Adding Chemo to Standard Care No Help for Cervical Cancer

Women with locally advanced cervical cancer had similar survival whether they received primary chemoradiation therapy (CRT) or CRT followed by adjuvant chemotherapy, a large randomized trial showed.

The 5-year overall survival (OS) rate was 72% with adjuvant chemotherapy and 71% with primary CRT alone; the progression-free survival (PFS) rate was 63% versus 61%. Serious adverse events (AEs), particularly AEs typical of chemotherapy, occurred substantially more often in patients who received adjuvant chemotherapy.

The findings support the current standard of care — pelvic radiotherapy with concurrent weekly cisplatin — said Linda Mileshkin, MD, of the Peter MacCallum Cancer Center in Melbourne, Australia, during the American Society of Clinical Oncology (ASCO) virtual meeting.

“These findings do not support the use of adjuvant chemotherapy with carboplatin and paclitaxel after chemoradiation with weekly cisplatin,” she noted during a press briefing that preceded the meeting. “Further research should focus on adjuvant therapies that may be more tolerable and effective when given after standard therapy.”

Immunotherapy is a prime candidate for treatment beyond CRT.

“We know that immunotherapy can have a benefit in the treatment of metastatic disease and there are three or four studies ongoing around the world, looking at randomizing women to adjuvant immunotherapy or not after chemoradiation,” Mileshkin said in response to a question from the virtual audience. “That approach has been found to be successful in lung cancer, so we’re very interested to see the results of those studies.”

Not only did the study reaffirm the current standard of care for locally advanced cervical cancer, it provided another demonstration of the importance of randomized clinical trials, even when the results are negative, said Lori Pierce, MD, of the University of Michigan, who moderated the discussion.

“This is an important trial, and the results clearly show that patients with locally advanced cervical cancer do not benefit from adjuvant chemotherapy,” said Pierce. “Physicians who are currently using adjuvant chemotherapy based on preliminary data and the promise that it could work, will see that it does not work and that they need to discontinue that practice. What adjuvant chemotherapy did do is cause unnecessary side effects for the patients who received it.”

“This tells us that as clinical researchers, we need more trials for patients with locally advanced cervical cancer, using a different therapeutic approach,” she added.

Concurrent chemoradiation with cisplatin and brachytherapy has been the standard of care for locally advanced cervical cancer for more than 20 years. An individual patient data meta-analysis of 18 clinical trials confirmed a survival advantage with concurrent CRT versus radiotherapy alone.

Most cervical cancer deaths are due to the development of distant metastases, Mileshkin noted. Results from several small but influential studies suggested that additional chemotherapy after CRT might address the issue, and some centers changed their clinical practice on the basis of the data.

To clarify whether adjuvant chemotherapy has a role in locally advanced cervical cancer, investigators in the international phase III OUTBACK trial randomized 919 patients to cisplatin and radiation with or without adjuvant carboplatin-paclitaxel chemotherapy. The primary endpoint was 5-year OS. Key secondary endpoints were 5-year PFS, AEs, and patterns of disease recurrence.

The trial had statistical power to detect an 8% absolute improvement in 5-year OS, from 72% with CRT alone to 80% with CRT plus adjuvant chemotherapy. The primary analysis showed almost identical 5-year OS (HR 0.90, 95% CI 0.70-1.17, P=0.8). Similarly, the absolute 2% difference in 5-year PFS did not achieve statistical significance (P=0.61). The pattern of disease recurrence also did not differ between treatment groups.

“Even when we looked at subsets of women with high-risk disease, such as those with node-positive involvement, there was no benefit from the intervention,” said Mileshkin.

During the first 12 months of follow-up, grade 3-5 serious AEs occurred in 81% of patients randomized to adjuvant chemotherapy compared with 62% of patients who received standard care.

Mileshkin said 22% of patients assigned to adjuvant chemotherapy did not begin the added treatment.