Among the women who received chemotherapy, 2,527 (72.0%) began chemotherapy within 6 weeks of surgery, 838 (23.9%) initiated therapy 6–12 weeks after surgery, and 147 (4.2%) began treatment more than 12 weeks after surgery. The first cycle of chemotherapy was started within 6 weeks of surgery in 75.2% of women who did not undergo extended cytoreduction, in 68.2% of those who had one extended procedure, and in 67.4% of patients who underwent two or more procedures (P<.001). Chemotherapy was begun more than 12 weeks after surgery in 3.1% of women who did not experience a perioperative complication, in 3.9% of those who had one perioperative complication, and in 8.2% of patients who had two or more complications (P<.001).
Predictors of delay of initiation of chemotherapy for more than 6 weeks included advanced age, black race (OR 1.67, 95% CI 1.12–2.48), stage IIIA disease (OR 1.59, 95% CI 1.02–2.48), performance of one (OR 1.38, 95% CI 1.15–1.66) or two or more (OR 1.37, 95% CI 1.12–1.69) radical cytoreductive procedures, one (OR 1.40, 95% CI 1.17–1.66) or two or more (OR 2.74, 95% CI 2.23–3.38) perioperative complications, and significant medical comorbidity (OR 1.62, 95% CI 1.29–2.04). For every 14 patients who underwent one extended procedure and for every 13 who had two extended procedures, one patient had a delay in receipt of chemotherapy. For every 14 patients who had one complication and for every four who had two complications, one patient had a delay in receipt of chemotherapy. In contrast, patients diagnosed more recently were less likely to experience a greater than 6-week delay in initiation of chemotherapy. Prolonged delay (more than 12 weeks) in initiation of chemotherapy was associated with advanced age, significant medical comorbidity, and two or more perioperative complications (OR 2.72, 95% CI 1.78–4.16). Patients diagnosed more recently were less likely to experience a prolonged delay to initiation of chemotherapy.
The effect of complications and delay of initiation of chemotherapy on ovarian cancer-specific survival are shown in Table 4. In a model fully adjusted for patient and tumor characteristics as well as perioperative complications and time to initiation of chemotherapy, one complication had no effect on survival (hazard ratio 1.05, 95% CI 0.94–1.16) but the occurrence of two or more complications increased the risk of death from ovarian cancer (hazard ratio 1.31, 95% CI 1.15–1.49). Cancer-specific survival was similar for women who initiated therapy at more than 6 or 6–12 weeks but was inferior in those who began chemotherapy more than 12 weeks after surgery (hazard ratio 1.32, 95% CI 1.07–1.64). The effect of complications and time to initiation of chemotherapy had similar effects on overall survival. In Kaplan-Meier analyses, complications (P=.002) and time to initiation of chemotherapy (P<.001) remained associated with survival (Figs. 1 and 2).
Our findings suggest that there is widespread variability in the way adjuvant chemotherapy is administered in women with advanced-stage ovarian cancer. Patient characteristics including age and comorbidity significantly influence the use and timing of chemotherapy. We previously demonstrated that delayed initiation of chemotherapy and truncated treatment negatively influence survival and in the current study sought to explore the factors that underlie these patterns of chemotherapy use.8 Extended primary cytoreduction and the occurrence of perioperative complications did not increase the risk of omission chemotherapy but are associated with delayed initiation of chemotherapy. Both delayed initiation of chemotherapy and the occurrence of perioperative complications independently influenced survival.
Timely administration of appropriate chemotherapy is an important quality metric for patients with advanced-stage ovarian cancer who undergo curative intent treatment.6 Omission of chemotherapy is relatively common for women with ovarian cancer, especially among elderly women.7,9 A prior population-based report noted that nearly one-fourth of women with stage III–IV tumors did not receive chemotherapy after debulking surgery. In this analysis, advanced age, black race, increased comorbidity, and stage IV cancer were all predictors of not receiving both chemotherapy and surgery.7
Although omission of chemotherapy is clearly detrimental, studies addressing the effect of delayed initiation of chemotherapy on outcomes have reported mixed findings.8,24 – 27 Although observational studies from the United States and Italy failed to find an association between delayed initiation of chemotherapy and survival, a prospective trial suggested that delayed initiation of treatment adversely affected survival.24 – 27 In the current study we noted that 12% of women with advanced-stage ovarian cancer did not receive chemotherapy, whereas 24% of patients who were treated did not begin chemotherapy until more than 6 weeks after surgery. Perhaps more importantly, we noted that delayed initiation of chemotherapy adversely affected survival; those women who began therapy more than 12 weeks after surgery were 32% more likely to die from their tumors.
A prolonged convalescence from extensive cytoreductive surgery may theoretically result in delay or omission of chemotherapy. The morbidity of cytoreduction is particularly significant for patients who undergo extended resections of the abdominal viscera and is disproportionately high in the elderly.2,3,5,23,28 – 30 Relatively little data have been reported to describe the effect of cytoreduction on receipt of chemotherapy. A single-institution report noted that 94% of patients who underwent upper abdominal debulking were able to receive postoperative chemotherapy.3 Although extended cytoreduction was not associated with omission of chemotherapy in our cohort, it was associated with delayed initiation of chemotherapy.
