Concomitant chemoradiation should be standard for locally advanced cervical cancer

MADRID — Neoadjuvant chemotherapy followed by radical surgery did not improve outcomes compared with cisplatin-based concurrent chemoradiation for women with locally advanced squamous carcinoma of the cervix, according to results of a randomized controlled trial presented at the European Society for Medical Oncology Congress.

Perspective from Domenica Lorusso, MD, PhD

An estimated 528,000 new cases of cervical cancer are diagnosed worldwide each year, and approximately 266,000 women die of the disease annually. Many patients — particularly those in less developed countries — present with locally advanced disease, meaning the cancer has invaded the tissue that surrounds the cervix.

“Giving radiotherapy and simultaneous chemotherapy using cisplatin has been the standard treatment for close to 20 years based on the results of several large high-quality trials,” Sudeep Gupta, MD, DM, professor of medical oncology at Tata Memorial Center in India, said during a press conference. “However, despite treatment, about 25% to 40% of patients relapse and die of their disease.”

An alternative treatment strategy that consists of neoadjuvant chemotherapy followed by radical surgery is practiced in many parts of the world — particularly in Europe and Asia — despite a lack of evidence about its efficacy, Gupta said.

Gupta and colleagues conducted a single-center trial at Tata Memorial Centre, the largest cancer hospital in India, to compare neoadjuvant chemotherapy followed by radical surgery with standard concomitant chemoradiation.

The trial, initiated in 2003, included 633 women with stage IB2 (17%), IIA (25%) or IIB (57.2%) squamous cell carcinoma of the cervix.

Researchers randomly assigned 316 women to neoadjuvant chemotherapy — comprised of three cycles of paclitaxel 175 mg/m² and carboplatin area under the curve 5-6 every 3 weeks — followed by radical hysterectomy. The other 317 received concomitant chemoradiation, which included standard pelvic radiation plus five cycles of cisplatin 40 mg/m² once per week for 5 weeks. Postoperative radiation was administered per protocol criteria.

Treatment arms were balanced with regard to disease stage, patient age, performance status, hemoglobin and radiological pelvic lymph node status.

DFS served as the primary endpoint. Secondary endpoints included OS and toxicity.

Median follow-up was 58.5 months. By that time, 30% of patients in the chemotherapy/surgery group and 23% in the chemoradiation group had relapsed or died. Researchers reported 5-year DFS rates of 69.3% in the chemotherapy/surgery group and 76.7% in the chemoradiation group (HR = 1.38; 95% CI, 1.02-1.87).

Results showed no significant difference in 5-year OS (74.8% vs. 74.7%; HR = 1.02; 95% CI, 0.75-1.39).

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When researchers adjusted data to account for prognostic factors, they determined neoadjuvant chemotherapy followed by surgery was not superior for DFS or OS.

Gupta and colleagues measured acute and delayed toxicities of treatment in both groups.

At 2 years, results showed no significantly differences between the chemotherapy/surgery group and chemoradiation group with regard to rectal toxicity (2.2% vs. 3.5%) or bladder toxicity (1.6% vs. 3.5%). However, researchers reported double the incidence of vaginal toxicity in the chemoradiation group (25.6% vs. 12%; P < .001).

“This is a robust trial with 635 patients, and we believe these data are definitive,” Gupta said. “Chemotherapy followed by surgery is not superior to radiotherapy and simultaneous chemotherapy in locally advanced cervical cancer. Chemotherapy followed by surgery should not be routinely practiced. Concomitant chemoradiation therapy should be the standard treatment.” – by Mark Leiser

Reference:

Gupta S, et a. Abstract 928O. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: The researchers report no relevant financial disclosures.

Perspective

Domenica Lorusso, MD, PhD

With about 53,000 new cases a year and about 26,000 deaths each year, cervical cancer is the third most common cancer among women and the third most common cause of death among women. Importantly, it is also an indication of great social inequality, because 85% of new cases and 87% of deaths due to the disease occur in undeveloped countries, where no primary or secondary prevention exists. Five-year progression-free survival for these patients is about 60% and 5-year overall survival is 66%. That means there is great room for improvement in the treatment of these patients.

In 1999, concurrent chemoradiation became the standard of care for the treatment of cervical cancer after studies reported a significant increase in overall survival and progression-free survival. Unfortunately, this therapy is not as widespread as we need, particularly in undeveloped countries.

Until now, retrospective comparisons of the two strategies used to treat cervical cancer — neoadjuvant chemotherapy followed by radical surgery, or cisplatin-based concurrent chemoradiation — showed no difference in overall survival or oncologic outcomes.

Unfortunately, Dr. Gupta’s trial did not reach its primary endpoint of disease-free survival, which suggests neoadjuvant chemotherapy followed by surgery is not superior to concurrent chemoradiation.

How can we explain these data? Unfortunately, this trial was prematurely stopped due to a slow accrual and about 100 fewer patients than the anticipated 730. I guess if enrollment was higher, the results would be the same, but we do not know how many events were lacking to support the preplanned statistical hypothesis. According to literature, the expected 5-year disease-free survival with concurrent chemoradiation is 65%. In this study, 76% of patients were free of disease at the time of evaluation. The total dose received by the patients is 100 Gy, which is the upper limit of reported guidelines.

How can we explain why the standard arm performed so poorly? It’s possible to imagine there are ethnic differences in the response to chemoradiation. Could cisplatin-paclitaxel be considered the standard of care in chemonaive patients? Could the study results have been different if cisplatin was used instead of paclitaxel? I’m not sure of the answer to that yet, but I am sure there is great room for improvement in neoadjuvant chemotherapy strategies.

My other consideration is about the study’s endpoint. Is PFS a valid primary endpoint for the upfront treatment in locally advanced cervical cancer? It is important to await the results of another trial addressing the same issue, but what about the toxicities? More than 3 months after the completion of treatment, patients in the standard arm still reported rectal, bladder and vaginal toxicities. More importantly, 2 years after the completion of treatment, one out of four patients still reported vaginal distress. This greatly impacted patients’ quality of life.

Guidelines suggest neoadjuvant chemotherapy followed by surgery still remains an option in countries where chemoradiation is not available. The EORTC 55994 trial will confirm whether these results will be different in different populations. In my opinion, there are two or three other situations in which neoadjuvant chemotherapy still might be recommended — for instance, when fertility sparing is an issue. Literature data support the use of neoadjuvant chemotherapy followed by surgery for a tumor larger than 2 cm. Another important option is pregnancy. It has been calculated that two out of 1,000 pregnancies present with cervical cancer. When pregnancy is a priority for the mother, literature data support the use of neoadjuvant chemotherapy in the second trimester of pregnancy without impairment for the mother or the baby.

What will the standard of care be in 2 to 3 years? Literature suggests that, when we combine systemic chemotherapy with chemoradiation, we are able to improve progression-free and overall survival.

In conclusion, yes, concurrent chemoradiation still remains the standard of care in locally advanced cervical cancer. But I strongly suggest we wait for the results of the EORTC trial to confirm the strategies of neoadjuvant chemotherapy followed by surgery because, in some situations, this is the only strategy we have to cure our patient. Finally, the EORTC trial will clarify if concurrent chemoradiation still remains the standard of care or whether we should add systemic chemotherapy as a new standard.

Domenica Lorusso, MD, PhD

Fondazione IRCCS

National Cancer Institute of Milan

Disclosures: Lorusso reports no relevant financial disclosures.