Targeted Therapies May Improve Survival in Patients with Ovarian Cancer

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Currently, ovarian cancer is the fifth leading cause of cancer death, and each year approximately 20,000 women in the United States are diagnosed with the disease.1

Women diagnosed with early-stage ovarian cancer are often successfully treated with initial therapies including surgery;  however, patients who experience disease relapse are often a challenge to treat.

Now, there is hope that new targeted therapies following initial chemotherapy may significantly help extend disease-free survival.  The most studied agent, bevacizumab (Avastin®), has shown significant promise and now a similar agent, pazopanib (Votrient®) has been found to provide a statistically significant and clinically meaningful progression-free survival (PFS) benefit in patients with advanced ovarian cancer. 

Potential with Pazopanib

A phase 3 study of women with advanced ovarian cancer has demonstrated that pazopanib, an oral, multikinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3, can prolong disease-free survival by 5.6 months compared with placebo when given after initial chemotherapy.2 In this study, 940 patients with stage 3/4 ovarian, fallopian tube, and primary peritoneal cancer were randomly assigned to receive either pazopanib or placebo daily for 24 months.  All of the patients had undergone prior surgery as well as five or more rounds of successful chemotherapy. The researchers found that PFS was 17.9 months for the patients receiving pazopanib and 12.3 months for the placebo group after a median follow-up of 24 months.

“Most women go into remission, but we have an enormous problem with relapse.  Up to 80% of patients will relapse after initial therapy,” said Carol Aghajanian, MD, Chief of the Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center, New York, NY.  “This study looked at PFS and there was an improvement.  The advantage with this agent is that it is a pill and not an intravenous infusion.”

Currently, pazopanib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of kidney cancer and soft tissue sarcoma. No maintenance therapies are currently approved for ovarian cancer in the United States. However, bevacizumab is registered for concurrent use with chemotherapy for ovarian cancer and subsequently as maintenance therapy in Europe, based on a clinical trial that reported increased PFS.3

While this new study is suggesting that pazopanib may be an effective agent as maintenance therapy, there is concern about the agent's side-effect profile.  In this study, pazopanib was associated with a higher incidence of adverse events; serious adverse events were more than twice as common in the pazopanib arm compared with the placebo arm (26% vs 11%, respectively).  The most common adverse events for the pazopanib arm were hypertension, diarrhea, nausea, headache, and neutropenia.  Fatal severe adverse events occurred in three patients on pazopanib and one patient in the placebo group during the study period.2

“The question is when to use these drugs,” said Dr. Aghajanian in an interview with ChemotherapyAdvisor.com.  “The survival rates have been improving but we have more work to do.” 

Dr. Aghajanian said one of the current ovarian cancer research goals is to combine pazopanib with other targeted therapies in order to personalize therapy according to patient characteristics and tumor profiles. 

Evidence Behind Bevacizumab

A study recently completed by Dr. Aghajanian and her colleagues suggests that the addition of bevacizumab to cytotoxic chemotherapy may produce dramatically higher response rates than chemotherapy alone in patients with recurrent, serous borderline (SB) or low-grade serous (LGS) ovarian cancer.4 The study included 17 patients, where 10 had LGS ovarian cancer, three had LGS primary peritoneal cancer, and four had SB disease; and the mean number of prior therapies was 3.4 (range: 1-9). 

In recurrent or persistent SB or LGS ovarian cancer, the best overall response rate (RR) of 40% was observed in patients treated with bevacizumab, either alone or in combination with chemotherapy.  “[The study] is quite supportive that bevacizumab is important in this setting,” said Dr. Aghajanian.

In addition, Francisco Xynos, MD, Director of Gynecologic Oncology at Saint Louis University School of Medicine, St. Louis, MO, told ChemotherapyAdvisor.com. “The significance of maintenance therapy with bevacizumab or pazopanib has not yet been scientifically proven.  Maintenance therapy with anti-angiogenic drugs has proven to improve the disease-free survival. However, so far it has not proven to improve overall survival. Since disease-free survival is important, I still think these drugs have a role in the treatment of ovarian cancer.” 