The occurrence of perioperative complications has a major effect on subsequent treatment and survival. An analysis of over 100,000 patients recorded in the National Surgical Quality Improvement Project noted that the occurrence of a major perioperative complication was the strongest predictor of postoperative mortality and resulted in a 69% reduction in survival.31 Complications also influence use of chemotherapy. A report of patients with stage III colorectal cancer noted that the occurrence of a postoperative complication was associated with a 76% increased chance of not receiving subsequent chemotherapy.32 Although surgical complications had little effect on ultimate receipt of chemotherapy in our cohort, complications did significantly delay the initiation of chemotherapy. The effect of complications on timing of initiation of chemotherapy was particularly pronounced in patients who experienced multiple postoperative complications. We also noted that complications not only influenced time to initiation of chemotherapy, but influenced survival; patients with more than two complications were 31% more likely to die from ovarian cancer independent of the effect of timing to initiation of chemotherapy. Although many surgeons feel that the morbidity of cytoreduction is offset by its benefits, our findings highlight the potential pitfalls of this approach.
Although our study benefits from the inclusion of a large number of patients, we recognize a number of important limitations. Complications may be underrecorded in claims data. To minimize this bias, we included only major perioperative complications that were likely to generate a claim.33,34 Although we were able to capture extended radical procedures using ICD-9-CM codes, it is impossible to determine the “degree” of cytoreduction performed using administrative data. To account for this limitation, sensitivity analyses were performed in which the ICD-9-CM and Current Procedural Terminology codes for cytoreduction were incorporated into the calculated radical procedure score. In these analyses, our estimates of morbidity and the influence of extended cytoreduction on receipt and timing of chemotherapy were largely unchanged. Although we include comorbidity in our analysis, data on performance status were lacking. Performance status not only influences treatment, but also the risk of complications. Some of the SEER registries included did not collect data for the entire study period. Our analysis focused on elderly Medicare recipients and these findings may not be generalizable to younger patients with ovarian cancer. Detailed data on physician characteristics for a substantial number of physicians in our cohort were lacking and we did not include this variable in the analysis. Finally, our analysis was unable to account for individual patient and physician preferences that undoubtedly influenced treatment.
Our findings provide support for more individualized treatment schemas for women with ovarian cancer.35,36 These data build on prior work that has shown that cytoreduction, particularly with resection of the abdominal viscera, is associated with an increased rate of complications and these complications may in turn lead to prolonged delay in the initiation of chemotherapy.10,23,28,30,37,38 Given that advanced age and greater medical comorbidity are not only risk factors for perioperative complications, but also independent risks of delay and omission of chemotherapy, these would be potential populations in which alternative treatment strategies such as neoadjuvant chemotherapy might be considered. Further prospective studies to guide the development of individualized treatment strategies for women with epithelial ovarian cancer are clearly needed.
1. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 1975;42:101–4.
2. Chi DS, Franklin CC, Levine DA, Akselrod F, Sabbatini P, Jarnagin WR, et al.. Improved optimal cytoreduction rates for stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancer: a change in surgical approach. Gynecol Oncol 2004;94:650–4.
3. Chi DS, Zivanovic O, Levinson KL, Kolev V, Huh J, Dottino J, et al.. The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas. Gynecol Oncol 2010;119:38–42.
4. Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8.
5. Gerestein CG, Damhuis RA, Burger CW, Kooi GS. Postoperative mortality after primary cytoreductive surgery for advanced stage epithelial ovarian cancer: a systematic review. Gynecol Oncol 2009;114:523–7.
6. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. Version 2.2010. 2010. Available at: www.nccn.org
. Retrieved August 3, 2012.
7. Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Trends in treatment of advanced epithelial ovarian cancer in the Medicare population. Gynecol Oncol 2011;122:100–6.
8. Wright J, Doan T, McBride R, Jacobson J, Hershman D. Variability in chemotherapy delivery for elderly women with advanced stage ovarian cancer and its impact on survival. Br J Cancer 2008;98:1197–203.
9. Sundararajan V, Hershman D, Grann VR, Jacobson JS, Neugut AI. Variations in the use of chemotherapy for elderly patients with advanced ovarian cancer: a population-based study. J Clin Oncol 2002;20:173–8.
10. 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.
11. Earle CC, Schrag D, Neville BA, Yabroff KR, Topor M, Fahey A, et al.. Effect of surgeon specialty on processes of care and outcomes for ovarian cancer patients. J Natl Cancer Inst 2006;98:172–80.
12. Schrag D, Earle C, Xu F, Panageas KS, Yabroff KR, Bristow RE, et al.. Associations between hospital and surgeon procedure volumes and patient outcomes after ovarian cancer resection. J Natl Cancer Inst 2006;98:163–71.
