- Email: [email protected]
Splenectomy in the context of primary cytoreductive operations for advanced epithelial ovarian cancer
Gynecologic Oncology 100 (2006) 344 – 348 www.elsevier.com/locate/ygyno
Splenectomy in the context of primary cytoreductive operations for advanced epithelial ovarian cancer Scott M. Eisenkop a,*, Nick M. Spirtos b, Wei-Chien Michael Lin a b
a Women’s Cancer Center, Southern California, 4835 Van Nuys Blvd., Suite 109, Sherman Oaks, CA 91403, USA Women’s Cancer Center, University of Nevada School of Medicine, 3131 La Canada Ave., Suite 110, Las Vegas, NV 89101, USA
Received 15 April 2005 Available online 3 October 2005
Abstract Objective. To determine if the need to perform splenectomy due to metastatic disease in the context of complete primary cytoreduction for ovarian cancer diminishes the prognosis for survival. Methods. Between 1990 and 2004, 356 stage IIIC epithelial ovarian cancer patients underwent resection of all visible disease before systemic platinum-based combination chemotherapy. Forty-nine (13.8%) required a splenectomy due to metastatic disease. Survival was analyzed (log rank) on the basis of whether splenectomy was necessary. The frequency of performing other procedures, operative time, blood loss, transfusion rate, and hospitalization, was compared (Chi-square test; discrete and binomial data, t test; continuous data) on the basis of whether a splenectomy was required. Results. Survival was not influenced (log rank) by the requirement of splenectomy (required; median 56.4 months, estimated 5-year survival of 48% vs. not required; median 76.8 months, estimated 5-year survival of 58% P = 0.4). The splenectomy subgroup more commonly required enbloc resection of reproductive organs with rectosigmoid (89.8% vs. 55.7%, P < 0.001), diaphragm stripping (63.3% vs. 33.6%, < 0.001)), fullthickness diaphragm resection (28.6% vs. 9.4%, P < 0.001), and resection of grossly positive retroperitoneal nodes (67.3% vs. 46.3%, P = 0.006). The splenectomy group had a longer operative time (238 min vs. 192 min, P = 0.004), estimated blood loss (1663 ml vs. 1167 ml, P = 0.001), transfusion rate (5.3 units prbc vs. 3.2 units prbc, P = 0.002), and hospitalization (16.1 vs. 12.2 days P = 0.001). Conclusions. The need for splenectomy to achieve complete cytoreduction is a reflection of advanced disease but is not a manifestation of tumor biology precluding long-term survival. D 2005 Elsevier Inc. All rights reserved. Keywords: Splenectomy; Ovarian cancer; Cytoreduction
Introduction Numerous reports have demonstrated the completeness of primary cytoreductive operations for advanced epithelial ovarian cancer to correlate with the prognosis for survival [1 –7]. However, it has been suggested that a widespread upper abdominal tumor burden reflects ‘‘biologically aggressive’’ disease and that requirement of extensive as opposed to minimal upper abdominal operations to attain a visibly disease-free cytoreductive outcome may diminish or preclude the possibility of long-term survival [8– 12]. Hence, the extent to which the natural history of advanced stage epithelial ovarian cancer can be
altered if multiple upper abdominal procedures are necessary to accomplish ‘‘optimal’’ or complete cytoreduction remains somewhat controversial. The need to perform splenectomy in particular has been suggested to reflect a disease that is ‘‘biologically aggressive’’, and the appropriateness of splenectomy in the context of primary cytoreductive operations has been questioned [11,12]. In this series, we analyze whether the necessity to perform a splenectomy to achieve complete cytoreduction for stage IIIC epithelial ovarian cancer, due to splenic involvement with metastatic disease, increases morbidity and diminishes the probability of survival. Methods and materials
* Corresponding author. Fax: +1 818 905 1930. E-mail address: [email protected] (S.M. Eisenkop). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.08.036
Between 1990 and June 2004, 404 patients with stage IIIC epithelial ovarian cancer underwent primary cytoreductive surgery by members of the Encino –
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348 Tarzana division of the Woman’s Cancer Center, of which 356 (88.1%) were cytoreduced to a visibly disease-free outcome. Of those completely cytoreduced, 49 (13.8%) required a splenectomy to accomplish complete cytoreduction in the context of their procedures. The extent of disease present before cytoreduction, morbidity, and subsequent survival of patients requiring a splenectomy is compared to the 307 completely cytoreduced patients not requiring a splenectomy. Some of the database was previously used to address relative influences of tumor volume before surgery and cytoreductive outcome on survival [7]. After abdominal exploration, omentectomy was usually performed, at which time the spleen was palpated and inspected. Superficial metastatic implants involving the surface, hilum, vasculature, and pancreatic tail were ablated with an argon beam coagulator or aspirated with a cavitron ultrasonic aspirator [13,14]. Implants on the posterior surface of the spleen were ablated or aspirated after first mobilizing the spleen. Splenectomy was performed for (1) involvement of the splenic surface, hilum, and/or vasculature with bulky disease contiguous with omental metastases, (2) isolated or confluent hilar and/ or capsular metastases that could not be resected, ablated, or aspirated, (3) parenchymal metastases. After division of the gastrosplenic and splenorenal ligaments and separation of the spleen from the splenic flexure of the colon, the splenic vessels were clamped, cut and ligated with 0-vicrly or transected with a 35-mm endoscopic stapler (endoscopic linear cutter; Ethicon Instruments, endoscopic GIA; US Surgical). For patients with extensive disease involving the splenic hilum and pancreatic tail, the distal pancreas was mobilized with electrocautery and/or an endoscopic stapler. The splenic artery and vein were then dissected away from the pancreas and either clamped, cut and ligated with 0-vicryl suture or hemocliped. The pancreas was then divided with