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Survival impact of multiple bowel resections in patients undergoing primary cytoreductive surgery for advanced ovarian cancer: A case–control study
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Gynecologic Oncology 107 (2007) 495 – 499 www.elsevier.com/locate/ygyno
Survival impact of multiple bowel resections in patients undergoing primary cytoreductive surgery for advanced ovarian cancer: A case–control study Ritu Salani a,⁎, Marianna L. Zahurak b , Antonio Santillan a , Robert L. Giuntoli II a , Robert E. Bristow a,c a
The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA b Department of Biostatistics, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA c Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA Received 14 May 2007 Available online 12 September 2007
Abstract Objective. To evaluate clinicopathological factors and survival outcome of patients with advanced epithelial ovarian carcinoma undergoing multiple bowel resections to achieve optimal (≤ 1 cm) cytoreduction. Methods. A case–control study was performed identifying patients undergoing optimal primary cytoreductive surgery with ≥ 2 bowel resections between 10/1997 and 2/2006. The two control groups consisted of (1) patients undergoing optimal cytoreduction with ≤ 1 bowel resections matched [1:2] for age and stage and (2) patients left with suboptimal disease. Cox proportional hazards model were used to evaluate the effects of demographic and surgico-pathologic factors on survival outcome. Results. A total of 34 patients underwent ≥ 2 bowel resections. Sixty-eight patients underwent ≤ 1 bowel resections. All patients had optimal cytoreduction and 40/102 patients (39.2%) underwent complete cytoreduction. Patients undergoing multiple bowel resections experienced a higher EBL (700 v 500 mL, p = 0.01) and longer LOS (10 v 7 days, p = 0.01) compared to patients with ≤ 1 bowel resections. Multivariate analysis revealed the amount of residual disease to be a statistically significant and radiation therapy to the right pelvic sidewall and cul-de-sac independent predictor of overall survival. The median overall survival time for patients undergoing ≥ 2 bowel resections was 28.3 months, which was comparable to patients undergoing ≤ 1 bowel resections, (37.8 months, p = 0.09) but statistically significantly superior to patients left with suboptimal residual disease (12 months, p = 0.02). Conclusions. Although primary surgery that includes ≥ 2 bowel resections is associated with longer LOS and a higher EBL, such extensive procedures are warranted if they will contribute to an overall optimal residual disease state. © 2007 Elsevier Inc. All rights reserved. Keywords: Ovarian carcinoma; Primary cytoreductive surgery; Bowel resection
Introduction Ovarian cancer is the fourth leading cause of cancer-related death among women in the United States, with an estimated 23,000 cases and 16,000 deaths in 2006 [1]. Although there are many factors influencing survival for patients with ovarian cancer, one of the most significant is the volume of residual disease following primary cytoreductive surgery [2–5]. Previous studies ⁎ Corresponding author. 600 N Wolfe St/ Phipps 281, Baltimore, MD 21287, USA. Fax: +1 410 614 8718. E-mail address: [email protected] (R. Salani). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.08.003
have shown that residual disease volume ≤1 cm in maximal diameter confers a survival benefit [2–5]. Furthermore, complete cytoreduction (removal of all visible disease) provides an improvement in overall survival compared to optimal cytoreduction (macroscopic residual disease less than 1cm) [6–10]. As a majority of ovarian cancer cases present in advanced stages of the disease, more extensive procedures may be required in order to achieve optimal cytoreduction. These procedures may include bowel resection(s) and upper abdominal surgery such as diaphragmatic stripping, splenectomy and liver resection [11– 18]. These surgical efforts have been shown to improve survival when optimal cytoreduction is attainable. However, the survival
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Table 1 List of bowel resections performed Single bowel resections Rectosigmoid only Ileum Transverse colon Total
22 6 3 31
Simple linear regression models were used to compare study groups with respect to age, length of stay and blood loss. Cost data and length of stay were transformed with the logarithmic transformation before statistical analyses. Significance tests were performed on the transformed data. Means are reported on the natural scale. All confidence intervals (CI) are at the 95% level and all pvalues are two sided.
