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.
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