A single administration of intraperitoneal chemotherapy given under hyperthermic conditions at the end of cytoreductive surgery extends overall survival by almost a year in women with advanced ovarian cancer compared with surgery alone.
The results come from a multicenter, open-label phase 3 study from the Netherlands published in the January 19 issue of the New England Journal of Medicine.
“In prior studies evaluating postoperative intraperitoneal chemotherapy, side effects and complications were frequent and commonly lead to discontinuation of the treatment,” lead author Willemien van Driel, MD, PhD, the Netherlands Cancer Institute, Amsterdam, told Medscape Medical News in an email.
“However, we did not observe any differences in side effects or complications when combining surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) compared to surgery alone, so patients tolerate the procedure well and have the same number of days of admission in the hospital and no delays to restarting chemotherapy following surgery,” he added.
“Given [this], plus an improved overall survival of [almost] 1 year in favor of the group treated with HIPEC, these are the main advantages of using this approach,” Dr van Driel observed.
In an accompanying editoral, David Spriggs, MD, and Oliver Zivanovic, MD, both from the Memorial Sloan Kettering Cancer Center in New York City, say that the outcomes of the current trial are “certainly encouraging,” but they have reservations about what elements contributed to the results of the Dutch study, and they wonder how this approach might work in the routine care of patients with ovarian cancer who are being treated elsewhere.
This randomized trial is “a very important first step,” they write, but it “should not drive changes in practice yet.”
Study Details
The trial was conducted in 245 patients with stage III ovarian, fallopian tube, or peritoneal cancer whose disease was at least stable following three cycles of neoadjuvant chemotherapy. The neoadjuvant chemotherapy consisted of carboplatin (area under the curve, 5 to 6 mg/mL/min) plus paclitaxel (175 mg/m2).
Patients received three more cycles of the same chemotherapy following surgery.
For the trial, patients were randomly assigned to receive either interval cytoreductive surgery accompanied by HIPEC (n = 122) or interval cytoreductive surgery alone (n = 123).
Participants underwent either complete cytoreductive surgery resulting in no visible disease or optimal cytoreductive surgery that resulted in the presence of one or more residual tumors of less than 2.5 mm to 10 mm in diameter.
“Following the surgical procedure, the abdomen is heated through circulation of heated saline,” Dr van Driel explained.
Once the temperature reaches 41° C (105.8° F), cisplatin, at a dose of 100 mg/m2, is perfused throughout the abdomen for 90 min, after which the cavity is drained. The HIPEC treatment takes 120 min to perform.
The primary end point was recurrence-free survival.
Survival Extended by Nearly 1 Year
At a median follow-up of 4.7 years, the risk for disease recurrence or death was 34% lower in the surgery-plus-HIPEC group than in the surgery-alone group, with 81% and 89% of each group, respectively, experiencing either disease recurrence of death (P = .003).
“The median recurrence-free survival was 3.5 months longer in the group that underwent cytoreduction surgery with HIPEC than in the group that underwent surgery alone,” the investigators add. Median recurrence-free survival was 14.2 months for the patients who received additional HIPEC and 10.7 months for the surgery-alone group.
At the time of follow-up assessment, 50% of patients in the HIPEC-plus-surgery arm had died, compared to 62% of those in the surgery-alone group.
Median overall survival was 45.7 months in the surgery-plus-HIPEC group compared with 33.9 months in the surgery-alone group, a difference in overall survival of 11.8 months in favor of the HIPEC-plus-surgery approach.
In contrast, there was no difference between the two groups in the median time between the end of surgery and reinitiation of chemotherapy, at about 30 days in both groups.
Nor was there any difference in the percentage of patients who completed all three cycles of postoperative chemotherapy, at approximately 90% in both groups. Quality-of-life outcomes were also similar over time.
Adverse events were similar in the two arms: 27% patients in the surgery-plus-HIPEC group developed grade 3 or 4 adverse events, as did 25% of patients in the surgery-alone group. The most common events were abdominal pain, infection, and ileus.
On the other hand, higher rates of other adverse consequences did occur in the surgery-plus-HIPEC group among the small subgroup of patients who required a bowel resection.
Only 59 patients of the total of 245 involved in the study underwent surgery of the large bowel, with virtually identical numbers for both groups, Dr van Driel emphasized.
In this subgroup of patients, 72% of the surgery-plus-HIPEC group required either an ileostomy or a colostomy, compared with only 43% of patients in the surgery-alone arm (P = .04).
“Of these patients, 13 in the surgery-only group had a stoma, compared with 21 of those in the surgery-plus-HIPEC group,” he noted.
There is no evidence that the rate of anastomatic leakage is higher after HIPEC. “The reason for a stoma may well have been out of precaution,” Dr van Driel speculated. The possibility of having a stoma should be discussed with patients prior to surgery for the treatment of ovarian cancer, he added.
Importantly from a hospital perspective, the median duration of the operative procedure among patients in the surgery-plus-HIPEC group was 338 min, compared to 192 min for the surgery-alone group.
The total length of hospital stay was also slightly longer for the surgery-plus-HIPEC arm, at a median of 10 days, compared to a median of 8 days in the surgery-alone arm. This included 1 day in the intensive care unit, as required by the protocol, the researchers note.
Given, however, that the investigators did not observe an increase in complications with the additional use of HIPEC, patients could be cared for on a regular ward if the surgery-plus-HIPEC approach is adopted elsewhere, Dr van Driel suggested.
Questions Over Where Benefit Comes From
The results from this randomized trial “represent the most convincing information to date that a single administration of hyperthermic intraperitoneal chemotherapy (HIPEC) delivered at the end of a surgical resection of ovarian cancer may provide a meaningful advantage for a defined group of patients with cancer,” comment the editorialists, Dr Spriggs and Dr Zivanovic.
However, many questions remain about the treatment as administered in this trial, including questions as to which elements contributed to the improved overall survival that was seen.
For example, there is uncertainty as to whether the benefit seen with HIPEC in the trial simply reflected the dose of cisplatin used, or whether it was because chemotherapy was administered intraperitoneally.
There is also uncertainty as to whetehr hyperthermia is necessary to boost the effectiveness of the approach, and also whether intraperitoneal administration of chemotherapy has any advantages over routine postoperative chemotherapy.
The editorialists also point out that the results seen in this multicenter Dutch trial might not be reproducible in centers where surgeons are not as familiar with the procedure and where expertise with HIPEC might not be commensurate with that of the Dutch.
Importantly, they ask what the cost of administering additional HIPEC might be compared with standard surgery.
“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,” the editorialists argue.
“The assessment of a cost-benefit ratio warrants serious consideration,” they add.
The study was supported by the Dutch Cancer Society. Dr van Driel and most coauthors have disclosed no relevant financial relationships. Two coauthors have financial relationships with industry. Dr De Hingh has received grant support from Roche, KWF–Dutch Cancer Foundation, and Covidien, as well as nonfinancial support from Ipsen outside the submitted work. Dr Sonke has received grant support from AstraZeneca, Merck, Novartis, and Roche outside the submitted work. Dr Spriggs is employed by the New England Journal of Medicine as associate editor. Dr Zivanovic has disclosed no relevant financial relationships.
N Engl J Med. 2018;178:230-40, 293-294.
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