Results Multiple bowel resections Rectosigmoid and ileum Rectosigmoid and transverse colon Transverse colon and ileum Jejunum and ileum Rectosigmoid and cecum Rectosigmoid, ileum, transverse colon Total
17 10 2 1 1 3 34
impact of extensive intestinal surgery in the setting of optimal residual disease has not been well described. Therefore, the purpose of this study was to evaluate the survival outcome of patients undergoing multiple (≥ 2) bowel resections in order to achieve optimal cytoreduction compared to patients undergoing one or no bowel resections and those patients left with bulky residual disease. Methods Approval to conduct this study was obtained from the Johns Hopkins Medical Institutions (JHMI) Clinical Research Committee and Joint Committee on Clinical Investigation. All patients with pathologically confirmed Stage IIIC or IV epithelial ovarian cancer undergoing primary surgery at JHMI between October 1997 and February 2006 were retrospectively identified from institutional tumor registry databases. Patients were excluded from the study for the following: histology consistent with low-grade, borderline, carcinosarcoma or non-epithelial carcinoma, or the administration of neoadjuvant chemotherapy (treatment with chemotherapy agents prior to surgical cytoreductive surgery). Patients undergoing optimal primary cytoreductive surgery, defined as residual disease ≤1 cm, with two or more bowel resections were identified as cases. Two control groups were utilized for comparison. The first control group was selected as patients undergoing optimal primary cytoreductive surgery with one or less bowel resections, matched at a ratio of two controls to each case by age and stage. The second control group of patients consisted of patients undergoing primary cytoreductive surgery with suboptimal residual disease, defined as greater than 1 cm, irrespective of the number of bowel resections. Individual subject data were collected retrospectively from inpatient and ambulatory medical records. Surgical and pathology reports from the primary surgery were reviewed in all cases. The following peri-operative information was abstracted: patient age at diagnosis, date of surgery, FIGO stage of disease, surgical procedures performed, presence and amount of ascites, volume of residual disease and estimated blood loss (EBL). Postoperative information recorded included the length of hospital stay (LOS), and postoperative morbidity occurring within 30 days of surgery. Surveillance information included adjuvant therapy administered, the date of last follow-up, and/or the date of death.
A total of 34 patients met study inclusion criteria and underwent ≥ 2 bowel resections as part of optimal primary cytoreductive surgery for ovarian cancer. A total of 68 patients were identified as having undergone optimal primary cytoreduction with ≤ 1 bowel resection. This group consisted specifically of 31 patients requiring one bowel resection and 37 patients who required no bowel resections. The group of patients, who underwent suboptimal cytoreductive surgery, consisted of 23 patients. In this subgroup, 3 patients underwent one bowel resection and two underwent multiple bowel resections. Pathology reports documented involvement of the portion of bowel resected in all cases. A complete list of bowel resections performed in patients who underwent optimal cytoreductive surgery is listed in Table 1. Additionally, 2 of the 70 patients (2.9%) undergoing bowel resections had a proximal diverting ostomy at the time of primary surgery, which were performed if the reanastomosis site was under tension or in the setting of infection/sepsis. Clinicopathological patient characteristics are summarized in Table 2. Complete cytoreduction was achieved in 31 of 68 (45.6%) patients undergoing one or no bowel resections and 9 of 34 (26.5%) patients undergoing ≥ 2 bowel resections. Following initial surgery, all patients received adjuvant chemotherapy with combination platinum-based and taxane chemotherapy, excluding two patients who suffered postoperative mortality. Patients with optimal cytoreduction who underwent ≥ 2 bowel resections experienced a higher median EBL, 700 mL, compared to a median EBL of 500 mL for patients who underwent one or no bowel resections (p = 0.01). Length of hospital stay was also significantly longer in patients who underwent multiple bowel resections compared to patients who underwent one or no bowel resections, median LOS of 10 days compared to 7 days, respectively. (p = 0.01). Major postoperative complications occurred in 30 (29.4%) of the 102 patients undergoing optimal cytoreductive surgery Table 2 Clinicopathological characteristics
Statistical analysis The major statistical endpoint of this study was survival. Event time distributions for this endpoint were estimated using the method of Kaplan and Meier [19] and compared using the log-rank statistic [20] or the proportional hazards regression model [21]. Factors of primary interest in this study were the number of bowel resections and the level of residual disease. Other factors tested for prognostic value included, age, stage and ascites. Covariates having some prognostic value in univariate analyses were entered into multivariate Cox proportional hazards model and nonsignficant factors removed in a stepwise fashion. Hazard ratios are expressed relative to a baseline reference category.