a 55-mm linear cutter (Ethicon Instruments) or GIA (US Surgical) using thin tissue/ vascular staples. When possible, the pancreatic duct was identified with magnification and separately clipped with a small hemoclip. Subsequently, diaphragmatic, peritoneal, and serosal metastases were ablated, aspirated, or resected using described techniques [13 – 16]. The internal reproductive organs were excised en-bloc with contiguous metastases involving adjacent pelvic peritoneum. Modified posterior pelvic exenteration and low rectal anastomosis were performed for contiguous involvement of the cul-desac and rectosigmoid colon [17]. Pelvic and paraaortic lymph node dissections were performed to remove grossly involved lymph nodes and possible occult nodal disease [18,19]. Prior to closure of the abdomen, a Jackson – Pratt or Blake drain was placed in the left upper quadrant near the distal pancreas and at other locations if indicated. Postoperatively, all patients had gastric rest with a nasogastric tube until passage of flatus via rectal function or fecal diversion. Additionally, those with pancreatic trauma (tumor requiring ablation, aspiration, or distal pancreatectomy) also received total parenteral nutrition (TPN) and were treated with intravenous sandostatin (100 mcg q 8 h) for 7 – 10 days [20 – 22]. Drains placed in the left upper quadrant were removed after sandostatin was discontinued (if used), and any minimal output was confirmed to have normal serum levels of amylase and lipase. If drainage had elevated levels of amylase and/or lipase, sandostatin and hyperalimentation were continued until resolution of pancreatic leakage. After tolerating a full liquid or soft diet, ambulating, and being afebrile without antibiotics for 24 h, most patients either had a subcutaneous venous access devise placed and received platinum-based combination chemotherapy or were discharged. Patients who had a splenectomy received a pneumococcal vaccine postoperatively and at recommended time intervals, throughout the period of accrual [23,24]. Currently, most patients are vaccinated during their hospitalization and every 5 years thereafter. Influenza and meningococcal vaccines have been used more recently when available [25,26]. Variation of disease characteristics amongst the groups was analyzed with the Chi-square test for discrete and binomial data and t test for continuous data. Follow-up information was recorded to the date of last contact or death. Survival time was calculated from the day of primary cytoreductive surgery to the date of last contact or death. The Kaplan – Meier method was used to estimate the survival distribution of the subgroups. Deaths due to all causes were included as endpoints in the Kaplan – Meier analysis. Log rank statistics tested the equality of the survival curves. Comparison of the results from this investigation with other published outcomes was accomplished with a literature review using the Unabridged Medline as accessed through Version 4.28 of Knowledge Finder software (Aries Systems Corporation, North Andover, Maryland).
345
Results Within the cohort, the subgroup requiring a splenectomy was significantly older, had more extensive disease by multiple criteria, and required several procedures with a greater frequency (Table 1). The total operative time, estimated blood loss, units of blood transfused, and hospital stay were greater for patients who had a splenectomy, although an equivalent fraction were treated with chemotherapy before discharge (Table 2). Patients requiring splenectomy had an insignificant trend to more frequently experience some morbid events, although a higher incidence of thrombocytosis was not observed (Table 2). Prolonged (> 10 days) pancreatic leakage occurred in 3 (6.1%) patients within the splenectomy group. All pancreatic leakage resolved after management with sandostatin, hyperalimentation, and drainage. The overall median survival was 72.7 months and estimated 5-year survival 56%. The median survival of 56.4 months and Table 1 Patient characteristics Characteristic
Splenectomy required
Splenectomy not required
P valuea
Age (years): Mean Median Range
64.8 66.9 39.4 – 82.4
61.5 61.9 24.1 – 91.2
0.05
GOG performance status 0–1 2–3 Unspecified
5 (10.2%) 43 (87.8%) 1 (2.0%)
115 (37.5%) 189 (61.6%) 3 (0.9%)
<0.001
39 (79.6%)
241 (78.5%)
10 (20.4%)
66 (21.5%)
0.90
Grade of tumor: 1–2 3
6 (12.2%) 43 (87.8%)
86 (28.1%) 221 (71.9%)
0.02
Volume of ascites: 1 l >1 l Unspecified
4 (8.2%) 44 (89.8%) 1 (2.0%)
135 (44.0%) 170 (55.4%) 2 (0.6%)
<0.001
Largest dimensions of metastatic disease: 10 cm 5 (10.2%) >10 cm 44 (89.8%)
92 (30.0%) 215 (70.0%)
0.004
44 (89.8%)
171 (55.7%)
<0.001
31 (63.3%) 14 (28.6%) 33 (67.3%)
103 (33.6%) 29 (9.4%) 142 (46.3%)
<0.001 <0.001 0.006
Histology: Serous or unspecified adenocarcinoma Other (endometroid, mucinous, clear cell, transitional cell, mixed)
Operative procedures Modified posterior pelvic exenteration Diaphragm stripping Diaphragm resection Excision of grossly positive pelvic and/or aortic lymph nodes
a Chi-square test for analysis of discrete and binomial data, t test for analysis of variance for continuous data.
346
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348
Table 2 Operative outcomes Outcome Total operative time (min): Total estimated blood loss: (ml) Units PRBC transfused: (perioperatively) Hospital stay (days):
Mean Median Range Mean Median Range Mean Median Range Mean Median Range
Complications (total) Reoperation (hemorrhage) Coagulopathy (all causes) Sepsis (all causes) Deep venous thrombosis Pneumonia and/or respiratory distress syndrome Pulmonary embolus Postoperative death (all causes within 28 days)
Splenectomy required
Splenectomy not required
P valuea
238 245 130 – 490 1663 1500 700 – 6000 5.3 5 2 – 12 16.1 15 7 – 62
192.8 175 70 – 410 1167 900 50 – 7000 3.2 3 0 – 15 12.2 11 3 – 60
0.004
1 7 6 2 3
3 (1.0%) 27 (8.8%) 29 (9.4%) 6 (2.0%) 9 (2.9%)
0.40 0.30 0.60 0.30 0.20
4 (1.3%) 5 (1.6%)
0.50 0.60
(2.0%) (14.3%) (12.2%) (4.1%) (6.1%)
1 (2.0%) 1 (2.0%)
0.001
0.002
0.001
a
Chi-square test for analysis of discrete and binomial data, t test for analysis of variance for continuous data.
