In the JournalsPerspective

Hyperthermic intraperitoneal chemotherapy prolongs ovarian cancer survival

The addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery prolonged RFS and OS without increasing toxicity among patients with stage III epithelial ovarian cancer, according to randomized open-label phase 3 study results published in The New England Journal of Medicine.

Treatment for advanced ovarian cancer involves reducing tumor burden through surgery and six cycles of IV chemotherapy, or interval cytoreductive surgery after three cycles of chemotherapy.

The intraperitoneal delivery of chemotherapy — or injection directly into the peritoneal cavity — enhances drug delivery and improves outcomes by more efficiently eliminating residual microscopic peritoneal disease than IV delivery.

Hyperthermic intraperitoneal chemotherapy is delivered during surgery with elevated body temperature.

“Hyperthermia increases the penetration of chemotherapy at the peritoneal surface and increases the sensitivity of the cancer to chemotherapy by impairing DNA repair,” Willemien J. van Driel, MD, PhD, of the department of gynecology at Netherlands Cancer Institute, and colleagues wrote. “Hyperthermia also induces apoptosis and activates heat-shock proteins that serve as receptors for natural killer cells, inhibits angiogenesis and has a direct cytotoxic effect by promoting the denaturation of proteins.”

van Driel and colleagues evaluated whether the addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery would improve outcomes among 245 patients receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.

All patients had at least stable disease after three cycles of carboplatin and paclitaxel. At the time of surgery — for cases in which surgery would result in complete or optimal cytoreduction — researchers randomly assigned patients to undergo interval cytoreductive surgery with (n = 122) or without (n = 123) hyperthermic intraperitoneal chemotherapy with 100 mg/m2 cisplatin. Patients underwent three additional cycles of carboplatin and paclitaxel postoperatively.

RFS served as the primary endpoint. Secondary endpoints included OS, safety and health-related quality of life.

Median follow-up was 4.7 years.

In the intent-to-treat analysis, disease recurrence or death occurred among 99 patients (81%) who underwent hyperthermic intraperitoneal chemotherapy and 110 patients (89%) who did not (HR = 0.66; 95% CI, 0.5-0.87).

Patients who underwent hyperthermic intraperitoneal chemotherapy also showed longer median RFS (14.2 months vs. 10.7 months) and OS (45.7 months vs. 33.9 months).

Sixty-one patients (50%) in the hyperthermic intraperitoneal chemotherapy group died, compared with 76 patients (62%) in the surgery-alone group (HR = 0.67; 95% CI, 0.48-0.94).

Grade 3 or grade 4 adverse events — the most common of which included abdominal pain, infection and ileus — occurred among 25% of the surgery group and 27% of the hyperthermic intraperitoneal chemotherapy group, which was not a significant difference.

Among patients who underwent bowel resection — which included 30 in the surgery group and 29 in the hyperthermic intraperitoneal chemotherapy group — significantly more of those who received hyperthermic intraperitoneal chemotherapy underwent colostomy or ileostomy (72% vs. 43%; P = .04).

“Because there is no evidence that hyperthermic intraperitoneal chemotherapy for ovarian cancer is associated with a higher rate of anastomotic leakage than the rate without hyperthermic intraperitoneal chemotherapy, this difference in the rate of colostomy or ileostomy could reflect the surgeons’ preference,” the researchers wrote.

Researchers observed no differences between the groups in health-related quality of life.

“Uptake of postoperative IV chemotherapy plus intraperitoneal chemotherapy in clinical practice is limited by increased side effects, including catheter-related complications, and the inconvenience of administering therapy intraperitoneally,” the researchers wrote. “In the current trial, we evaluated hyperthermic intraperitoneal chemotherapy as a single administration of intraperitoneal chemotherapy during surgery to overcome the side effects and inconvenience of serial adjuvant intraperitoneal chemotherapy and to improve the distribution of heated chemotherapy in the abdominal cavity.”

A single administration of hyperthermic intraperitoneal chemotherapy has different pharmacokinetics and pharmacodynamics than repeated intraperitoneal chemotherapy, which could explain the difference is side effects, the researchers added.

“Additional trials are needed to determine the ways in which hyperthermic intraperitoneal chemotherapy differs from postoperative IV or intraperitoneal chemotherapy and whether hyperthermic intraperitoneal chemotherapy is also effective after primary cytoreductive surgery,” they wrote.

Although these data show promise, questions remain about how to apply this technique in routine care, David R. Spriggs, MD, and Oliver Zivanovic, MD, both of Memorial Sloan Kettering Cancer Institute, wrote in a related editorial.

“The extra time needed in the operating room, the longer duration of hospitalization, and the increased use of diverting colostomies or ileostomies will all increase the overall cost of treatment,” Spriggs and Zivanovic wrote. “The assessment of a cost-benefit ratio warrants serious consideration.”

Also, it’s unclear whether these findings can be reproduced at centers with less experience administering hyperthermic intraperitoneal chemotherapy and who should be considered for this approach, Spriggs and Zivanovic wrote.

“The authors enrolled only patients who underwent interval cytoreductive surgery after receiving three cycles of neoadjuvant chemotherapy for the primary treatment of ovarian cancer,” they wrote.

Although hyperthermic intraperitoneal chemotherapy improved outcomes over surgery alone, neither group demonstrated the approximately 2-year median PFS reported for patients who underwent optimal cytoreduction at initial surgery, Spriggs and Zivanovic noted.

“Well-designed clinical trials may eventually identify other subgroups of patients with ovarian cancer who are undergoing therapeutic interventions that differ from those of the population eligible for this trial and might benefit from intraoperative administration of hyperthermic intraperitoneal chemotherapy, but the results of the current trial cannot yet be extrapolated to any other conditions or clinical settings,” they added. – by Alexandra Todak

Disclosures: van Driel reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures. Spriggs reports employment as associate editor of The New England Journal of Medicine. Zivanovic reports no relevant financial disclosures.

The addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery prolonged RFS and OS without increasing toxicity among patients with stage III epithelial ovarian cancer, according to randomized open-label phase 3 study results published in The New England Journal of Medicine.

Treatment for advanced ovarian cancer involves reducing tumor burden through surgery and six cycles of IV chemotherapy, or interval cytoreductive surgery after three cycles of chemotherapy.

The intraperitoneal delivery of chemotherapy — or injection directly into the peritoneal cavity — enhances drug delivery and improves outcomes by more efficiently eliminating residual microscopic peritoneal disease than IV delivery.

Hyperthermic intraperitoneal chemotherapy is delivered during surgery with elevated body temperature.

“Hyperthermia increases the penetration of chemotherapy at the peritoneal surface and increases the sensitivity of the cancer to chemotherapy by impairing DNA repair,” Willemien J. van Driel, MD, PhD, of the department of gynecology at Netherlands Cancer Institute, and colleagues wrote. “Hyperthermia also induces apoptosis and activates heat-shock proteins that serve as receptors for natural killer cells, inhibits angiogenesis and has a direct cytotoxic effect by promoting the denaturation of proteins.”

van Driel and colleagues evaluated whether the addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery would improve outcomes among 245 patients receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.

All patients had at least stable disease after three cycles of carboplatin and paclitaxel. At the time of surgery — for cases in which surgery would result in complete or optimal cytoreduction — researchers randomly assigned patients to undergo interval cytoreductive surgery with (n = 122) or without (n = 123) hyperthermic intraperitoneal chemotherapy with 100 mg/m2 cisplatin. Patients underwent three additional cycles of carboplatin and paclitaxel postoperatively.

RFS served as the primary endpoint. Secondary endpoints included OS, safety and health-related quality of life.

Median follow-up was 4.7 years.

In the intent-to-treat analysis, disease recurrence or death occurred among 99 patients (81%) who underwent hyperthermic intraperitoneal chemotherapy and 110 patients (89%) who did not (HR = 0.66; 95% CI, 0.5-0.87).

Patients who underwent hyperthermic intraperitoneal chemotherapy also showed longer median RFS (14.2 months vs. 10.7 months) and OS (45.7 months vs. 33.9 months).

Sixty-one patients (50%) in the hyperthermic intraperitoneal chemotherapy group died, compared with 76 patients (62%) in the surgery-alone group (HR = 0.67; 95% CI, 0.48-0.94).

Grade 3 or grade 4 adverse events — the most common of which included abdominal pain, infection and ileus — occurred among 25% of the surgery group and 27% of the hyperthermic intraperitoneal chemotherapy group, which was not a significant difference.

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Among patients who underwent bowel resection — which included 30 in the surgery group and 29 in the hyperthermic intraperitoneal chemotherapy group — significantly more of those who received hyperthermic intraperitoneal chemotherapy underwent colostomy or ileostomy (72% vs. 43%; P = .04).

“Because there is no evidence that hyperthermic intraperitoneal chemotherapy for ovarian cancer is associated with a higher rate of anastomotic leakage than the rate without hyperthermic intraperitoneal chemotherapy, this difference in the rate of colostomy or ileostomy could reflect the surgeons’ preference,” the researchers wrote.

Researchers observed no differences between the groups in health-related quality of life.

