Obstetrics and Gynecology

Ovarian Cancer - Novel Therapeutic Approaches

Targeted Therapies in Ovarian Cancer

1. What every clinician should know

Adjuvant chemotherapy after optimal primary cytoreductive surgery has been shown to improve progression-free and overall survival in patients with epithelial ovarian cancer. Several randomized controlled trials have established first-line treatment with combination platinum-paclitaxel chemotherapy as standard of care in patients with advanced ovarian cancer, with response rates of over 80%.

However, most patients eventually relapse, with a median progression-free survival of 18 months. Resistance to platinum-based chemotherapy is central to the poor overall survival associated with ovarian cancer. Response rates to second-line agents such as liposomal doxorubicin, gemcitabine or topotecan decrease with each subsequent relapse due to chemoresistance, leading to a 5-year overall survival of 30-40%. Therefore, it is important to explore new targeted therapies aimed at treatment of advanced and recurrent ovarian cancer and overcoming chemoresistance.

Understanding the biology of ovarian carcinoma and the development of chemotherapy resistance has led to the development of molecularly targeted therapies. Many small-molecule inhibitors and monoclonal antibodies have been developed to target pathways critical for tumor angiogenesis, cell survival and growth, and metastasis. However, because of the heterogeneous biology of ovarian cancer, there is no predominant deregulated pathway in all ovarian cancers. Therefore, patient selection for individualized application of targeted therapies is essential.

In this chapter, we provide an overview of current targeted therapies in ovarian cancer being investigated, including mechanism of action, dosing and side effects. The goal is to provide information for physicians and other health care providers who are interested in the key elements needed to make appropriate decisions in the counseling and treatment of patients with advanced and recurrent ovarian cancer.

Anti-angiogenesis therapies

Angiogenesis, or the formation of new blood vessels, facilitates cancer growth and metastasis. Therapies targeting angiogenesis and associated growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), have been shown to inhibit new blood vessel growth and induce tumor cell apoptosis.

VEGF inhibitors

Bevacizumab

Bevacizumab (Avastin®, Genentech-Roche) is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor A (VEGFA). It is currently approved by the Food and Drug Administration (FDA) for use in renal cell, non-small cell lung, and colorectal cancers and glioblastoma. The FDA recently revoked approval for the use of bevacizumab in metastatic breast cancer. Phase II trials using single-agent bevacizumab in recurrent, platinum-resistant ovarian cancer yielded response rates of 15- 25%.

Bevacizumab is being investigated in phase III trials as a component of front-line therapy in combination with platinum-paclitaxel based regimens, and as a single-agent as maintenance therapy with promising results. It is also being investigated in platinum-sensitive recurrent ovarian cancer in combination with carboplatin/gemcitabine and paclitaxel/carboplatin, as well as in platinum-resistant ovarian cancer in combination with traditional second-line agents. Because of the progression-free survival (PFS) endpoints being met in phase III clinical trials, bevacizumab is being considered for FDA approval in ovarian cancer.

Patients to consider for bevacizumab therapy: 1) front-line therapy for stage III and IV epithelial ovarian cancer patients following cytoreductive surgery in combination with a platinum-paclitaxel based regimen followed by maintenance therapy as a single-agent; 2) combination therapy for recurrent or persistent epithelial ovarian cancer with second-line regimens (e.g. weekly taxanes or gemcitabine). Standard dosing of bevacizumab is 10 mg/kg IV every 2 weeks or 15mg/kg IV every 3 weeks.

Precautions should be taken in patients with pre-existing hypertension; recent or upcoming surgery (within 30 days), especially with bowel involvement; cardiovascular disease; and renal dysfunction. Women of childbearing potential are advised to avoid becoming pregnant and against breastfeeding while receiving bevacizumab. Patients should discontinue therapy if they have a severe adverse reaction, such as uncontrolled hypertension, gastrointestinal perforation or vascular events, related to bevacizumab.

