Chemoradiation Prevails in Cervical Cancer Trial Reduced disease-free survival with neoadjuvant chemotherapy plus surgery

Patients with locally advanced cervical cancer had significantly increased disease-free survival (DFS) when treated with chemoradiation instead of neoadjuvant chemotherapy followed by radical surgery, a large randomized trial showed.

The chemoradiation group had a median DFS rate of 76.7% compared with 69.3% for the patients assigned to neoadjuvant chemotherapy and surgery. Overall survival did not differ between treatment groups.

Chemoradiation was associated with more late (≥24 months) toxicity, Sudeep Gupta, MD, of Tata Memorial Center in Mumbai, India, and co-authors reported in the Journal of Clinical Oncology.

"Our study has answered a long-standing and important clinical question in the treatment of patients with locally advanced cervical cancer. Concomitant chemoradiation using single-agent weekly cisplatin results in a significantly increased DFS rate compared with neoadjuvant chemotherapy followed by radical surgery in this patient population."

Historically, radiotherapy formed the basis of treatment for locally advanced cervical cancer, encompassing stages IB2 to IVA. Definitive surgery remained an option for patients with stage IB2 or IIA disease, the authors noted. Studies showing improved outcomes with concurrent radiotherapy led to adoption of the strategy as standard of care for locally advanced disease, despite the fact that a substantial proportion of patients have recurrences and distant failure.

Neoadjuvant chemotherapy, followed by radical surgery, has been viewed as a strategy with the potential to improve disease control and reduce toxicity associated with concurrent chemoradiation, the authors continued, noting that clinicians in many parts of the world adopted the strategy despite the fact that supporting evidence came from only small studies and meta-analyses.

The lack of level 1 evidence therefore provided the impetus for the phase III randomized trial conducted by Gupta and colleagues.

Investigators in the single-center trial screened 1,713 patients and randomized 635 with FIGO stage IB2, IIA, or IIB squamous-cell disease to two treatment strategies: concurrent cisplatin and definitive radiotherapy or three cycles of carboplatin-paclitaxel neoadjuvant chemotherapy with response assessment after cycles two and three, followed by Piver-Rutledge class III radical abdominal hysterectomy with lymph-node dissection. Patients who did not respond or had disease progression at the end of neoadjuvant chemotherapy were crossed over to the other arm.

The primary endpoint was DFS. After a median follow-up of 58.5 months in surviving patients, the DFS analysis yielded a hazard ratio of 1.38 in favor of chemoradiation, representing a significant improvement in 5-year DFS in favor of concurrent chemoradiation (95% CI 1.02-1.87, P=0.038). Five-year overall survival was 75.4% with concurrent chemoradiation and 74.7% with neoadjuvant chemotherapy and surgery.

Late toxicities that occurred more often with concurrent chemoradiation included rectal (3.5% versus 2.2%, bladder (3.5% versus 1.6%), and vaginal (25.6% versus 12.0%) problems.

The authors of two separate letters cited several shortcomings of the study that limit interpretation and extrapolation.

The results did not adequately account for the 21.5% of patients who crossed over from surgery to chemoradiation, wrote Vineet Govinda Gupta, MD, and Vineeta Goel, MD, of Max Super Specialty Hospital in Delhi, India. The crossover group comprised two sets of patients: those who did not achieve a partial response after two cycles of neoadjuvant therapy, and those who had inoperable disease after three cycles of neoadjuvant therapy. Both subgroups had worse outcomes as compared with patients who had surgery.

"Patients who had chemotherapy-resistant operable disease may in fact still have been possible candidates for surgical resection," said Gupta and Goel. "A worthwhile exercise would be to compare the outcomes of these two sets of patients with each other and with the population of patients who actually underwent curative surgery because this would help us determine if the inferior outcomes of the overall population were restricted to the chemotherapy-resistant population or the inoperable one."

The authors of the second letter questioned the duration of neoadjuvant therapy (three cycles), given a lack of consensus about optimal duration and evidence that patients who respond usually do so after one to two cycles. Additionally, some evidence suggests the neoadjuvant regimen of carboplatin and paclitaxel used in the study is inferior to cisplatin and paclitaxel.

Finally, the National Comprehensive Cancer Network recommends surgery for patients with stage IIA1 disease and chemoradiation for stages IB2, IIA2, and IIB disease. All four groups were combined in the current study.

"Generally, the number of cycles and number of chemotherapeutic neoadjuvant chemotherapy schemes are important for the prognosis of patients with locally advanced squamous cervical cancer," wrote Wen Zou, MD, of Second Xiangya Hospital of Central South University in Changsha, China, and co-authors. "Moreover, it is also crucial to determine who will benefit from neoadjuvant chemotherapy or concurrent chemoradiation therapy before the start of treatment."

In a reply, Sudeep Gupta and colleagues addressed each point raised in the letters and said the observations did not limit the clinical applicability of their findings and concluded: "The results of our study suggest that concomitant chemoradiotherapy should be the standard treatment in patients with locally advanced cervical cancer."

Source:https://www.medpagetoday.com/hematologyoncology/cervicalcancer/73543