In Search of Success: Surgical Alternatives for Ovarian Cancer

Investigators at Mount Sinai Medical Center in New York, NY, have been examining the effectiveness of various treatments for recurrent ovarian cancer. Current practices employ chemotherapy for recurrent disease, but secondary cytoreductive surgery (SCS) is increasingly being offered.  Data from SEER-Medicare 1997-2007 were reviewed and the authors identified 1,623 women with recurrent ovarian cancer.5

Among these patients, 72% received secondary chemotherapy, 15% received both chemotherapy and surgery, fewer than 2% received secondary surgery, and 12% received hospice care and no active treatment.  The researchers found that women treated with both secondary surgery and chemotherapy survived longer than patients treated with either chemotherapy or surgery.  In addition, the study suggested that women who were black or older at the time of recurrence tended to have worse survival. 

“We found that secondary cytoreductive surgery was always more effective than chemotherapy alone, which in turn was always more effective than no treatment.  If there was one thing that surprised me, it was the large proportion of women who did not undergo any primary surgical treatment,” said lead study investigator Nina Bickell, MD, Professor of Medicine at Mount Sinai School of Medicine.

Furthermore, Dr. Xynos, who has treated more than 400 women with ovarian cancer over the past three decades, has seen improvements in survival in patients who can achieve complete resection. “However, taking into account all patients with ovarian cancer, the improvement has not been significant,” Dr. Xynos told ChemotherapyAdvisor.com, which emphasizes the need for continued research in this area.

Is There a Role for Therapy with Statins or Aspirin?

Danish researchers have just recently completed a study that suggests aspirin therapy may decrease the risk for serous ovarian cancer. The study included 756 women with epithelial ovarian cancer and found that women taking aspirin on a regular basis decreased their risk for serous ovarian cancer (odds ratio, 0.60).  However, there was no decrease for ovarian cancer risk in women who regularly used non-aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, or other types of pain relievers.6

Researchers in Haifa, Israel, recently looked at statin and aspirin use and the risk for venous thromboembolic events (VTEs).  VTEs are associated with significant morbidity and mortality, and patients with ovarian cancer are known to be at a particularly increased risk for VTEs, according to the researchers. They found that aspirin use was associated with a reduced incidence of VTE. However, the reduced risk was only borderline statistically significant (P=0.054); statin use, on the other hand, did not affect the incidence of VTEs.7

Summary

Despite the advances made with the targeted therapies bevacizumab and pazopanib in extending disease-free survival in patients with recurrent advanced ovarian cancer, further research is needed to prove the effectiveness of these and other treatments for recurrent disease.

While aspirin has been shown to reduce the risk of developing serous ovarian cancer in women with epithelial cancer, there is still a large population of women with this condition who are not receiving the appropriate treatment, and thus do not see improvements in survival times. This trend demonstrates that, despite advancements, there is still a large unmet need in the management of ovarian cancer that should be addressed. 



References

1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009 Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2013. http://www.cdc.gov/uscs.

2. DuBois A, Floquet A, Weon Kim J, et al.  Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): results of an international Intergroup trial (AGO-OVAR16). J Clin Oncol 31, 2013 (suppl; abstr LBA5503)

3. Roche's Avastin Receives EU Approval For Ovarian Cancer. Medical News Today, December 25, 2011. http://www.medicalnewstoday.com/articles/239705.php. Last accessed July 25, 2013.

4. Grisham R, Salab R, Zhouc Q, et al. Bevacizumab (Bev) for treatment of recurrent serous borderline (SB) or low-grade serous (LGS) ovarian cancer: A retrospective review of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. J Clin Oncol 31, 2013 (suppl; abstr 5545)

5. Bickell N, Deb P, Prasad Hayes M, et al. Comparative effectiveness of treatments for recurrent ovarian cancer.  J Clin Oncol 31, 2013 (suppl; abstr e16551). 

6. Ammundsen HB, Faber MT, Jensen A, et al. Use of analgesic drugs and risk of ovarian cancer: results from a Danish case-control study. Acta Obstet Gynecol Scand 2012 Sep;91(9):1094-102

7. Rennart HS, Rennart G, Lavie O, et al. Statin and aspirin use and risk of VTEs in ovarian cancer patients. J Clin Oncol 31, 2013 (suppl; abstr 5576).

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