estimated 5-year survival of 48% for the subgroup requiring a splenectomy was not significantly different from the median survival of 76.8 months and the estimated 5-year survival of 58% for the remainder of the cohort not requiring a splenectomy (P = 0.4) (Fig. 1). Discussion Median and long-term survival for patients with advanced stage epithelial ovarian cancer have been consistently reported to correlate with the completeness of primary cytoreductive surgery [1 –7]. Nevertheless, relative influences of treatment strategy and ‘‘innate biological properties’’ of disease on the prognosis for long-term survival or cure remain somewhat controversial. It has been proposed that ‘‘optimal’’ and complete cytoreduction may be achievable due to patterns of metastasis that are manifestations of disease with diminished ‘‘biological aggressiveness’’ rather than operative effort, and that patients with extensive intra-abdominal tumor burdens undergoing ‘‘optimal’’ and complete cytoreduction may not benefit because ‘‘innate tumor biology’’ precludes significant alteration of the natural history of disease [8 –12]. The extent to which the intra-abdominal tumor burden present before surgery influences survival has been investigated by correlating survival subsequent to ‘‘optimal’’ or complete cytoreduction with various findings that reflect the tumor burden, such as presence or absence of disease and contiguous metastases at anatomic locations, as well as necessity of specific procedures in the context of primary cytoreduction [7 –10,27 – 29]. The largest series of 213 patients with stage IIIC disease correlating survival with the need to perform specific procedures in the
context of complete cytoreductive operations reported survival to not be influenced by the need to perform a bowel resection, modified posterior pelvic exenteration, diaphragm stripping, full-thickness diaphragm resection, and excision of grossly positive retroperitoneal lymph nodes [29]. Few investigators specifically address the relationship between the necessity of splenectomy in the context of primary cytoreduction and subsequent survival. While some conclude splenectomy to be indicated if required to accomplish ‘‘optimal’’ cytoreduction in a primary or recurrent setting, others designate the procedure to be ‘‘ultra-radical’’ and unjustified on the basis of available data [11,12,30 –36]. A survey of members and candidate members of the Society of Gynecologic Oncologists revealed that 60.1% of respondents excise the omentum en-bloc with spleen T distal pancreas to achieve ‘‘optimal’’ cytoreduction, while 16.2% do not perform splenectomy T distal pancreatectomy due to inexperience, and 23.7% do not perform the procedure due to concerns about morbidity or lack of data establishing efficacy [36]. Ayhan et al. retrospectively reported 34 patients cytoreduced to < 1 cm residual disease over a 12-year period that underwent splenectomy in the context of primary cytoreductive operations, of which 18 had parenchymal metastases [35]. Patients with splenic metastases had an insignificant trend ( P > 0.05) towards less favorable survival, relative to those not requiring splenectomy. The authors concluded that complete cytoreduction confers a survival benefit whether splenic parenchyma was involved or not and recommended splenectomy if necessary to achieve ‘‘optimal’’ cytoreduction [35]. In a prospective series of 408 patients with stage IIIC epithelial ovarian cancer, the relationship between the extent of disease and survival was investigated by assigning a numerical rank (0 –3) correlating with the extent of disease present at the start of surgery for 5 anatomic regions [7]. For the left upper quadrant, a rank of 1 was allotted if metastases were limited to the infra-colic omentum, a rank of 2 for confluent disease extending to the gastro-colic ligament, and a rank of 3 assigned for confluent disease involving the infra-colic omentum/gastro-colic liga-
Fig. 1. Survival stratified by necessity of splenectomy. Solid line—splenectomy not needed, dotted line—splenectomy necessary. P = 0.4 (log rank).
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348
ment and adjacent structures such as the spleen. Rankings at the left upper quadrant did not independently influence survival. Independent influences on survival were only observed for the sum of rankings (P = 0.05) and completeness of cytoreduction (P = 0.001). The current series is the largest to investigate the need to perform splenectomy to achieve complete primary cytoreduction for patients with advanced epithelial ovarian cancer and document statistically equivalent survival to those who are completely cytoreduced but do not require splenectomy in the context of their operations (Fig. 1). Patients requiring splenectomy in the current series did have an insignificant trend towards diminished survival relative to those not requiring splenectomy. However, they were more elderly with poorer performance status and had significantly more extensive disease throughout the abdomen, as manifested by findings such as a larger volume of ascites as well as the more frequent requirement of MPE (89.8% vs. 55.7%, P < 0.001), diaphragm stripping (63.3% vs. 33.6%, P < 0.001)), full-thickness diaphragm resection (28.6% vs. 9.4%, P < 0.001), and resection of grossly positive retroperitoneal nodes 67.3% vs. 46.3%, P = 0.006) (Table 1, Fig. 1). Hence, results of the current series confirm previous findings that a trend towards less favorable survival of patients requiring splenectomy is a reflection of previously reported negative prognostic indicators rather than the necessity of splenectomy being an indicator of ‘‘biologically aggressive’’ disease that diminishes or precludes the prognosis of long-term survival or cure [1 –7,30,35]. Morbidity associated with splenectomy is reported to be acceptable [30 – 32]. Although reported in other settings, transient thrombocytosis was uncommonly observed in the current series. Presumably multiple factors offset the effect of splenectomy, including postoperative hemodilution and anemia, as well as myelosuppression from chemotherapy [37]. The insignificant trend for patients requiring splenectomy in the current series to experience some complications more frequently than those not requiring splenectomy is undoubtedly a consequence of their poorer performance status and necessity of significantly more extensive operations to achieve complete cytoreduction (Tables 1,2). Hence, results of the current series confirm any increase in morbidity and/or hospitalization associated with splenectomy to be due to the necessity of more extensive procedures in multiple anatomic locations, rather than performance of splenectomy specifically [30 –32]. Of note, risk of early complications such as pancreatic fistula resulting from distal pancreatectomy to address confluent disease adherent to the splenic hilum and pancreas can be reduced by using sandostatin with TPN for 7 to 10 days. Efficacy of sandostatin/TPN in preventing complications due to pancreatic trauma and surgery has been demonstrated in prospective, randomized settings [20 – 22]. Long-term infectious complications of splenectomy are effectively prevented with appropriate vaccination [23 –26]. Although recommended in some settings, we defer preoperative vaccination due to uncertainty of which patients will require splenectomy and concerns of potential side effects to delay surgery or complicate postoperative care [37,38].
