The hesitancy of clinicians to use intraperitoneal therapy is likely attributed to higher toxicity, inconvenience, catheter complications, flaws in clinical trial design, and uncertain long-term benefits.— Bradley J. Monk, MD, FACS, FACOG
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Based on pharmacokinetic and preclinical data, there appears to be a biologic advantage to the use of intraperitoneal chemotherapy in treating some malignancies confined to the abdomen. Since most ovarian, fallopian tube, and peritoneal cancers present and recur in the peritoneal cavity, this setting is potentially an ideal scenario for intraperitoneal therapy.
Compared to intravenous treatment, intraperitoneal administration of cisplatin can achieve an approximate 20-fold greater concentration in the tumor. This pharmacokinetic advantage of intraperitoneal therapy is particularly evident in smaller lesions (< 3–5 mm) and avascular tumors, since penetration is limited in bulky cancers, and intravenous therapy is probably adequate in well-perfused tumors.
Key Trials
Three large intergroup randomized phase III trials (Gynecologic Oncology Group [GOG] protocols 104, 114, and 172) have demonstrated that intraperitoneal therapy resulted in a 20% to 30% reduction in death over intravenous therapy in advanced, low-volume epithelial ovarian cancer.1-3 The results of GOG 172 prompted the National Cancer Institute (NCI) to broadcast a clinical alert in January 2006 stating that intraperitoneal chemotherapy improves survival in patients compared to intravenous treatment alone. A subsequent meta-analysis with over 10 years of follow-up suggested a sustained benefit of intraperitoneal chemotherapy over intravenous treatment.4
Unfortunately, the experimental arm in GOG 172 included not only intraperitoneal therapy, but also a weekly schedule and higher doses compared to the every-3-week intravenous cisplatin-containing (rather than carboplatin-based) control arm. These confounding factors are often overlooked, and the improvement in overall survival in the experimental intraperitoneal arm is often attributed entirely to the intraperitoneal route of administration.
Despite the positive clinical trial results and the subsequent NCI alert, intraperitoneal treatment has not been widely accepted as the standard of care in the United States and is infrequently used in Europe.5 The hesitancy of clinicians to use intraperitoneal therapy is likely attributed to higher toxicity, inconvenience, catheter complications, flaws in clinical trial design, and uncertain long-term benefits.
More recently, a fourth randomized phase III trial of 1,560 subjects (GOG 252) has reported negative results.6 This was the largest phase III study and the only clinical trial that isolated the impact of intraperitoneal chemotherapy administration. Many believed that this higher-quality and resoundingly negative study superseded the prior positive studies and ended this 3-decade debate.
New Data
In January 2018, van Driel et al published a provocative study of hyperthermic intraperitoneal chemotherapy (aka HIPEC) in The New England Journal of Medicine.7 The study was conducted in 245 patients with advanced epithelial ovarian cancer who had at least stable disease after three cycles of neoadjuvant carboplatin and paclitaxel. It is reviewed in this issue of The ASCO Post.
Patients were randomized at the time of surgery to undergo interval cytoreductive surgery either with or without the administration of hyperthermic intraperitoneal chemotherapy using cisplatin (100 mg/m2). This cisplatin dose was the same as in GOG 172. Randomization was performed only if surgery would result in no visible disease (complete cytoreduction) or in cases where it was deemed feasible that surgery would result in 1 or more residual tumors measuring 10 mm or less in diameter (optimal cytoreduction). The enrolled patients with small-volume disease were similar to the populations in the three prior GOG studies.
Study Limitations
Although theprimary endpoint was recurrence-free survival, van Driel et al primarily focused on the immature (but provocative) overall survival data. Additionally, their protocol-based statistical assumption of 18 months for the median recurrence-free survival in the control arm was not anywhere near the reported recurrence-free survival in the study (10.7 months), suggesting underperformance in the control arm could explain the statistical difference between arms. Furthermore, the improvement in recurrence-free survival (from 10.7 to 14.2 months) is virtually identical to results seen with the much simpler and more broadly adopted approach of adding bevacizumab (Avastin) to the front-line treatment of epithelial ovarian cancer.
