Obstetrics & Gynecology:
Effect of Radical Cytoreductive Surgery on Omission and Delay of Chemotherapy for Advanced-Stage Ovarian Cancer
Wright, Jason D. MD; Herzog, Thomas J. MD; Neugut, Alfred I. MD, PhD; Burke, William M. MD; Lu, Yu-Shiang MS; Lewin, Sharyn N. MD; Hershman, Dawn L. MD
From the Departments of Obstetrics and Gynecology and Medicine, Columbia University College of Physicians and Surgeons, the Department of Epidemiology, Mailman School of Public Health, Columbia University, and the Herbert Irving Comprehensive Cancer Center, New York, New York.
Dr. Hershman is the recipient of a grant from the National Cancer Institute (NCI R01 CA134964).
Corresponding author: Jason D. Wright, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, 8th Floor New York, NY 10032; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: Cytoreductive surgery is associated with extensive morbidity and may delay chemotherapy. We examined the associations among cytoreduction, perioperative complications, and delay or omission of chemotherapy.
METHODS: Women aged 65 years or older with stage III–IV ovarian cancer who were treated with surgery from 1991–2005 and recorded in the Surveillance, Epidemiology, and End Results–Medicare database were examined. We estimated the influence of extended cytoreduction as well as the occurrence of major perioperative complications on receipt and timing of chemotherapy and survival.
RESULTS: Among 3,991 patients, 479 (12%) failed to receive chemotherapy. Of those treated with chemotherapy, 2,527 (72%) initiated treatment within 6 weeks of surgery, 838 (24%) within 6–12 weeks, and 147 (4%) more than 12 weeks after surgery. In a multivariable model, older patients, those with comorbidities, mucinous tumors, and stage IV neoplasms were more likely not to receive chemotherapy (P<.05). Extended cytoreduction and the occurrence of postoperative complications were not associated with omission of chemotherapy but were associated with chemotherapy delay. 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. The occurrence of more than two perioperative complications (hazard ratio 1.31, 95% confidence interval [CI] 1.15–1.49) and initiation of chemotherapy more than 12 weeks after surgery (hazard ratio 1.32, 95% CI 1.07–1.64) were associated with decreased survival.
CONCLUSION: Extended cytoreductive surgery and perioperative complications significantly delay initiation but do not increase the chance of omission of chemotherapy for women with ovarian cancer.
LEVEL OF EVIDENCE: II
Standard treatment paradigms for advanced-stage ovarian cancer rely on surgical cytoreduction or debulking followed by adjuvant chemotherapy.1 The goal of cytoreductive surgery is the resection of all grossly visible tumor within the abdominal cavity. The surgery is extensive and often requires the resection of portions of the gastrointestinal and genitourinary tracts in addition to the ovaries.2–4 Despite the benefits of cytoreduction, the procedure is associated with substantial perioperative morbidity.2–5 Adjuvant chemotherapy is recommended after the completion of surgery.6
A number of studies have reported widespread variation in the quality of adjuvant chemotherapy for women with ovarian cancer.7–10 Failure to initiate chemotherapy, inappropriate choice of agents, and truncated treatment courses all appear to be relatively common.7–10 Prior work has shown that, in addition to clinical and demographic characteristics such as age and comorbidity, physician and hospital factors also affect the allocation of care for patients with ovarian cancer.8,11,12 Despite these associations, the reasons why adjuvant chemotherapy is underused in ovarian cancer remain incompletely understood.
Despite the efficacy of cytoreduction, the procedure is of little benefit if chemotherapy is omitted or excessively delayed after the surgery. This is a particular concern because the operation is associated with significant morbidity and is often performed in elderly patients with extensive medical comorbidity. Patients who do not tolerate aggressive primary surgery followed by chemotherapy may benefit from alternative treatment strategies such as neoadjuvant chemotherapy.13,14 The goal of our study was to estimate the effect of surgical cytoreduction on the quality of chemotherapy delivery in women with ovarian cancer. Specifically, we estimated the influence of extended cytoreduction and nonfatal surgical complications on the receipt and timing of chemotherapy.
MATERIALS AND METHODS
The linked Surveillance, Epidemiology, and End Results (SEER)–Medicare database was used for analysis.15 Surveillance, Epidemiology, and End Results is a population-based cancer registry that provides data on tumor histology, location, stage, treatment, and survival as well as demographic and selected census tract-level information. The Medicare database includes information on patients with Medicare part A (inpatient) and part B (outpatient) including billed claims and diagnoses. These two files are linked and provide data on initial services and all follow-up. Exemption from the Columbia University institutional review board was obtained. The SEER–Medicare has been validated and used in a number of outcomes studies.15–17
We analyzed women with epithelial ovarian cancer diagnosed between January 1, 1991, and December 31, 2005. Only patients aged 65 years or older with stage III–IV tumors who underwent primary cancer-directed surgery were included.11,12 Women who received neoadjuvant chemotherapy before surgery and those patients who did not undergo surgery were excluded from the analysis. We excluded patients who were enrolled in a non-Medicare health maintenance organization because the billing claims for these patients are not submitted to Medicare for reimbursement.18 Only patients who survived for more than 6 months after cancer-directed surgery were included in the analysis.