347
The current series may be criticized for being retrospective and because survival was not stratified on the basis of specific indications for splenectomy. Survival was not stratified on the basis of whether the spleen was involved with contiguous omental disease, confluent surface metastases, parenchymal disease, or disease obligating distal pancreatectomy because of a small number of patients in each subgroup and difficulty classifying into subgroups due to combination and ambiguity of spread patterns. Furthermore, the fundamental objective of this investigation was to determine whether the necessity of splenectomy to accomplish complete cytoreduction significantly diminished the probability of survival, without focusing on a specific splenic spread pattern. Although a randomized trial may be the optimal method of evaluating any treatment strategy, it is probably impractical to investigate efficacy of splenectomy at the time of primary cytoreduction using a randomized trial. A clinical situation in which complete cytoreduction is accomplished with the exception of residual disease necessitating splenectomy is relatively uncommon, as demonstrated by the current series and others [30 – 32,35]. Furthermore, those convinced that splenectomy is justified in the context of primary cytoreduction may not participate for ethical reasons. Participation by others who are skeptical of the efficacy of splenectomy and may have minimal experience performing the procedure might produce a high incidence of complications. Hence, a large multi-institutional prospective observational study could both confirm findings of the current series and determine whether necessity to perform splenectomy for specific anatomic indications (parenchymal vs. hilar vs. surface vs. combined) in the context of primary cytoreduction influences the probability of survival as well as confirm application of the results to patients with small volume (< 1 cm) macroscopic disease, an issue we could not address due to a small number of patients. In conclusion, the current series demonstrates that necessity of splenectomy to achieve a visibly disease-free outcome in the context of primary cytoreduction for advanced epithelial ovarian cancer does not significantly diminish the potential for long-term survival or cure. Although an insignificant trend towards diminished survival was noted for patients requiring splenectomy, such an observation is merely a reflection of correlation of the need for splenectomy with extensive intraabdominal metastatic disease, a finding previously demonstrated to have a minimally significant influence on the probability of survival for patients who undergo complete cytoreduction [7]. Furthermore, the fundamental question of clinical relevance is not whether a finding such as the extent of metastatic disease at an anatomic location or necessity of any specific procedure to achieve complete cytoreduction diminishes the prognosis for survival, but whether the procedure is either unjustified due to morbidity or the probability of long-term survival is compromised enough to preclude benefit from the procedure. Clearly, unless medical issues impose undue risk or other metastatic disease cannot be resected, ablated, or aspirated, the current series and other reports indicate that if needed to accomplish complete cytoreduction, splenectomy is justified [35].
348
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348
References [1] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian cancer. Natl Cancer Inst Monogr 1978;42:131 – 6. [2] Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for ovarian cancer. Obstet Gynecol 1983;61: 413 – 20. [3] 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. [4] Alberts DS, Liu PY, Hannigan EV, O’Tolle R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950 – 5. [5] Bristow RE, Tomacruz RS, Armstrong DK, Trimble ELS, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002; 20:1248 – 59. [6] Omura GA, Bundy BN, Berek JS, Curry S, Delgado G, Mortel R. Randomized trial of cyclophosphamide plus cisplatin with or without doxirubicin in ovarian carcinoma: a gynecologic oncology group study. J Clin Oncol 1989;7:457 – 65. [7] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci SP. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with ovarian cancer. A prospective study. Gynecol Oncol 2003;90:390 – 6. [8] Potter ME, Partridge EE, Hatch KD, Soong S, Austin JM, Shingelton HM. Primary surgical therapy for ovarian cancer: how much and when. Gynecol Oncol 1992;40:195 – 200. [9] 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. [10] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in smallvolume stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol 1992;47:167 – 71. [11] Berman ML. Future directions in the surgical management of ovarian cancer. Gynecol Oncol 2003;92:33 – 9. [12] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269 – 74. [13] Brand E, Pearlman N. Electrosurgical debulking of ovarian cancer: a new technique using the Argon Beam Coagulator. Gynecol Oncol 1990; 39:115 – 8. [14] Rose PG. The cavitronal ultrasonic surgical aspirator for cytoreduction in advanced ovarian cancer. Am J Obstet Gynecol 1992;166:843 – 6. [15] 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. [16] Fanning J, Hilgers RD. Loop electrosurgical excision procedure for intensified cytoreduction surgery of ovarian cancer. Gynecol Oncol 1995; 57:188 – 90. [17] Eisenkop SM, Nalick RH, Teng NNH. Modified posterior exenteration for ovarian cancer. Obstet Gynecol 1991;78:879 – 85. [18] Spirtos NM, Gross GM, Freddo JL, Ballon SC. Cytoreductive surgery in advanced epithelial cancer of the ovary: the impact of aortic and pelvic lymphadenectomy. Gynecol Oncol 1995;56:345 – 52.
[19] Eisenkop SM, Spirtos NM. The clinical significance of occult macroscopically positive retroperitoneal nodes in patients with epithelial ovarian cancer. Gynecol Oncol 2001;82:143 – 9. [20] Lansen FT, Adams DB, Anderson MC. Treatment of external pancreatic fistulas with somatostatin. Am Surg 1989;55:695 – 8. [21] Freiss H, Buchler MW. Efficacy of somatostatin and its analogues in pancreatic surgery and pancreatic disorders. Digestion 1996; 57(Suppl 1):97 – 102. [22] Montorsi M, Zago M, Mosca F, Capussotti L, Zotti E, Ribotta G, et al. Efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections: a prospective, controlled, randomized trial. Surgery 1995;117:26 – 31. [23] Butler J, Breiman R, Campbell J, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. J Am Med Assoc 1993;270:1826 – 31. [24] Brigden ML, Pattullo A, Brown G. Pneumococcal vaccine administration associated with splenectomy: the need for improved education, documentation, and the use of a practical checklist. Am J Hematol 2000; 65:25 – 9. [25] Funk EM, Schlimok G, Ehret W, Witte J. The current status of vaccination and antibiotic prophylaxis in splenectomy. Chirung 1997;68:586 – 90. [26] Kyaw MH, Holmes EM, Chalmers J, Jones IG, Campbell H. A survey of vaccine coverage and antibiotic prophylaxis in splenectomised patients in Scotland. J Clin Pathol 2002;55:472 – 4. [27] 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. [28] Le T, Krepart GV, Lotocki RJ, Heywood MS. Does debulking surgery improve survival in biologically aggressive ovarian cancer. Gynecol Oncol 1997;67:208 – 14. [29] Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction for ovarian cancer. Is there a correlation with ‘‘biological aggressiveness’’ and survival? Gynecol Oncol 2001;82:435 – 41. [30] Chen LM, Leuchter RS, Lagasse LD, Karlan BY. Splenectomy and surgical cytoreduction for ovarian cancer. Gynecol Oncol 2000;77:362 – 8. [31] Sonnendecker EW, Guidozzi F, Margolius KA. Splenectomy during primary cytoreductive surgery for ovarian cancer. Gynecol Oncol 1989;35:301 – 6. [32] Scarabelli C, Campagnutta E, Zarelli A, De Piero G, Volpe R, Coran F. Splenectomy in cytoreductive surgery in ovarian cancer. Minerva Ginecol 1993;45:19 – 25. [33] Gemignani ML, Chi DS, Gurin CC, Curtin JP, Barakat RR. Splenectomy in recurrent epithelial ovarian cancer. Gynecol Oncol 1999;72:407 – 10. [34] Farias-Eisner R, Braly P, Berek JS. Solitary recurrent metastasis of epithelial ovarian cancer in the spleen. Gynecol Oncol 1993;48:338 – 41. [35] Ayhan A, Al RA, Baykal C, Demirtas E, Ayhan A, Yuce K. The influence of splenic metastases on survival in FIGO stage IIIC epithelial ovarian cancer. Int J Gynecol Cancer 2004;14:51 – 6. [36] Eisenkop SM, Spirtos NM. What are the current surgical objectives, strategies, and technical capabilities of gynecologic oncologists treating advanced epithelial ovarian cancer? Gynecol Oncol 2001;82: 489 – 97. [37] Sitzman FC. Contraindications and complications in vaccinations. Wien Med Wochenschr 1987;137:564 – 8. [38] Morrow CP, Curtin JP. Surgery for ovarian neoplasia. Gynecologic cancer surgery. New York’ Churchill Livingstone; 1996.
