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

Other Developments in Recurrent Ovarian Cancer

EGF Receptor Targeting

The EGF receptor family contains the EGF receptor, Her2/neu, Erb3 and Erb4. Ligand-induced receptor activation leads to receptor dimerization, tyrosine kinase activation and induction of further downstream signaling pathways regulating gene expression, as well as cell differentiation, proliferation, survival and death.

In a variety of solid tumors therapeutic targeting of members of the EGF receptor family has been established.

Most recently, the results of the EORTC 55041 trial were presented.[54] The international, prospective randomized trial examined the effects of erlotinib maintenance therapy subsequent to completion of standard first-line platinum-based chemotherapy in ovarian cancer patients. Patients showing no evidence of disease progression after first-line chemotherapy were randomized to receive either erlotinib 150 mg daily for 2 years or observation. Patients were not selected for EGF receptor expression. PFS and overall survival were not different for the groups. A group of patients was analyzed for EGF receptor mutation. Similarly, there was no therapeutic effect in either group (with or without receptor mutation).[54]

Trastuzumab,[55] erlotinib,[56] gefitinib,[57] cetuximab[58] and vandetanib[59] showed no or only minor activity in recurrent ovarian cancer.

By contrast, the Her2-binding monoclonal antibody pertuzumab showed beneficial effects in women with recurrent, platinum-resistant ovarian cancer in combination with gemcitabine. In a subgroup analysis on tumors expressing low levels of Her3 mRNA, the addition of pertuzumab to gemcitabine achieved better results with respect to progression and survival than gemcitabine alone.[60] Hematologic toxicity was increased due to pertuzumab in addition to gemcitabine.[60]

Panitumumab, an EGF receptor-binding, fully humanized antibody is currently being tested in combination with chemotherapy in clinical trials in platinum-sensitive and -resistant recurrent ovarian cancer.[102]

PARP Inhibition

PARP represents a family of DNA-repairing enzymes. PARP enzymes are involved in the repair processes of DNA damage and double strand breaks. Inhibitors of PARP-1 revealed cytotoxicity in cancer cells bearing a defect in another DNA repair system, homologous recombination.[61] BRCAness in the absence of the familial BRCA1 or BRCA2 mutations summarizes a phenotype of specific DNA repair defects, which seems to be associated with an increased risk of ovarian cancer recurrence and platinum resistance.[62]

In a randomized Phase II trial, the PARP inhibitor olaparib proved to be as effective with respect to PFS and objective response rate as PLD in ovarian cancer patients relapsing within 12 months after prior platinum-based chemotherapy.[52] Olaparib maintenance therapy in recurrent, platinum-sensitive, high-grade serous ovarian cancer significantly improved PFS compared with the placebo control (median 8.4 vs 4.8 months from randomization on completion of chemotherapy; HR for progression or death: 0.35; 95% CI: 0.25–0.49; p < 0.001).[63]

Phase II trials testing the combination of the PARP inhibitor iniparib with carboplatin and gemcitabine chemotherapy provided evidence of feasibility, safety and encouraging activity in platinum-sensitive and -resistant ovarian cancer.[64]

Translational and clinical research still has to explore the clinical potential of PARP inhibition in recurrent ovarian cancer.

Inhibition of other signaling pathways and receptors including PI3K–AKT, mTor, Src, Ras–Raf, IGF receptor and folate receptor is under investigation. Also, basic, translational and clinical research still has to explore the potential of the respective inhibitors in recurrent ovarian cancer. Intensive research is required to identify predictive markers in patients so far unselected for treatment decision.

Endocrine Therapy

Hormonal treatment is an integrated strategy in recurrent ovarian cancer. Depending on prior lines of chemotherapy, pre-existing toxic side effects, and the wishes and general condition of the patients, agents such as medroxyprogesterone acetate, tamoxifen, GnRH analogs and selective estrogen receptor modulators might be selected to achieve some beneficial effects.[57,65,66]

Hyperthermic Intraperitoneal Chemotherapy in Recurrent Ovarian Cancer

Hyperthermic intraperitoneal chemotherapy (HIPEC) is supposed to improve the prognosis in recurrent ovarian cancer, even more so when combined with cytoreductive surgery. A retrospective analysis of 40 patients, where 31 of these received surgery and HIPEC, provided data on feasibility and safety of the procedures.[67] There are some single-center, nonrandomized, prospective clinical trials further supporting the feasibility and safety of cytoreductive surgery combined with HIPEC, and even more indicating some beneficial effects.[68–70] Agents used for the HIPEC procedure include oxaliplatin, doxorubicin, cisplatin and mitomycin C. Nevertheless, safety issues have to be raised, owing to intraoperative severe morbidity ranging from 0 to 40% and mortality rate varying from 0 to 10%, according to a systematic review.[71] Severe toxicities include hematologic and nonhematologic effects such as raised serum creatinine, gastrointestinal anastomosis insufficiency, intestinal perforation and septic complications.[72] No prospective randomized trials are available to clarify the role of HIPEC in recurrent ovarian cancer. HIPEC does not avoid or replace systemic chemotherapy for recurrent disease.

