Adjuvant chemo following chemoradiation as treatment for locally advanced cervical cancer compared to chemoradiation alone

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Published: 10 Jun 2021
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Dr Linda Mileshkin - Peter MacCallum Cancer Center, Melbourne, Australia

Dr Linda Mileshkin speaks to ecancer about the OUTBACK trial. Initially, she talks about the background of the study.

Dr Mileshkin explains that despite chemoradiation, the standard treatment for locally advanced cervical cancer, a significant percentage of women relapse and die of distant metastatic disease. The international randomised phase III OUTBACK trial was designed to determine the effects on survival of giving adjuvant chemotherapy after chemoradiation.

Dr Mileshkin then discusses the methodology and results of the trial. The findings from the study showed that women with locally advanced cervical cancer receiving adjuvant chemotherapy after standard cisplatin-based chemoradiation did not experience improved overall or progression-free survival. In addition, the therapy was associated with increased side effects. In the end, she mentions the future impact of this study.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

The reason that we designed the OUTBACK trial was because we know that not everyone is cured with standard cisplatin-based chemoradiation if they have locally advanced cervical cancer. In fact, we knew from the meta-analysis of previous results that confirmed the reason why we use cisplatin during radiation, that about one in three, or up to one in two, patients will relapse after standard therapy. Unfortunately, many women will go on to develop distant metastatic disease and that ultimately causes them to die from their cancer.

So we wanted to test the hypothesis of whether additional adjuvant chemotherapy following standard chemoradiation would reduce the rate of people developing distant metastatic disease and dying from cervix cancer, similar to what we do routinely in other types of cancers and recently have also started to do in endometrial cancer.

What was the methodology of your study?

The methodology of the OUTBACK trial was that we ran an international academic randomised controlled trial to test our hypothesis. Women were randomised 1:1 in an open fashion if they had locally advanced cervix cancer and were suitable for usual treatment to receive standard cisplatin-based chemoradiation along with brachytherapy, or the same followed by four cycles of carboplatin and paclitaxel chemotherapy. The primary objective of the study was to determine if the five year overall survival rate was improved with the addition of adjuvant chemotherapy.

What were the key findings?

We learned a lot from the OUTBACK trial which did take several years to accrue and to follow women up. We were able to analyse the trial in March of this year when we had a median follow-up of five years in both arms, so very mature follow-up to look at overall survival.

What we learned was that the five-year overall survival rate was very similar between the two arms, being 71% in the standard chemoradiation arm and 72% in those who received the adjuvant chemotherapy. We also found that the progression free survival rate was very similar between the two arms with some early separation of the curves but then them coming together subsequently so that there was no statistical significant difference found.

We found that the patterns of relapse were also similar between the arms in terms of local and distant metastatic relapse. We also found that toxicity was significantly increased in the adjuvant chemotherapy arm and this was not unexpected toxicity but chemotherapy toxicity as you would expect with carboplatin and paclitaxel. So things like alopecia, haematological toxicity, gastrointestinal toxicity, fatigue, myalgia and peripheral neuropathy were all increased in the women that received the adjuvant chemotherapy. However, the febrile neutropenia rate was 2% in both arms, actually, and we had no study related deaths or any sign of late toxicity.

Another important thing that we learned as part of the OUTBACK trial was that we ended up with 22% of women in the adjuvant chemotherapy arm actually not starting any of this planned treatment. This occurred for a number of reasons. We randomised people prior to the start of chemoradiation and we found that a number of women and their doctors at completion of chemoradiation felt it was not appropriate or they didn’t want to go ahead with further chemotherapy at that point. So the strongest predictor of not starting further adjuvant chemotherapy was women who didn’t complete their initial chemoradiation component completely. But we also saw that older women, above the age of 60, and also those of non-Caucasian background were more than twice as likely not to start any of the planned adjuvant chemotherapy.

The other thing that we learned along the way was that, in fact, survival rates and relapse rates have improved over time since the meta-analysis was published some time back now. In fact, we ended up having to increase our sample size because of the fact that some women in the intervention arm weren’t receiving the intervention but also because the relapse rate was much lower than expected when we first designed the trial. So it was good in a way to see that, in fact, women in both arms of the trials did well and in general 70% of women were not relapsing in either arm.

How can these results impact the future treatment of cervical cancer?

OUTBACK was planned to build on the results of some previous studies. There were a couple of influential prior studies that examined the role of adjuvant chemotherapy and these were smaller studies but potentially thought to be flawed in their design. On the basis of these and the interest in the OUTBACK trial, in fact, some centres changed practice prematurely and started prescribing the adjuvant chemotherapy. Doctors always want to do better for their patients and maybe hoped that women who had high risk disease might have benefitted from the intervention. In fact, now we know from the OUTBACK trial that this is not the case. So we would recommend that that practice should stop and that the standard treatment should be cisplatin-based chemoradiation alone.

We’ve still got a lot of work to do in trying to improve outcomes in cervical cancer. It’s obviously important that we really support and broaden initiatives around the world to prevent cervical cancer in terms of making sure that more women have access to both screening and vaccination against HPV. It’s still important to recognise that locally advanced cervix cancer isn’t cured in all women and we still have a significant percentage of women relapsing so we need to work on what we can do to make this better. If we can reduce the toxicity of standard therapy and improve the percentage of women that we can get through treatment this will certainly help but we have a very strong international cooperative group in gynaecological cancer called the GCIG and with that group around the world we’re working on a number of trials to test out other things in this setting. For example, would it help if we gave a short course of chemotherapy before chemoradiation? This is being tested in a trial called INTERLACE. There are also a number of trials saying, ‘Well, maybe we’ve maxed out chemotherapy but would other types of drugs help?’ So there are ongoing trials looking at the role of giving additional adjuvant immunotherapy or, indeed, various types of target therapies following chemoradiation. So we still have lots of work to do and await the results of the ongoing trials with interest.