Median age Stage III IV Ascites EBL LOS Residual disease Complete Optimal
Multiple bowel resections (n = 34)
0–1 bowel resections (n = 68)
Suboptional debulking (n = 23)
63.5 26 8 2000 700 10
62 52 16 550 500 7
p = 0.01 p = 0.01
66 19 4 1250 550 9
9 (26.5%) 25 (73.5%)
30 (44.1%) 28 (55.9%)
p = 0.76 p = 0.09
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Table 3 Postoperative complications 0–1 bowel resection Cellulitis Fistulas/breakdown Respiratory distress Pneumonia/pulmonary embolus Prolonged ileus Sepsis Retained sponge Postoperative death
4 (5.9%) 3 (4.4%) 2 (2.9%) 4 (5.9%)
2 bowel resections 4 (11.8%) 2 (5.9%) 2 (5.9%) 3 (8.8%) 2 (5.9%) 1 (2.9%)
1 (1.5%) 14 (20.6%)
2 (5.9%) 16 (47.1%), p b 0.01
(Table 3). There were 14/68 complications in the group undergoing one or no bowel resections: 20.6% (95% CI: 11.7%, 32.1%), compared to 16/34 in the group undergoing two bowel resections: 47.1% (95% CI: 29.8%, 64.9%), p b 0.01. This included two postoperative deaths; one in an elderly patient who developed refractory sepsis and another in a patient who developed a massive pulmonary embolism. Survival analysis The median follow-up of surviving patients was 19.3 months from the time of surgery and the median survival was 37 months for all patients with optimal residual disease. A total of five different clinical and pathological variables were analyzed for prognostic significance on univariate and multivariate analysis. The optimal group had twice the risk of death compared to the complete reduction group, HR = 2.2 (95% CI: 1.08, 4.44, p = 0.03), and the risk in the suboptimal group was almost six times the risk in the complete group 5.9 (95% CI: 2.7, 13.0, p b .0001).
Fig. 2. Overall survival for patients undergoing complete cytoreduction. Patients with ≤1 bowel resection had a median survival of 46.5 months; patients with two or more bowel resections the median survival was not reached with 60% alive at 28 months follow-up ( p = 0.76). , bowel resections; , ≥2 bowel resections.
Survival analysis revealed that patients with one or no bowel resections had a median survival of 37.8 months and patients with ≥ 2 bowel resections had a median survival of 28.3 months ( p = 0.09). Patients who underwent suboptimal cytoreductive surgery, regardless of the number of bowel resections, had a median survival of 12 months, which was statistically significantly worse compared to patients undergoing multiple bowel resections ( p = 0.02) (Fig. 1). When patients who underwent complete cytoreductive surgery were analyzed, the median survival was 46.5 months for patients with one or no bowel resections, and for patients who underwent multiple bowel resections, median survival was not reached with 60% alive at 28 months follow-up (p = 0.76) (Fig. 2). Discussion
Fig. 1. Overall survival time according to residual disease. Patients with one or no bowel resections had a median survival of 37.8 months; patients with two or more bowel resections had a median survival of 28.3 months ( p = 0.09); and patients with suboptimal cytoreductive surgery had a median survival of 12 months ( p = 0.02). , 0–1 bowel resections; , ≥2 bowel resections; , suboptimal resection.
The inverse relationship between residual disease after cytoreductive surgery and survival in ovarian carcinoma was first conclusively demonstrated in 1975 by Griffiths et al. [2]. Since then, multiple studies have shown that cytoreductive surgery that achieves residual disease ≤1 to 2 cm in maximal diameter is associated with improved survival [3–5]. The ability to achieve optimal cytoreduction may require the need to perform radical procedures. The benefits of performing these extensive procedures, such as extrapelvic bowel resection, diaphragm stripping or resection, modified posterior pelvic exenterations, peritoneal implant ablation and retroperitoneal lymph node dissection, have been shown for patients with extensive disease [11]. A recent study by Aletti et al. [7] showed that residual disease was the only independent predictor of survival and complete cytoreduction resulted in a superior survival. The requirement for radical surgery also correlated with optimal
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cytoreduction and improved survival [7]. Eisenhauer et al. [8] noted that the addition of upper abdominal surgery in order to achieve optimal cytoreduction resulted in better median progression-free and overall survival compared to patients who underwent suboptimal cytoreduction and comparable survival to patients undergoing optimal cytoreduction with standard procedures. Furthermore, Cliby et al. [12] reviewed patients undergoing radical debulking procedures such as diaphragmatic resections, bowel resections, hepatic resection and splenectomy, which could be performed with tolerable morbidity while contributing to the surgical cytoreductive effort. Bowel resection is one of the more common procedures required to remove bulky metastatic ovarian cancer. It has been estimated that bowel resections are required in approximately 50% of optimal cytoreductive operations [11,22–24]. Multiple authors have also shown that the need to perform a bowel resection which contributes to small volume residual disease is associated with a better overall survival and comparable to patients who did not require a bowel resection [13–15,17,25]. Gillette-Cloven et al. [13] reported that optimal cytoreduction, with or without a bowel resection, conferred improved survival with a median survival of 35 months compared to a median survival of 18 months for patients undergoing suboptimal cytoreduction. The performance of a bowel resection may contribute to a complete cytoreductive surgical effort, which has been associated with a more significant influence on overall survival compared to patients undergoing optimal cytoreduction with visible residual disease [2,6,7,10,11,26–28]. Additionally, studies