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Intraperitoneal chemotherapy after ovarian cancer surgery slows disease progression
CHICAGO — The addition of intraperitoneal chemotherapy to adjuvant IV chemotherapy reduced the rate of disease progression in some women with advanced ovarian cancer, according to results of a randomized phase 2 study presented at the ASCO Annual Meeting.
The combination also appeared well tolerated.
“These data, taken in the context of other intraperitoneal studies, give information to both patients and clinicians about how to incorporate this treatment in women undergoing neoadjuvant therapy,” Helen Mackay, MD, divisional head of medical oncology and hematology at Sunnybrook Odette Cancer Centre in Toronto, said during a press conference.
Epithelial ovarian cancer is the fifth most common malignancy in women. No population-based screening tool exists, and women with early-stage disease often are asymptomatic. Consequently, about two-thirds of women present with stage III or stage IV cancer, leading to high mortality rates.
Approximately 40% of women with epithelial ovarian cancer in the United States receive neoadjuvant chemotherapy, and prior randomized trials showed intraperitoneal chemotherapy reduced risk for death in select patients who underwent upfront optimal cytoreductive surgery.
Researchers with the Gynecologic Cancer Intergroup conducted the OV21/PETROC trial to assess whether women who received neoadjuvant IV chemotherapy followed by delayed debulking surgery derived benefit from the addition of intraperitoneal chemotherapy to adjuvant IV chemotherapy.
Mackay and colleagues initially enrolled 275 women (median age, 62 years) with stage IIIB to stage IV epithelial ovarian cancer. Most women (82%) had stage IIIC disease, defined as cancer spread into the intraperitoneal cavity.
All study participants received three to four courses of neoadjuvant platinum-based chemotherapy and then underwent surgery, with resection to less than 1 cm.
After surgery, patients received one of three adjuvant regimens.
Patients in one group received a standard regimen of 135 mg/m2 IV paclitaxel plus IV carboplatin (area under the curve, 5/6) on day 1, plus 60 mg/m2 IV paclitaxel on day 8.
Patients in a second group received 135 mg/m2 IV paclitaxel plus 75 mg/m2 intraperitoneal cisplatin and 60 mg/m2 intraperitoneal paclitaxel on day 8.
Patients in the third group received 135 mg/m2 IV paclitaxel plus intraperitoneal carboplatin (area under the curve, 5/6) on day 1, followed by 60 mg/m2 intraperitoneal paclitaxel on day 8.
“One of the contributing causes of limited uptake of intraperitoneal therapy is the tolerability of intraperitoneal cisplatin,” Mackay said.
At the end of the first stage of this trial, an independent data and safety monitoring committee advised researchers to drop the regimen that included intraperitoneal cisplatin. This decision was based on both efficacy and tolerability, Mackay said.
Researchers subsequently focused their analysis on IV chemotherapy alone vs. the experimental regimen that included intraperitoneal carboplatin.
Mackay presented data from 200 patients randomly assigned 1:1 to each arm. Both regimens were administered for three 21-day cycles, and baseline characteristics were similar between groups.
Progression rate at 9 months served as the primary endpoint. Secondary endpoints included PFS and OS. Researchers stratified results by cooperative group, residual disease (macroscopic vs. microscopic), reason for neoadjuvant chemotherapy (nonresectable disease vs. other), and timing of intraperitoneal catheter insertion (intraoperative vs. postoperative).
A majority of patients in both groups completed all three treatment cycles (IV chemotherapy alone, 93.7%; IV plus intraperitoneal chemotherapy, 84.8%).
In the intention-to-treat population, a higher percentage of patients assigned IV chemotherapy alone experienced disease progression at 9 months (42.2% vs. 23.3%; stratified P = .06; unstratified P = .03).
Median PFS was similar between those assigned IV chemotherapy alone and those who received intraperitoneal carboplatin (11.3 months vs. 12.5 months; HR = 0.82; 95% CI, 0.57-1.17).
Researchers reported longer median OS among patients who received intraperitoneal carboplatin (59.3 months vs. 38.1 months; HR = 0.8; 95% CI, 0.47-1.35), but the difference did not reach statistical significance.
“Although this [trial] was not statistically powered to evaluate survival, our results offer information on how to incorporate intraperitoneal chemotherapy when women receive neoadjuvant chemotherapy followed by debulking surgery,” Mackay said. “The findings also offer supportive and additional information to the previous published adjuvant randomized trials that showed an improvement in OS when intraperitoneal chemotherapy was given following initial optimal debulking surgery.”
