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Is time to chemotherapy a determinant of prognosis in advanced-stage ovarian cancer?
Gynecologic Oncology 104 (2007) 212 – 216 www.elsevier.com/locate/ygyno
Is time to chemotherapy a determinant of prognosis in advanced-stage ovarian cancer? Giovanni D. Aletti a , Harry J. Long b , Karl C. Podratz a , William A. Cliby a,⁎ a
Division of Gynecologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA b Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
Received 22 May 2006 Available online 4 October 2006 Presented at The Annual Meeting on Women's Cancer, Palm Springs, California, March 22–26, 2006
Abstract Objectives. Clinicians often question when to start chemotherapy after patients undergo surgery for ovarian cancer. A major unproven concern is whether a long postoperative delay reduces the benefits of an extensive procedure and leads to disease progression. Our objectives were to evaluate the correlation between clinical and pathologic variables and to evaluate the effect of the “time to chemotherapy” (TTC) interval on survival. Methods. We retrospectively studied data from 218 patients with International Federation of Gynecology and Obstetrics stage IIIC or IV ovarian cancer (TNM stage T3c or T4) who were consecutively treated between January 1, 1994, and December 31, 1998. Results. Mean age at diagnosis was 64 years (range, 24–87 years; median, 65 years), and 206 patients received postoperative platinum-based chemotherapy. Mean TTC interval was 26 days (range, 7–79 days; median, 25 days). No correlation was found between operative time and TTC interval length (P = 0.99). Age and performance of rectosigmoidectomy were correlated with longer TTC interval (P = 0.009 and P = 0.005, respectively), but TTC was not a predictor of overall survival (odds ratio, 1.00; 95% confidence interval, 0.98–1.01; P = 0.85). Differences in TTC interval length (≤ 17 days, 18–26 days, 27–33 days, or ≥34 days) did not affect survival (P = 0.93). Even after categorizing patients by residual disease (< 1 cm or ≥ 1 cm), no statistically significant effect of TTC on prognosis was identified. Conclusions. Concerns about the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach for patients with advanced ovarian cancer. © 2006 Elsevier Inc. All rights reserved. Keywords: Chemotherapy timing; Ovarian cancer; Residual disease; Surgery
Introduction Ovarian cancer is the most severe gynecologic malignancy in terms of aggressiveness and survival, with approximately 16,000 deaths and 22,000 new cases estimated to occur in the United States during 2005 [1]. Griffiths [2] was the first to show in 1975 that the diameter of the remaining tumor after cytoreductive surgery is the principal determinant of prognosis in patients affected by ovarian cancer. Other prospective and retrospective studies have confirmed this observation [3–5]. In Abbreviations: DFS, disease-free survival; RD, residual disease; TTC, time to chemotherapy. ⁎ Corresponding author. E-mail address: [email protected] (W.A. Cliby). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.07.045
patients with advanced ovarian cancer, the goal of cytoreductive surgery is to minimize the amount of residual disease (RD). This aim can be achieved with different techniques that are used more frequently as gynecologic oncologists gain experience with advanced cytoreductive procedures (e.g., diaphragm stripping or resection, bowel resection, splenectomy, and liver resection) [6–11]. Radical surgical procedures used to treat patients with advanced ovarian cancer have resulted in acceptable morbidity rates [12]. We recently reported that patients with advanced ovarian cancer benefit from radical procedures such as diaphragm stripping, resection, or ablation, bowel resection, intensive peritoneal ablation, or splenectomy [13]. A major unproven concern about these radical procedures is that waiting too long after surgery to initiate chemotherapy may reduce the
G.D. Aletti et al. / Gynecologic Oncology 104 (2007) 212–216
benefits of surgery, thereby leading to disease progression. Furthermore, complications often occur after such intensive procedures and may prolong the recovery period. In the present study, we sought to evaluate the impact of the “time to chemotherapy” (TTC) interval, defined as the length of time between surgery and initiation of chemotherapy, on the survival of patients who underwent primary cytoreductive surgery and subsequent chemotherapy. We found that concerns about the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach for patients with advanced ovarian cancer.
213
Table 1 Patient characteristics and tumor features (n = 218) Variable
Patients No.
