The median number of infusions of chemotherapy delivered intraperitoneally among the women in the intraperitoneal cohort was 6 (interquartile range 3–10). Within this group, 12.7% received 12 or more infusions of intraperitoneal treatment (corresponding to 6 cycles of treatment). In contrast, 21.8% received two or less infusions of intraperitoneal treatment, the equivalent of only one cycle of therapy (Appendix 2, available online at http://links.lww.com/AOG/A803).
Within the cohort, 21.3% who had standard chemotherapy, 34.7% of women received intraperitoneal chemotherapy, and 25.2% of those receiving a dose-dense regimen were hospitalized with a claim for a chemotherapy-related complication (P<.001) (Table 2). Two or more hospitalizations were recorded in 6.3%, 12.6%, and 6.8% for each chemotherapy regimen, respectively (P<.001). Emergency department visits for a chemotherapy-related complication were required in 18.3% of women administered standard chemotherapy, 26.3% of patients treated with intraperitoneal chemotherapy, and 20.3% for those receiving dose-dense treatment (P<.001). Two or more emergency department visits were required in 5.4%, 8.5%, and 7.6% of the groups, respectively (P<.001).
Women who received intraperitoneal chemotherapy had a higher rate of complications overall and in each of the subcategories compared with the other groups (Table 3). The most frequent chemotherapy-associated complication was gastrointestinal disorders, which were noted in 13.3% after standard therapy, 24.7% of women who received intraperitoneal chemotherapy, and 13.7% of those treated with dose-dense therapy (P<.001). Electrolyte disorders were seen in 11.6%, 22.7%, and 12.9% (P<.001) of women, respectively, and infectious complications were documented in 15.4%, 18.9%, and 15.4% of the three groups, respectively (P=.04). The individual complications are displayed in Appendix 3, available online at http://links.lww.com/AOG/A803.
Among those who were hospitalized, the per-patient winsorized mean cost of hospitalizations was $6,353 (95% CI $5,790–6,917) after standard chemotherapy, $7,974 (95% CI $6,804–9,144) after intraperitoneal chemotherapy, and $7,516 (95% CI $6,202–8,831) for dose-dense chemotherapy (P=.03) (Table 1).
Despite the efficacy of intraperitoneal chemotherapy for ovarian cancer, we noted only modest use of the treatment. In contrast, the use of dose-dense chemotherapy appears to be increasing rapidly. Complications and side effects are substantially more common after intraperitoneal chemotherapy than other treatment modalities.
The efficacy of intraperitoneal chemotherapy has been demonstrated in multiple randomized controlled trials.5,6,10 In the GOG's protocol 172, intraperitoneal chemotherapy was associated with a 16-month improvement in survival compared with standard intravenous chemotherapy (66 compared with 50 months); however, intraperitoneal therapy was also substantially more toxic.5 We also noted a higher rate of hospitalizations and emergency department visits with intraperitoneal chemotherapy compared with both standard and dose-dense treatment regimens.
Despite the survival advantage of intraperitoneal chemotherapy, uptake has been poor.18–20 In an analysis of six National Comprehensive Cancer Network institutions, only 41% of eligible patients received intraperitonealchemotherapy.20 A report of Medicare beneficiaries found that just 3.5% of women received intraperitoneal chemotherapy.19 Our findings were similar; only 15% of patients with ovarian cancer receiving chemotherapy in the community were treated with intraperitoneal therapy. Similar to the data from the National Comprehensive Cancer Network, in our cohort, the use of intraperitoneal treatment plateaued from 2009 to 2013.
Toxicity and logistic challenges are major barriers to the utilization and completion of intraperitoneal chemotherapy.21,22 In the GOG's study, only 42% of patients completed all six cycles of intraperitoneal treatment; in a study of National Comprehensive Cancer Network institutions, patients received a median of five cycles of intraperitoneal therapy.5,20 We found that women frequently received a limited amount of therapy intraperitoneally. In our cohort, 22% of women only received one or two infusions of intraperitoneal therapy. Although suboptimal, receipt of even a limited number of intraperitoneal infusions appears to confer a survival benefit over standard therapy.5,23 To improve tolerability and maximize drug delivery, a number of modified intraperitoneal regimens have been described.20,24,25
Although use of intraperitoneal therapy plateaued, administration of dose-dense chemotherapy increased substantially over time. The first large, randomized trial of dose-dense chemotherapy was reported in 2009.7,8 Long-term follow-up of this cohort demonstrated a median survival of 100.5 months for women with advanced-stage ovarian cancer treated with dose-dense chemotherapy compared with 62 months for those who received conventional therapy.7 However, a recent cooperative study in the United States failed to show a benefit for dose-dense chemotherapy compared with conventional 3-week dosing.26 In our cohort, use of dose-dense chemotherapy more than doubled from 8.7% in 2009 to 18.1% by 2013. Hospitalizations and chemotherapy-associated complications were slightly greater than conventional chemotherapy.