Aflibercept (VEGF Trap)

Aflibercept is a novel VEGF fusion protein that prevents ligand binding to vascular endothelial growth factor receptors (VEGFR). Phase II trials using aflibercept as a single-agent or in combination with taxane therapy in recurrent, platinum-resistant ovarian cancer showed significant antitumor activity and prevention of ascites reaccumulation. Patients with recurrent or persistent epithelial ovarian cancer can be considered for aflibercept therapy in a clinical trial setting. Dosing of aflibercept is either 4 mg/kg IV every 2 weeks or 6 mg/kg IV every 3 weeks. Because aflibercept has a mechanism of action similar to that of bevacizumab, similar precautions should be taken. Although it is not currently FDA approved, based on its encouraging clinical activity, it may be integrated into clinical use in the future.

Side effects of VEGF Inhibitors

Specific adverse events have been noted with VEGF inhibitors. Hypertension is one of the most common side effects, with an incidence of 20-30% with bevacizumab and 10-15% with aflibercept. Caution should be taken in patients with pre-existing hypertension or those currently on anti-hypertensive agents. All patients on VEGF inhibitors should have routine blood pressure surveillance at least every 3 weeks while on therapy. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and calcium-channel blockers are effective first-line antihypertensive agents.

There is a general consensus that VEGF inhibitors should be stopped if hypertension cannot be controlled using the standard oral dosing of two anti-hypertensive agents or in patients who have a hypertensive crisis. Asymptomatic proteinuria can occur due to VEGF-dependent glomerular endothelial injury in 30-40% of patients on bevacizumab and around 5% in patients on aflibercept. Patients should undergo monitoring with regular dipstick urinalysis while on therapy. Those with a dipstick reading of 2 or more should undergo a 24-hour urine total protein collection. VEGF inhibitors should be discontinued in patients excreting at least 2g of protein in a 24-hour period.

There are other less common but still significant adverse effects associated with VEGF inhibitors. Gastrointestinal perforation has been associated with VEGF inhibitor therapy with an incidence of up to 10%. Patients with recurrent ovarian cancer have risk factors including previous gastrointestinal surgery, carcinomatosis compromising bowel function and poor nutrition. Exposure to three or more prior chemotherapeutic regimens and patients with inflammatory bowel disease were most strongly associated with intestinal perforation.

Maintaining a high index of suspicion in patients presenting with fever, leukocytosis or abdominal pain while on therapy is warranted. Patients on VEGF inhibitor therapy have an increased likelihood of postoperative complications including bleeding, thrombosis, and compromised wound healing. Many recommend a gap of at least 30 days between discontinuing the VEGF inhibitor and major surgery.

Other potentially serious side effects reported in trials include an increased risk of arterial thromboembolic events (ATE), but not venous thromboembolic events (VTE). Patients with cerebrovascular accidents or myocardial ischemic events should be taken off VEGF inhibitor therapy. Patients with VTE can resume VEGF inhibitor therapy while on full-dose anticoagulation but with caution because of an increased bleeding tendency with VEGF antagonism.

VEGF/PDGF inhibitors

Sunitinib and Sorafenib

Sunitinib (Sutent®, Pfizer) and sorafenib (Nexavar®, Onyx and Bayer Healthcare Pharmaceuticals) belong to a group of VEGF-receptor tyrosine-kinase inhibitors (RTKIs) with activity against both VEGFR and PDGFR. Sunitinib is FDA approved for use in neuroendocrine pancreatic cancer, metastatic renal cell carcinoma and gastrointestinal stromal tumors (GIST). Sorafenib is FDA approved for use in hepatocellular and metastatic renal cell carcinoma.

Because these oral agents have proven antitumor activity in renal clear cell carcinoma, this has led to interest in pursuing these agents in clinical trials in patients with ovarian clear cell carcinoma due to similar gene profiles. Recent phase II studies with single agent sorafenib or sunitinib in advanced or recurrent epithelial ovarian cancer have shown some activity. There are ongoing phase II studies using these agents in combination with carboplatin and paclitaxel.

