Don S. Dizon, MD, discusses future directions for precision medicine approaches in ovarian cancer.  

Dr Dizon on the Future of Precision Medicine in Ovarian Cancer Management

Don S. Dizon, MD, FACP, FASCO, director, Pelvic Malignancies Program, director, Hematology-Oncology Outpatient Clinics, Lifespan Cancer Institute; head, Community Outreach and Engagement, Legorreta Cancer Center; director, Medical Oncology, Rhode Island Hospital; professor, medicine, The Warren Alpert Medical School of Brown University, discusses future directions for precision medicine approaches in the management of ovarian cancer, as highlighted in his presentation at the Second Annual Miami Cancer Institute Precision Oncology Symposium.

Dizon begins by stating that the integration of next-generation sequencing (NGS) into ovarian cancer management is likely to increase in the near future. Rather than solely focusing on specific mutations, NGS provides a comprehensive view of the genetic landscape of tumors, offering insights into potential therapeutic targets and pathways, Dizon explains. This approach allows for a more nuanced understanding of individual tumors and can guide personalized treatment strategies based on a tumor’s unique genetic profile, he adds.

Companies are exploring specific pathways and mutations relevant to ovarian cancer through tailored phase 1 trials, often using the “basket” approach where patients with specific genetic or genomic alterations are grouped together, Dizon continues. With the increasing interest and investment in gynecological cancers, including ovarian cancer, companies will likely dedicate more resources to research aimed at identifying actionable targets and developing targeted therapies, according to Dizon. Companies may explore specific pathways and mutations through phase 1 trials that include ovarian cancer as a single cohort, he suggests.

Efforts to use immunotherapy will continue within ovarian cancer, Dizon states. This research will explore targets, such as MUC1, that are commonly expressed in ovarian cancers, he says. Antigens targeting MUC1 could be used to drive responses through the development of novel antibody-drug conjugates, Dizon says. Additionally, CAR T-cell therapies are being investigated to harness the immune system's ability to recognize and destroy cancer cells, he notes.

Overall, the integration of NGS and the exploration of targeted therapies and immunotherapies reflect a paradigm shift toward precision medicine in ovarian cancer, Dizon concludes.

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Don S. Dizon, MD, FACP, FASCO, discusses future directions for precision medicine approaches in ovarian cancer.


Dr Dizon on the Prevalence of Sexual Challenges in Patients WithBreast Cancer 

Don S. Dizon, MD, director, Pelvic Malignancies Program, Lifespan Cancer Institute, head, Community Outreach and Engagement, Legorreta Cancer Center, director, Medical Oncology, Rhode Island Hospital, and professor of medicine, The Warren Alpert Medical School of Brown University, underscores the prevalence of challenges pertaining to sexual intimacy in patients with cancer, specifically discussing those with breast cancer.

Dizon explains that approximately 50% to 90% of patients with cancer report some degree of adversity that impacts various domains of sexuality, including arousal, desire, orgasm, and satisfaction. He explains that symptoms of low sexual desire are often reported by patients, which can be attributed to a wide range of causes, including physical discomfort such as vaginal pain and dryness; and dynamics of a relationship, which can often lack structured dialogue about sex following a cancer diagnosis.

Regarding interventions and resources for sexual health support, Dizon highlights the persisting reluctance within the broader field of oncology to directly address this topic, attributing this partly to inadequate training amongst oncologists on topics pertaining to sexuality in relation to their specialty.

Nevertheless, Dizon notes that it is crucial to recognize sexual health as a potential adverse effect in patients with cancer and encourage patients to voice their concerns openly to their health care providers. Available resources include patient-centric platforms like Living Beyond Breast Cancer.

Dizon also references the Permission, Limited Information, Specific Suggestions, and Intensive Therapy (PLISSIT) model, which represents a structured approach to navigating sexual health discussions within the comfort zones of both patients and providers.

Emphasizing the need for oncologists to address sexual health concerns openly, Dizon concludes by saying available resources and structured models like PLISSIT can provide comprehensive support to patients with breast cancer experiencing post-diagnosis sexual challenges.

Don S. Dizon, MD, on the prevalence of sexual complications in patients with breast cancer. 