Patient characteristics Age, years Mean (range) Median ASA grade 1 2 3 4 Unknown
%
63.3 (24–87) 64 7 95 102 9 5
3.2 43.6 46.8 4.1 2.3
174 44
79.8 20.2
1 13 204
0.5 6.0 93.6
143 2 20 8 3 21 19 2
65.6 0.9 9.2 3.7 1.4 9.6 8.7 0.9
201 17
92.2 7.8
44 97 27 50
20.2 44.5 12.4 22.9
Materials and methods Relevant clinical data were abstracted from operative reports, hospital and outpatient clinical notes, the Mayo Clinic Cancer Center Registry database, and correspondence from referral institutions. Patients with a diagnosis of primary epithelial ovarian cancer who had undergone primary surgery at Mayo Clinic between January 1, 1994 and December 31, 1998 were identified from surgical and hospital records. Disease status before surgery was recorded in the operative notes for statistical analysis. The study was approved by the Mayo Foundation Institutional Review Board. All study patients were assessed and classified according to the American Society of Anesthesiology physical status grades before surgery. Surgical stage and cancer grade were defined using criteria from the International Federation of Gynecology and Obstetrics [14]. Patients with stage IIIC or IV ovarian cancer (TNM stage T3c or T4) were included in the study if they underwent primary surgical exploration at our institution and received a postoperative diagnosis of epithelial ovarian cancer. Patients who underwent surgical exploration at another institution or received chemotherapy before surgery and their referral to Mayo Clinic were excluded. After surgery, all patients received first-line platinum-based chemotherapy, either alone or in combination with paclitaxel or cyclophosphamide, for 6 to 8 courses, every 3 to 4 weeks, according to the different treatment protocols in effect during the years of the study. We did not restrict our analysis only to patients who received paclitaxel nor did we stratify patients according to chemotherapy regimen; we did not find a significant survival difference between the paclitaxelcombination group and all other patients in our cohort. Patients were excluded from the study if data from the first chemotherapy course were not reported. No patient received consolidation therapy at the time of the study. Only 1 patient had intraperitoneal chemotherapy, and the patient's data were included in the analysis. For statistical analysis, patient characteristics were categorized as follows: American Society of Anesthesiology grades 1 and 2 versus 3 and 4; histologic grade 3 versus 1 and 2; and histologic subtype serous versus all other subtypes. Operative time was categorized as less than 200 min or 200 min and longer (median value). For TTC, patients were categorized by quartiles: ≤ 17 days, 18–26 days, 27–33 days, or ≥ 34 days after surgery. RD was divided into 4 categories: RD of 0 (no gross tumor), macroscopic RD less than 1 cm, RD 1 cm or greater but less than or equal to 2 cm, and RD greater than 2 cm. Statistical analysis was performed by using the Student's t test, logistic regression analysis, and the log-rank test. We measured overall survival in all cases. Disease-free survival (DFS), defined as the time from diagnosis to the first progression of disease, was measured when data were available. Survival curves were plotted using the Kaplan–Meier method. Differences were considered statistically significant at P < 0.05. JMP statistical software (version 5.1, SAS Institute Inc, Cary, North Carolina) was used for the analysis.
Results Data were examined from 218 patients with a diagnosis of International Federation of Gynecology and Obstetrics stage IIIC or IV ovarian cancer (TNM stage T3c or T4). Patient characteristics and tumor features are summarized in Table 1.
Tumor features FIGO stage IIIC IV FIGO grade 1 2 3 Histologic findings Serous Mucinous Endometrioid Clear cell Transitional cell Mixed Seroanaplastic Müllerian origin Cytologic findings Positive Negative RD, cm None detectable <1 1–2 >2
ASA, American Society of Anesthesiologists; FIGO, International Federation of Gynecology and Obstetrics; RD, residual disease.
Primary surgery was performed with the intent to diagnose, stage, and surgically reduce tumor volume. Mean operative time was 215 min (median, 200 min; range, 40–480 min). Mean TTC was 26 days (median, 26 days). The upper and lower quartiles for TTC were 17 and 33 days, respectively. Five patients (2%) died less than 30 days after surgery. Thirteen patients (6%) did not receive chemotherapy because of rapid disease progression, patient refusal, inadequate performance status, or perioperative death; all 13 died less than 3.5 months after surgery and were not included in subsequent analyses. Aggressive surgical procedures such as diaphragm stripping, resection, or ablation, rectosigmoidectomy, intensive peritoneal ablation, splenectomy, and hepatectomy were correlated with a longer operative time and less RD (data not shown). Nevertheless, of all the surgical procedures, only rectosigmoidectomy was correlated with the TTC interval (Table 2), which suggests that, after most surgical procedures, a standard recovery period is sufficient unless postoperative complications occur. The TTC
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Table 2 Correlation between patient variables and the “time to chemotherapy” interval length Variable Age, years <65 ≥ 65 ASA grade 3 and 4 1 and 2 Operative time, minutes <200 ≥ 200 Rectosigmoidectomy Yes No Diaphragm surgery (stripping, resection, ablation) Yes No Other radical procedures (splenectomy, bowel resection, hepatectomy, intensive peritoneal ablation) Yes No RD, cm b 0 <1 1–2 >2
Mean TTC, days P value a 0.009 24.2 28.7 0.58 26.6 25.7 0.99 26.2 26.3 0.005 30.2 24.8 0.86 26.6 26.2 0.10
28.5 25.4 NS 27.7 25.1 26.4 27.5
ASA, American Society of Anesthesiologists; NS, not significant; RD, residual disease; TTC, time to chemotherapy. a Student's t test was used for analysis. Differences were considered statistically significant at P < 0.05. b Patients in each subgroup were compared to all others.