Patients with recurrent or persistent epithelial ovarian cancer can be considered for therapy with sunitinib or sorafenib in a clinical trial setting. Standard dosing of sorafenib is 400 mg orally BID, and sunitinib is 37.5 mg orally once daily. Precautions should be taken in patients with cardiovascular disease, pre-existing hypertension, cardiac arrhythmias and recent or upcoming surgery (within 30 days), especially with bowel involvement. Women of childbearing potential are advised to avoid becoming pregnant and against breastfeeding while receiving sorafenib or sunitinib. Patients should have therapy discontinued if they experience a severe adverse reaction related to either agent.

Side effects of VEGF/PDGF inhibitors

In comparison to direct VEGF inhibitors, sorafenib and sunitinib have fewer side effects of hypertension, proteinuria, vascular thromboembolism, bleeding risk and gastrointestinal perforation. However, there are other more common adverse events reported with these agents. Reversible cardiac toxicity has been seen with sorafenib and sunitinib, with a 10% or greater reduction in left-ventricular ejection fraction (LVEF) in up to 28% of patients. Baseline and periodic assessment of LVEF may be useful while on therapy. Prolongation of the QTc interval has been seen with these agents, especially in combination with other medications that prolong the QTc interval.

Patients should have a baseline electrocardiogram (ECG) and close electrolyte monitoring during therapy. Therapy should be discontinued if congestive heart failure or arrhythmias precipitated by QTc prolongation develop while on therapy. Hypertension also can occur with sorafenib and sunitinib; however, it usually occurs early in the course of treatment and can be managed with anti-hypertensive therapy. Patients should have blood pressure surveillance weekly during the first 6 weeks of therapy, then periodically thereafter.

A hand-foot skin reaction, or acral erythema, is a pathognomonic dermatologic toxicity associated with both sorafenib and sunitinib in up to 50% of patients. Common symptoms of the hand-foot skin reaction include dysethesia and paresthesia, erythema, edema, hyperkeratosis, dryness and blisters. Pharmacologic management can include clobetasol cream, systemic corticosteroids, vitamin E, topical dimethyl-sulfoxide or pyridoxine. Rapid symptom improvement can occur with temporary cessation of therapy. Other skin reactions associated with sorafenib and sunitinib include subungual splinter hemorrhages, hair depigmentation, and erythematous follicular papules and pustules appearing in areas rich in sebaceous glands.

Additionally, gastrointestinal toxicity with diarrhea and mucositis is a common dose-limiting side effect that can occur in up to 50% of patients. Oral hydration and anti-diarrheal agents can be used for mild symptoms. Treatment should be interrupted if severe symptoms develop until diarrhea or mucositis resolves. Elevation in bilirubin and liver enzymes can occur with sunitinib and should be monitored closely throughout therapy. Sunitinib should be interrupted for grade 3 or 4 related hepatotoxicity and discontinued if there is no resolution.

Abnormal thyroid function can occur in up to 80% of patients on sunitinib. Baseline thyroid function evaluation and surveillance every 2-3 months in patients on sunitinib is recommended, with hormone replacement in those diagnosed with hypothyroidism. Hypophosphatemia can occur with sorafenib and close electrolyte monitoring is recommended while on therapy.

