Cervical Cancer: NAC Plus CRT Inferior to CRT Alone

The addition of neoadjuvant chemotherapy (NAC) using the combination of cisplatin and gemcitabine (Gemzar) followed by chemoradiation (CRT) did not improve outcomes for women with locally advanced cervical cancer compared with standard-of-care CRT alone, a randomized phase II study showed.

At a median follow-up of 31.7 months, progression-free survival (PFS) at 3 years -- the study's primary endpoint -- was statistically inferior, at 40.9% (95% CI 27.2%-54.1%) for patients who received upfront NAC followed by CRT compared with 60.4% (95% CI 44.1%-73.3%) for patients who received CRT alone (hazard ratio [HR] 1.84, 95% CI 1.04-3.26, P=0.033), Samantha Cabral S. da Costa, MD, of Universidade de Sao Paulo in Brazil, and colleagues reported.

Similarly, the study published online in the Journal of Clinical Oncology, showed that the complete response rates were significantly lower with additional NAC, at 56.3% compared with 80.3% for the CRT arm; overall survival, again at 3 years, was almost three times lower at 60.7% in the additional-NAC arm compared with 86.8% for the CRT-alone arm (HR 2.79, 95% CI 1.29-6.01, P=0.006).

Toxicities, however, were comparable between the two treatment groups, although hypomagnesemia and neuropathy were both more common in patients who received NAC.

"Particularly in developing countries, the incidence of cervical cancer is high, and access to radiotherapy facilities is limited ... resulting in a delay in treatment initiation, which contributes to a worse prognosis," the researchers noted in explaining the rationale for the study. Thus, if a survival benefit could be demonstrated with additional NAC, "this may reduce delays in treatment and improve outcomes in communities with scarce resources."

The team concluded that given the disappointing results of the study, the standard treatment for locally advanced cervical cancer should therefore remain concurrent cisplatin-based CRT.

The study is noteworthy because it "disproves the concept that 'more is better,'" said Don Dizon, MD, of Lifespan Cancer Institute in Providence, Rhode Island.

The data showed that "neoadjuvant chemotherapy compromises the ability to provide definitive chemotherapy with radiation therapy, and more importantly, results in significantly worse outcomes in terms of both progression free and overall survival," Dizon told MedPage Today via email. "Whether the question of neoadjuvant chemotherapy in this context warrants further study is really very questionable, at best, and I believe our efforts internationally must concentrate on better ways to deliver concomitant systemic therapy and evaluating the potential role of extended treatment in patients with high-risk disease, such as positive para-aortic nodes."

Study Details

The study, called CIRCE (Chemotherapy Induction followed by Chemoradiation for Locally Advanced Cervical Cancer), was carried out in a single academic cancer center (Instituto do Cancer do Estado de Sao Paulo), and included 107 patients with stages IIB to IVA locally advanced cervical cancer.

Most patients presented with stages IIB (43.9% of participants) or IIIB (44.8%) disease, with squamous cell carcinoma the most common histology (87.8%).

The upfront doublet regimen consisted of intravenous cisplatin 50 mg/m² on day 1, and gemcitabine 1,000 mg/m² on days 1 and 8 every 3 weeks for three cycles. This was followed by standard CRT, initiated 3 to 4 weeks after patients received their last cycle of NAC.

The control group received standard CRT alone, which as used in Brazil consisted of weekly cisplatin at 40 mg/m² for 6 weeks given concurrently with radiotherapy, da Costa and co-authors noted. About 94% of patients completed all concurrent chemotherapy cycles in the CRT-alone group compared with 80% of those in the NAC group.

Both the duration and the cumulative dose of radiotherapy received were similar between the two treatment groups.

The most common early adverse events (AEs) in both groups were myelosuppression, gastrointestinal symptoms, and dysuria, the team reported. However, the rates of hypomagnesemia were considerably higher in the added-NAC arm than in the CRT-alone arm (27.2% vs 7.6%, respectively), as was the incidence of neuropathy (25.4% vs 1.9%, respectively; P=0.002).

Possible Reasons for NAC's Detrimental Effect

In contrast, the rates of late AEs were similar between the groups. "The reasons for a possible detrimental effect of neoadjuvant treatment are unclear," the authors observed. One explanation may be that the toxicity associated with NAC compromised clinicians' ability to deliver concurrent CRT, as more patients in the NAC arm (20%) discontinued concurrent chemotherapy compared with the CRT-alone arm (5.8%).

It is also possible that the need to delay standard CRT because patients received NAC first might also have been detrimental to patient outcomes, da Costa and colleagues speculated. "Tumor cells possibly may have acquired resistance through NAC," as prior exposure to cisplatin may have led to platinum-induced radioresistance to the cisplatin portion of the CRT regimen.

The researchers noted that when suboptimal regimens are used for whatever reason, tumor regrowth might be accelerated after the receipt of chemotherapy, further supporting the hypothesis that a long cycle length and the low-dose intensity of the cisplatin used in this study may have caused the negative effects seen with additional NAC.

"It is imperative to continue studying other treatment strategies to improve outcomes, as well as alternatives to overcome poor access to radiotherapy facilities in developing countries," da Costa and colleagues wrote.

Study limitations, the team noted, included the fact that it was a phase II study with a limited sample size.

Asked for her perspective, Mary McCormack, MD, of University College Hospital in London, who was not involved with the study, said she agreed with the authors' theory that the greater level of toxicity associated with the neoadjuvant regimen may well have led to higher discontinuation rates in patients who received NAC versus those who received CRT alone. "Secondly, we know from previous studies that long cycle duration of treatment is associated with worse outcomes," she told MedPage Today.

McCormack said this means the problem could be not just the time it took to deliver NAC before CRT was initiated but also that each cycle of chemotherapy was 21 days, after which there was a gap of 3-4 weeks between the completion of NAC and the commencement of CRT.

"I believe that gap was detrimental," in that the tumor was able to acquire chemoresistance before CRT could be initiated and hence outcomes were poorer among patients who received upfront NAC, she said.

McCormack noted that the ongoing INTERLACE trial (Induction Chemotherapy Plus Chemoradiation as First Line Treatment for Locally Advanced Cervical Cancer) -- of which she is principal investigator -- has been designed to address these issues. Patients with locally advanced cervical cancer will receive short-cycle chemotherapy given in weekly treatments for 6-8 weeks followed immediately by chemoradiation. INTERLACE is also using a different combination of drugs than the cisplatin-gemcitabine doublet used in the CIRCE study.

"So we are looking at a different regimen consisting of weekly drug and no interval between the two treatments, and I think those factors may make a difference," McCormack said.

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