Adjuvant Chemo vs Radiotherapy Alone in Cervical Cancer

New findings on radiation plus adjuvant chemotherapy in patients with intermediate-risk cervical cancer seem to spell the end for the dual therapy in this group. 

Results from a phase 3 clinical trial of 316 women who’d had radical hysterectomies found that adjuvant chemotherapy as treatment for their early-stage, intermediate-risk cervical carcinoma did not improve outcomes but did increase toxicity. The results were the inverse of the study’s intention. 

The NRG-GOG 0263 (NCT01101451) study failed to reach its endpoint of improving recurrence-free survival through the addition of cisplatin chemotherapy, confirming instead that cisplatin chemotherapy given adjuvantly with radiotherapy is not a superior alternative in this cohort. The results were presented during a plenary session of the Society of Gynecologic Oncology Annual Meeting on Women’s Cancers in Seattle, Washington.

The current standard of care in this cohort is for radiotherapy alone, although the National Comprehensive Cancer Network (NCCN) guidelines place adjuvant chemotherapy in category 2B recommendations. 

“Perhaps the NCCN guidelines will have to change what it says here,” Andrew Berchuck, MD, chief of gynecologic oncology and professor of obstetrics and gynecology at Duke University School of Medicine in Durham, North Carolina, told Medscape Medical News. Berchuck was not involved in the clinical trial.

The National Cancer Institute lists adjuvant chemotherapy first in its guidelines for this group.

Another study published online this month in JAMA Oncology concluded that morbidity in these patients could be reduced if the use of chemoradiotherapy were de-escalated. 

This population-based cohort study of 1116 women, conducted by Núria Agustí Garcia, MD, postdoctoral fellow at The University of Texas MD Anderson Cancer Center in Houston, and colleagues, found no significant overall survival benefit of adjuvant chemotherapy in intermediate-risk cervical cancer, and that when it was given, patients tended to have larger tumors and nonsquamous cell history. 

The 5-year survival rate in patients who received chemoradiotherapy was 87%, compared with an 87% 5-year survival rate in those who received radiotherapy alone (hazard ratio = 0.85; 95% CI, 0.59-1.23; P =.38). 

If the standard of care in this cohort is radiation only, and outcomes are not better in adjuvant treatment, then why is there a controversy at all, and why are some investigators such as Agustí Garcia attempting to clarify adjuvant treatment’s effects?

Experts say it’s because of the history of adjuvant chemotherapy in more advanced cervical cancer and the extrapolations clinicians made when treating patients with intermediate risk.

What Is the History of Adjuvant Treatment in Cervical Cancer?

Concomitant therapies in intermediate-risk cervical cancer began in the late 1990s, at a time when it was found effective in more advanced disease, according to Berchuck, who also was not involved in the population study.

“Say back then, you had a stage IIIb cervical cancer. With external radiation alone, followed by brachytherapy internally, the cure rate for something like that would have been maybe 50 or 60%,” Berchuck said in an interview. “Adding cisplatin improved the cure rate by about 15%.”

That cisplatin improved survival rates in advanced disease, led to using it in less advanced cases, according to Berchuck. “The idea here was that if the pathology report indicated a larger tumor involving the lymphatics, the risk of recurrence went up to about 20%, so by adding chemo to postsurgical radiotherapy, you could improve things more than with just radiation alone,” Berchuck said. 

Studies of adjuvant chemotherapy in advanced cervical cancers confused the matter, according to Agustí Garcia. 

“The theoretical benefit of adding chemotherapy to radiotherapy for patients with intermediate-risk cervical cancer has been extrapolated from studies on locally advanced or high-risk cases, for example, those with parametrial or lymph node metastases,” Agustí Garcia said in an interview.

“However, before its implementation, there was no solid evidence supporting this approach in intermediate-risk patients,” she said. “The oncologic behavior of this subgroup may differ, and in the absence of parametrial or lymph node metastasis, chemotherapy may not be necessary.”

Do Both Studies Suggest That Radiotherapy Has Become More Effective Recently?

“Probably. Modern radiation techniques, such as IMRT [intensity-modulated radiation therapy] and IGRT [image-guided radiation therapy] are more effective than historical techniques,” said Amer Karam, MD, a clinical professor of obstetrics and gynecology at Stanford University in Palo Alto, California. Karam was not involved in either study mentioned previously.

Agustí Garcia said that while it’s true radiotherapy techniques have improved, these advancements primarily impact morbidity rather than survival outcomes.

“The lack of survival benefit from concomitant chemotherapy in intermediate-risk patients suggests that such benefit may never have existed in this subgroup,” she said.

What Explains Why Overall Survival Did Not Significantly Differ Between Patients Who Received Radiotherapy Alone and Those Who Received Chemoradiotherapy?

For Karam, there is a question as to whether chemosensitization mechanisms in radiation therapy, such as reactive oxygen species, inhibition of DNA repair, modulating tumor microenvironment, and cell cycle arrest — all used to induce apoptosis — are as efficacious as once thought.

“Also, systemic chemosensitization may not be as effective at controlling systemic disease beyond the pelvis and radiation field,” he said.

“Radiation is extremely effective in cervical cancer,” said Berchuck. “When you’re giving radiation in a situation like this where there is none, to only microscopic disease, it makes sense that radiation could be effective by itself.”

Why in the JAMA Oncology Study Were Larger Tumor Size and Nonsquamous Histology Associated With the Use of Chemoradiotherapy?

All experts agreed this is likely because this subgroup of patients with larger tumors is typically seen as being at higher risk for recurrence. This might be due to what Karam called an “unfavorable histology” and certain tumor characteristics, including depth of invasion.

Yet Agustí Garcia said, in her study, even after propensity score matching, adjuvant chemotherapy did not demonstrate any survival benefit in this subgroup.

“The importance of performing propensity score matching in our analysis was to ensure that populations with comparable baseline recurrence and death risks were being evaluated fairly,” she told Medscape Medical News.

Do These Findings Change Clinical Practice for Intermediate-Risk Cervical Cancer Treatment?

For Karam, the new evidence in intermediate-risk cervical cancer confirms rather than changes clinical practice. “The standard of care was radiation therapy alone, which is now confirmed, based on the results of GOG 263,” Karam said. “The standard of care for these patients will remain the same.”

Agustí Garcia said her study results can help “refine” clinical practice.

“The results suggest that adjuvant therapy could be safely de-escalated in intermediate-risk cervical cancer,” Agustí Garcia said. 

“We should avoid chemotherapy when there is no evidence-based benefit, reserving its use for locally advanced or high-risk cases, refining clinical guidelines to ensure treatment recommendations are based on higher-quality evidence, thereby standardizing care and reducing overtreatment,” she continued. “Current guidelines lack consensus and rely on lower-quality evidence.”

Agustí Garcia reported grants from Fundación Alfonso Martín Escudero. Berchuck has no disclosures. Karam reported royalties from UpToDate and that he is a speaker for AstraZeneca.