“Uptake of postoperative IV chemotherapy plus intraperitoneal chemotherapy in clinical practice is limited by increased side effects, including catheter-related complications, and the inconvenience of administering therapy intraperitoneally,” the researchers wrote. “In the current trial, we evaluated hyperthermic intraperitoneal chemotherapy as a single administration of intraperitoneal chemotherapy during surgery to overcome the side effects and inconvenience of serial adjuvant intraperitoneal chemotherapy and to improve the distribution of heated chemotherapy in the abdominal cavity.”

A single administration of hyperthermic intraperitoneal chemotherapy has different pharmacokinetics and pharmacodynamics than repeated intraperitoneal chemotherapy, which could explain the difference is side effects, the researchers added.

“Additional trials are needed to determine the ways in which hyperthermic intraperitoneal chemotherapy differs from postoperative IV or intraperitoneal chemotherapy and whether hyperthermic intraperitoneal chemotherapy is also effective after primary cytoreductive surgery,” they wrote.

Although these data show promise, questions remain about how to apply this technique in routine care, David R. Spriggs, MD, and Oliver Zivanovic, MD, both of Memorial Sloan Kettering Cancer Institute, wrote in a related editorial.

“The extra time needed in the operating room, the longer duration of hospitalization, and the increased use of diverting colostomies or ileostomies will all increase the overall cost of treatment,” Spriggs and Zivanovic wrote. “The assessment of a cost-benefit ratio warrants serious consideration.”

Also, it’s unclear whether these findings can be reproduced at centers with less experience administering hyperthermic intraperitoneal chemotherapy and who should be considered for this approach, Spriggs and Zivanovic wrote.

“The authors enrolled only patients who underwent interval cytoreductive surgery after receiving three cycles of neoadjuvant chemotherapy for the primary treatment of ovarian cancer,” they wrote.

Although hyperthermic intraperitoneal chemotherapy improved outcomes over surgery alone, neither group demonstrated the approximately 2-year median PFS reported for patients who underwent optimal cytoreduction at initial surgery, Spriggs and Zivanovic noted.

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“Well-designed clinical trials may eventually identify other subgroups of patients with ovarian cancer who are undergoing therapeutic interventions that differ from those of the population eligible for this trial and might benefit from intraoperative administration of hyperthermic intraperitoneal chemotherapy, but the results of the current trial cannot yet be extrapolated to any other conditions or clinical settings,” they added. – by Alexandra Todak

Disclosures: van Driel reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures. Spriggs reports employment as associate editor of The New England Journal of Medicine. Zivanovic reports no relevant financial disclosures.

    Perspective

    Stephen C. Rubin

    Stephen C. Rubin

    The role of intraperitoneal chemotherapy in the management of advanced ovarian cancer has been intensively studied for several decades. Delivering chemotherapy directly into the abdominal cavity is attractive in this disease because it allows higher concentrations of drug to be delivered directly to the area of the tumor. Prior large-scale randomized trials of repeated cycles of intraperitoneal chemotherapy delivered via an implanted abdominal catheter have shown improved outcomes compared with IV chemotherapy, but catheter-related problems, increased toxicity and logistical issues have limited the adoption of intraperitoneal chemotherapy. In the meantime, advances in IV chemotherapy for ovarian cancer — including neoadjuvant and dose-dense regimens — as well as the development of new targeted agents, have further relegated intraperitoneal chemotherapy to the sidelines.

    The study by van Driel and colleagues has incorporated IP chemotherapy into the treatment of advanced ovarian cancer in a way that seems to eliminate some of the problems traditionally associated with it. In a multicenter randomized trial, women with advanced ovarian cancer who had responded to three cycles of neoadjuvant carboplatin and paclitaxel received interval cytoreductive surgery. If clinicians could cytoreduce the patient’s cancer to optimal or no residual tumor, they underwent random assignment to receive or not receive intraoperative hyperthermic intraperitoneal chemotherapy with cisplatin.

    Hyperthermic intraperitoneal chemotherapy is delivered as a single treatment in the operating room during cytoreductive surgery, and eliminates the catheter-related problems seen with traditional intraperitoneal chemotherapy delivered in multiple postoperative cycles. Heating the chemotherapy to 40° C also increases the penetration of the drug, and increases the sensitivity of the cancer cells to chemotherapy by inhibiting DNA repair.

    The results of this well-done study are impressive, showing improvements in RFS of 3.5 months and OS of almost 12 months, with no increase in serious adverse events. Although hyperthermic intraperitoneal chemotherapy increases expense by adding about 2 hours to the surgical time, the results of this study are likely to stimulate increased interest in this technique.


    Stephen C. Rubin, MD
    Fox Chase Cancer Center

    Disclosures: Rubin reports no relevant financial disclosures.