Dr Dizon on the Prevalence of Sexual Challenges in Patients With Breast Cancer 

There is an ever-growing variety of social media platforms, which, depending on the reader, can be either exciting or not. For the enthusiastic early adopter, these channels offer a new experience and the chance to broaden social and professional circles. For others, the growth of social media is overwhelming, and with each new medium, they may become even less willing to explore any of them.

	Patients Are Online and They Want Information About You

However, it is important that clinicians engage with social media primarily because we risk our reputations by not knowing what is being said, shared, and discussed about us online. In this article we will expand on these points and provide steps to help harness the Web and manage your online public persona.

The Internet has become a staple of society, both on a local and a global scale. It has resulted in the formation of online platforms and communities, and has changed the ways we can interact with others. By some reports, there are almost 1.3 billion people on Facebook

 and 255 million monthly active users on Twitter.

Estimates are that 35% of adults in the United States have gone online to diagnose a health condition,

 and other data suggest that patients might be choosing their healthcare providers based on online peer reviews.

 As a testament to this, online physician rating sites are widely available and appear to be frequently utilized.

The reach of social media extends to clinicians as well. In the 2014 American Medical Association Insurance’s survey of over 4000 US physicians, social media usage was noted by 79% of those under age 40, 62% of those age 40 to 59, and 53% of those age 60 to 69.

 Some physicians have recognized the shift from traditional models of information seeking and sharing, and actively discuss healthcare issues in a public way. Physician-led blogs such as Kevin MD (www.kevinmd.com) and 33 Charts (33charts.com) publicly discuss issues that affect those that work within healthcare.

In the oncology space, online blogs also have gained in popularity. Connection (connection.asco. org), the American Society of Clinical Oncology’s (ASCO) forum for the exchange of views on topical issues in the field of oncology, was recognized for its relevance and credibility with a 2014 Award for Publication Excellence (APEX) for site content. The blog authors write frankly about issues relating to oncology practice. Readers are invited to comment on the public blog posts, which often leads to authors answering questions directly from the reading public.

In recognition of these shifts in information gathering and sharing both amongst clinicians and the wider public, as well as the evolving working relationship between clinician and patient, we will suggest ways to cultivate and monitor your online persona and methods to approach using social media in your daily life.

These issues are relevant to oncology because information seeking has been changed by widespread access to the Internet. Indeed, some data show that among those who search for cancer information, 55% turn to the Internet as their initial source; only 25% went to their healthcare provider first.

	Protecting Your Online Reputation: The Digital Footprint and Beyond

However,clinicians must not assume that all information that’s available is accurate. In today’s Internet culture, anyone can write, post, or tweet an article, opinion, or otherwise. This access to “unfiltered” information can be misleading to patients, or even dangerous. A recent example concerned the dissemination of cancer information reported from “John” Hopkins University,

 which necessitated a point-by-point vigorous defense by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University with input from its faculty.

The digital footprint is the track that remains online after you have engaged in any activities on the Web. Conceptually, it is integral to your online reputation.8 It has both a passive and an active component, and understanding both is important.

The “passive” component is generated by identifying information from your computer or mobile device and by the way in which you access the Internet (eg, via the unique identifier attached to the computer you use to go online — the Internet protocol address—and your Internet service provider). Furthermore, passive data are recorded in your Internet browsing history (which records the sites you visit) and in the “cookies” that are collected by websites (cookies are small pieces of digital information that enable a previously visited site to recognize you immediately). Such information can be potentially collected, stored, and indexed online. While these pieces of virtual information (or “metadata”) are not easily linked with you personally, they could be.

The “active” component of your digital footprint is a record of what you write, blog, tweet, or post online, whether that is the pictures you post on a site like Instagram or the video you post on YouTube. If you’re not careful, who you are in your private life may blur with the image you are projecting as a professional. This has led for some to call for a separation of professional and personal personas on social media, such as Mostaghimi and Crotty’s concept of dual passports,

 in which two different identities are utilized—one strictly for a professional presence and the other for personal activities. However, others have argued that such a separation is not only impossible (there is no anonymity on the Web), but may be unfair to the patients we serve because it robs those we care for of the opportunity of knowing us as people, not providers.

Whether clinicians choose to share their personal lives on social media sites is an individual choice. However, being cognizant that those reading your posts may indeed be your own patients is critical.

