Annual Meeting in the plenary session, the OUTBACK trial was presented. This study looked at adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone. It was a collaborative trial between the Australian New Zealand Gynecologic Oncology Group, the Radiation Therapy Oncology Group and NRG Oncology. At the time the study was developed, I was the chair of the NRG Cervical Cancer Committee, a position that I held for 11 years.

Can you explain the study design?

In 1999, the National Cancer Institute had a clinical alert, saying that chemotherapy of weekly cisplatin should be added to radiation in the treatment of locally advanced cervical cancer and in 1999, became the clinical standard. In the recurrent setting, cervical cancer had historically been considered chemotherapy resistant. Working again through the Historical Gynecologic Oncology Group, now 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 a global systemic therapy for cervical cancer in the recurrence setting as platinum taxane of either cisplatin or carboplatin with paclitaxel.

With this new discovery, we decided to launch a very ambitious randomized phase 3 trial taking patients with locally advanced cervical cancer being treated with radiation and randomizing them in a 1:1 basis to 4 additional cycles of carboplatin, paclitaxel, delivered at an area under the curve of 5 and paclitaxel at 155 milligrams per square meter. It was a little bit of an unusual dose because these patients had all received prior radiation, which increases the toxicity from cytotoxic chemotherapy. It was a very ambitious trial. The study was initially slated to enroll 780 patients and was increased to 900 and had an 80% power with a 2-sided alpha of 5% for an absolute improvement of 8% in OS.

While this trial was going on, in 2013, a study was presented at ASCO and we got FDA approval for the addition of bevacizumab (Avastin) to the use of platinum taxane chemotherapy in recurrent cervical cancer. It changed the standard of care while the standard was ongoing. Recently, we also had 2 phase 3 trials of checkpoint inhibitors that have further evolved the standard of care.

Having said that, this trial reported at ASCO 2021, showed that there was no difference when 4 additional cycles of carboplatin and paclitaxel was added to chemotherapy. There was no difference in the 5-year OS, which in the chemotherapy radiation alone group was 71%.

When there were 4 additional cycles of carboplatin and paclitaxel after chemotherapy and radiation, the 5-year survival was 1% greater with a hazard ratio of .90 and confidence interval of .70 overlapping 1 with an upper boundary of 1.17.

Interestingly, there was also no improvement in PFS. The 5-year PFS was 61% versus 63%. There was also no improvement in local regional control. There was a slight improvement numerically in local control, but not substantially. If anything, as we looked at the subset analysis, which was hypothesis generating, the patients greater than 60 did better without the additions of chemotherapy. So, in looking at the important prognostic factors, not only could we not identify subset where it worked, we actually identified a subset in which it appeared not to work.

Can you talk about the reasoning behind adding these additional cycles of chemotherapy to this treatment plan?

The OUTBACK trial identified a group of patients who were at high risk for recurrence, meaning that the tumors were too large for radical surgery with the hypothesis being that chemotherapy could improve the OS and perhaps the cure rate by cytotoxic destruction of micro-metastatic disease.

What impact do you believe these results will have on the clinical or community oncology setting?

We've seen the evolution that cervical cancer is indeed sensitive to chemotherapy. NRG Oncology and the Historical Gynecologic Oncology Group has been very impactful in defining the role of radiation in systemic therapy and treating cervical cancer, particularly locally advanced cervical cancer. This is a wonderful opportunity to improve on that outcome, particularly with the discovery over the last decade or so that cervical cancer is actually a chemotherapy-sensitive disease, rather than a chemotherapy-resistant disease. Because of that, these date were impactful because they show that it doesn't.

There are well intentioned providers who are giving additional cycles of chemotherapy after chemotherapy and radiation in locally advanced cervical cancer without evidence. It needs to stop because it doesn't provide any benefit. That's the impact of this research.

There are 4 lessons learned from the OUTBACK trial. And we should utilize 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 crossover is common, or switching as we call it, the end point should never be OS. It should be PFS. Now as it turns out, it probably wouldn't have been positive anyways.

The second lesson is you have to use right agents at the time. The right agents at the time were carboplatin/paclitaxel, but as I mentioned in 2014, bevacizumab and carboplatin/paclitaxel became the global standard. And today, we have 2 randomized phase 3 trials of checkpoint inhibitors.

Third, we need to enroll the right patients. These patients that were enrolled, were actually not at high risk for recurrence, most of them were cured. So, we need to identify patients at the highest unmet medical need, enroll those patients with the right end point, and treat the with the right agents.

Finally, patients who receive radiation and chemotherapy are pretty beat up at the end of their treatment. Twenty percent of the patients, in fact, didn't even complete their chemotherapy and radiation. If you don't complete it, you're certainly not going to transition to a maintenance phase. Even when they finished it, another 20% or so didn't transition to a maintenance phase. So, if we want to change the impact of chemotherapy and radiation, this idea of a switch maintenance strategy after chemotherapy and radiation, is probably not wise. It may be better to start the systemic therapy during the radiation which after all, is when the systemic therapy cisplatin is started.

_REFERENCE:

_{Mileskin LR, Moore KN, Barnes E, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). J Clin Oncol. 39(18):L8A3. doi: 10.1200/JCO.2021.39.15_suppl.LBA3.}