Q: We know that cisplatin and radiotherapy has been a standard of care in cervical cancer for over 2 decades. How do you think the treatment of cervical cancer has evolved over the last 5 years or so?
Richard T. Penson, MD
Associate Professor Harvard Medical School Clinical Director, Medical and Gynecological Oncology
Massachusetts General Hospital Boston, MA
A: The report from DuenÌƒas-GonzaÌlez et al1
showed that two drugs combined with radio- therapy are better than one, but there is a lot of toxicity with such a regimen, and the field is waiting for results from the OUTBACK study (NCT01414608), which is looking at cisplatin chemoradiation with and without four cycles of adjuvant paclitaxel and carboplatin, and there is another international study looking at paclitaxel/ cisplatin concurrent treatment. We do think that two chemotherapies are better than one, but we only use cisplatin with radiation at the moment, because the toxicity of a gemcitabine/platinum combination is unacceptable. I have used gem- citabine/cisplatin maybe in at most three or four cases without incident, but these were carefully selected patients. We use a lot of 5-FU/cisplatin for recurrent cervical disease, and we use a lot of mitomycin C/5-FU for vulvar cancer. In terms of targeted therapy, we have not combined beva- cizumab with cisplatin/radiation, but we have combined it with radiation in a phase II trial. We are also interested in erlotinib with cisplatin/ radiation, but neither of these combinations are as yet a standard of care.Q: How has the role of VEGF receptor, EGFR, and other molecular pathways evolved in the treatment of cervical cancer?
A: In terms of combining cisplatin/paclitaxel or topotecan/paclitaxel with bevacizumab, the Tewari paper confirms that as a new standard.2
About 40% of patients in the United States are getting one of those combinations right now, many receiving carboplatin/paclitaxel because of another randomized controlled trial run by the Japanese Gynecological Group. Adding bevaci- zumab to cisplatin/paclitaxel or carboplatin/pa- clitaxel is now the standard. The main problem with this approach is that approximately 9% of patients in the Tewari study had either fistulas or gastrointestinal perforations. So there is a high and morbid complication rate, and you have to select patients carefully. As for cervical cancer in general, the VEGF/ VEGFR pathway is big, but there have not been much data on the TKIs as yet. EGFR, on the other hand, has been a bit disappointing. Interest in EGFR has been eclipsed by data about the phos- phatidylinositol (PI3) kinase pathway. This is currently the most exciting target, but other targets, such as AKT and MET, are also thought to be important. We have a trial under way with trametinib and a PI3 kinase inhibitor, GSK2126458 (NCT01958112), and a lot of people are combining biologics in novel combinations for recur- rent cervical cancer. Overall, we think about 40% of the patients have identifiable targets or mutations that are exploitable. Cervical cancer is very much what we call an oncogene-addicted tumor, like EGFR-driven lung cancer. It is possible that more than one-third of cervical cancer is like that and could be treated with oral medication as primary therapy. Accordingly, we do mutational testing when patients have incurable disease (ie, unresectable, refractory, or recurrent).Q: What do you think have been some of the other promising developments over the past year?
A: I think another key development has been the adoptive immunotherapy study presented by Hinrichs and colleagues at this year’s American Society of Clinical Oncology (ASCO) meeting. This is really big news, and there is a lot of interest in using this approach for patients with metastatic cervical cancer.3
Q: How do you think the treatment of cervical cancer evolved over the last 5 years or so?
Bradley J. Monk, MD
Director, Division of Gynecologic Oncology Vice Chair, Department of Obstetrics and Gynecology
University of Arizona Cancer Center Phoenix, AZ
A: There has really been no evolution in the primary treatment of cervical cancer over the last 5 years; it’s all about educating people, and certainly treatment is generally based on stage and the condition of the patient. The standard remains chemotherapy in combination with radiotherapy for the primary treatment of locally advanced disease, as we have summarized previously.4
Q: Where do you see targeted therapies (eg, VEGFR- and EGFR-targeted agents) playing a role in the treatment of cervical cancer? A: Last month, based on our New England Journal of Medicine paper,5
we received FDA approval and National Comprehensive Cancer Network (NCCN) Level 1 recommendation for bevacizumab in met- astatic cervical cancer (combining bevacizumab with doublet chemotherapy).2,5
So the big news in this regard is that standard treatment for metastatic disease is now triplet therapy, consisting of plati- num, paclitaxel, and bevacizumab. By comparison, for all intents and purposes, anti-EGFR agents are of minimal or no activity in cervical cancer. In a randomized trial comparing an anti-VEGFR tyrosine kinase inhibitor, or TKI, versus an anti-EGFR TKI, the VEGFR-targeted agent (pazopanib) was shown to be more active than the EGFR-targeted therapy (lapatinib), and similar negative results have also been seen for the anti-EGFR antibody, cetuximab,in women with advanced and recurrent cervical cancer.6,7
So, although EGFR is known to be over- expressed, the data have shown that it really is inactive and it has been largely a distraction in cervical cancer.