Age at diagnosis was categorized into 5-year intervals. We recoded the SEER marital status variable as married, not married, and unknown. We generated an aggregate socioeconomic status score from education, poverty level, and income data from the 2000 census tract data, as described previously by Du and colleagues.19 Patients' scores were ranked on a scale of 1–5 by use of the formula that incorporated education, poverty, and income-weighted equally with 1 being the lowest value. To estimate the prevalence of comorbid disease in our cohort, we used the Klabunde adaptation of the Charlson comorbidity index (ie, the Klabunde–Charlson index).20,21 Medicare inpatient and outpatient claims were searched for diagnostic codes of the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).22 Each condition was weighted, and patients were assigned a score that was based on the Klabunde–Charlson index.21 Area of residence was categorized as metropolitan or nonmetropolitan and tumor grade grouped as well, moderately, or poorly differentiated or unknown. Tumor histology was classified as serous, mucinous, endometrioid, or other.
In addition to oophorectomy and cytoreduction, the following extended radical cytoreductive procedures were recorded for each patient based on Current Procedural Terminology and ICD-9-CM codes: lymphadenectomy, small bowel resection, colon resection, rectosigmoid resection, hepatectomy, bladder resection, diaphragm resection, and splenectomy. A composite score for the number of extended radical cytoreductive procedures performed in each patient was calculated and recorded as 0, 1, or 2 or more.
Major perioperative complications were examined.23 Intraoperative complications included bladder injury, ureteral injury, intestinal injury, vascular injury, and other operative injury. Postoperative complications included wound complications, abscess, hemorrhage, bowel obstruction, ileus, venous thromboembolism, myocardial infarction, cardiopulmonary arrest, respiratory failure, renal failure, stroke, bacteremia or sepsis, shock, and pneumonia. A composite score for the number of these complications noted for each patient was calculated and recorded as 0, 1, or 2 or more.
The major outcomes of the analysis were receipt of chemotherapy and timing of initiation of the first cycle of chemotherapy. Patients who did not receive chemotherapy within 12 months after surgical resection were considered not to have received chemotherapy. Initiation of chemotherapy was defined as the time until receipt of the first cycle of chemotherapy after surgery. Initiation of treatment was categorized as less than 6 weeks, 6–12 weeks, and greater than 12 weeks.
Predictors of receipt of chemotherapy and time to initiation of chemotherapy were compared using χ2 tests. The number needed to harm was calculated to determine the number of patients who underwent extended cytoreduction or who had perioperative complications who would have had delayed initiation of chemotherapy as a result. Multivariable logistic regression models were developed to estimate the effect of perioperative complications and extended surgical cytoreduction of receipt and initiation of chemotherapy while controlling for other clinical variables. Cox proportional hazards models were used to calculate the hazard ratio of overall and cancer-specific survival. We first developed models that included either timing of initiation of chemotherapy or number of perioperative complications and then calculated a fully adjusted model including both timing of initiation of chemotherapy and complications. All of the Cox models are adjusted for confounding demographic and clinical characteristics. Kaplan-Meier curves were developed to compare survival based on timing to initiation of chemotherapy and number of complications. The results were compared using the log-rank test. All analyses were conducted with SAS 93. All statistical tests were two-sided.
A total of 3,991 patients who underwent cancer-directed surgery for stage III or IV ovarian cancer were identified. The cohort included 3,512 (88.0%) women who received postoperative chemotherapy and 479 (12.0%) patients who did not undergo chemotherapy (Table 1). Chemotherapy was not initiated in 12.9% of patients who underwent no radical procedures, 11.5% of women who had one extended cytoreductive procedure, and 10.0% of those who had two or more procedures (P=.11). No chemotherapy was administered to 12.8% of patients with no perioperative complications, 10.3% of women who had one complication, and 12.8% of patients who had two or more complications (P=.08).
In a multivariable model, older patients, single women, those with stage IIIA or IV disease, those with mucinous tumors, and patients with more medical comorbidities were more likely to forego chemotherapy (P<.05 for each) (Tables 2 and 3). In contrast, patients treated more recently and those with moderately and poorly differentiated tumors were more likely to receive chemotherapy (P<.05 for both). The number of radical procedures performed had no effect on ultimate receipt of chemotherapy. Women who had a single perioperative complication (odds ratio [OR] 9.73, 95% confidence interval [CI] 0.57–0.93) were more likely to receive chemotherapy than those without any major complications. Multiple perioperative complications (OR 0.94, 95% CI 0.71–1.26) had no effect on ultimate receipt of chemotherapy.
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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