have shown that bowel resection(s) can be performed with an acceptable risk of complications and postoperative morbidity [9,13,14,21,29–31]. In this study, we evaluated patients with ovarian cancer who required multiple bowel resections in order to achieve optimal cytoreduction. The need to perform multiple bowel resections was associated with a longer hospitalization, higher surgical blood loss and higher rate of complications during optimal primary cytoreductive surgery. However, the requirement for ≥ 2 bowel resections to achieve optimal residual disease was associated with an overall median survival time of 28.3 months which was inferior to but not statistically different from patients left with optimal residual disease when ≤ 1 bowel resection was required (37.8 months, p = 0.09). Irrespective of the number of bowel resections, optimal residual disease was associated with a statistically superior survival outcome compared to patients left with bulky residual disease. These data suggest that the requirement for multiple bowel resections in order to achieve optimal cytoreduction for advanced ovarian cancer may reflect extensive disease. There are limitations of this study that must be considered when evaluating the results of this study. First, although we made every effort to include all eligible patients, the number of subjects undergoing ≥ 2 bowel resections was relatively limited. It is possible that with extended follow-up, the survival curves for patients undergoing ≥ 2 bowel resections and those with ≤1 bowel resection may diverge to the point of a statistically significant difference. Secondly, as a case–control study, the patient
population selected, although homogenous with respect to disease, may not be reflective of all patients with ovarian cancer. Third, the primary study group consisted of patients with extensive disease, as evidenced by the frequent requirement for proactive surgical procedures. This may have contributed to the relatively short median survival times observed, at least in comparison to other contemporary and less select cohorts of patients with advanced stage ovarian cancer. A fourth limitation is that we did not assess for differences in chemotherapy regimens administered following disease recurrence, which may have impacted overall survival. Despite these limitations, the current data suggest that multiple bowel resections are warranted as a part of primary cytoreductive surgery for ovarian cancer if it contributes to an optimal, or ideally complete, residual disease state. 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] Chi DS, Liao JB, Leon LF, Venkatraman ES, Hensley ML, Bhaskaran D, et al. Identification of prognostic factors in advanced epithelial ovarian carcinoma. Gynecol Oncol 2001;82(3):532–7. [4] Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170: 974–80. [5] Ozols RF, Rubin SC, Thomas GM, Robboy SJ. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC, Barakat RR, Markman M, Randall ME, editors. Principles and practices of gynecologic oncology. 4th edition. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 895–977. [6] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90(2):390–6. [7] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Levine DA, Poynor EA, Aghajanian C, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer. Gynecol Oncol 2006;103:1083–90. [8] 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. [9] Scarabelli C, Gallo A, Franceschi S, Campagnutta E, De G, Giorda G, et al. Primary cytoreductive surgery with rectosigmoid colon resection for patients with advanced epithelial ovarian carcinoma. Cancer 2000;88(2): 389–97. [10] Eisenkop SM, Friedman RL, Wang H. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–6. [11] 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. [12] 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. [13] Gillette-Cloven N, Burger RA, Monk BJ, McMeekin DS, Vasilev S, DiSaia PJ, et al. Bowel resection at the time of primary cytoreduction for epithelial ovarian cancer. J Am Coll Surg 2001;193:626–32. [14] Weber AM, Kennedy AW. The role of bowel resection in the primary surgical debulking of carcinoma of the ovary. J Am Coll Surg 1994;179: 465–70.
R. Salani et al. / Gynecologic Oncology 107 (2007) 495–499 [15] Hammond RH, Houghton CRS. The role of bowel surgery in the primary treatment of epithelial ovarian cancer. Aust N Z J Obstet Gynaecol 1990; 30:166–9. [16] 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. [17] Shimada M, Kigawa J, Minagawa Y, Irie T, Takahashi M, Terakawa N. Significance of cytoreductive surgery including bowel resection for patients with advanced ovarian cancer. Am J Clin Oncol 1999;22(5):481–4. [18] Tebes SJ, Cardosi R, Hoffman MS. Colorectal resection in patients with ovarian and primary peritoneal carcinoma. Am J Obstet Gynecol 2006; 195(2):585–9. [19] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–80. [20] Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. JNCI 1959;22:719–48. [21] Cox DR. Regression models and life-tables (with discussion). J Roy Statist Soc (B) 1972;34:187–220. [22] Kuhn W, Florack G, Roder J, Schmalfeldt B, Pache L, Rust M, et al. The influence of upper abdominal surgery on perioperative morbidity and mortality in patients with advanced ovarian cancer FIGO III and FIGO IV. Int J Gynecol Cancer 1998;8:56–63. [23] Jaeger W, Ackermann S, Kessler H, Katalinic A, Lang N. The effect of bowel resection on survival in advanced epithelial ovarian cancer. Gynecol Oncol 2001;83:286–91. [24] Hoffman MS, Griffin D, Tebes S, Cardosi RJ, Martino MA, Fiorica JV, et al. Sites of bowel resected to achieve optimal ovarian cancer cytoreduction:
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[30]
[31]
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implications regarding surgical management. Am J Obstet Gynecol 2005; 193:582–6. Estes JM, Leath CA, Straughn JM, Rocconi RP, Kirby TO, Huh WK, et al. Bowel resection at the time of primary debulking for epithelial ovarian carcinoma: outcomes in patients treated with platinum and taxane-based chemotherapy. J Am Coll Surg 2006;203(4):527–32. Makar AP, Baekelandt M, Trope CG, Kristensen GB. The prognostic significance of residual disease, FIGO substage, tumor histology, and grade in patients with FIGO stage III ovarian cancer. Gynecol Oncol 1995; 56:175–80. Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for ovarian cancer. Obstet Gynecol 1983;61: 413–20. Naik R, Nordin A, Cross PA, Hemming D, Lopes AB, Monaghan JM. Complete cytoreduction: is epithelial ovarian cancer confined to the pelvis biologically different from bulky abdominal disease? Gynecol Oncol 2000; 78:176–80. Mourton SM, Temple LK, Abu-Rustum NR, Gemignani ML, Sonoda Y, Bochner BH, et al. Morbidity of rectosigmoid resection and primary anastomosis in patients undergoing primary cytoreductive surgery for advanced epithelial ovarian cancer. Gynecol Oncol 2005;99(3): 608–14. Clayton RD, Obermair A, Hammond IG, Leung YC, McCartney AJ. The Western Australian experience of the use of en bloc resection of ovarian cancer with concomitant rectosigmoid colectomy. Gynecol Oncol 2002;84(1):53–7. Tamussino KF, Lim PC, Webb MJ, Lee RA, Lesnick TG. Gastrointestinal surgery in patients with ovarian cancer. Gynecol Oncol 2001;80:79–84.
Gynecologic Oncology 107 (2007) 495 – 499 www.elsevier.com/locate/ygyno
Survival impact of multiple bowel resections in patients undergoing primary cytoreductive surgery for advanced ovarian cancer: A case–control study Ritu Salani a,⁎, Marianna L. Zahurak b , Antonio Santillan a , Robert L. Giuntoli II a , Robert E. Bristow a,c a
The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA b Department of Biostatistics, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA c Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA Received 14 May 2007 Available online 12 September 2007
Abstract Objective. To evaluate clinicopathological factors and survival outcome of patients with advanced epithelial ovarian carcinoma undergoing multiple bowel resections to achieve optimal (≤ 1 cm) cytoreduction. Methods. A case–control study was performed identifying patients undergoing optimal primary cytoreductive surgery with ≥ 2 bowel resections between 10/1997 and 2/2006. The two control groups consisted of (1) patients undergoing optimal cytoreduction with ≤ 1 bowel resections matched [1:2] for age and stage and (2) patients left with suboptimal disease. Cox proportional hazards model were used to evaluate the effects of demographic and surgico-pathologic factors on survival outcome. Results. A total of 34 patients underwent ≥ 2 bowel resections. Sixty-eight patients underwent ≤ 1 bowel resections. All patients had optimal cytoreduction and 40/102 patients (39.2%) underwent complete cytoreduction. Patients undergoing multiple bowel resections experienced a higher EBL (700 v 500 mL, p = 0.01) and longer LOS (10 v 7 days, p = 0.01) compared to patients with ≤ 1 bowel resections. Multivariate analysis revealed the amount of residual disease to be a statistically significant and radiation therapy to the right pelvic sidewall and cul-de-sac independent predictor of overall survival. The median overall survival time for patients undergoing ≥ 2 bowel resections was 28.3 months, which was comparable to patients undergoing ≤ 1 bowel resections, (37.8 months, p = 0.09) but statistically significantly superior to patients left with suboptimal residual disease (12 months, p = 0.02). Conclusions. Although primary surgery that includes ≥ 2 bowel resections is associated with longer LOS and a higher EBL, such extensive procedures are warranted if they will contribute to an overall optimal residual disease state. © 2007 Elsevier Inc. All rights reserved. Keywords: Ovarian carcinoma; Primary cytoreductive surgery; Bowel resection
Introduction Ovarian cancer is the fourth leading cause of cancer-related death among women in the United States, with an estimated 23,000 cases and 16,000 deaths in 2006 [1]. Although there are many factors influencing survival for patients with ovarian cancer, one of the most significant is the volume of residual disease following primary cytoreductive surgery [2–5]. Previous studies ⁎ Corresponding author. 600 N Wolfe St/ Phipps 281, Baltimore, MD 21287, USA. Fax: +1 410 614 8718. E-mail address: [email protected] (R. Salani). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.08.003
have shown that residual disease volume ≤1 cm in maximal diameter confers a survival benefit [2–5]. Furthermore, complete cytoreduction (removal of all visible disease) provides an improvement in overall survival compared to optimal cytoreduction (macroscopic residual disease less than 1cm) [6–10]. As a majority of ovarian cancer cases present in advanced stages of the disease, more extensive procedures may be required in order to achieve optimal cytoreduction. These procedures may include bowel resection(s) and upper abdominal surgery such as diaphragmatic stripping, splenectomy and liver resection [11– 18]. These surgical efforts have been shown to improve survival when optimal cytoreduction is attainable. However, the survival
496
R. Salani et al. / Gynecologic Oncology 107 (2007) 495–499
Table 1 List of bowel resections performed Single bowel resections Rectosigmoid only Ileum Transverse colon Total
22 6 3 31
Simple linear regression models were used to compare study groups with respect to age, length of stay and blood loss. Cost data and length of stay were transformed with the logarithmic transformation before statistical analyses. Significance tests were performed on the transformed data. Means are reported on the natural scale. All confidence intervals (CI) are at the 95% level and all pvalues are two sided.
