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-resistant/Refractory Ovarian Cancer

Patients with platinum-resistant/refractory ovarian cancer have poor prognosis and might also be classified as chemotherapy-resistant/refractory ovarian cancer.[3] Single-agent therapies used to treat this subset of patients include paclitaxel, PLD and topotecan. The response rate is in the 10–15% range and overall survival is approximately 12 months.[40] Research is focusing on improving chemotherapy, introducing targeted agents and overcoming platinum resistance.

Conventional 5-day schedule topotecan was compared with weekly topotecan in a randomized Phase II trial by the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group.[41] A total of 194 patients were randomized to receive either topotecan 4 mg/m2 on days 1, 8 and 15 or topotecan 1.25 mg/m2 on days 1–5. Clinical benefit and PFS were slightly better in the conventional topotecan treatment group compared with the weekly schedule. The favorable toxicity profile and comparable overall survival qualify the weekly schedule as a viable treatment option.[41]

Combination chemotherapy in platinum-resistant ovarian cancer eventually fails to improve overall survival but increases toxicity. The CARTAXHY trial performed by Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) compared weekly paclitaxel alone with weekly paclitaxel combined with carboplatin (AUC 4 on day 1 every 4 weeks) or weekly topotecan.[42] PFS was not significantly different; the combination regimens were more toxic than weekly paclitaxel alone.

The introduction of other chemotherapy agents is of interest. Irinotecan,[43] nanoparticles, albumin-bound paclitaxel[44] and sagopilone (a synthetic epothilone)[45] demonstrated some efficacy and warrant further research. The concept of chemosensitizing is supported by laboratory findings. The impact of a histone deacetylase inhibitor, belinostat, was investigated in 29 women with platinum-resistant ovarian cancer.[46] Belinostat was given daily for 5 days with carboplatin on day 3. The results indicated only low activity of belinostat.[46] The possibility of overcoming platinum- and chemoresistance in ovarian cancer thus remains to be further elucidated.

The poor prognosis of chemoresistant ovarian cancer has resulted in numerous clinical trials investigating the therapeutic potential of targeted agents. Single-agent activity is low to modest for most of the tested compounds. However, these agents might be suitable partners for combination with classical chemotherapeutics.

The combination of aflibercept with docetaxel achieved an encouraging objective response rate in platinum-resistant ovarian cancer.[47] The combination therapy caused the known and expected side effects. Further clinical trials using this combination are expected.

By contrast, the combination of sorafenib and weekly topotecan caused significant hematologic and nonhematologic toxicities.[48] Hence, administration of full doses was precluded, resulting in modest activity in platinum-resistant ovarian cancer.

The combination of bevacizumab and oral cyclophosphamide induced some clinical benefit in heavily pretreated and platinum-resistant ovarian cancer and was well tolerated.[49]

The international AURELIA trial is investigating the effects and safety of bevacizumab in combination with different chemotherapies (paclitaxel, topotecan and PLD) in platinum-resistant or refractory recurrent ovarian cancer.[102]

Drug targeting represents a further strategy. EC-145 is a folate-targeted vinca alkaloid. Superiority of EC-145 with PLD over PLD alone was proven with respect to PFS (24.0 vs 11.7 weeks; HR: 0.497; p = 0.014).[50] These results support further clinical trials with EC-145.

AEZS-108, a luteinizing hormone releasing hormone agonist, linked to doxorubicin, was investigated for safety and efficacy in platinum-resistant ovarian cancer.[51] The achieved objective response rate was 11.6% in heavily nontreated platinum-resistant ovarian cancer patients. The concept of drug targeting requires and clearly warrants further investigation.

Until now, no Phase III trials have established any new therapeutic strategy as superior compared with existing therapies in platinum-resistant ovarian cancer.

More importantly, new developments in targeted therapy will most likely not replace established chemotherapy strategies but eventually additively or synergistically increase combined therapeutic efficacy. Although some, or modest, single-agent activity of targeted therapeutics has been shown in recurrent ovarian cancer (e.g., for PARP inhibition),[52] the majority of data support the combination of classical chemotherapeutics with targeted agents. Different modes of action, some sensitizing activity and different safety profiles qualify such combinations for further therapeutic investigations and interventions. Especially in platinum-resistant recurrent ovarian cancer, single-agent activity, either of chemotherapy or of targeted therapy, is quite modest. The international AURELIA trial is investigating the effects and safety of bevacizumab in combination with different chemotherapies (paclitaxel, topotecan and PLD) in platinum-resistant or refractory recurrent ovarian cancer.[102] The recently presented data of the AURELIA trial proved the combination of bevacizumab with chemotherapy as superior to chemotherapy alone in terms of PFS.[53]

Promising therapeutic targets include angiogenesis pathways (e.g., VEGF and its receptors), DNA repair mechanism (e.g., PARP) and growth factor receptors and their intracellular pathways (e.g., Her3 receptor). Primary or secondary resistance to targeted therapy still remains an obstacle in ovarian cancer therapy. Therefore, the combination of targeted agents further warrants research for efficacy and tolerability.

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