Other agents

Angiogenesis inhibitors are a new class of agents currently being investigated in ovarian cancer. A recent phase II randomized trial demonstrated activity for a selective angiopoietin 1/2-neutralizing peptibody, AMG 386 (trebananib, Amgen), in combination with low-dose weekly paclitaxel for recurrent ovarian cancer. Dosing schedules used in this study included a high-dose 10 mg/kg IV once weekly or low-dose 3 mg/kg IV once weekly. Patients with recurrent or persistent epithelial ovarian cancer can be considered for AMG 386 therapy in a clinical trial setting. Adverse events reported in this study included hypertension, thromboembolic events, peripheral edema, and hypokalemia. Three phase III trials were initiated using trebananib; TRINOVA-1, which followed the Phase II, combining paclitaxel with trebananib at a higher dose (15 mg/kg IV once weekly), TRINOVA-2 a placebo controlled phase III trial in platinum-resistant patients using pegylated liposomal doxorubicin alone or in combination with trebananib, and a phase III trial of paclitaxel and carboplatin plus or minus trebananib in previously untreated, advanced stage ovarian cancer patients. TRINOVA-1, the first trial to report, randomized 919 patients to either weekly paclitaxel or weekly paclitaxel and trebananib. Eligibility criteria included patients with up to 3 lines of prior therapy and a platinum-free interval of less than 12 months. The primary endpoint was progression-free survival. Patients on the combination arm had a significant reduction in the hazard for progression compared with chemotherapy alone (HR: 0.66, 95%CI: 0.57-0.77; median: 5.4 months vs 7.2 months, P<0.001). The effect appeared to be robust over the stratification factors including, prior anti-angiogenesis therapy and number of prior chemotherapy regimens. Overall, adverse events were similar between the arms, including class-specific toxicities associated with angiogenesis therapies, such as, hypertension, thrombotic events, impaired wound healing, hemorrhage and proteinuria. However, localized edema was approximately twice as common in the combination arm versus, but was generally low grade. Interim analysis of overall survival was similar between the arms. In addition, there are two phase III trials that used AMG 386 in recurrent ovarian cancer in combination with either weekly paclitaxel or pegylated liposomal doxorubicin.

Several oral agents that block VEGFR, PDGFR, and FGFR through receptor tyrosine-kinase activity have been evaluated in phase II trials in women with recurrent ovarian cancer, including cediranib (Astra-Zeneca), pazopanib (GlaxoSmithKline), and BIBF-1120 (Boehringer Ingelheim) with promising results. Common side effects reported with these agents include gastrointestinal toxicity, including nausea and diarrhea, hypertension and reversible liver enzyme elevation. The preliminary clinical activity and manageable safety profile has prompted further clinical evaluations with phase III trials in frontline (BIBF-1120), maintenance (pazopanib), and recurrent disease (cediranib) settings.

XL-184 (Cabozantinib, Exelixis) is a new oral MET/VEGFR2 inhibitor being evaluated in phase II trials and has shown response rates of 18-22% in platinum-resistant and 28% in platinum-sensitive patients. Commonly reported side effects of XL-184 include fatigue, nausea and vomiting, diarrhea and palmar-plantar erythrodysesthesia. Less frequent but serious side effects include gastrointestinal perforation in 3% of patients. Because of the preliminary response rates with XL-184, a non-randomized expansion cohort is currently accruing patients in platinum-resistant and refractory ovarian cancer.

Another targeted area that has been investigated in ovarian cancer, although with limited activity, is the epidermal growth factor receptor (EGFR). EGFR is overexpressed in 70% of ovarian cancers and is associated with advanced disease at presentation, poor prognosis and chemoresistance. Single agent studies of EGFR tyrosine kinase inhibitors, such as erlotinib (Genentech-Astellas Oncology) and gefitinib (Astra-Zeneca), and monoclonal antibodies against EGFR, such as cetuximab (Bristol-Myers), have only shown modest activity in phase II trials in recurrent ovarian cancer.

Overexpression of Her2 (ERBB2) is also observed in ovarian cancer; however the exact percentage varies widely in the literature. A monoclonal antibody against Her2, trastuzumab (Herceptin®, Genentech), has been studied as a single-agent in phase II trials in patients that demonstrated overexpression of Her2 by immunohistochemistry, but with limited activity. There was no relationship between Her2 expression and clinical response and overall response was much less than in phase II breast cancer trials.

