Moving Away From IP Chemotherapy in Advanced Ovarian Cancer

Bradley J. Monk, MD

The treatment of women with advanced-stage epithelial ovarian cancer (EOC) is aggressive surgical cytoreduction and platinum-based combination chemotherapy. The timing and the extent of surgery have direct implications on the selection of subsequent treatment of patients with EOC. Frontline chemotherapeutic regimens have evolved through a series of large multi-institutional randomized clinical trials that led to a combination of a platinum with a taxane. Subsequent clinical trials have focused on maximizing the benefit of this combination through different dosing schedules, routes of administration, durations of treatment, and combinations with other agents, including biologics and maintenance therapy.

Surgical cytoreduction is a critical component of the treatment of patients with newly diagnosed advanced ovarian cancer.¹ The benefit of bulk—reducing surgery was reported by the Gynecologic Oncology Group (GOG) in 1992. Results from the GOG 52 study showed a direct correlation between the extent of surgical cytoreduction (amount of postsurgical tumor residuum) and progression-free survival (PFS) and overall survival (OS). This f inding has been observed in multiple other studies and several meta-analyses. Optimal cytoreduction is defined as no gross residual disease (R0). This is based on the strong differential impact on PFS and OS within the previously defined optimal (<1 cm residual) cohort for those with small-volume macroscopic residual disease and those with R0. If R0 is not achievable, the goal of primary cytoreduction becomes safely achieving as little residual disease as possible.

An alternative strategy for patients who are not likely to achieve optimal cytoreduction or who are not surgical candidates is neoadjuvant chemotherapy (NACT). The European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada reported their combined experience with NACT.² Results from the EORTC 55971 trial demonstrated that patients who are treated with 3 cycles of platinum-based NACT followed by surgical cytoreduction and continued chemotherapy have outcomes equivalent to those of patients who undergo primary surgical cytoreduction followed by chemotherapy (PFS, 12 vs 12 months; OS, 29 vs 30 months).

Cisplatin became the cornerstone of chemotherapy for EOC in 1986 when the results of GOG 47 were reported. Patients treated with cyclophosphamide, doxorubicin, and cisplatin had longer PFS and OS than those treated with cyclophosphamide and doxorubicin (PFS, 13.1 vs 7.7 months; OS, 19.3 vs 16.4 months). GOG 111 compared cisplatin and cyclophosphamide with cisplatin and paclitaxel. Paclitaxel provided another improvement in PFS (18.0 vs 13.3 months) and OS (36.9 vs 24.8 months), establishing the current standard of combination chemotherapy with a platinum and a taxane. Subsequent trials demonstrated the therapeutic equivalency of cisplatin and carboplatin (GOG 158), with a PFS of 19.4 versus 20.7 months and an OS of 48.7 versus 57.4 months (P >.05), respectively; a European trial (AGO-OVAR3) confirmed these results. Carboplatin had a better toxicity profile than did cisplatin, with fewer gastrointestinal, renal, metabolic, and leukopenic events but higher frequency of thrombocytopenia. The quality of life (QoL) for patients receiving carboplatin was superior to QoL for those receiving cisplatin.³

The role of intraperitoneal (IP) chemotherapy in EOC has been a controversial subject for almost 3 decades. Three large intergroup phase III trials (GOG 104, 114, 172) have demonstrated a survival benefit with IP versus intravenous (IV) therapy in advanced, low-volume EOC.⁴ Despite the positive clinical trial results and a subsequent National Cancer Institute clinical update in 2006 stating that IP delivers superior OS compared with IV treatment alone, IP treatment has not been widely accepted as the standard of care in the United States and is used infrequently in Europe. The hesitancy of clinicians to use IP therapy is likely attributed to higher toxicity, inconvenience, catheter complications, and clinical trial design issues. More recently, a fourth randomized phase III trial, GOG 252, failed to show a survival advantage associated with IP cisplatin and IP carboplatin over dosedense IV paclitaxel and carboplatin.⁵

The GOG⁶ and the EORTC⁷ added bevacizumab (Avastin) to paclitaxel and carboplatin. GOG 218 compared conventional paclitaxel and carboplatin with paclitaxel and carboplatin with concomitant bevacizumab (15 mg/kg) with or without maintenance bevacizumab. There was no advantage to adding bevacizumab during chemotherapy only. The arm including maintenance bevacizumab demonstrated a significant improvement in PFS compared with placebo (12.0 vs 18.2 months; HR, 0.62; 95% CI, 0.520.75; P <.0001) and led to the FDA approval of this triplet on June 13, 2018.

The role of bevacizumab with a dosedense paclitaxel⁸ and carboplatin IV regimen has recently been investigated. GOG 262⁹ suggested no benefit from using dose-dense paclitaxel over conventional paclitaxel every 3 weeks in combination with carboplatin and bevacizumab.

Finally, the newest agents approved by the FDA to treat ovarian cancer are inhibitors of the PARP enzyme. These agents are now being moved into the frontline in a molecularly defined population (BRCA mutation positive).¹⁰ SOLO1 was an international, randomized, double-blind, phase III trial to evaluate the efficacy of olaparib (Lynparza) as maintenance therapy in patients with newly diagnosed advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had a complete or partial clinical response after platinum-based chemotherapy.¹¹ The patients were randomly assigned 2:1 to receive olaparib tablets (300 mg twice daily) or placebo.

A total of 388 patients had a centrally confirmed germline BRCA1/2 mutation, and 2 patients had a centrally confirmed somatic BRCA1/2 mutation. After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan-Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs 27%; HR, 0.30;95% CI, 0.23-0.41; P <.001) (Figure). Adverse events were consistent with the known toxic effects of olaparib.

Figure. SOLO1 PFS By Investigator Assessment

In summary, patients with newly diagnosed advanced EOC should undergo surgical cytoreduction, ideally prior to the initiation of IV carboplatin and paclitaxel. When patients’ medical status or when the extent of disease precludes optimal debulking, interval surgery after 3 cycles of neoadjuvant chemotherapy is acceptable. Adding bevacizumab to the second cycle of chemotherapy and continuing singleagent bevacizumab in maintenance is now FDA approved in unselected patients. Most recently, unprecedented data support the use of maintenance olaparib following response to IV chemotherapy when a BRCA1/2 mutation (somatic or germline) is identified. This mandates early universal BRCA gene testing. Finally, the pendulum has swung away from IP chemotherapy.

References

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