Associate Professor Harvard Medical School Clinical Director, Medical and Gynecological Oncology

		Massachusetts General Hospital Boston, MA

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?

A: The report from DuenÌƒas-GonzaÌlez et al

 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.

 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.

Director, Division of Gynecologic Oncology Vice Chair, Department of Obstetrics and Gynecology

			University of Arizona Cancer Center Phoenix, AZ 

Q: How do you think the treatment of cervical cancer evolved over the last 5 years or so?

	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.

 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,

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).

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.

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.

Q: What are some of the other promising approaches under investigation for cervical cancer treatment?

  A: I believe the future of cervical cancer treat- ment is immunotherapy. The paper presented at this year’s ASCO meeting showing the utility of adoptive immunotherapy in cervical cancer has certainly been a significant development.

 Another immunotherapy strategy that has shown promise is the Advaxis approach, which utilizes a live attenuated bacterial system, Listeria monocyvtogenes, to introduce HPV antigens and promote T-cell activation and antitumor immunity; the ongoing GOG-0265 trial is currently investigating this approach, so this is very exciting news from ASCO as well.

Director, Research Principal Investigator, NRG Oncology and GOG Legacy

		University of California Irvine Medical Center Orange, CA

Q: We know that cisplatin/radiotherapy has been a standard of care in cervical cancer for over 2 decades. How do you think the treatment of cer- vical cancer evolved over the last 5 years or so?

A: For early-stage cervical cancer, more conser- vative surgery has been adopted, especially for women who wish to retain childbearing capac- ity. Otherwise, for early-stage cervical cancer (Federation of Gynecology and Obstetrics [FIGO] stages IA2-IB1), robotic radical hysterectomy with bilateral salpingectomy and bilateral pelvic lymph node dissection has become increasingly more common. For locally advanced cervical can- cer (FIGO stages IB2-IVA), concurrent chemoradiation followed by high-dose rate brachytherapy remains the gold standard. Finally, for metastatic (FIGO stage IVB) and recurrent cervical cancer, the biggest breakthrough has come from Gynecologic Oncology Group Protocol 240, which studied the incorporation of antiangiogenesis therapy using bevacizumab together with either cisplatin plus paclitaxel chemotherapy or topotecan plus paclitaxel chemotherapy.

 This study demonstrated significantly improved overall survival without a significant deterioration in quality of life in women receiving chemotherapy plus bevacizumab, and led to the FDA approval of bevacizumab for advanced cervical cancer on August 14, 2014.

Q: What are some of the most promising targeted therapies currently under investigation for cervical cancer?

A: Currently, antiangiogenesis drugs such as bevacizumab, as well as the anti-programmed death receptor 1 agent nivolumab, are promising. Mammalian target of rapamycin (mTOR) inhibitors may also be active in some populations.

Q: How has the role of the VEGFR, EGFR, and other molecular pathways evolved in the treatment of cervical cancer?

A: Anti-VEGFR therapy using pazopanib has been shown to be superior to anti-EGFR therapy using lapatinib in a randomized phase II trial of women with recurrent cervical cancer.

 Overall, the most important pathway remains the VEGF-dependent angiogenesis pathway. The mTOR pathway may also be important in select populations.

		Key Clinical Findings in Cervical Cancer

 A role for antiangiogenesis therapies in advanced/recurrent cervical cancer is suggested by the finding that pazopanib, a tyrosine kinase inhibitor targeted at angiogenesis receptors, significantly improves progres- sion-free survival (PFS), and overall survival (OS). Efficacy of pazopanib is superior to that of an EGFR-targeted therapy, lapatinib.

 The impact of adding gemcitabine to concurrent chemoradiotherapy (external beam radiotherapy with cisplatin) in patients with locally advanced cervical cancer (stage IIN to IVA disease) was investigated in a phase III open-label randomized study. The results show a significant improvement in PFS, OS, and time to progressive disease with the addition of gemcitabine to chemoradiotherapy; these benefits were obtained at the expense of a significant increase in grade 3 and 4 toxicity.

 The impact of adding bevacizumab, an antibody directed against vascular endothelial growth factor, to nonplatinum combination chemotherapy (cisplatin/paclitaxel or topotecan/paclitaxel) was investigated in patients with advanced cervical cancer. The results demonstrate a significant improvement in OS and response rate for patients randomized to bevacizumab with chemotherapy compared with chemotherapy alone. Grade 2 or higher hypertension, grade 3 thromboembolic events, and grade 3 gastrointestinal fistulas were more common with the bevacizumab combination.

The use of human papillomavirus (HPV)-targeted lymphocytes for the treatment of metastatic cervical cancer is investigated in a small proof-of-concept study presented at the 2014 American Society of Clinical Oncology Meeting. The results show that durable, complete tumor regression can occur in patients infused with HPV-reactive T-cells and set the stage for further study of this treatment modality.

			Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. 

			Hinrichs CS, Stevanovic S, Draper L, et al. HPV-targeted tumor-infiltrating lymphocytes for cervical cancer. 

			Monk BJ, Tewari KS, Koh WJ. Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions. J Clin Oncol. 2007;25(20):2952-2965.

			Monk BJ, Tewari KS. Evidence-based therapy for recurrent cervical cancer. 

			Monk BJ, Mas Lopez L, Zarba JJ, et al. Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. 

			Santin AD, Sill MW, McMeekin DS, et al. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. 

			Advaxis Inc. Advaxis provides a clinical development update for its immunotherapy, ADXS- HPV, for the treatment of cervical cancer. http://content.stockpr.com/_news/ad- vaxis/2014-09-09_Advaxis_Provides_a_Clinical_Develop- ment_Update_for_764.pdf. Accessed September 22, 2014.

			Huh WK, Brady WE, Moore KN, et al. A phase II study of live-attenuated Listeria monocytogenes immuno- therapy (ADXS11-001) in the treatment of persistent or recurrent cancer of the cervix (GOG-0265). 

Articles

Dr. Richard T. Penson, Dr. Bradley J. Monk,  and Dr. Krishnansu S. Tewari discuss the evolution of cervical cancer treatment over the past five years. 

By Peter J. Sciavolino, PhD

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How Is Treatment Changing for Patients With Cervical Cancer? Three Experts Weigh In