Splenectomy in the context of primary cytoreductive operations for advanced epithelial ovarian cancer Scott M. Eisenkop a,*, Nick M. Spirtos b, Wei-Chien Michael Lin a b
a Women’s Cancer Center, Southern California, 4835 Van Nuys Blvd., Suite 109, Sherman Oaks, CA 91403, USA Women’s Cancer Center, University of Nevada School of Medicine, 3131 La Canada Ave., Suite 110, Las Vegas, NV 89101, USA
Received 15 April 2005 Available online 3 October 2005
Abstract Objective. To determine if the need to perform splenectomy due to metastatic disease in the context of complete primary cytoreduction for ovarian cancer diminishes the prognosis for survival. Methods. Between 1990 and 2004, 356 stage IIIC epithelial ovarian cancer patients underwent resection of all visible disease before systemic platinum-based combination chemotherapy. Forty-nine (13.8%) required a splenectomy due to metastatic disease. Survival was analyzed (log rank) on the basis of whether splenectomy was necessary. The frequency of performing other procedures, operative time, blood loss, transfusion rate, and hospitalization, was compared (Chi-square test; discrete and binomial data, t test; continuous data) on the basis of whether a splenectomy was required. Results. Survival was not influenced (log rank) by the requirement of splenectomy (required; median 56.4 months, estimated 5-year survival of 48% vs. not required; median 76.8 months, estimated 5-year survival of 58% P = 0.4). The splenectomy subgroup more commonly required enbloc resection of reproductive organs with rectosigmoid (89.8% vs. 55.7%, P < 0.001), diaphragm stripping (63.3% vs. 33.6%, < 0.001)), fullthickness diaphragm resection (28.6% vs. 9.4%, P < 0.001), and resection of grossly positive retroperitoneal nodes (67.3% vs. 46.3%, P = 0.006). The splenectomy group had a longer operative time (238 min vs. 192 min, P = 0.004), estimated blood loss (1663 ml vs. 1167 ml, P = 0.001), transfusion rate (5.3 units prbc vs. 3.2 units prbc, P = 0.002), and hospitalization (16.1 vs. 12.2 days P = 0.001). Conclusions. The need for splenectomy to achieve complete cytoreduction is a reflection of advanced disease but is not a manifestation of tumor biology precluding long-term survival. D 2005 Elsevier Inc. All rights reserved. Keywords: Splenectomy; Ovarian cancer; Cytoreduction
Introduction Numerous reports have demonstrated the completeness of primary cytoreductive operations for advanced epithelial ovarian cancer to correlate with the prognosis for survival [1 –7]. However, it has been suggested that a widespread upper abdominal tumor burden reflects ‘‘biologically aggressive’’ disease and that requirement of extensive as opposed to minimal upper abdominal operations to attain a visibly disease-free cytoreductive outcome may diminish or preclude the possibility of long-term survival [8– 12]. Hence, the extent to which the natural history of advanced stage epithelial ovarian cancer can be
altered if multiple upper abdominal procedures are necessary to accomplish ‘‘optimal’’ or complete cytoreduction remains somewhat controversial. The need to perform splenectomy in particular has been suggested to reflect a disease that is ‘‘biologically aggressive’’, and the appropriateness of splenectomy in the context of primary cytoreductive operations has been questioned [11,12]. In this series, we analyze whether the necessity to perform a splenectomy to achieve complete cytoreduction for stage IIIC epithelial ovarian cancer, due to splenic involvement with metastatic disease, increases morbidity and diminishes the probability of survival. Methods and materials
* Corresponding author. Fax: +1 818 905 1930. E-mail address: [email protected] (S.M. Eisenkop). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.08.036
Between 1990 and June 2004, 404 patients with stage IIIC epithelial ovarian cancer underwent primary cytoreductive surgery by members of the Encino –
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348 Tarzana division of the Woman’s Cancer Center, of which 356 (88.1%) were cytoreduced to a visibly disease-free outcome. Of those completely cytoreduced, 49 (13.8%) required a splenectomy to accomplish complete cytoreduction in the context of their procedures. The extent of disease present before cytoreduction, morbidity, and subsequent survival of patients requiring a splenectomy is compared to the 307 completely cytoreduced patients not requiring a splenectomy. Some of the database was previously used to address relative influences of tumor volume before surgery and cytoreductive outcome on survival [7]. After abdominal exploration, omentectomy was usually performed, at which time the spleen was palpated and inspected. Superficial metastatic implants involving the surface, hilum, vasculature, and pancreatic tail were ablated with an argon beam coagulator or aspirated with a cavitron ultrasonic aspirator [13,14]. Implants on the posterior surface of the spleen were ablated or aspirated after first mobilizing the spleen. Splenectomy was performed for (1) involvement of the splenic surface, hilum, and/or vasculature with bulky disease contiguous with omental metastases, (2) isolated or confluent hilar and/ or capsular metastases that could not be resected, ablated, or aspirated, (3) parenchymal metastases. After division of the gastrosplenic and splenorenal ligaments and separation of the spleen from the splenic flexure of the colon, the splenic vessels were clamped, cut and ligated with 0-vicrly or transected with a 35-mm endoscopic stapler (endoscopic linear