Virotherapy: So Far No Clinical Evidence

Virotherapy showed encouraging effects in preclinical models. 10 years ago, a Phase I trial was described investigating the application of the adenovirus dl1520 (ONYX-015) with the E1B 55-kD gene deleted, leading to the lysis of p53-deficient tumor cells.[73] ONYX-015 has shown efficacy in a preclinical tumor model. Four different dose cohorts were evaluated. The most common toxicities related to virus administration were flu-like symptoms, emesis and abdominal pain. The maximum tolerated dose was not reached at 1011 plaque-forming units. There was no obvious evidence of clinical or radiologic response in any patient. Blood samples indicated viral replication and host immune response.[73] Oncolytic measles virus was used in a Phase I trial to evaluate feasibility and toxicity in recurrent ovarian cancer.[74] A total of 21 patients were treated with measles virus administered intraperitoneally revealing no dose-limiting toxicity. There were no objective responses; however, five of 21 patients had a significant decrease in CA-125 levels.[74] Currently, clinical Phase I and II trials using an oncolytic reovirus are ongoing to further evaluate safety and efficacy of viral therapy in recurrent ovarian cancer.[75,102]

Vaccination: No Breakthrough

Vaccination research has been focused on p53 vaccines. Patients with recurrent ovarian cancer were immunized four times with p53-synthetic long peptide.[76] The treatment plan included an intravenous application of cyclophosphamide prior to immunization to affect Tregs. A variety of immunological parameters were determined including Treg number and activity, and the number of vaccine-induced p53-specific IFN-γ-producing T cells. There was no objective tumor response.[76] Vaccination with wild-type p53, either subcutaneously or with wild-type p53 peptide-pulsed dendritic cells intravenously, revealed no significant differences with respect to immune response parameters.[77] No objective response was observed in this small Phase II trial in recurrent ovarian cancer.

A different approach is described with adoptive T-cell immunotherapy. Adoptive T-cell immunotherapy using autologous lymphocytes requires the participation of Ag-specific CD4+ and CD8+ T cells.[78] Peripheral blood T cells of patients with recurrent ovarian cancer were stimulated with MUC peptide and reinfused intraperitoneally. Three monthly treatment cycles were performed. Among other immunologic parameters, peripheral blood lymphocytes from all patients showed elevated MUC1 cytolytic activity in vitro following therapy; however, these immunologic responses did not correlate with therapeutic efficacy.[78] There was some clinical efficacy in two out of four patients.

Vaccination strategies are crossing the border from bench to bedside. A vaccination approach and target still remain to be elucidated, and will require the cooperation of basic and clinical research.

Radiation Treatment for Selected Patients

Intraoperative radiation (IORT) combined with intraoperative chemotherapy was tested in a series of primary and recurrent ovarian cancer. Pelvic radiotherapy was intraoperatively delivered using a 12-MeV electron beam.[79] The small series showed better effects of IORT combined with intraperitoneal chemotherapy compared with IORT and intravenous chemotherapy.[79] The major complication of IORT was neuropathy in 11.1% of patients. The feasibility of IORT was confirmed in an investigation reporting on 20 patients with recurrent ovarian cancer.[80]

These and other investigations[81] indicate a boosting role of IORT in some patients receiving surgery for recurrent ovarian cancer with the chance to achieve at least beneficial effects with respect to local tumor control.

The potential of low-dose whole abdominal irradiation as a sensitizer for docetaxel chemotherapy in patients with platinum-resistant ovarian cancer represents a different approach.[82] This treatment achieved no objective response; however, the combination of low-dose whole abdominal irradiation and an adjusted dose of docetaxel weekly was feasible and tolerable and warrants further investigations.[82]

These most recent published trials indicate a minor role of radiotherapy in recurrent ovarian cancer, which might be delivered as IORT or external beam application in selected patients requiring additional measures to achieve sporadic local tumor control.

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