PARP inhibitor therapies

Poly (ADP-ribose) polymerase (PARP) is a key enzyme involved in the repair of DNA single-strand breaks using the base excision repair pathway. PARP inhibition results in the accumulation of DNA single-strand breaks, which can eventually lead to double-strand breaks. Double-strand breaks are repaired by homologous recombination DNA repair mechanisms, which require functional BRCA1 and BRCA2 activity. In the absence of BRCA1 or BRCA2, due to somatic mutations or epigenetic silencing, alternative DNA repair pathways are used resulting in chromosomal instability and cell death. Thus, the use of PARP inhibitors in BRCA mutation carriers results in synthetic lethality.

Olaparib (AZD 2281, AstraZeneca) is an oral PARP inhibitor currently being evaluated through phase II trials in recurrent ovarian cancer patients with BRCA mutations. However, in addition to germline mutations in the BRCA gene, there have been recent studies suggesting that up to 50% of patients with sporadic high-grade epithelial ovarian cancer have loss of BRCA function either through genetic or epigenetic mechanisms.

A recent phase II trial supported this by using olaparib as maintenance treatment in patients with recurrent platinum-sensitive epithelial ovarian cancer following treatment with two or more platinum-containing regimens. Patients on olaparib had a significantly longer progression-free survival (8.4 vs. 4.8 months) and time to progression by CA-125 or RECIST (8.3 vs. 3.7 months) compared to placebo regardless of germline BRCA mutation status. There are also other PARP inhibitors in development and currently undergoing phase II trials in ovarian cancer, including iniparib (Sanofi-aventis) and veliparib (Abbott Laboratories). PARP inhibitors are currently not FDA approved for any cancer-related therapy. Ongoing clinical trials continue to support movement towards FDA approval in breast and ovarian cancer.

Patients with recurrent or persistent epithelial ovarian cancer, with either germline or epigenetic BRCA mutations, can be considered for PARP inhibitor therapy in a clinical trial setting. Standard dosing for olaparib is 400 mg orally twice daily. Olaparib has a relatively good safety profile. The most common reported adverse events are fatigue, nausea and vomiting, with a low incidence of myelosuppression.

Metronomic chemotherapy

Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. The shortened time between cycles prevents effective recovery of the damaged tumor vasculature and has anti-angiogenic properties, making the tumor more sensitive to the chemotherapy. Examples of this being used in clinical practice include low-dose metronomic oral cyclophosphamide and bevacizumab in recurrent ovarian cancer.

Phase II studies using this regimen have demonstrated a 24% response rate in recurrent ovarian cancer patients that received up to two prior chemotherapy regimens. Patients with recurrent or persistent epithelial ovarian cancer can be considered for treatment using this regimen in clinical practice. Dosing for metronomic oral cyclophosphamide is 50 mg orally once daily and for bevacizumab is 10 mg/kg IV every 2 weeks or 15 mg/kg IV every 3 weeks. Most common side effects related to this regimen reported are hypertension, fatigue and pain. Rates of gastrointestinal perforation were 4% on the metronomic therapy in combination with bevacizumab.

Dose-dense chemotherapy, a variant of metronomic chemotherapy, has also been shown to be effective in a phase III study performed by the Japanese Gynecologic Oncology Group. Weekly IV dose-dense paclitaxel in combination with IV carboplatin every 3 weeks showed a statistically significant improvement in progression-free survival (28 vs. 17.8 months) compared to those receiving the standard 3-week dosing of both agents. Overall survival was also higher in the dose-dense group (72% vs. 65%) compared to the conventional group.

Patients can be considered for dose-dense paclitaxel as front-line therapy for stage III and IV epithelial ovarian cancer patients who underwent cytoreductive surgery in combination with a platinum agent, or in recurrent or persistent epithelial ovarian cancer. Standard dosing for the dose-dense paclitaxel regimen is 80 mg/m2 IV once weekly for 3 weeks. Adverse events including neutropenia and anemia were more common in the dose-dense regimen compared to conventional dosing. The dose-dense paclitaxel regimen is currently being studied in phase III clinical trials in the U.S. by the Gynecologic Oncology Group in combination with either IV or intraperitoneal carboplatin and bevacizumab.

2. What is the evidence for specific management and treatment recommendations?

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