Taken together, the footprint is a key to your online reputation. Information shared online can be accessed widely and can give others an idea of who you are—both professionally and personally. Indeed, there may be very little distinction between them. If your reputation were solely under your control, it would not be worth worrying about. Unfortunately, it is not this easy&mdash;it takes work.

Although you cannot exclusively control your online reputation, there are various ways to curate it, and we propose a framework of four “Ds” to explain these steps: (1) discovery; (2) definition; (3) dissemination; (4) defense (

: All clinicians should actively monitor professional information available online; this can be done by performing an audit of what is readily available online about you, your practice, and your reputation, sometimes referred to as a “professional audit.” This involves conducting a Web-based search on the most common search engines (Google, Yahoo, Bing, and Ask). Search by your full name and various combinations of your name, along with your associated practice, institution, city, state, etc. Perform the same search on public websites that specialize in rating clinicians, professional society websites, patient-related websites, and content-sharing sites (

). An audit will give you a sense of what information is currently available and an indication of what potential patients and colleagues will see when they search for information about you or your practice.

		Table 2. Examples of Sites to Utilize for Personal and Professional Self Audits

					American Society of Clinical Oncology

					American Association for Cancer Research

 After gathering the search results, perform a thorough analysis. Use the information to visualize something of a “narrative arc” that represents the sum total characterization, sentiment, and tone of the information. With a clearer definition, decide whether that story is accurate or not. If you are satisfied with what is presented, no further action is necessary, although you should continue to perform these professional audits online at least every quarter or so. In most cases, clinicians will discover content that is either inaccurate or, in their opinion, unfair, making further action appropriate.

Curating your online reputation means actively disseminating the information you want to be available. This can be done by creating a digital “biography” to serve as your preferred narrative and placing it on multiple platforms (listed in 

) to increase the likelihood that the information you want to be seen actually appears first in search engines. In addition to creating a personal narrative, engaging in social media networks is another means to disseminate your professional presence.

		Table 3. Examples of Oncology-Specific Social Media Sites

					Treatment Diaries tweet chat (#treatdiarieschat)

					Hospice and Palliative Medicine (#hpm)

					American Society of Clinical Oncology (ASCO) Connection

					What We Talk About - Massachusetts General Hospital

					Dr. Len’s Cancer Blog - American Cancer Society

Articles

It is important that clinicians engage with social media, since reputations are at risk by not knowing what is being said, shared, and discussed online about them online.

Clinical Oncology in the 21st Century: Reflections on how Healthcare Providers Should Manage Their Public Personas on Social Media

Don S. Dizon, MD, Assistant in Medicine, Medical Gynecologic Oncology, Massachusetts General Hospital, explains the relationship between PTEN mutations and mTOR inhibitors in endometrial cancer.

PTEN mutations most commonly mark type I endometrial cancer. In addition to PTEN mutations, endometrial cancer also activates the mTOR and PI3K/AKT pathways. Dizon says that the evaluations with mTOR inhibitors, which can block PTEN, have been mixed. Trials involving the mTOR inhibitors temsirolimus, deferolimus, and everolimus suggest that the treatments can be used in patients who have been less pretreated. In a National Cancer Institute of Canada study, the response rate for patients with no prior chemotherapy fell from 25% to 9% when patients did have prior chemotherapy, Dizon says.

Dizon says that there is a need to identify a population based on the PTEN mutation that would benefit from treatment. The end goal would be to conduct an enriched study in that population.

Dr. Dizon on PTEN Mutations in Endometrial Cancer

I have just returned from the 21st Interdisciplinary Conference of the National Consortium of Breast Centers, which I want to become known as the Vegas Breast Conference. There was over 1000 attendees at this year's meeting. What makes it special is that it is not specialty-driven in its content or in those who attend. It truly is an interdisciplinary meeting comprised of physicians of all sorts (medical oncology, breast surgery, radiology, internal medicine, family medicine, obstetrics-gynecologgists, radiation oncologists), nurses, nurse practitioners, breast center navigators, radiologic technologists, survivors, and advocates. I can honestly say that I come back more motivated than ever to treat the women (and men,  as I learned from after an eloquent and impassioned talk from survivor Brian Shappell this year during the Survivorship session) with breast cancer and to work in an Interdisciplinary environment.