cutter; Ethicon Instruments, endoscopic GIA; US Surgical). For patients with extensive disease involving the splenic hilum and pancreatic tail, the distal pancreas was mobilized with electrocautery and/or an endoscopic stapler. The splenic artery and vein were then dissected away from the pancreas and either clamped, cut and ligated with 0-vicryl suture or hemocliped. The pancreas was then divided with a 55-mm linear cutter (Ethicon Instruments) or GIA (US Surgical) using thin tissue/ vascular staples. When possible, the pancreatic duct was identified with magnification and separately clipped with a small hemoclip. Subsequently, diaphragmatic, peritoneal, and serosal metastases were ablated, aspirated, or resected using described techniques [13 – 16]. The internal reproductive organs were excised en-bloc with contiguous metastases involving adjacent pelvic peritoneum. Modified posterior pelvic exenteration and low rectal anastomosis were performed for contiguous involvement of the cul-desac and rectosigmoid colon [17]. Pelvic and paraaortic lymph node dissections were performed to remove grossly involved lymph nodes and possible occult nodal disease [18,19]. Prior to closure of the abdomen, a Jackson – Pratt or Blake drain was placed in the left upper quadrant near the distal pancreas and at other locations if indicated. Postoperatively, all patients had gastric rest with a nasogastric tube until passage of flatus via rectal function or fecal diversion. Additionally, those with pancreatic trauma (tumor requiring ablation, aspiration, or distal pancreatectomy) also received total parenteral nutrition (TPN) and were treated with intravenous sandostatin (100 mcg q 8 h) for 7 – 10 days [20 – 22]. Drains placed in the left upper quadrant were removed after sandostatin was discontinued (if used), and any minimal output was confirmed to have normal serum levels of amylase and lipase. If drainage had elevated levels of amylase and/or lipase, sandostatin and hyperalimentation were continued until resolution of pancreatic leakage. After tolerating a full liquid or soft diet, ambulating, and being afebrile without antibiotics for 24 h, most patients either had a subcutaneous venous access devise placed and received platinum-based combination chemotherapy or were discharged. Patients who had a splenectomy received a pneumococcal vaccine postoperatively and at recommended time intervals, throughout the period of accrual [23,24]. Currently, most patients are vaccinated during their hospitalization and every 5 years thereafter. Influenza and meningococcal vaccines have been used more recently when available [25,26]. Variation of disease characteristics amongst the groups was analyzed with the Chi-square test for discrete and binomial data and t test for continuous data. Follow-up information was recorded to the date of last contact or death. Survival time was calculated from the day of primary cytoreductive surgery to the date of last contact or death. The Kaplan – Meier method was used to estimate the survival distribution of the subgroups. Deaths due to all causes were included as endpoints in the Kaplan – Meier analysis. Log rank statistics tested the equality of the survival curves. Comparison of the results from this investigation with other published outcomes was accomplished with a literature review using the Unabridged Medline as accessed through Version 4.28 of Knowledge Finder software (Aries Systems Corporation, North Andover, Maryland).
345
Results Within the cohort, the subgroup requiring a splenectomy was significantly older, had more extensive disease by multiple criteria, and required several procedures with a greater frequency (Table 1). The total operative time, estimated blood loss, units of blood transfused, and hospital stay were greater for patients who had a splenectomy, although an equivalent fraction were treated with chemotherapy before discharge (Table 2). Patients requiring splenectomy had an insignificant trend to more frequently experience some morbid events, although a higher incidence of thrombocytosis was not observed (Table 2). Prolonged (> 10 days) pancreatic leakage occurred in 3 (6.1%) patients within the splenectomy group. All pancreatic leakage resolved after management with sandostatin, hyperalimentation, and drainage. The overall median survival was 72.7 months and estimated 5-year survival 56%. The median survival of 56.4 months and Table 1 Patient characteristics Characteristic
Splenectomy required
Splenectomy not required
P valuea
Age (years): Mean Median Range
64.8 66.9 39.4 – 82.4
61.5 61.9 24.1 – 91.2
0.05
GOG performance status 0–1 2–3 Unspecified
5 (10.2%) 43 (87.8%) 1 (2.0%)
115 (37.5%) 189 (61.6%) 3 (0.9%)
<0.001
39 (79.6%)
241 (78.5%)
10 (20.4%)
66 (21.5%)
0.90
Grade of tumor: 1–2 3
6 (12.2%) 43 (87.8%)
86 (28.1%) 221 (71.9%)
0.02
Volume of ascites: 1 l >1 l Unspecified
4 (8.2%) 44 (89.8%) 1 (2.0%)
135 (44.0%) 170 (55.4%) 2 (0.6%)
<0.001
Largest dimensions of metastatic disease: 10 cm 5 (10.2%) >10 cm 44 (89.8%)
92 (30.0%) 215 (70.0%)
0.004
44 (89.8%)
171 (55.7%)
<0.001
31 (63.3%) 14 (28.6%) 33 (67.3%)
103 (33.6%) 29 (9.4%) 142 (46.3%)
<0.001 <0.001 0.006
Histology: Serous or unspecified adenocarcinoma Other (endometroid, mucinous, clear cell, transitional cell, mixed)
Operative procedures Modified posterior pelvic exenteration Diaphragm stripping Diaphragm resection Excision of grossly positive pelvic and/or aortic lymph nodes
a Chi-square test for analysis of discrete and binomial data, t test for analysis of variance for continuous data.
