Platinum-based treatment has been considered the standard of care for patients with locally advanced and metastatic cervical cancer. In a recent article published in Cancer, Nogueira-Rodrigues et al reported the results of a single-arm study of 36 patients with locally advanced cervical cancer. Patients entering the study had to have previously untreated International Federation of Gynecology and Obstetrics stage IIB to IIIB squamous cell carcinoma. Treatment with erlotinib, cisplatin, and radiotherapy/brachytherapy yielded a complete response rate of 94.4%. The 3-year cumulative overall survival (OS) and progression-free survival (PFS) rates were 80.6% and 73.8%, respectively. The median PFS and OS rates in this study were 69.4% and 72.2%, respectively. Nogueira-Rodrigues et al interpreted their data positively, concluding that treatment with erlotinib, cisplatin, and radiotherapy is safe and has significant activity against locally advanced cervical cancer.
We believe that the findings of this nonrandomized, open-label, single-institutional, phase 2 trial are encouraging but should be interpreted with caution for several reasons. The primary endpoint of this trial was to determine response rates rather than survival analysis. In addition, because this study was small with only 36 evaluable women and because it had no control group, it would be impossible to draw any definitive conclusions regarding the effectiveness of the therapy. The combination treatment failed to prevent further disease progression in 31% of patients despite such a high overall response rate. It is interesting to note that the median PFS and OS rates in the study by Nogueira-Rodrigues et al are similar to previously reported data. The percentage of patients who were eligible for the study and were offered participation remains unclear. Approximately 12% of enrolled patients were excluded from efficacy analyses for various reasons, which may bias the results in favor of the treatment. The results of this trial can represent patients who were highly selected: those who might benefit substantially from treatment were more likely to be enrolled. Patients with positive paraaortic lymph nodes, who historically have a poorer prognosis, were excluded.[3, 4] Although they are treated in the same manner at most institutions, why were the patients with adenocarcinoma of the cervix not included in this study? Previous studies have suggested that patients with cervical adenocarcinoma bear a worse prognosis and lower OS. It is also possible that the high response rate observed in the study by Nogueira-Rodrigues et al could be related to improvements in radiotherapy techniques, better patient selection, and a stage migration effect. We also would like to point out that the landmark studies used for comparison in Table 3 of the article were performed more than a decade ago.
With the use of platinum-based chemoradiation as a standard of care for patients with locally advanced disease, the search for non—platinum-based therapy is important. In modern oncology, we are experiencing a paradigm shift toward novel targeted agents. To our knowledge, no biological agent to date has been approved for use in patients with cervical cancer. However, a significant improvement in OS recently was observed among patients with advanced cervical cancer who were treated with antiangiogenic therapy. Furthermore, the results of ongoing studies assessing the role of epidermal growth factor receptor inhibition in combination with chemoradiation would be helpful (ClinicalTrials.gov identifiers: NCT00104910 and NCT00957411). We do need treatments that improve survival, and build on the small steps that have been made in this area of unmet need. The quest for improved cure rates for patients with locally advanced cervical cancer is paramount and future research that 1) includes a true control group, 2) involves patients with both squamous and adenocarcinoma histology, 3) uses disease-free survival or OS as the primary endpoints, and (4) is adequately powered will further elucidate the value of this regimen in the management of patients with advanced cervical cancer.