On our Sunday plenary we indeed heard from the now former Chairman of the United States Preventive Services Task Force, Ned Calonge, and from our former Past-President of the NCoBC, Jay Parikh. They spoke on the controversy surrounding the 2009 guidelines on Screening Mammography published by the USPSTF, which we as a society have on record as being opposed to.

This presentation was so illuminating because Dr. Calonge showed all of us that the Task Force is indeed made up of human beings. He reminded us that the Task Force's mission is to review the evidence in support of screening methodologies in the cold light of evidence-based scientific methods and that it must be done in the absence of special interests, patients, and passions. But what was more striking was the revelation of the time course on the release of the recommendations. While its release occurred after President Obama took office and during the debate on health care reform, Dr. Calonge reminded us that his audience was intended to be primary care providers: internists, pediatricians, family physicians, and ob-gynecologists. He also reminded us that during the time of deliberation and release of the guidelines, the President was not Obama, but George Bush, and that there had been no talk of health care reform. There had been no expectation that the USPSTF recommendations would be tied to coverage and reimbursement decisions.

As equally informative was the discussion by Jay Parikh who raised the issues of the analysis undertaken by the Task Force. Flaws in methodology of the included randomized trials were brought to light, as were the countless studies performed in populations. While the latter were not randomized, the important question was: should they be completely ignored in the analysis. Dr Parikh went on to personalize the issue for those of us who work in breast centers and who have seen and discussed screening and seen women go through a diagnosis and treatment of breast cancer. Above all, Dr. Parikh made the point that none of us exist in a vacuum, that in medicine we treat patients and not numbers, and that passion should not be ignored.

While I doubt that many minds were changed in the audience (which is by definition made up of those who work in, participate in, and advocate for breast centers) I do believe the objective of the session was achieved: to understand the context of the recommendations, to provide a comprehensive look at ALL of the audience, so that in the end, each of us could make our own conclusions, which we could then take to our patients.

For more information, see Kate Madden Yee's excellent summary of this session at 

I have just returned from the 21st Interdisciplinary Conference of the National Consortium of Breast Centers

Update from the National Consortium of Breast Centers

	In the United States, gynecologic cancers affect nearly 80,000 women annually and are the cause of death in more than 25,000 women.

 Cancers arising in the uterus are the most common, with 42,000 cases in 2009, followed by 21,500 cases of ovarian cancer, and 11,270 cases of cervical cancer.

 Although ovarian cancer is not the most common gynecologic cancer, it remains the most lethal. More women die each year from ovarian cancer than from uterine and cervical cancers combined.

	Chemotherapy in the adjuvant setting is the standard of care for most gynecologic malignancies. For ovarian cancer, chemotherapy consists of a platinum and taxane. It is indicated in women with grade 3 stage IB or IC disease and in all women with a diagnosis of stage II disease or higher.

 In advanced uterine cancer, randomized trials have shown that chemotherapy is superior to radiation therapy in the adjuvant setting. Based on completed clinical trials, standard of care consists of a 3-drug combination of doxorubicin, cisplatin, and paclitaxel.

 This regimen, however, is associated with excessive toxicities, so most centers use carboplatin and paclitaxel in an alternative regimen. Recently, a randomized trial comparing these 2 treatments completed enrollment and results are eagerly anticipated.

	In cervical cancer, chemoradiation with cisplatin is a curative regimen in women with locally advanced disease and can be used as primary therapy in lieu of radical hysterectomy. A recent trial from South America compared chemoradiation with a combined approach of chemoradiation followed by systemic combination chemotherapy using cisplatin and gemcitabine (Gemzar).

At the American Society of Clinical Oncology (ASCO) meeting in 2009, the study investigators reported that adjuvant systemic chemotherapy improved disease-free and overall survival in women with cervical cancer. This raises the possibility that adjuvant chemotherapy may someday play a larger role in the treatment of cervical cancer.

	The use of adjuvant or first-line chemotherapy has led to improvement in survival outcomes for women with gynecologic cancers. Still, for those women who experience relapse, the disease is often incurable and most will likely succumb to it. While there are treatment options for recurrent gynecologic cancers, trials have generally focused on ovarian cancer, leaving it up to patients and their providers to extrapolate from the data how the treatments might apply to cervical or uterine cancers.A number of agents are approved to treat first or subsequent ovarian cancer relapses. In endometrial cancer, however, the US Food and Drug Administration has not approved any agent for second-line therapy. Thus, there is a desperate need to broaden options and improve the outcomes for women with recurrent disease. Several promising treatments are in development for gynecologic cancers.

	Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF)-alpha.

 It is approved for use in colorectal cancer, non—small cell lung cancer, and breast cancer. Recently completed trials indicate it may also be highly active in gynecologic cancers (

	Burger and colleagues reported the results of Gynecologic Oncology Group (GOG) 170D, a phase II trial of bevacizumab in women with recurrent ovarian cancer.

 Eligible patients had measurable or assessable disease and had received up to 2 previous chemo-therapy regimens. Platinum-sensitive patients with a treatment-free interval of ≥12 months were required to have been re-treated with a platinum-based regimen. The study accrued 64 patients, of which 62 were evaluable. The overall response rate (ORR) was 21% (90% confidence interval [CI], 12.9%-31.3%), and 32 (52%) patients had stable disease as their best response. At 6-month follow-up, 40% had progression-free survival (PFS; 90% CI, 30%-53.6%). In this study, grade 3-4 gastrointestinal (GI) toxicity was rare, but 9.7% of patients developed grade 3-4 hypertension. Overall, toxicities were primarily grade 1-2. The most common adverse events were pain (50%), constitutional symptoms (45.6%), hepatic toxicity (33%), renal complications (30%), proteinuria (30%), anemia (30.6%), leukopenia (29%), hemorrhage (23%), diarrhea (21%), constipation (20%), coagulation problems (18%), nausea (15%), and hypertension (13%). While there were no reports of GI perforation in this study, a similar study conducted by Genentech was halted after 11% of participants experienced GI perforation.

 Prior treatment appeared to correlate with an increased risk of GI perforation; 24% of patients treated with 3 previous regimens experienced perforation, while no perforations occurred in patients who received ≤2 prior regimens.

	Two large randomized trials have recently closed; one evaluated bevacizumab as part of an upfront treatment strategy with carboplatin and paclitaxel (GOG 218), and the other (OCEANS) evaluated bevacizumab in women with relapsed platinum-sensitive recurrent ovarian cancer using a chemotherapy backbone of carboplatin and gemcitabine.

 Bevacizumab is also being used in GOG 252, a phase III, randomized, 3-arm trial evaluating 2 different intraperitoneal regimens compared with standard intravenous therapy. Bevacizumab will be administered in all arms concomitant to chemotherapy and for 52 weeks after chemotherapy (

 The GOG 213 study will randomize the “platinum-sensitive” population of women who experience relapse ≥6 months from the end of primary treatment to carboplatin and paclitaxel, with or without bevacizumab (

	The data on the effects of bevacizumab on gynecologic malignancies extends beyond ovarian cancer. In GOG 227C, Monk and colleagues studied single-agent bevacizumab in women with previously treated cervical cancer.

 Eligible patients had recurrent squamous or adenosquamous carcinomas of the cervix with measurable disease and were permitted to have had prior treatment with cisplatin-based chemoradiation and ≤2 prior cytotoxic regimens. Investigators enrolled 50 patients, of which 46 were treated. The ORR was 11%, with 24% of patients having PFS of ≥6 months. Toxicities in this study were similar to those reported by Burger and colleagues, with few grade 3 or 4 events. There was one death due to a grade 5 infection, possibly treatment related. These results led to GOG 240, a randomized trial that is currently enrolling patients with recurrent cervical cancer. Participants will be randomized to topotecan (Hycamtin)/paclitaxel versus cisplatin/paclitaxel, with a second randomization to bevacizumab or placebo (

	Finally, at the 2009 ASCO annual meeting, Aghajanian and colleagues presented data from GOG 229E, a phase II trial of bevacizumab in 56 women who had received ≤2 prior lines of cytotoxic treatment for recurrent or metastatic endometrial cancer.

 There were 53 evaluable patients, and 53% had received radiation therapy. Bevacizumab produced a 13% ORR and a 6-month PFS rate of 40%. Further evaluation in this population is ongoing in GOG 86P (

	a phase II randomized trial evaluating a carboplatin/tubulin-stabilizer backbone with either bevacizumab or temsirolimus (Torisel).