346
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348
Table 2 Operative outcomes Outcome Total operative time (min): Total estimated blood loss: (ml) Units PRBC transfused: (perioperatively) Hospital stay (days):
Mean Median Range Mean Median Range Mean Median Range Mean Median Range
Complications (total) Reoperation (hemorrhage) Coagulopathy (all causes) Sepsis (all causes) Deep venous thrombosis Pneumonia and/or respiratory distress syndrome Pulmonary embolus Postoperative death (all causes within 28 days)
Splenectomy required
Splenectomy not required
P valuea
238 245 130 – 490 1663 1500 700 – 6000 5.3 5 2 – 12 16.1 15 7 – 62
192.8 175 70 – 410 1167 900 50 – 7000 3.2 3 0 – 15 12.2 11 3 – 60
0.004
1 7 6 2 3
3 (1.0%) 27 (8.8%) 29 (9.4%) 6 (2.0%) 9 (2.9%)
0.40 0.30 0.60 0.30 0.20
4 (1.3%) 5 (1.6%)
0.50 0.60
(2.0%) (14.3%) (12.2%) (4.1%) (6.1%)
1 (2.0%) 1 (2.0%)
0.001
0.002
0.001
a
Chi-square test for analysis of discrete and binomial data, t test for analysis of variance for continuous data.
estimated 5-year survival of 48% for the subgroup requiring a splenectomy was not significantly different from the median survival of 76.8 months and the estimated 5-year survival of 58% for the remainder of the cohort not requiring a splenectomy (P = 0.4) (Fig. 1). Discussion Median and long-term survival for patients with advanced stage epithelial ovarian cancer have been consistently reported to correlate with the completeness of primary cytoreductive surgery [1 –7]. Nevertheless, relative influences of treatment strategy and ‘‘innate biological properties’’ of disease on the prognosis for long-term survival or cure remain somewhat controversial. It has been proposed that ‘‘optimal’’ and complete cytoreduction may be achievable due to patterns of metastasis that are manifestations of disease with diminished ‘‘biological aggressiveness’’ rather than operative effort, and that patients with extensive intra-abdominal tumor burdens undergoing ‘‘optimal’’ and complete cytoreduction may not benefit because ‘‘innate tumor biology’’ precludes significant alteration of the natural history of disease [8 –12]. The extent to which the intra-abdominal tumor burden present before surgery influences survival has been investigated by correlating survival subsequent to ‘‘optimal’’ or complete cytoreduction with various findings that reflect the tumor burden, such as presence or absence of disease and contiguous metastases at anatomic locations, as well as necessity of specific procedures in the context of primary cytoreduction [7 –10,27 – 29]. The largest series of 213 patients with stage IIIC disease correlating survival with the need to perform specific procedures in the
context of complete cytoreductive operations reported survival to not be influenced by the need to perform a bowel resection, modified posterior pelvic exenteration, diaphragm stripping, full-thickness diaphragm resection, and excision of grossly positive retroperitoneal lymph nodes [29]. Few investigators specifically address the relationship between the necessity of splenectomy in the context of primary cytoreduction and subsequent survival. While some conclude splenectomy to be indicated if required to accomplish ‘‘optimal’’ cytoreduction in a primary or recurrent setting, others designate the procedure to be ‘‘ultra-radical’’ and unjustified on the basis of available data [11,12,30 –36]. A survey of members and candidate members of the Society of Gynecologic Oncologists revealed that 60.1% of respondents excise the omentum en-bloc with spleen T distal pancreas to achieve ‘‘optimal’’ cytoreduction, while 16.2% do not perform splenectomy T distal pancreatectomy due to inexperience, and 23.7% do not perform the procedure due to concerns about morbidity or lack of data establishing efficacy [36]. Ayhan et al. retrospectively reported 34 patients cytoreduced to < 1 cm residual disease over a 12-year period that underwent splenectomy in the context of primary cytoreductive operations, of which 18 had parenchymal metastases [35]. Patients with splenic metastases had an insignificant trend ( P > 0.05) towards less favorable survival, relative to those not requiring splenectomy. The authors concluded that complete cytoreduction confers a survival benefit whether splenic parenchyma was involved or not and recommended splenectomy if necessary to achieve ‘‘optimal’’ cytoreduction [35]. In a prospective series of 408 patients with stage IIIC epithelial ovarian cancer, the relationship between the extent of disease and survival was investigated by assigning a numerical rank (0 –3) correlating with the extent of disease present at the start of surgery for 5 anatomic regions [7]. For the left upper quadrant, a rank of 1 was allotted if metastases were limited to the infra-colic omentum, a rank of 2 for confluent disease extending to the gastro-colic ligament, and a rank of 3 assigned for confluent disease involving the infra-colic omentum/gastro-colic liga-
Fig. 1. Survival stratified by necessity of splenectomy. Solid line—splenectomy not needed, dotted line—splenectomy necessary. P = 0.4 (log rank).
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348
ment and adjacent structures such as the spleen. Rankings at the left upper quadrant did not independently influence survival. Independent influences on survival were only observed for the sum of rankings (P = 0.05) and completeness of cytoreduction (P = 0.001). The current series is the largest to investigate the need to perform splenectomy to achieve complete primary cytoreduction for patients with advanced epithelial ovarian cancer and document statistically equivalent survival to those who are completely cytoreduced but do not require splenectomy in the context of their operations (Fig. 1). Patients requiring splenectomy in the current series did have an insignificant trend towards diminished survival relative to those not requiring splenectomy. However, they were more elderly with poorer performance status and had significantly more extensive disease throughout the abdomen, as manifested by findings such as a larger volume of ascites as well as the more frequent requirement of MPE (89.8% vs. 55.7%, P < 0.001), diaphragm stripping (63.3% vs. 33.6%, P < 0.001)), full-thickness diaphragm resection (28.6% vs. 9.4%, P < 0.001), and resection of grossly positive retroperitoneal nodes 67.3% vs. 46.3%, P = 0.006) (Table 1, Fig. 1). Hence, results of the current series confirm previous findings that a trend towards less favorable survival of patients requiring splenectomy is a reflection of previously reported negative prognostic indicators rather than the necessity of splenectomy being an indicator of ‘‘biologically aggressive’’ disease that diminishes or precludes the prognosis of long-term survival or cure [1 –7,30,35]. Morbidity associated with splenectomy is reported to be acceptable [30 – 32]. Although reported in other settings, transient thrombocytosis was uncommonly observed in the current series. Presumably multiple factors offset the effect of splenectomy, including postoperative hemodilution and anemia, as well as myelosuppression from chemotherapy [37]. The insignificant trend for patients requiring splenectomy in the current series to experience some complications more frequently than those not requiring splenectomy is undoubtedly a consequence of their poorer performance status and necessity of significantly more extensive operations to achieve complete cytoreduction (Tables 1,2). Hence, results of the current series confirm any increase in morbidity and/or hospitalization associated with splenectomy to be due to the necessity of more extensive procedures in multiple anatomic locations, rather than performance of splenectomy specifically [30 –32]. Of note, risk of early complications such as pancreatic fistula resulting from distal pancreatectomy to address confluent disease adherent to the splenic hilum and pancreas can be reduced by using sandostatin with TPN for 7 to 10 days. Efficacy of sandostatin/TPN in preventing complications due to pancreatic trauma and surgery has been demonstrated in prospective, randomized settings [20 – 22]. Long-term infectious complications of splenectomy are effectively prevented with appropriate vaccination [23 –26]. Although recommended in some settings, we defer preoperative vaccination due to uncertainty of which patients will require splenectomy and concerns of potential side effects to delay surgery or complicate postoperative care [37,38].
