Adding hyperthermic intraperitoneal chemotherapy (HIPEC) to primary cytoreductive surgery (PCS) is associated with better survival outcomes in patients with stage III epithelial ovarian cancer, according to results from a retrospective study published in JAMA Network Open.
Of all gynecological malignant neoplasms, ovarian cancer is the leading cause of death, and standard treatment for surgical candidates is currently comprised of primary PCS with platinum/paclitaxel-based chemotherapy. But some studies have shown that intraperitoneal chemotherapy may have advantages over intravenous treatments.
“Theoretically, the permeability of anticancer drugs is improved by intraperitoneal delivery combined with hyperthermia, which increases the accumulation of the drug in the cancer cells. Moreover, as a consequence of the loss of cellular DNA repair capacity, the cytotoxic effect appears to be amplified, leading to higher sensitivity to chemotherapy. Many studies have suggested that cytoreductive surgery followed by HIPEC could prolong the overall survival (OS) of patients with advanced ovarian cancer,” wrote Ziying Lei, MD, of the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China, and fellow authors from the Chinese Peritoneal Oncology Study Group.
In this multicenter study, they included 584 patients (mean age: 55.0 years) with stage III primary epithelial ovarian cancer who were treated with either PCS only (n=159) or with PCS combined with HIPEC (n=425), whom they followed for a median of 42.2 months. In all, 421 patients had a complete surgery—defined as residual lesions ≤1.0 cm in diameter—and 163 an incomplete surgery. The HIPEC regimen was comprised of cisplatin at a dose of 50 mg/m2, given on days 1,3, and 5.
After adjusting for treatment weighting, researchers found that patients who underwent PCS with HIPEC had a longer median survival time compared with those undergoing PCS alone (49.8 versus 34.0 months, respectively; 95% CI: 45.2-60.2 and 28.9-41.5). Combination treatment with PCS and HIPEC also brought about higher 3-year overall survival rates compared with PCS alone (60.3% versus 49.5%; 95% CI: 55.3%-65.0% and 41.0%-57.4%; weight HR: 0.64; 95% CI: 0.50-0.82; P ˂ 0.001).
When patients were stratified further based on complete and incomplete surgeries, those treated with PCS and HIPEC had significant better survival compared with those treated with PCS alone, except for 3-year overall survival in the incomplete surgeries group.
Among patients who had complete surgical procedures, median survival was 53.9 months in those who received PCS with HIPEC, compared with 42.3 months (95% CI: 31.1-59.3; P=0.02). Three-year survival rates were, respectively, 65.9% (95% CI: 60.1%-71.2%) and 55.4% (95% CI: 44.7%-64.8%; P=0.04).
In patients who underwent incomplete surgical procedures, median survival was 29.2 months (95% CI: 22.3-45.4) in those who received PCS/HIPEC, compared with 19.9 (11.6-39.1; P=0.03) months in those treated with PCS alone. Three-year overall survival rates were 44.3% (95% CI: 34.6%-53.4%) and 36.7% (95% CI: 23.4%-50.1%; P=0.19), respectively.
In both groups, the most common grade 3/4 adverse events included electrolyte disturbances, anemia, leukopenia, and neutropenia. Patients treated with PCS and HIPEC had more frequent Grade 3/4 electrolyte disturbances compared with those treated with PCS alone (28.1% vs 11.5%, P ˂ 0.001). Researchers found no between-group differences in toxic, nonhematologic effects. Patients treated with PCS alone had a shorter mean hospital stay and time to first flatus (P ˂ 0.001 and P=0.04, respectively).
Limitations of the study include its retrospective design, lack of homogeneity, higher rate of incomplete surgeries, and lack of statistical superiority of adjuvant HIPEC in 3-year overall survival patients who had incomplete surgery.
To address some of these limitations, Lei and colleagues have begun a new, large, prospective, multicenter, randomized, controlled, phase III trial to compare PCS followed by HIPEC with PCS alone in patients with stage III epithelial ovarian cancer.
“Advanced epithelial ovarian cancer (EOC) has a well-characterized pattern of spread; the cancer cells tend to stay within the peritoneal cavity, attaching to organ surfaces and only invading superficial layers. This pattern makes intraperitoneal chemotherapy an attractive alternative to conventional systemic chemotherapy in select patients with EOC, although it can be poorly tolerated,” wrote Raanan Alter, MD, of The University of Chicago, and fellow authors in an accompanying editorial.
They noted that this study was well designed and laid out strict inclusion criteria.
“[T]he study by Lei et al adds to recent evidence indicating that the addition of intraperitoneal chemotherapy with HIPEC, whether upfront or at interval debulking, might improve overall survival. It would appear to us, after reviewing the available published evidence supporting the use of HIPEC, that one should discuss the use of HIPEC preoperatively with patients with stage III, low-volume disease who are thought to likely experience optimal (R0) cytoreduction,” wrote Alter and colleagues.
“From the data presented by Lei et al, one could argue that even patients with large volumes of residual disease could benefit from HIPEC with PCS, but the data are less convincing and need further investigation. We expect that remaining questions will be conclusively answered by a phase III randomized trial that just opened this year,” they concluded.
Addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to primary cytoreductive surgery (PCS) led to an almost 16-month increase in survival compared with treatment with PCS alone.
Combination treatment with PCS/HIPEC also increased 3-year overall survival by nearly 11 percentage points.
E.C. Meszaros, Contributing Writer, BreakingMED™
This study was supported by the Guangzhou Key Medical Discipline Construction Project Fund, the Guangzhou High-Level Clinical Key Specialty Construction, the Translational Medicine Innovation Platform Construction Project of Guangdong Province (Prevention and Treatment of Peritoneal Metastasis), and the National Natural Science Foundation of China.
Lei and Alter reported no conflicts of interest.
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