Fewer patients assigned intraperitoneal carboplatin experienced severe side effects (16% vs. 23%), but the difference was not statistically significant.
Researchers reported no significant between-group differences in quality of life.
“In order to better define which patients truly benefit from this approach, correlative studies on tissue samples collected in the study are ongoing,” Mackay said. “If we can identify the long-term survivors, we hope this will help us better predict who truly benefits from this approach.”– by Mark Leiser
Reference :
Mackay H, et al. Abstract LBA5503. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Mackay reports travel, accommodations and expenses from AstraZeneca. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Investigators have long debated the utility of IP chemotherapy, and despite three randomized trials demonstrating superiority of the IP arm, widespread adoption has lagged. The noteworthy aspect of this study is the setting: postneoadjuvant chemotherapy and interval debulking, as these patients had three to four courses of IV chemotherapy prior to debulking surgery. The only IP component of this trial was three courses of IP or IV chemotherapy after surgery, and it would be remarkable to see a drastic impact on outcomes with this as the only variable.
Interestingly, the arm that was dropped in the first stage of the study contained cisplatin, the agent used in the previous studies demonstrating the utility of IP chemotherapy. This in itself is a shift from the most common approach. Also, the IV control arm had paclitaxel on days 1 and 8, a departure from the standard IV chemotherapy regimens administered on day 1 only — this is almost a dose-dense regimen, and therefore makes it an unusual control.
This trial did not proceed as originally planned. Although it was designed as a phase 3 trial, it was revised to a phase 2 trial due to low accrual and funding. Additionally, the primary endpoint was initially PFS, but was changed midway through to an unusual alternate primary endpoint: the percentage of patients who were progression free at 9 months (PD9). Ultimately, the primary endpoint did not reach statistical significance in an intention-to-treat analysis, but only reached statistical significance in patients who received the intended treatment. This leads the reader to question why these patients dropped off prior to receiving treatment.
Also, although it would be useful to see if patients with BRCA mutations derived any benefit from an IP approach — as has been observed in other trials — this information is not provided.
Importantly, PFS and OS are not significantly different between arms, and this is the take-home message of the trial. Although the percentage of patients who were progression free at 9 months is possibly improved, this may be a statistical aberration, since intention-to-treat PD9, PFS and OS were no different between arms.
Therefore, despite the researchers’ conclusions, this appears to be a negative trial. IP chemotherapy does not appear to be clinically beneficial in this setting.
Perspective
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This is yet another example of international collaboration looking at intraperitoneal treatment but in a very novel way. This looked at women with advanced ovarian cancer, all of whom received primary chemotherapy before surgery. We have not known what the best strategy is for that group of women. Although this is not a phase 3 study, I think the data are very provocative and suggest there is a role for intraperitoneal therapy for such patients.
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This is one of the last two big randomized trials that will finally help define the role for intraperitoneal (IP) chemotherapy in epithelial ovarian cancer. We were all waiting for this Canadian study, and we are still waiting for the Japanese study. However, that study is not yet closed for accrual, so we will have to wait a couple of years for those data.
Over the last 20 years, there were three major studies that all showed an advantage for IP chemotherapy, but with very poor uptake in clinical practice. Then, GOG-252, the fourth — and what we thought would be the final study — was presented in March, which was essentially a negative study, was considered a death knell to IP therapy. Of note, this was a phase 2 trial and they are not going to complete a phase 3 clinical trial. There had been a lot of discussion about why it was negative, and the evaluation of IP therapy has persisted because it is such a rational approach.
Then a study like this current one comes out as a positive study, again suggesting a meaningful impact on survival, and these data reverse the curse.
The positive interpretation is that, if one were to look at the specific time point of 9 months out from when patients went on trial, after closing the IP cisplatin arm for toxicity and lack of better efficacy, there was substantially better (36% improvement) PFS with IP carboplatin. Now, when looking at survival, the rate was 55% better with IP carboplatin and it was nearly twice as good as IV therapy.
This will always be remembered as study too small, to have impact but it absolutely keeps the hope alive for advocates of IP therapy. If you look at the international recommendations in the United States, people tend to say that patients should be informed about this as a potentially advantageous therapy. Most people anticipate that at some point we will move on from IP therapy in favor of targeted therapies. These data are not definitive enough to move the field forward, but they do keep the therapy alive as an option for carefully selected patients.
Reference:
Walker JL, et al. A phase 3 clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube and primary peritoneal carcinoma NCI-supplied agent(s): bevacizumab. Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA.