The issue of neoadjuvant chemotherapy prior to radiotherapy for cervical cancer remains unproven. Theoretical benefits of neoadjuvant chemotherapy include the eradication of micrometastases and reduction in tumor size prior to definitive treatment. A Cochrane meta-analysis published in 2004 by Tierney evaluated 2074 patients from 18 studies that compared neoadjuvant chemotherapy before radiotherapy with radiotherapy alone [35]. Combining all of the trials together showed no evidence of benefit for neoadjuvant chemotherapy, but there was a high level of statistical heterogeneity. Results were then reanalyzed according to how chemotherapy was delivered, and this showed a trend toward a survival advantage for more intense chemotherapy given either in cycles of less than 14 days or using cisplatin doses of greater than 25 mg/m². Giving cisplatin at lower doses or over longer intervals appeared to be detrimental to outcome.

Interest in neoadjuvant chemotherapy prior to chemoradiotherapy has now been rekindled using dose-dense regimens. One such is the combination of carboplatin and paclitaxel given weekly for 6 weeks prior to standard cisplatin chemoradiotherapy which has shown a high response rate and good tolerability [36]. A phase 3 randomized controlled trial “INTERLACE” is currently underway to evaluate this approach.

An alternative, widely used approach in other tumor sites is to consider additional chemotherapy following definitive treatment with the aim of improving survival. This has so far been less successful in cervical cancer. There were encouraging results from a study of 515 patients randomized either to concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin or standard concurrent cisplatin chemoradiotherapy in patients with stage IIB to IVA carcinoma of the cervix [36]. Progression-free survival at 3 years was 74% in the experimental arm compared to 65% in the control group (P = 0.029). Overall survival and time to progressive disease were also significantly improved. But with grade 3/4 toxicity in the experimental group almost double that seen in the control group (87% versus 46%), and two treatment-related deaths, this novel regimen is unlikely to be widely used without modification and further evaluation.

The outback trial is an international randomized phase 3 trial of adjuvant carboplatin and paclitaxel following standard primary radical chemoradiotherapy underway. With an estimated 800 patients to be entered, it should help define the role of additional chemotherapy (https://​clinicaltrials.​gov/​ct2/​show/​NCT01414608).

After surgery for early cervical cancer, certain histopathological features increase the risk of recurrence and reduce progression-free survival. These include positive pelvic lymph nodes, lymphovascular space invasion, parametrial involvement, positive margins, and tumor size of greater than 4 cm. With one or more of these features, the 5-year survival drops to between 50% and 70% [37]. It is well recognized that combining surgery and radiotherapy increases the acute and late morbidities associated with both modalities. A 2009 Cochrane review considered the role of adjuvant radiotherapy following surgery in early cervical cancer [38]. Only two trials (397 women) fulfilled the criteria for evaluation. They showed that while adjuvant radiotherapy reduced the risk of local recurrence by between 40% and 90%, it did not confer a statistically significant survival benefit. This highlights the importance of carefully selecting the initial primary treatment for an individual patient and of assessing the risks and benefits for each patient before considering the role of adjuvant radiotherapy.

For women with relapse after radiation, provided relapsed disease is confined to the central pelvis, the only potentially curative option is pelvic exenteration. However, this procedure carries with it a high morbidity and mortality, with less than 50% of patients surviving 5 years [39].

The prognosis for patients who develop recurrent disease and cannot be offered radical treatment of either salvage surgery or chemoradiotherapy remains poor, in the order of 6 months to 2 years. The only options are palliative chemotherapy or best supportive care.

There have been no randomized trials comparing chemotherapy to best supportive care in advanced cervical carcinoma. Cisplatin has been used for nearly three decades to treat recurrent and metastatic cancer and remains the mainstay of treatment. However, the short survival and low response rates to available treatments warrant innovative approaches.

Long et al. in GOG-0179, a randomized phase 3 trial, demonstrated for the first time a statistically significant survival advantage for combination chemotherapy over single-agent cisplatin in advanced cervical cancer [40]. Cisplatin was compared to cisplatin + topotecan and a methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) arm. The MVAC arm was closed due to four treatment-related deaths among 63 patients and was not included in the final analysis. Of the remaining patients, 146 received cisplatin and 147 cisplatin and topotecan. This trial demonstrated improved progression-free survival (PFS) and overall survival (OS) when compared with single-agent therapy, with median OS of 9.4 and 6.5 months (P = 0.017) and PFS of 4.6 and 2.9 months (P = 0.014).

The GOG then instituted a multi-arm trial in 2003 with four different platinum-based intravenous doublets containing topotecan, paclitaxel, vinorelbine, or gemcitabine. None of the experimental regimens, however, were found to be superior to the control arm of cisplatin plus paclitaxel [41].

The disappointing results with conventional chemotherapy agents have led to the incorporation of targeted agents with standard chemotherapy regimens. The American study GOG 240 compared the overall survival of 450 patients with stage IVB, recurrent, or persistent carcinoma of the cervix treated with paclitaxel in combination with cisplatin or topotecan with or without the vascular endothelial growth factor inhibitor bevacizumab. This has shown a statistically significant overall survival benefit with the addition of bevacizumab of 3.7 months (13.3 versus 17 months) [42].

Other agents have been looked at in phase 2 trials and show promise. For example, cediranib is an inhibitor of all three vascular endothelial growth factor receptor (VEGF-1, VEGF-2, VEGF-3) tyrosine kinases, thereby blocking VEGF signaling and angiogenesis. In a double-blind phase 2 study, the addition of cediranib to standard carboplatin and paclitaxel chemotherapy improved progression-free survival (8.1 versus 6.7 months) [43]. Although promising, this drug is not being pursued by the pharmaceutical industry.