	Unlike bevacizumab, aflibercept is a fusion protein between the Fc region of human immunoglobulin (Ig) G1 and the extracellular domains of human VEGF-receptors 1 (VEGFR1) and 2 (VEGFR2). In 2007, Tew reported preliminary results of a multicenter trial, after 162 women out of a planned 200 were accrued and treated with afilbercept.

 All the women had platinum-resistant ovarian cancer and had been treated with ≤4 prior lines of chemotherapy. Radiologic criteria indicated that 13 patients (8%) achieved partial response (PR); 21 patients (13%) had at least a 50% decline in levels of cancer antigen (CA)-125. Adverse effects were similar to those associated with bevacizumab.

	Another pilot study evaluated the ability of aflibercept to reduce the rate of repeated paracentesis in women with recurrent ovarian cancer and recurrent ascites.

 Of 10 patients enrolled at the time of presentation, 8 met the primary criteria for response, defined as a doubling in time to first paracentesis on study compared with the baseline average before the study. There appeared to be considerable toxicity, with a 40% rate of bowel obstruction, 30% rate of severe nausea and vomiting, and 20% rate of anorexia, edema, or global clinical deterioration. While data on the activity of afilbercept in other gynecologic neoplasms has yet to be presented, GOG 229F—a phase II trial investigating afilbercept in women with recurrent or metastatic endometrial cancer&mdash;has completed enrollment.

	Moving beyond the antiangiogenic approach of VEGFR inhibition to block the formation of tumor vasculature, a new mechanism has emerged. This new class of drugs, termed vascular disrupting agents (VDAs), targets pericytes and endothelial cells of established tumor vasculature.

 Fosbretabulin, which is a combretastatin A4 phosphate (CA4P), is one such VDA in clinical development. It causes microtubule destabilization by binding the beta subunit of endothelial tubulin, resulting in disruption of the endothelial cytoskeleton. Additionally, fosbretabulin selectively disrupts cell-cell interaction of the vascular endothelial cadherin/beta-catenin complex, resulting in increased vascular permeability and reduced blood flow to the tumor.

	Fosbretabulin has been under investigation in ovarian cancer, with results presented at the 2009 ASCO Annual Meeting. A phase II trial enrolled women with platinum-resistant ovarian cancer, which was strictly defined as a treatment-free interval of <6 months from the end of previous platinum treatment to the start of trial therapy.

 The regimen called for carboplatin area under the curve equal to 5 and paclitaxel 175 mg/m

 delivered on day 1, with fosbretabulin 63 mg/m

 delivered 24 hours later. Of the 44 patients treated, 20% were taxane-naïve. The ORR by radiographic assessment or CA-125 criteria was 25%. Grade 3-4 pain was seen in >10% of patients. Nearly one-quarter (23%) of patients developed hypertension ~1 hour after administration of fosbretabulin, but all cases were grade 1-2 in severity and resolved within 4 hours. No significant or progressive increase in blood pressure was observed with successive courses of therapy, nor was there significant hematologic toxicity beyond what would be expected with chemotherapy alone. The GOG plans to further test this agent.

	Numerous other anti-vascular therapies are also under development, with more recent agents broadening beyond sole blockade of VEGF and exerting inhibition on other proteins, such as those against receptors for platelet-derived growth factor or fibroblast growth factor.Some target other angiogenic receptors, such as the platelet-derived growth factor receptor and fibroblast growth factor receptor. Others operate on other pathways, including those mediated by c-Kit and RAS/RAF (

	Belinostat is a hydroxymate type I histone deactylase (HDAC) inhibitor that leads to the acetylation of H3 and H4 histones and tubulin.

 In vitro and in vivo studies showed that belinostat was highly active in ovarian cancer cell lines, including multidrug-resistant cell lines, and showed synergy with platinums and taxanes.

The mechanism of synergy with carboplatin is believed to result from HDAC inhibition causing relaxation of DNA, which increases the ability of platinum salts to access the DNA.

Tubulin is a common target of both belinostat and taxanes; hence, belinostat may work by enhancing tublin’s activity.

	At the 2008 ASCO annual meeting, Finkler presented data from a phase II study of carboplatin, paclitaxel, and belino-

	stat in a cohort of 31 women with relapsed ovarian cancer who had received ≤3 prior regimens.