We acknowledge a number of important limitations. First, claims data may undercapture side effects and toxicity, especially symptoms not captured well on billing claims. To mitigate this bias, we selected only major complications that are likely to generate a claim. We recognize that these complications may not necessarily be attributable to chemotherapy itself, but may be the result of surgical complications or other underlying medical conditions. Second, given missed infusions and schedule alterations, classification of dose-dense chemotherapy has to be based on a ratio or number of infusions of each drug. We performed a series of sensitivity analyses of the data and chose a conservative definition of dose-dense chemotherapy. Although we cannot exclude the possibility of misclassification of a small number of women, any misclassification would bias our findings toward the null hypothesis. Furthermore, because of this classification schema, it is difficult to ascertain the true number of cycles obtained for comparisons. Third, we are unable to capture dose reductions and alterations in treatment. Fourth, MarketScan lacks data on a number of clinical and demographic factors as well as tumor characteristics. Importantly, the goal of our study was not to examine survival, but rather toxicity based on the type of chemotherapy used.
Our data have a number of important implications. First, the toxicity profiles and complications we noted for all three regimens were greater than what has been reported in clinical trials and selected studies from referral centers. Hospitalization rates in our series were 2.5 times higher for both intraperitoneal and conventional chemotherapy than reported for patients treated at comprehensive cancer centers.20 As such, caution should be used when generalizing the results of patients treated on protocol and at selected referral centers to the general population.12 Second, there was substantial variability in not only the choice of chemotherapy regimens, but also the quality of treatment. In our cohort a large majority of women receiving intraperitoneal chemotherapy received a small number of infusions of drug intraperitoneally. Prior work has shown that the quality of chemotherapy for ovarian cancer is highly variable; chemotherapy is frequently omitted when indicated or delivered in a suboptimal manner.27,28 Going forward, strategies to optimize adjuvant chemotherapy for women with ovarian cancer are clearly needed.
1. Wright JD, Chen L, Tergas AI, Patankar S, Burke WM, Hou JY, et al.. Trends in relative survival for ovarian cancer from 1975 to 2011. Obstet Gynecol 2015;125:1345–52.
2. Omura GA, Bundy BN, Berek JS, Curry S, Delgado G, Mortel R. Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1989;7:457–65.
3. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al.. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1–6.
4. Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al.. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92:699–708.
5. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al.. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43.
6. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, 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: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:1001–7.
7. Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, et al.. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020–6.
8. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, et al.. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009;374:1331–8.
9. Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, De Placido S, et al.. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014;15:396–405.
10. Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA, et al.. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950–5.
11. McGlynn EA, Asch SM, Adams J, Keesey J, Hicks J, DeCristofaro A, et al.. The quality of health care delivered to adults in the United States. N Engl J Med 2003;348:2635–45.
12. Unger JM, Barlow WE, Martin DP, Ramsey SD, Leblanc M, Etzioni R, et al.. Comparison of survival outcomes among cancer patients treated in and out of clinical trials. J Natl Cancer Inst 2014;106:dju002.
14. Hassett MJ, O'Malley AJ, Pakes JR, Newhouse JP, Earle CC. Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer. J Natl Cancer Inst 2006;98:1108–17.
15. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83.
16. Joynt KE, Orav EJ, Jha AK. Association between hospital conversions to for-profit status and clinical and economic outcomes. JAMA 2014;312:1644–52.
17. Ly DP, Jha AK, Epstein AM. The association between hospital margins, quality of care, and closure or other change in operating status. J Gen Intern Med 2011;26:1291–6.
18. Bowles EJ, Wernli KJ, Gray HJ, Bogart A, Delate T, O'Keeffe-Rosetti M, et al.. Diffusion of intraperitoneal chemotherapy in women with advanced ovarian cancer in community settings 2003-2008: the effect of the NCI clinical recommendation. Front Oncol 2014;4:43.
19. Fairfield KM, Murray K, LaChance JA, Wierman HR, Earle CC, Trimble EL, et al.. Intraperitoneal chemotherapy among women in the Medicare population with epithelial ovarian cancer. Gynecol Oncol 2014;134:473–7.
20. Wright AA, Cronin A, Milne DE, Bookman MA, Burger RA, Cohn DE, et al.. Use and effectiveness of intraperitoneal chemotherapy for treatment of ovarian cancer. J Clin Oncol 2015;33:2841–7.
21. Naumann RW, Sukumvanich P, Edwards RP. Practice patterns of intraperitoneal chemotherapy in women with ovarian cancer. Gynecol Oncol 2009;114:37–41.
22. Walker JL, Armstrong DK, Huang HQ, Fowler J, Webster K, Burger RA, et al.. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. Gynecol Oncol 2006;100:27–32.
23. Tewari D, Java JJ, Salani R, Armstrong DK, Markman M, Herzog T, 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 2015;33:1460–6.
24. Berry E, Matthews KS, Singh DK, Buttin BM, Lurain JR, Alvarez RD, et al.. An outpatient intraperitoneal chemotherapy regimen for advanced ovarian cancer. Gynecol Oncol 2009;113:63–7.
25. Gray HJ, Shah CA, Swensen RE, Tamimi HK, Goff BA. Alternative intraperitoneal chemotherapy regimens for optimally debulked ovarian cancer. Gynecol Oncol 2010;116:340–4.
26. Chan JK, Brady MF, Penson RT, Huang H, Birrer MJ, Walker JL, et al.. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med 2016;374:738–48.
27. Fairfield KM, Murray K, Lucas FL, Wierman HR, Earle CC, Trimble EL, et al.. Completion of adjuvant chemotherapy and use of health services for older women with epithelial ovarian cancer. J Clin Oncol 2011;29:3921–6.
28. Wright JD, Ananth CV, Tsui J, Glied SA, Burke WM, Lu YS, et al.. Comparative effectiveness of upfront treatment strategies in elderly women with ovarian cancer. Cancer 2014;120:1246–54.