interval was also affected by age, suggesting that a prolonged recovery period for older patients was necessary. We investigated the effect of TTC on survival. Patients were categorized into 4 groups by TTC interval length (groups were established by TTC quartile values: ≤17 days, 18–26 days, 27– 33 days, or ≥ 34 days after surgery). Overall survival rates were similar for all groups (Fig. 1). After 5 years, the survival rates
were 32% (TTC, ≤ 17 days), 34% (TTC, 18–26 days), 44% (TTC, 27–33 days), and 35% (TTC, ≥ 34 days) (P = 0.93, logrank test). Upon multivariate analysis, RD was the only independent variable that predicted survival (Table 3). When survival analysis was restricted to patients with RD less than 1 cm, no survival benefits were evident for patients who started chemotherapy earlier (Fig. 2A); after 5 years, the survival rates were 44% (TTC, ≤ 17 days), 45% (TTC, 18–26 days), 55% (TTC, 27–33 days), and 51.5% (TTC, ≥ 34 days) (P = 0.93, log-rank test). Similarly, patients with RD greater than 1 cm did not show TTC interval-dependent differences in overall survival (Fig. 2B); after 5 years, the survival rates were 6.5% (TTC, ≤ 17 days), 6.5% (TTC, 18–26 days), 17% (TTC, 2733 days), and 6% (TTC, ≥ 34 days) (P = 0.51, log-rank test). Lastly, we investigated the effect of TTC on DFS. Information about DFS was available for 183 patients. Patients were categorized into the 4 subgroups by TTC interval length. DFS rates were similar for all groups (Fig. 3). Five-year DFS rates were 11.5% (TTC, ≤ 17 days), 13.4% (TTC, 18–26 days), 13.2% (TTC, 27–33 days), and 13.5% (TTC, ≥ 34 days) (P = 0.74, log-rank test). No difference in DFS was measured when the analysis was restricted to patients with RD less than 1 cm (P = 0.72, log-rank test) or RD greater than 1 cm (P = 0.64, log-rank test). Discussion Despite the introduction of platinum-based chemotherapy in the 1980s, the overall survival of women with aggressive ovarian cancer has remained dramatically low. Postoperative combination treatment with a platinum-based medication (e.g., cisplatin or carboplatin) and a taxane is the standard first-line chemotherapy regimen for patients with advanced ovarian cancer [15,16]. The treatment shows promising effects in a high
Table 3 Prognostic factors for patients with FIGO stage IIIC or IV ovarian cancer (n = 203) Variable
Risk ratio
Age, >65 years vs ≤65 years 1.44 ASA grade, 3 and 4 vs 1 and 2 1.56 FIGO stage, IV vs IIIC b 1.55 Histology, serous vs others 0.83 Histologic grade, 3 vs 1 and 2 1.50 TTC interval, continuous 1.00 RD, cm <1 vs 0 3.39 1–2 vs 0 6.52 >2 vs 0 12.71 Fig. 1. Overall survival of patients with International Federation of Obstetricians and Gynecologists stage IIIC or IV ovarian cancer (TNM stage T3c or T4) (n = 205). All patients received chemotherapy after primary surgery. Patients were grouped by the number of days between surgery and initiation of chemotherapy (P = 0.93, log-rank test).
95% P value confidence Univariate Multivariate a interval 1.03–2.01 1.12–2.20 1.02–2.28 0.58–1.18 0.76–3.55 0.98–1.01
0.03 0.009 0.04 0.83 0.26 0.85
1.95–6.30 <0.001 3.35–13.15 6.92–24.70
0.82 0.54 0.70
<0.001
ASA, American Society of Anesthesiologists; FIGO, International Federation of Gynecology and Obstetrics; RD, residual disease; TTC, time to chemotherapy. a Risk ratios were calculated with the Cox proportional hazards regression model. Variables with significant P values after univariate analysis were included in the multivariate model. Overall survival was used as the end point. b Equivalent to TNM stage T4 versus T3c.
