First Phase III Trial Report of Survival Improvements in Locally Advanced Cervical Cancer with Combination Chemotherapy

First Phase III Trial Report of Survival Improvements in Locally Advanced Cervical Cancer with Combination Chemotherapy


New findings from an ambitious study set a higher bar for the treatment of locally advanced cervical cancer. During Sunday’s Gynecologic Cancer Oral Abstract Session, Alfonso Dueñas-González, MD, PhD, of the Unidad de Investigación Biomédica en Cáncer, Mexico, presented data from a randomized phase III study demonstrating that the addition of gemcitabine to cisplatin with concurrent radiotherapy significantly enhances survival (p = 0.029) compared with the current standard of single-agent cisplatin and concurrent radiotherapy in women with stage IIB to IVA disease (CRA5507).

“It’s important to note that in this era of molecularly targeted therapy, a well-designed clinical trial of cytotoxic chemotherapy has produced a significant improvement in overall survival and progression-free survival in a patient population that has urgently needed new therapies,” said Discussant Amit M. Oza, MD, of Princess Margaret Hospital, Canada.

Cervical cancer is the second leading cause of cancer-related deaths in women worldwide. Concurrent chemoradiotherapy represents the current standard of care for locally advanced cervical cancer. However, the 5-year relative survival rate is approximately 60%, and the disease has substantial rates of distant recurrence.

Data from phase I and II studies suggest that gemcitabine is synergistic with both cisplatin and radiotherapy and boosts the response to therapy. To confirm these observations in a large population of patients with stage IIB to IVA cervical cancer one arm of 259 women was treated with radiotherapy and adjuvant gemcitabine and cisplatin, and a second arm of 256 women was treated with cisplatin chemoradiotherapy and radiotherapy. In both arms, 6 weekly cycles of cisplatin were delivered in conjunction with pelvic radiotherapy lasting 5.4 weeks, followed by 1 week of brachytherapy. The experimental arm also received weekly gemcitabine during the chemoradiotherapy period, as well as two cycles of adjuvant gemcitabine and cisplatin spaced 3 weeks apart following brachytherapy.

All women were chemotherapy- and radiotherapy-naive upon study enrollment. Only 6.2% had adenocarcinoma, and patients were largely divided into those with stage IIB (61.4%) or stage IIIB disease (36.5%). Women in both arms received similar doses of chemotherapy, although women assigned to the experimental arm did receive a longer duration of radiotherapy in comparison with the control arm (median duration of total radiotherapy: 49 vs. 45 days; p < 0.001).

Three years after initial treatment, a significant progression-free survival advantage was evident for women who received dual-agent chemoradiotherapy and adjuvant therapy compared with those who received standard care (Fig. 1). Similar improvements at 3 years were also evident for overall survival (78.2% vs. 69.1%; hazard ratio [HR]: 0.68; 95% CI: 0.49-0.95; p = 0.022) and time to progression (80.7% vs. 67.0%; HR: 0.53; 95% CI: 0.37-0.77; p = 0.001).

Although rates of local failure were similar between the experimental and control arms (11.2% vs. 16.4%; p = 0.097), a significant difference appeared for rates of distant disease failure (8.1% vs. 16.4%; p = 0.005), suggesting that combination chemotherapy and/or adjuvant chemotherapy enhances control of subclinical metastases.

Both Drs. Dueñas-González and Oza acknowledged that the study design makes it difficult to ascribe the survival improvements to combination chemotherapy, adjuvant therapy, or both. Further studies will be needed to delineate the relative contributions of these treatment components to clinical outcomes.

The improvements in survival outcomes for patients assigned to the experimental arm did come at the expense of increased toxicity. Significantly more patients assigned to combination chemotherapy — compared with the control arm — experienced at least one serious adverse event (33% vs. 12%; p = 0.005), at least one adverse event leading to treatment discontinuation (18% vs. 1%; p = 0.001), and at least one adverse event leading to hospitalization (30% vs. 11%; p = 0.003). In addition, two drug-toxicity–related deaths occurred in the experimental arm compared with none in the control arm.

Dr. Dueñas-González said that the increase in toxicity observed with the gemcitabine and cisplatin combination was expected given the addition of a second chemotherapeutic agent, but he did note that the incidence of grade 3/4 events was low overall and deemed the toxicity to be clinically acceptable and manageable in the context of the survival benefits observed.

During his discussion of this trial, Dr. Oza remarked, “I can accept that the evidence supports concurrent chemoradiation and adjuvant chemotherapy as being the new standard of care. However, I think confirmatory clinical trials are needed to determine whether gemcitabine is the optimal second agent.” He also recommended further investigating the optimal sequence and duration of therapy and the long-term efficacy and toxicity of the combination and adjuvant approaches.