13. Vergote I, Trop é CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al.. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53.
14. Hou JY, Kelly MG, Yu H, McAlpine JN, Azodi M, Rutherford TJ, et al.. Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease. Gynecol Oncol 2007;105:211–7.
15. Potosky AL, Riley GF, Lubitz JD, Mentnech RM, Kessler LG. Potential for cancer related health services research using a linked Medicare-tumor registry database. Med Care 1993;31:732–48.
16. Du X, Freeman JL, Warren JL, Nattinger AB, Zhang D, Goodwin JS. Accuracy and completeness of Medicare claims data for surgical treatment of breast cancer. Med Care 2000;38:719–27.
17. Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care 2002;40(suppl):IV-3–18.
18. Hershman DL, Buono DL, Malin J, McBride R, Tsai WY, Neugut AI. Patterns of use and risks associated with erythropoiesis-stimulating agents among Medicare patients with cancer. J Natl Cancer Inst 2009;101:1633–41.
19. Du XL, Fang S, Vernon SW, El-Serag H, Shih YT, Davila J, et al.. Racial disparities and socioeconomic status in association with survival in a large population-based cohort of elderly patients with colon cancer. Cancer 2007;110:660–9.
20. Charlson ME, Sax FL, MacKenzie CR, Fields SD, Braham RL, Douglas RG Jr. Assessing illness severity: does clinical judgment work? J Chronic Dis 1986;39:439–52.
21. Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol 2000;53:1258–67.
22. World Health Organization. International classification of diseases, 9th revision. Geneva (Switzerland): World Health Organization: 2008.
23. Wright JD, Lewin SN, Deutsch I, Burke WM, Sun X, Neugut AI, et al.. Defining the limits of radical cytoreductive surgery for ovarian cancer. Gynecol Oncol 2011;123:467–73.
24. 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.
25. Gadducci A, Sartori E, Landoni F, Zola P, Maggino T, Maggioni A, et al.. Relationship between time interval from primary surgery to the start of taxane- plus platinum-based chemotherapy and clinical outcome of patients with advanced epithelial ovarian cancer: results of a multicenter retrospective Italian study. J Clin Oncol 2005;23:751–8.
26. Aletti GD, Long HJ, Podratz KC, Cliby WA. Is time to chemotherapy a determinant of prognosis in advanced-stage ovarian cancer? Gynecol Oncol 2007;104:212–6.
27. Flynn PM, Paul J, Cruickshank DJ. Does the interval from primary surgery to chemotherapy influence progression-free survival in ovarian cancer? Gynecol Oncol 2002;86:354–7.
28. Cloven NG, Manetta A, Berman ML, Kohler MF, DiSaia PJ. Management of ovarian cancer in patients older than 80 years of age. Gynecol Oncol 1999;73:137–9.
29. Hightower RD, Nguyen HN, Averette HE, Hoskins W, Harrison T, Steren A. National survey of ovarian carcinoma. IV: Patterns of care and related survival for older patients. Cancer 1994;73:377–83.
30. Thrall MM, Goff BA, Symons RG, Flum DR, Gray HJ. Thirty-day mortality after primary cytoreductive surgery for advanced ovarian cancer in the elderly. Obstet Gynecol 2011;118:537–47.
31. Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ. Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg 2005;242:326–41.
32. Hendren S, Birkmeyer JD, Yin H, Banerjee M, Sonnenday C, Morris AM. Surgical complications are associated with omission of chemotherapy for stage III colorectal cancer. Dis Colon Rectum 2010;53:1587–93.
33. Lawthers AG, McCarthy EP, Davis RB, Peterson LE, Palmer RH, Iezzoni LI. Identification of in-hospital complications from claims data. Is it valid? Med Care 2000;38:785–95.
34. Iezzoni LI, Daley J, Heeren T, Iezzoni LI, Daley J, Heeren T, et al.. Identifying complications of care using administrative data.et al. Identifying complications of care using administrative data. Med Care 1994;32:700–15.
35. Aletti GD, Santillan A, Eisenhauer EL, Hu J, Aletti G, Podratz KC, et al.. A new frontier for quality of care in gynecologic oncology surgery: multi-institutional assessment of short-term outcomes for ovarian cancer using a risk-adjusted model. Gynecol Oncol 2007;107:99–106.
36. Kondalsamy-Chennakesavan S, Bouman C, De Jong S, Sanday K, Nicklin J, Land R, et al.. Clinical audit in gynecological cancer surgery: development of a risk scoring system to predict adverse events. Gynecol Oncol 2009;115:329–33.
37. Janda M, Youlden DR, Baade PD, Jackson D, Obermair A. Elderly patients with stage III or IV ovarian cancer: should they receive standard care? Int J Gynecol Cancer 2008;18:896–907.
38. Alphs HH, Zahurak ML, Bristow RE, Diaz-Montes TP. Predictors of surgical outcome and survival among elderly women diagnosed with ovarian and primary peritoneal cancer. Gynecol Oncol 2006;103:1048–53.