G.D. Aletti et al. / Gynecologic Oncology 104 (2007) 212–216
Fig. 2. Overall survival of patients with International Federation of Obstetricians and Gynecologists stage IIIC or IV ovarian cancer (TNM stage T3c or T4) (n = 205). Patients were grouped by the number of days between surgery and initiation of chemotherapy. (A) Patients with residual disease less than 1 cm (n = 137) (P = 0.93, log-rank test). (B) Patients with residual disease greater than 1 cm (n = 68) (P = 0.51, log-rank test).
percentage of patients (it has an initial response rate of up to 70%), but the development of chemoresistance is difficult to overcome. Although most tumors are chemosensitive when patients first present with disease, the 5-year survival rate is only 30% [17]. Chemotherapy resistance may develop along many pathways [18–20]. Alterations in cellular pharmacology (e.g., reduced medication accumulation), inactivation of cisplatin by sulfurcontaining molecules, and enhanced DNA repair may result in resistance to platinum-containing compounds. In addition to these factors, altered expression of proteins that regulate apoptosis may affect chemosensitivity. A major concern about the length of the TTC interval is whether waiting too long jeopardizes the clinical status of patients, especially those who have a prolonged recovery after aggressive surgery. Theoretically, a longer TTC interval increases the possibility that residual tumors will increase in volume and spread throughout the abdomen, thereby minimizing the effects of previous surgical efforts. Furthermore, during the TTC interval, tumor cells may develop mutations that confer chemoresistance, which reduces the potential benefit of firstline chemotherapy.
215
TTC data in the medical literature are contradictory. The Scottish Gynecological Cancer Trials Group report [21] included 472 patients from 4 studies who received platinumbased chemotherapy after surgery to treat ovarian cancer. Patients who received early postoperative chemotherapy had a shorter progression-free interval. This result was probably correlated to more extensive RD in that subgroup of patients [21]. Warwick et al. [22] reported that, in a cohort of 362 patients with advanced ovarian cancer, patients who received chemotherapy later had a poorer prognosis (univariate analysis). Upon multivariate analysis, the TTC interval did not have independent prognostic significance. In an Italian multicentric retrospective study [23], data from a cohort of 313 patients with advanced ovarian cancer who underwent surgery and received taxane- and platinum-based chemotherapy were analyzed retrospectively. The TTC interval did not appear to have any predictive value for response to treatment or prognostic relevance for survival. We undertook this study to answer the following clinical question: does a prolonged TTC interval affect the prognosis of patients with advanced ovarian cancer? Our institution has long maintained an aggressive treatment approach to ovarian cancer. In clinical practice, the most frequent reason for delaying the first chemotherapy course is to provide the patient with a longer postoperative recovery period, especially after extensive cytoreduction. In our homogeneous cohort of 218 patients with advanced ovarian cancer, retrospective analysis showed no correlation between performance of radical procedures and TTC interval length; the only exception was rectosigmoidectomy, which may be associated with greater morbidity. Neither operative time nor RD was correlated with the TTC interval. Furthermore, the TTC interval was not a predictor of survival in our cohort, even when we performed separate analyses of patients with RD less than 1 cm and patients with RD greater than 1 cm. Our results clearly indicate that concerns about surgical recovery or the length of the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach to treating patients with advanced ovarian cancer.
Fig. 3. Disease-free survival of patients with International Federation of Obstetricians and Gynecologists stage IIIC or IVovarian cancer (TNM stage T3c or T4) (n = 183). All patients received chemotherapy after primary surgery. Patients were grouped by the number of days between surgery and initiation of chemotherapy (P = 0.93, log-rank test).
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Acknowledgment Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic. References [1] Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30. [2] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 1975;42:101–4. [3] Hogberg T, Carstensen J, Simonsen E. Treatment results and prognostic factors in a population-based study of epithelial ovarian cancer. Gynecol Oncol 1993;48:38–49. [4] Baker TR, Piver MS, Hempling RE. Long term survival by cytoreductive surgery to less than 1 cm, induction weekly cisplatin and monthly cisplatin, doxorubicin, and cyclophosphamide therapy in advanced ovarian adenocarcinoma. Cancer 1994;74:656–63. [5] Randall TC, Rubin SC. Cytoreductive surgery for ovarian cancer. Surg Clin North Am 2001;81:871–83. [6] Bristow RE, del Carmen MG, Kaufman HS, Montz FJ. Radical oophorectomy with primary stapled colorectal anastomosis for resection of locally advanced epithelial ovarian cancer. J Am Coll Surg 2003; 197:565–74. [7] Chen LM, Leuchter RS, Lagasse LD, Karlan BY. Splenectomy and surgical cytoreduction for ovarian cancer. Gynecol Oncol 2000;77: 362–8. [8] Montz FJ, Schlaerth JB, Berek JS. Resection of diaphragmatic peritoneum and muscle: role in cytoreductive surgery for ovarian cancer. Gynecol Oncol 1989;35:338–40. [9] Merideth MA, Cliby WA, Keeney GL, Lesnick TG, Nagorney DM, Podratz KC. Hepatic resection for metachronous metastases from ovarian carcinoma. Gynecol Oncol 2003;89:16–21. [10] 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.