The ORR was 31%, and 1 patient had complete remission. When results were stratified by platinum-resistant status, women considered platinum-resistant following primary therapy had a PR rate of 17%. Toxicity was generally mild; the most commonly seen adverse effects were nausea (80%), vomiting (63%), fatigue (63%), and diarrhea (27%). The only grade 3-4 toxicity reported in >10% of participants was fatigue (17%). The GOG 126-T study is currently evaluating belinostat in combination with carboplatin in platinum-resistant patients.

	The epothilones are secondary metabolite macrolides produced by the myxobacterium 

Their mechanism of action is similar to taxanes, in so far as they inhibit disassembly of microtubules and induce apoptosis.

Two agents in this class are under evaluation in gynecologic cancers: patupilone (epothilone B, EPO906) and ixabepilone (Ixempra).

	This macrocytic polyketide was originally found to demonstrate potent cytotoxic activity in mammalian cells.

 It differs from paclitaxel in two significant ways: it is not formulated with polyoxyethylated castor oil (Cremophor), so infusion or hypersensitivity reactions may be less likely; and it is not a substrate for P-glycoprotein nor do tubulin mutations affect its efficacy (both are associated with resistance to paclitaxel).

	The results of an open-label phase I trial in women with advanced ovarian, fallopian tube, or primary peritoneal cancers was published in 2009.

 Patupilone was administered every 3 weeks, and response was measured by radiologic and CA-125 criteria. The ORR in this previously treated population was 20%, with median time to progression (TTP) of 16 months. Doses up to 11.0 mg/m

 were considered tolerable, with the most common toxicities being diarrhea, peripheral neuropathy, and fatigue. Grade 3 diarrhea was the most common serious adverse event reported. A phase III trial of patupilone versus pegylated liposomal doxorubicin (Doxil) in patients with recurrent ovarian cancer has completed accrual and results are eagerly anticipated.

	This drug is also a semisynthetic analog of epothilone B. In preclinical studies, it was shown to be active in paclitaxel-sensitive and paclitaxel-resistant cell lines. It appears unaffected by known mechanisms of drug resistance, such as P-glycoprotein overexpression. This may be related to the drug’s ability to suppress the dynamic instability of alpha/beta III microtubules in cells with increased levels of beta III tubulin.

 Ixabepilone is currently approved for use in metastatic breast cancer as a single agent following treatment with anthracyclines, taxanes, and capecitabine; and in combination with capecitabine after anthracyclines and taxanes.

	Trials have been conducted with ixabepilone in ovarian and endometrial cancers. In GOG 126-M, 49 women with platinum-resistant ovarian cancer were given ixabepilone on a 3-week on, 1-week off schedule.

The ORR was 14%, with a median TTP of 4.4 months. The incidence of grade 3-4 neutropenia was 20%, 3% of patients experienced grade 3 neuropathy.

	In a phase II study, 50 women with locally advanced, recurrent, or metastatic endometrial cancer (94% had previously received paclitaxel) were given ixabepilone every 3 weeks.

 The ORR was 12%, with 6 of the 50 women responding. At 6 months, 20% were progression free. The primary toxicity was myelosuppression, with a 52% incidence of severe neutropenia. Only 10% of patients reported grade 3-4 neuropathy. The findings have led to registration of a phase III randomized trial of ixabepilone versus either paclitaxel or doxorubicin as a second-line agent in women with recurrent, advanced, or metastatic endometrial cancer.

	The ongoing clinical research in gynecologic malignancies could result in a better biologic understanding of these complex disease processes, allowing us to move beyond the current standard of care, which relies heavily on cytotoxic therapy. The findings from the bevacizumab studies in gynecologic cancers have confirmed that angiogenic targeting is an important and clinically relevant strategy. The current phase III studies should define the role for this agent in standard management. In the future, it is likely that the incorporation of biologics into a chemotherapy backbone will be of interest to clinical researchers; however, the role of cytotoxic therapy in the management of most of these solid tumors will remain important in the short term.

	Scanning the clinical-trial landscape, it is gratifying to see how much work is going into finding effective treatments for ovarian cancer, the most fatal of all gynecologic neoplasms. Still, we must not forget that women are also living with and dying from cancers of the cervix and uterus, and, to a lesser extent, the vulva and vagina. We strongly urge the scientific community to broaden efforts into conducting much-needed trials in these other tumor types, to improve the standard of care for all gynecologic cancers.