The Changing Landscape of Therapeutic Strategies for Recurrent Ovarian Cancer

Klaus H Baumann; Uwe Wagner; Andreas du Bois

Disclosures

Future Oncol. 2012;8(9):1135-1147. 

In This Article

Platinum-sensitive Ovarian Cancer

Surgery: An Option That Deserves Thorough Consideration

It is not yet clear whether surgery in relapsed platinum-sensitive ovarian cancer will result in better overall survival.[17] This is not the case with respect to surgical measures in case of symptoms such as, for example, bowel or ureter obstruction. Here, surgery is required to relieve symptoms in patients if no contraindications are present.[18] However, the beneficial role of surgery in patients with recurrent platinum-sensitive ovarian cancer showing tumor load but only minor or no symptoms is still to be determined. Surgery may be considered if a complete tumor resection can be achieved.[19] The AGO Study Group has established factors to assess the likelihood of accomplishing a complete resection.[19] The factors are:

  • Complete resection at first surgery;

  • Good performance status;

  • Absence of ascites.[19,20]

These factors have been established in a prospective validation study,[19] and are currently under investigation in an international, multicenter, prospective randomized trial. The DESKTOP III trial will investigate the role of surgery in recurrent platinum-sensitive ovarian cancer.[101] Overall survival is the primary end point.[21] The importance of the DESKTOP III trial and its unique approach is underlined by the notion of Galaal et al.,[22] confirming the absence of randomized clinical trials within an immense amount of clinical research.

Chemotherapy: The Platinum Story

Platinum-based reinduction chemotherapy is the central high point in the therapeutic landscape in platinum-sensitive ovarian cancer. Carboplatin and paclitaxel, carboplatin and gemcitabine, or carboplatin and pegylated liposomal doxorubicin (PLD) have been established as effective strategies. Carboplatin was to replace cisplatin due to a better therapeutic ratio.[11,23] The addition of a second compound to platinum, such as paclitaxel[11,23] or gemcitabine,[24] clearly demonstrated the superiority of the combination over a platinum single agent. More recently, replacing paclitaxel with PLD within a noninferiority trial design proved that the combination of carboplatin and PLD was not inferior compared with the combination of carboplatin and paclitaxel, and was associated with an increased progression-free survival (PFS) and better therapeutic ratio.[25] Thus, the CALYPSO trial established carboplatin and PLD as a favorable choice in recurrent platinum-sensitive ovarian cancer. The temporary shortage of PLD from Summer 2011 was compensated by the other established treatment regimens.

Angiogenesis Inhibition: The Emergence of Bevacizumab

Inhibition of angiogenesis by agents such as bevacizumab is supposed to change the landscape not only in primary ovarian cancer therapy, but also for recurrent disease.[26,27] Four major Phase III trials investigating bevacizumab in primary platinum-sensitive and -resistant ovarian cancer have been reported and published, and have already started to influence current clinical practice. Bevacizumab maintenance therapy initiated with first-line chemotherapy and continued after the end of chemotherapy for up to 15 months resulted in an improved progression-free survival, and evidence is provided for a prolonged overall survival in high-risk patients in primary ovarian cancer.[12,13] The therapeutic potential of angiogenesis inhibitors such as the antibody bevacizumab and some tyrosine kinase inhibitors, such as sunitinib and sorafenib, has been seen in platinum-resistant and -sensitive ovarian cancer.[27–32] The majority of the data are available for bevacizumab. Bevacizumab is a monoclonal antibody directed against VEGF.[33] Recently, the OCEANS trial demonstrated the superiority of adding bevacizumab to carboplatin and gemcitabine chemotherapy compared with chemotherapy alone in recurrent platinum-sensitive ovarian cancer.[27] A total of 484 patients were randomized to receive either standard chemotherapy (carboplatin area under the curve [AUC] 4 on day 1 every 3 weeks and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks, up to ten cycles) and placebo (on day 1 every 3 weeks), or standard chemotherapy and bevacizumab (15 mg/kg on day 1 every 3 weeks until progression). The patients had no prior chemotherapy for recurrent platinum-sensitive ovarian cancer. PFS was significantly better in the experimental arm compared with the placebo control arm (12.4 vs 8.4 months; hazard ratio [HR]: 0.751; 95% CI: 0.388–0.605; p < 0.001).[27] Additionally, an interim analysis for overall survival favored the bevacizumab containing experimental arm (35.5 vs 29.9 months; HR: 0.484; 95% CI: 0.537–1.052; p < 0.094).[27] The adverse events were within the known side effects. There was no increase of bowel perforation or fistula formation due to bevacizumab treatment. Thus, the OCEANS trial not only proved the effectiveness of bevacizumab in combination with carboplatin and gemcitabine, but also provided valuable information on the safety and management of side effects. The combination of carboplatin and gemcitabine with bevacizumab improves the therapy in recurrent platinum-sensitive ovarian cancer. The addition of bevacizumab to other chemotherapy combinations and the concept of treatment beyond disease progression represent some research questions to resolve.

A number of other agents with an antiangiogenic mode of action are currently under investigation. Clinical trials in various phases include aflibercept (VEGF Trap), a fusion protein that binds the isoforms of VEGF, and several multitargeted tyrosine kinase inhibitors (e.g., BIBF 1120, cediranib, pazopanib and sorafenib) not restricted to blocking VEGF receptor pathways.[102] Inhibition of angiopoietin also provides a promising target and AMG 386 is a selective angiopoietin inhibitor. In a Phase II trial 161 female patients with recurrent ovarian cancer were randomized to either treatment with paclitaxel alone, or with paclitaxel combined with AMG 386. Two different doses of AMG 386 were used: 10 or 3 mg/kg. Progression-free survival was 7.2 months among patients receiving 10 mg/kg of AMG 386, 5.7 months among patients receiving 3 mg/kg of AMG 386 and 4.6 months among patients who were treated with paclitaxel alone.[34]

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