[11] Cliby W, Dowdy S, Feitoza SS, Gostout BS, Podratz KC. Diaphragm resection for ovarian cancer: technique and short-term complications. Gynecol Oncol 2004;94:655–60. [12] Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction of ovarian cancer: is there a correlation with “biological aggressiveness” and survival? Gynecol Oncol 2001;82:435–41. [13] Aletti GD, Dowdy SC, Gostout BS, Jones MB, Stanhope CR, Wilson TO, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol 2006;107:77–85. [14] Staging Announcement: FIGO Cancer Committee [announcement]. Gynecol Oncol 1986;25:383–5. [15] 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. [16] 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. [17] Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15–36. [18] Coukos G, Rubin SC. Chemotherapy resistance in ovarian cancer: new molecular perspectives. Obstet Gynecol 1998;91:783–92. [19] Sood AK, Buller RE. Drug resistance in ovarian cancer: from the laboratory to the clinic. Obstet Gynecol 1998;92:312–9. [20] Fraser M, Leung B, Jahani-Asl A, Yan X, Thompson WE, Tsang BK. Chemoresistance in human ovarian cancer: the role of apoptotic regulators. Reprod Biol Endocrinol 2003;1:66. [21] 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. [22] Warwick J, Kehoe S, Earl H, Luesley D, Redman C, Chan KK. Long-term follow-up of patients with advanced ovarian cancer treated in randomised clinical trials. Br J Cancer 1995;72:1513–7. [23] 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.
Is time to chemotherapy a determinant of prognosis in advanced-stage ovarian cancer? Giovanni D. Aletti a , Harry J. Long b , Karl C. Podratz a , William A. Cliby a,⁎ a
Division of Gynecologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA b Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
Received 22 May 2006 Available online 4 October 2006 Presented at The Annual Meeting on Women's Cancer, Palm Springs, California, March 22–26, 2006
Abstract Objectives. Clinicians often question when to start chemotherapy after patients undergo surgery for ovarian cancer. A major unproven concern is whether a long postoperative delay reduces the benefits of an extensive procedure and leads to disease progression. Our objectives were to evaluate the correlation between clinical and pathologic variables and to evaluate the effect of the “time to chemotherapy” (TTC) interval on survival. Methods. We retrospectively studied data from 218 patients with International Federation of Gynecology and Obstetrics stage IIIC or IV ovarian cancer (TNM stage T3c or T4) who were consecutively treated between January 1, 1994, and December 31, 1998. Results. Mean age at diagnosis was 64 years (range, 24–87 years; median, 65 years), and 206 patients received postoperative platinum-based chemotherapy. Mean TTC interval was 26 days (range, 7–79 days; median, 25 days). No correlation was found between operative time and TTC interval length (P = 0.99). Age and performance of rectosigmoidectomy were correlated with longer TTC interval (P = 0.009 and P = 0.005, respectively), but TTC was not a predictor of overall survival (odds ratio, 1.00; 95% confidence interval, 0.98–1.01; P = 0.85). Differences in TTC interval length (≤ 17 days, 18–26 days, 27–33 days, or ≥34 days) did not affect survival (P = 0.93). Even after categorizing patients by residual disease (< 1 cm or ≥ 1 cm), no statistically significant effect of TTC on prognosis was identified. Conclusions. Concerns about the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach for patients with advanced ovarian cancer. © 2006 Elsevier Inc. All rights reserved. Keywords: Chemotherapy timing; Ovarian cancer; Residual disease; Surgery
Introduction Ovarian cancer is the most severe gynecologic malignancy in terms of aggressiveness and survival, with approximately 16,000 deaths and 22,000 new cases estimated to occur in the United States during 2005 [1]. Griffiths [2] was the first to show in 1975 that the diameter of the remaining tumor after cytoreductive surgery is the principal determinant of prognosis in patients affected by ovarian cancer. Other prospective and retrospective studies have confirmed this observation [3–5]. In Abbreviations: DFS, disease-free survival; RD, residual disease; TTC, time to chemotherapy. ⁎ Corresponding author. E-mail address: [email protected] (W.A. Cliby). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.07.045
patients with advanced ovarian cancer, the goal of cytoreductive surgery is to minimize the amount of residual disease (RD). This aim can be achieved with different techniques that are used more frequently as gynecologic oncologists gain experience with advanced cytoreductive procedures (e.g., diaphragm stripping or resection, bowel resection, splenectomy, and liver resection) [6–11]. Radical surgical procedures used to treat patients with advanced ovarian cancer have resulted in acceptable morbidity rates [12]. We recently reported that patients with advanced ovarian cancer benefit from radical procedures such as diaphragm stripping, resection, or ablation, bowel resection, intensive peritoneal ablation, or splenectomy [13]. A major unproven concern about these radical procedures is that waiting too long after surgery to initiate chemotherapy may reduce the
G.D. Aletti et al. / Gynecologic Oncology 104 (2007) 212–216
benefits of surgery, thereby leading to disease progression. Furthermore, complications often occur after such intensive procedures and may prolong the recovery period. In the present study, we sought to evaluate the impact of the “time to chemotherapy” (TTC) interval, defined as the length of time between surgery and initiation of chemotherapy, on the survival of patients who underwent primary cytoreductive surgery and subsequent chemotherapy. We found that concerns about the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach for patients with advanced ovarian cancer.
213
Table 1 Patient characteristics and tumor features (n = 218) Variable
Patients No.
Patient characteristics Age, years Mean (range) Median ASA grade 1 2 3 4 Unknown
%
63.3 (24–87) 64 7 95 102 9 5
3.2 43.6 46.8 4.1 2.3
174 44
79.8 20.2
1 13 204
0.5 6.0 93.6
143 2 20 8 3 21 19 2
65.6 0.9 9.2 3.7 1.4 9.6 8.7 0.9
201 17
92.2 7.8
44 97 27 50
20.2 44.5 12.4 22.9
Materials and methods Relevant clinical data were abstracted from operative reports, hospital and outpatient clinical notes, the Mayo Clinic Cancer Center Registry database, and correspondence from referral institutions. Patients with a diagnosis of primary epithelial ovarian cancer who had undergone primary surgery at Mayo Clinic between January 1, 1994 and December 31, 1998 were identified from surgical and hospital records. Disease status before surgery was recorded in the operative notes for statistical analysis. The study was approved by the Mayo Foundation Institutional Review Board. All study patients were assessed and classified according to the American Society of Anesthesiology physical status grades before surgery. Surgical stage and cancer grade were defined using criteria from the International Federation of Gynecology and Obstetrics [14]. Patients with stage IIIC or IV ovarian cancer (TNM stage T3c or T4) were included in the study if they underwent primary surgical exploration at our institution and received a postoperative diagnosis of epithelial ovarian cancer. Patients who underwent surgical exploration at another institution or received chemotherapy before surgery and their referral to Mayo Clinic were excluded. After surgery, all patients received first-line platinum-based chemotherapy, either alone or in combination with paclitaxel or cyclophosphamide, for 6 to 8 courses, every 3 to 4 weeks, according to the different treatment protocols in effect during the years of the study. We did not restrict our analysis only to patients who received paclitaxel nor did we stratify patients according to chemotherapy regimen; we did not find a significant survival difference between the paclitaxelcombination group and all other patients in our cohort. Patients were excluded from the study if data from the first chemotherapy course were not reported. No patient received consolidation therapy at the time of the study. Only 1 patient had intraperitoneal chemotherapy, and the patient's data were included in the analysis. For statistical analysis, patient characteristics were categorized as follows: American Society of Anesthesiology grades 1 and 2 versus 3 and 4; histologic grade 3 versus 1 and 2; and histologic subtype serous versus all other subtypes. Operative time was categorized as less than 200 min or 200 min and longer (median value). For TTC, patients were categorized by quartiles: ≤ 17 days, 18–26 days, 27–33 days, or ≥ 34 days after surgery. RD was divided into 4 categories: RD of 0 (no gross tumor), macroscopic RD less than 1 cm, RD 1 cm or greater but less than or equal to 2 cm, and RD greater than 2 cm. Statistical analysis was performed by using the Student's t test, logistic regression analysis, and the log-rank test. We measured overall survival in all cases. Disease-free survival (DFS), defined as the time from diagnosis to the first progression of disease, was measured when data were available. Survival curves were plotted using the Kaplan–Meier method. Differences were considered statistically significant at P < 0.05. JMP statistical software (version 5.1, SAS Institute Inc, Cary, North Carolina) was used for the analysis.
Results Data were examined from 218 patients with a diagnosis of International Federation of Gynecology and Obstetrics stage IIIC or IV ovarian cancer (TNM stage T3c or T4). Patient characteristics and tumor features are summarized in Table 1.
Tumor features FIGO stage IIIC IV FIGO grade 1 2 3 Histologic findings Serous Mucinous Endometrioid Clear cell Transitional cell Mixed Seroanaplastic Müllerian origin Cytologic findings Positive Negative RD, cm None detectable <1 1–2 >2
ASA, American Society of Anesthesiologists; FIGO, International Federation of Gynecology and Obstetrics; RD, residual disease.
Primary surgery was performed with the intent to diagnose, stage, and surgically reduce tumor volume. Mean operative time was 215 min (median, 200 min; range, 40–480 min). Mean TTC was 26 days (median, 26 days). The upper and lower quartiles for TTC were 17 and 33 days, respectively. Five patients (2%) died less than 30 days after surgery. Thirteen patients (6%) did not receive chemotherapy because of rapid disease progression, patient refusal, inadequate performance status, or perioperative death; all 13 died less than 3.5 months after surgery and were not included in subsequent analyses. Aggressive surgical procedures such as diaphragm stripping, resection, or ablation, rectosigmoidectomy, intensive peritoneal ablation, splenectomy, and hepatectomy were correlated with a longer operative time and less RD (data not shown). Nevertheless, of all the surgical procedures, only rectosigmoidectomy was correlated with the TTC interval (Table 2), which suggests that, after most surgical procedures, a standard recovery period is sufficient unless postoperative complications occur. The TTC
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Table 2 Correlation between patient variables and the “time to chemotherapy” interval length Variable Age, years <65 ≥ 65 ASA grade 3 and 4 1 and 2 Operative time, minutes <200 ≥ 200 Rectosigmoidectomy Yes No Diaphragm surgery (stripping, resection, ablation) Yes No Other radical procedures (splenectomy, bowel resection, hepatectomy, intensive peritoneal ablation) Yes No RD, cm b 0 <1 1–2 >2
Mean TTC, days P value a 0.009 24.2 28.7 0.58 26.6 25.7 0.99 26.2 26.3 0.005 30.2 24.8 0.86 26.6 26.2 0.10
28.5 25.4 NS 27.7 25.1 26.4 27.5
ASA, American Society of Anesthesiologists; NS, not significant; RD, residual disease; TTC, time to chemotherapy. a Student's t test was used for analysis. Differences were considered statistically significant at P < 0.05. b Patients in each subgroup were compared to all others.
interval was also affected by age, suggesting that a prolonged recovery period for older patients was necessary. We investigated the effect of TTC on survival. Patients were categorized into 4 groups by TTC interval length (groups were established by TTC quartile values: ≤17 days, 18–26 days, 27– 33 days, or ≥ 34 days after surgery). Overall survival rates were similar for all groups (Fig. 1). After 5 years, the survival rates
were 32% (TTC, ≤ 17 days), 34% (TTC, 18–26 days), 44% (TTC, 27–33 days), and 35% (TTC, ≥ 34 days) (P = 0.93, logrank test). Upon multivariate analysis, RD was the only independent variable that predicted survival (Table 3). When survival analysis was restricted to patients with RD less than 1 cm, no survival benefits were evident for patients who started chemotherapy earlier (Fig. 2A); after 5 years, the survival rates were 44% (TTC, ≤ 17 days), 45% (TTC, 18–26 days), 55% (TTC, 27–33 days), and 51.5% (TTC, ≥ 34 days) (P = 0.93, log-rank test). Similarly, patients with RD greater than 1 cm did not show TTC interval-dependent differences in overall survival (Fig. 2B); after 5 years, the survival rates were 6.5% (TTC, ≤ 17 days), 6.5% (TTC, 18–26 days), 17% (TTC, 2733 days), and 6% (TTC, ≥ 34 days) (P = 0.51, log-rank test). Lastly, we investigated the effect of TTC on DFS. Information about DFS was available for 183 patients. Patients were categorized into the 4 subgroups by TTC interval length. DFS rates were similar for all groups (Fig. 3). Five-year DFS rates were 11.5% (TTC, ≤ 17 days), 13.4% (TTC, 18–26 days), 13.2% (TTC, 27–33 days), and 13.5% (TTC, ≥ 34 days) (P = 0.74, log-rank test). No difference in DFS was measured when the analysis was restricted to patients with RD less than 1 cm (P = 0.72, log-rank test) or RD greater than 1 cm (P = 0.64, log-rank test). Discussion Despite the introduction of platinum-based chemotherapy in the 1980s, the overall survival of women with aggressive ovarian cancer has remained dramatically low. Postoperative combination treatment with a platinum-based medication (e.g., cisplatin or carboplatin) and a taxane is the standard first-line chemotherapy regimen for patients with advanced ovarian cancer [15,16]. The treatment shows promising effects in a high
Table 3 Prognostic factors for patients with FIGO stage IIIC or IV ovarian cancer (n = 203) Variable
Risk ratio
Age, >65 years vs ≤65 years 1.44 ASA grade, 3 and 4 vs 1 and 2 1.56 FIGO stage, IV vs IIIC b 1.55 Histology, serous vs others 0.83 Histologic grade, 3 vs 1 and 2 1.50 TTC interval, continuous 1.00 RD, cm <1 vs 0 3.39 1–2 vs 0 6.52 >2 vs 0 12.71 Fig. 1. Overall survival of patients with International Federation of Obstetricians and Gynecologists stage IIIC or IV ovarian cancer (TNM stage T3c or T4) (n = 205). All patients received chemotherapy after primary surgery. Patients were grouped by the number of days between surgery and initiation of chemotherapy (P = 0.93, log-rank test).