GOG 218 was a double-blind, placebo-controlled, phase III trial that randomly assigned newly diagnosed women with stage III or IV epithelial ovarian cancer who had undergone debulking surgery to intravenous carboplatin and paclitaxel with placebo added in cycles 2 to 22 (control group), with bevacizumab (15 mg/kg) added in cycles 2 to 6 and placebo, in cycles 7 to 22, or with bevacizumab added in cycles 2 to 22 (“bevacizumab-throughout” group). Each cycle was 3 weeks in duration.
The median progression-free survival was 10.3 months in the control group and 14.1 in the bevacizumab-throughout group. Relative to the control treatment, the hazard ratio for disease progression or death was 0.717 (95% confidence interval = 0.625–0.824, P < .001). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2% vs 2.6%, respectively.8 This toxicity is particularly notable, as those treated with intraperitoneal chemotherapy in the current study had a higher rate of colostomy and ileostomy (11% vs 17%).7
Further Considerations
When considering new therapies such as hyperthermic intraperitoneal chemotherapy, the entire data set and clinical experience must be considered. In contrast to the van Driel et al study, many studies of this treatment modality have not met their primary endpoints, and others are still ongoing.9
Finally—and perhaps the most difficult issue—the current report failed to isolate the effect of hyperthermia. How important is the heated chemotherapy, or would perioperative standard room temperature intraperitoneal treatment be sufficient? Specifically, the positive results of the phase II OV21/PETROC study (a randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal vs intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer) make this point particularly relevant.10 Other flaws in all hyperthermic intraperitoneal chemotherapy studies include the lack of blinding and the imbalance in the number of chemotherapy cycles—in this case, six vs seven.
Conclusions
I WOULD LIKE to congratulate the authors for reporting this pioneering phase III trial. However, important questions remain about the study design and interpretation. Moreover, the long-term toxicities and benefits of hyperthermic intraperitoneal chemotherapy remain unknown.
Like all studies, the current report has many flaws and must be interpreted in the context of other hyperthermic intraperitoneal chemotherapy clinical trials. Additionally, targeted therapies such as bevacizumab may offer a better and more tolerable option in treating newly diagnosed epithelial ovarian cancer. Until more data are available from evidence-based studies, it is reasonable to conclude that a strategy of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy is rational and interesting, though still an investigative approach in the management of advanced-stage epithelial ovarian cancer.
DISCLOSURE: Dr. Monk has served as a consultant and/or speaker for AbbVie, -Advaxis, Amgen, AstraZeneca, Biodesix, Clovis, Genmab, Gradalis, ImmunoGen, Incyte, Janssen/Johnson & Johnson, Mateon, Merck, Myriad, Perthera, Pfizer, -Precision Oncology, Roche/Genentech, Takeda, Tesaro, and VBL.
REFERENCES
1. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950-1955, 1996.
2. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma. J Clin Oncol 19:1001-1007, 2001.
3. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34-43, 2006.
4. Tewari D, Java JJ, Salani R, et al: Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 33:1460-1466, 2015.
5. Monk BJ, Chan JK: Is intraperitoneal chemotherapy still an acceptable option in primary adjuvant chemotherapy for advanced ovarian cancer? Ann Oncol 28(suppl 8):viii40-viii45, 2017.
6. Walker JL, Brady MF, DiSilvestro PA, et al: A phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube, and primary peritoneal carcinoma: A GOG/NRG trial (GOG 252). 2016 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract 6. Presented March 21, 2016.
7. van Driel WJ, Koole SN, Sikorska K, et al: Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med 378:230-240, 2018.
8. Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473-2483, 2011.
9. Cowan RA, O’Cearbhaill RE, Zivanovic O, et al: Current status and future prospects of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) clinical trials in ovarian cancer. Int J Hyperthermia 33:548-553, 2017.
10. Provencher DM, Gallagher CJ, Parulekar WR, et al: A randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer. Ann Oncol 29:431-438, 2018.