Results Multiple bowel resections Rectosigmoid and ileum Rectosigmoid and transverse colon Transverse colon and ileum Jejunum and ileum Rectosigmoid and cecum Rectosigmoid, ileum, transverse colon Total
17 10 2 1 1 3 34
impact of extensive intestinal surgery in the setting of optimal residual disease has not been well described. Therefore, the purpose of this study was to evaluate the survival outcome of patients undergoing multiple (≥ 2) bowel resections in order to achieve optimal cytoreduction compared to patients undergoing one or no bowel resections and those patients left with bulky residual disease. Methods Approval to conduct this study was obtained from the Johns Hopkins Medical Institutions (JHMI) Clinical Research Committee and Joint Committee on Clinical Investigation. All patients with pathologically confirmed Stage IIIC or IV epithelial ovarian cancer undergoing primary surgery at JHMI between October 1997 and February 2006 were retrospectively identified from institutional tumor registry databases. Patients were excluded from the study for the following: histology consistent with low-grade, borderline, carcinosarcoma or non-epithelial carcinoma, or the administration of neoadjuvant chemotherapy (treatment with chemotherapy agents prior to surgical cytoreductive surgery). Patients undergoing optimal primary cytoreductive surgery, defined as residual disease ≤1 cm, with two or more bowel resections were identified as cases. Two control groups were utilized for comparison. The first control group was selected as patients undergoing optimal primary cytoreductive surgery with one or less bowel resections, matched at a ratio of two controls to each case by age and stage. The second control group of patients consisted of patients undergoing primary cytoreductive surgery with suboptimal residual disease, defined as greater than 1 cm, irrespective of the number of bowel resections. Individual subject data were collected retrospectively from inpatient and ambulatory medical records. Surgical and pathology reports from the primary surgery were reviewed in all cases. The following peri-operative information was abstracted: patient age at diagnosis, date of surgery, FIGO stage of disease, surgical procedures performed, presence and amount of ascites, volume of residual disease and estimated blood loss (EBL). Postoperative information recorded included the length of hospital stay (LOS), and postoperative morbidity occurring within 30 days of surgery. Surveillance information included adjuvant therapy administered, the date of last follow-up, and/or the date of death.
A total of 34 patients met study inclusion criteria and underwent ≥ 2 bowel resections as part of optimal primary cytoreductive surgery for ovarian cancer. A total of 68 patients were identified as having undergone optimal primary cytoreduction with ≤ 1 bowel resection. This group consisted specifically of 31 patients requiring one bowel resection and 37 patients who required no bowel resections. The group of patients, who underwent suboptimal cytoreductive surgery, consisted of 23 patients. In this subgroup, 3 patients underwent one bowel resection and two underwent multiple bowel resections. Pathology reports documented involvement of the portion of bowel resected in all cases. A complete list of bowel resections performed in patients who underwent optimal cytoreductive surgery is listed in Table 1. Additionally, 2 of the 70 patients (2.9%) undergoing bowel resections had a proximal diverting ostomy at the time of primary surgery, which were performed if the reanastomosis site was under tension or in the setting of infection/sepsis. Clinicopathological patient characteristics are summarized in Table 2. Complete cytoreduction was achieved in 31 of 68 (45.6%) patients undergoing one or no bowel resections and 9 of 34 (26.5%) patients undergoing ≥ 2 bowel resections. Following initial surgery, all patients received adjuvant chemotherapy with combination platinum-based and taxane chemotherapy, excluding two patients who suffered postoperative mortality. Patients with optimal cytoreduction who underwent ≥ 2 bowel resections experienced a higher median EBL, 700 mL, compared to a median EBL of 500 mL for patients who underwent one or no bowel resections (p = 0.01). Length of hospital stay was also significantly longer in patients who underwent multiple bowel resections compared to patients who underwent one or no bowel resections, median LOS of 10 days compared to 7 days, respectively. (p = 0.01). Major postoperative complications occurred in 30 (29.4%) of the 102 patients undergoing optimal cytoreductive surgery Table 2 Clinicopathological characteristics
Statistical analysis The major statistical endpoint of this study was survival. Event time distributions for this endpoint were estimated using the method of Kaplan and Meier [19] and compared using the log-rank statistic [20] or the proportional hazards regression model [21]. Factors of primary interest in this study were the number of bowel resections and the level of residual disease. Other factors tested for prognostic value included, age, stage and ascites. Covariates having some prognostic value in univariate analyses were entered into multivariate Cox proportional hazards model and nonsignficant factors removed in a stepwise fashion. Hazard ratios are expressed relative to a baseline reference category.
Median age Stage III IV Ascites EBL LOS Residual disease Complete Optimal
Multiple bowel resections (n = 34)
0–1 bowel resections (n = 68)
Suboptional debulking (n = 23)
63.5 26 8 2000 700 10
62 52 16 550 500 7
p = 0.01 p = 0.01
66 19 4 1250 550 9
9 (26.5%) 25 (73.5%)
30 (44.1%) 28 (55.9%)
p = 0.76 p = 0.09
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Table 3 Postoperative complications 0–1 bowel resection Cellulitis Fistulas/breakdown Respiratory distress Pneumonia/pulmonary embolus Prolonged ileus Sepsis Retained sponge Postoperative death
4 (5.9%) 3 (4.4%) 2 (2.9%) 4 (5.9%)
2 bowel resections 4 (11.8%) 2 (5.9%) 2 (5.9%) 3 (8.8%) 2 (5.9%) 1 (2.9%)
1 (1.5%) 14 (20.6%)
2 (5.9%) 16 (47.1%), p b 0.01
(Table 3). There were 14/68 complications in the group undergoing one or no bowel resections: 20.6% (95% CI: 11.7%, 32.1%), compared to 16/34 in the group undergoing two bowel resections: 47.1% (95% CI: 29.8%, 64.9%), p b 0.01. This included two postoperative deaths; one in an elderly patient who developed refractory sepsis and another in a patient who developed a massive pulmonary embolism. Survival analysis The median follow-up of surviving patients was 19.3 months from the time of surgery and the median survival was 37 months for all patients with optimal residual disease. A total of five different clinical and pathological variables were analyzed for prognostic significance on univariate and multivariate analysis. The optimal group had twice the risk of death compared to the complete reduction group, HR = 2.2 (95% CI: 1.08, 4.44, p = 0.03), and the risk in the suboptimal group was almost six times the risk in the complete group 5.9 (95% CI: 2.7, 13.0, p b .0001).
Fig. 2. Overall survival for patients undergoing complete cytoreduction. Patients with ≤1 bowel resection had a median survival of 46.5 months; patients with two or more bowel resections the median survival was not reached with 60% alive at 28 months follow-up ( p = 0.76). , bowel resections; , ≥2 bowel resections.
Survival analysis revealed that patients with one or no bowel resections had a median survival of 37.8 months and patients with ≥ 2 bowel resections had a median survival of 28.3 months ( p = 0.09). Patients who underwent suboptimal cytoreductive surgery, regardless of the number of bowel resections, had a median survival of 12 months, which was statistically significantly worse compared to patients undergoing multiple bowel resections ( p = 0.02) (Fig. 1). When patients who underwent complete cytoreductive surgery were analyzed, the median survival was 46.5 months for patients with one or no bowel resections, and for patients who underwent multiple bowel resections, median survival was not reached with 60% alive at 28 months follow-up (p = 0.76) (Fig. 2). Discussion
Fig. 1. Overall survival time according to residual disease. Patients with one or no bowel resections had a median survival of 37.8 months; patients with two or more bowel resections had a median survival of 28.3 months ( p = 0.09); and patients with suboptimal cytoreductive surgery had a median survival of 12 months ( p = 0.02). , 0–1 bowel resections; , ≥2 bowel resections; , suboptimal resection.