95% P value confidence Univariate Multivariate a interval 1.03–2.01 1.12–2.20 1.02–2.28 0.58–1.18 0.76–3.55 0.98–1.01
0.03 0.009 0.04 0.83 0.26 0.85
1.95–6.30 <0.001 3.35–13.15 6.92–24.70
0.82 0.54 0.70
<0.001
ASA, American Society of Anesthesiologists; FIGO, International Federation of Gynecology and Obstetrics; RD, residual disease; TTC, time to chemotherapy. a Risk ratios were calculated with the Cox proportional hazards regression model. Variables with significant P values after univariate analysis were included in the multivariate model. Overall survival was used as the end point. b Equivalent to TNM stage T4 versus T3c.
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Fig. 2. Overall survival of patients with International Federation of Obstetricians and Gynecologists stage IIIC or IV ovarian cancer (TNM stage T3c or T4) (n = 205). Patients were grouped by the number of days between surgery and initiation of chemotherapy. (A) Patients with residual disease less than 1 cm (n = 137) (P = 0.93, log-rank test). (B) Patients with residual disease greater than 1 cm (n = 68) (P = 0.51, log-rank test).
percentage of patients (it has an initial response rate of up to 70%), but the development of chemoresistance is difficult to overcome. Although most tumors are chemosensitive when patients first present with disease, the 5-year survival rate is only 30% [17]. Chemotherapy resistance may develop along many pathways [18–20]. Alterations in cellular pharmacology (e.g., reduced medication accumulation), inactivation of cisplatin by sulfurcontaining molecules, and enhanced DNA repair may result in resistance to platinum-containing compounds. In addition to these factors, altered expression of proteins that regulate apoptosis may affect chemosensitivity. A major concern about the length of the TTC interval is whether waiting too long jeopardizes the clinical status of patients, especially those who have a prolonged recovery after aggressive surgery. Theoretically, a longer TTC interval increases the possibility that residual tumors will increase in volume and spread throughout the abdomen, thereby minimizing the effects of previous surgical efforts. Furthermore, during the TTC interval, tumor cells may develop mutations that confer chemoresistance, which reduces the potential benefit of firstline chemotherapy.
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TTC data in the medical literature are contradictory. The Scottish Gynecological Cancer Trials Group report [21] included 472 patients from 4 studies who received platinumbased chemotherapy after surgery to treat ovarian cancer. Patients who received early postoperative chemotherapy had a shorter progression-free interval. This result was probably correlated to more extensive RD in that subgroup of patients [21]. Warwick et al. [22] reported that, in a cohort of 362 patients with advanced ovarian cancer, patients who received chemotherapy later had a poorer prognosis (univariate analysis). Upon multivariate analysis, the TTC interval did not have independent prognostic significance. In an Italian multicentric retrospective study [23], data from a cohort of 313 patients with advanced ovarian cancer who underwent surgery and received taxane- and platinum-based chemotherapy were analyzed retrospectively. The TTC interval did not appear to have any predictive value for response to treatment or prognostic relevance for survival. We undertook this study to answer the following clinical question: does a prolonged TTC interval affect the prognosis of patients with advanced ovarian cancer? Our institution has long maintained an aggressive treatment approach to ovarian cancer. In clinical practice, the most frequent reason for delaying the first chemotherapy course is to provide the patient with a longer postoperative recovery period, especially after extensive cytoreduction. In our homogeneous cohort of 218 patients with advanced ovarian cancer, retrospective analysis showed no correlation between performance of radical procedures and TTC interval length; the only exception was rectosigmoidectomy, which may be associated with greater morbidity. Neither operative time nor RD was correlated with the TTC interval. Furthermore, the TTC interval was not a predictor of survival in our cohort, even when we performed separate analyses of patients with RD less than 1 cm and patients with RD greater than 1 cm. Our results clearly indicate that concerns about surgical recovery or the length of the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach to treating patients with advanced ovarian cancer.
Fig. 3. Disease-free survival of patients with International Federation of Obstetricians and Gynecologists stage IIIC or IVovarian cancer (TNM stage T3c or T4) (n = 183). All patients received chemotherapy after primary surgery. Patients were grouped by the number of days between surgery and initiation of chemotherapy (P = 0.93, log-rank test).
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