The inverse relationship between residual disease after cytoreductive surgery and survival in ovarian carcinoma was first conclusively demonstrated in 1975 by Griffiths et al. [2]. Since then, multiple studies have shown that cytoreductive surgery that achieves residual disease ≤1 to 2 cm in maximal diameter is associated with improved survival [3–5]. The ability to achieve optimal cytoreduction may require the need to perform radical procedures. The benefits of performing these extensive procedures, such as extrapelvic bowel resection, diaphragm stripping or resection, modified posterior pelvic exenterations, peritoneal implant ablation and retroperitoneal lymph node dissection, have been shown for patients with extensive disease [11]. A recent study by Aletti et al. [7] showed that residual disease was the only independent predictor of survival and complete cytoreduction resulted in a superior survival. The requirement for radical surgery also correlated with optimal
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cytoreduction and improved survival [7]. Eisenhauer et al. [8] noted that the addition of upper abdominal surgery in order to achieve optimal cytoreduction resulted in better median progression-free and overall survival compared to patients who underwent suboptimal cytoreduction and comparable survival to patients undergoing optimal cytoreduction with standard procedures. Furthermore, Cliby et al. [12] reviewed patients undergoing radical debulking procedures such as diaphragmatic resections, bowel resections, hepatic resection and splenectomy, which could be performed with tolerable morbidity while contributing to the surgical cytoreductive effort. Bowel resection is one of the more common procedures required to remove bulky metastatic ovarian cancer. It has been estimated that bowel resections are required in approximately 50% of optimal cytoreductive operations [11,22–24]. Multiple authors have also shown that the need to perform a bowel resection which contributes to small volume residual disease is associated with a better overall survival and comparable to patients who did not require a bowel resection [13–15,17,25]. Gillette-Cloven et al. [13] reported that optimal cytoreduction, with or without a bowel resection, conferred improved survival with a median survival of 35 months compared to a median survival of 18 months for patients undergoing suboptimal cytoreduction. The performance of a bowel resection may contribute to a complete cytoreductive surgical effort, which has been associated with a more significant influence on overall survival compared to patients undergoing optimal cytoreduction with visible residual disease [2,6,7,10,11,26–28]. Additionally, studies have shown that bowel resection(s) can be performed with an acceptable risk of complications and postoperative morbidity [9,13,14,21,29–31]. In this study, we evaluated patients with ovarian cancer who required multiple bowel resections in order to achieve optimal cytoreduction. The need to perform multiple bowel resections was associated with a longer hospitalization, higher surgical blood loss and higher rate of complications during optimal primary cytoreductive surgery. However, the requirement for ≥ 2 bowel resections to achieve optimal residual disease was associated with an overall median survival time of 28.3 months which was inferior to but not statistically different from patients left with optimal residual disease when ≤ 1 bowel resection was required (37.8 months, p = 0.09). Irrespective of the number of bowel resections, optimal residual disease was associated with a statistically superior survival outcome compared to patients left with bulky residual disease. These data suggest that the requirement for multiple bowel resections in order to achieve optimal cytoreduction for advanced ovarian cancer may reflect extensive disease. There are limitations of this study that must be considered when evaluating the results of this study. First, although we made every effort to include all eligible patients, the number of subjects undergoing ≥ 2 bowel resections was relatively limited. It is possible that with extended follow-up, the survival curves for patients undergoing ≥ 2 bowel resections and those with ≤1 bowel resection may diverge to the point of a statistically significant difference. Secondly, as a case–control study, the patient
population selected, although homogenous with respect to disease, may not be reflective of all patients with ovarian cancer. Third, the primary study group consisted of patients with extensive disease, as evidenced by the frequent requirement for proactive surgical procedures. This may have contributed to the relatively short median survival times observed, at least in comparison to other contemporary and less select cohorts of patients with advanced stage ovarian cancer. A fourth limitation is that we did not assess for differences in chemotherapy regimens administered following disease recurrence, which may have impacted overall survival. Despite these limitations, the current data suggest that multiple bowel resections are warranted as a part of primary cytoreductive surgery for ovarian cancer if it contributes to an optimal, or ideally complete, residual disease state. 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] Chi DS, Liao JB, Leon LF, Venkatraman ES, Hensley ML, Bhaskaran D, et al. Identification of prognostic factors in advanced epithelial ovarian carcinoma. Gynecol Oncol 2001;82(3):532–7. [4] Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170: 974–80. [5] Ozols RF, Rubin SC, Thomas GM, Robboy SJ. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC, Barakat RR, Markman M, Randall ME, editors. Principles and practices of gynecologic oncology. 4th edition. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 895–977. [6] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90(2):390–6. [7] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Levine DA, Poynor EA, Aghajanian C, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer. Gynecol Oncol 2006;103:1083–90. [8] 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. [9] Scarabelli C, Gallo A, Franceschi S, Campagnutta E, De G, Giorda G, et al. Primary cytoreductive surgery with rectosigmoid colon resection for patients with advanced epithelial ovarian carcinoma. Cancer 2000;88(2): 389–97. [10] Eisenkop SM, Friedman RL, Wang H. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–6. [11] 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. [12] 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. [13] Gillette-Cloven N, Burger RA, Monk BJ, McMeekin DS, Vasilev S, DiSaia PJ, et al. Bowel resection at the time of primary cytoreduction for epithelial ovarian cancer. J Am Coll Surg 2001;193:626–32. [14] Weber AM, Kennedy AW. The role of bowel resection in the primary surgical debulking of carcinoma of the ovary. J Am Coll Surg 1994;179: 465–70.
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