347
The current series may be criticized for being retrospective and because survival was not stratified on the basis of specific indications for splenectomy. Survival was not stratified on the basis of whether the spleen was involved with contiguous omental disease, confluent surface metastases, parenchymal disease, or disease obligating distal pancreatectomy because of a small number of patients in each subgroup and difficulty classifying into subgroups due to combination and ambiguity of spread patterns. Furthermore, the fundamental objective of this investigation was to determine whether the necessity of splenectomy to accomplish complete cytoreduction significantly diminished the probability of survival, without focusing on a specific splenic spread pattern. Although a randomized trial may be the optimal method of evaluating any treatment strategy, it is probably impractical to investigate efficacy of splenectomy at the time of primary cytoreduction using a randomized trial. A clinical situation in which complete cytoreduction is accomplished with the exception of residual disease necessitating splenectomy is relatively uncommon, as demonstrated by the current series and others [30 – 32,35]. Furthermore, those convinced that splenectomy is justified in the context of primary cytoreduction may not participate for ethical reasons. Participation by others who are skeptical of the efficacy of splenectomy and may have minimal experience performing the procedure might produce a high incidence of complications. Hence, a large multi-institutional prospective observational study could both confirm findings of the current series and determine whether necessity to perform splenectomy for specific anatomic indications (parenchymal vs. hilar vs. surface vs. combined) in the context of primary cytoreduction influences the probability of survival as well as confirm application of the results to patients with small volume (< 1 cm) macroscopic disease, an issue we could not address due to a small number of patients. In conclusion, the current series demonstrates that necessity of splenectomy to achieve a visibly disease-free outcome in the context of primary cytoreduction for advanced epithelial ovarian cancer does not significantly diminish the potential for long-term survival or cure. Although an insignificant trend towards diminished survival was noted for patients requiring splenectomy, such an observation is merely a reflection of correlation of the need for splenectomy with extensive intraabdominal metastatic disease, a finding previously demonstrated to have a minimally significant influence on the probability of survival for patients who undergo complete cytoreduction [7]. Furthermore, the fundamental question of clinical relevance is not whether a finding such as the extent of metastatic disease at an anatomic location or necessity of any specific procedure to achieve complete cytoreduction diminishes the prognosis for survival, but whether the procedure is either unjustified due to morbidity or the probability of long-term survival is compromised enough to preclude benefit from the procedure. Clearly, unless medical issues impose undue risk or other metastatic disease cannot be resected, ablated, or aspirated, the current series and other reports indicate that if needed to accomplish complete cytoreduction, splenectomy is justified [35].
348
S.M. Eisenkop et al. / Gynecologic Oncology 100 (2006) 344 – 348
References [1] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian cancer. Natl Cancer Inst Monogr 1978;42:131 – 6. [2] Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for ovarian cancer. Obstet Gynecol 1983;61: 413 – 20. [3] 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. [4] Alberts DS, Liu PY, Hannigan EV, O’Tolle R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950 – 5. [5] Bristow RE, Tomacruz RS, Armstrong DK, Trimble ELS, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002; 20:1248 – 59. [6] Omura GA, Bundy BN, Berek JS, Curry S, Delgado G, Mortel R. Randomized trial of cyclophosphamide plus cisplatin with or without doxirubicin in ovarian carcinoma: a gynecologic oncology group study. J Clin Oncol 1989;7:457 – 65. [7] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci SP. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with ovarian cancer. A prospective study. Gynecol Oncol 2003;90:390 – 6. [8] Potter ME, Partridge EE, Hatch KD, Soong S, Austin JM, Shingelton HM. Primary surgical therapy for ovarian cancer: how much and when. Gynecol Oncol 1992;40:195 – 200. [9] 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. [10] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in smallvolume stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol 1992;47:167 – 71. [11] Berman ML. Future directions in the surgical management of ovarian cancer. Gynecol Oncol 2003;92:33 – 9. [12] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269 – 74. [13] Brand E, Pearlman N. Electrosurgical debulking of ovarian cancer: a new technique using the Argon Beam Coagulator. Gynecol Oncol 1990; 39:115 – 8. [14] Rose PG. The cavitronal ultrasonic surgical aspirator for cytoreduction in advanced ovarian cancer. Am J Obstet Gynecol 1992;166:843 – 6. [15] 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. [16] Fanning J, Hilgers RD. Loop electrosurgical excision procedure for intensified cytoreduction surgery of ovarian cancer. Gynecol Oncol 1995; 57:188 – 90. [17] Eisenkop SM, Nalick RH, Teng NNH. Modified posterior exenteration for ovarian cancer. Obstet Gynecol 1991;78:879 – 85. [18] Spirtos NM, Gross GM, Freddo JL, Ballon SC. Cytoreductive surgery in advanced epithelial cancer of the ovary: the impact of aortic and pelvic lymphadenectomy. Gynecol Oncol 1995;56:345 – 52.
[19] Eisenkop SM, Spirtos NM. The clinical significance of occult macroscopically positive retroperitoneal nodes in patients with epithelial ovarian cancer. Gynecol Oncol 2001;82:143 – 9. [20] Lansen FT, Adams DB, Anderson MC. Treatment of external pancreatic fistulas with somatostatin. Am Surg 1989;55:695 – 8. [21] Freiss H, Buchler MW. Efficacy of somatostatin and its analogues in pancreatic surgery and pancreatic disorders. Digestion 1996; 57(Suppl 1):97 – 102. [22] Montorsi M, Zago M, Mosca F, Capussotti L, Zotti E, Ribotta G, et al. Efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections: a prospective, controlled, randomized trial. Surgery 1995;117:26 – 31. [23] Butler J, Breiman R, Campbell J, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. J Am Med Assoc 1993;270:1826 – 31. [24] Brigden ML, Pattullo A, Brown G. Pneumococcal vaccine administration associated with splenectomy: the need for improved education, documentation, and the use of a practical checklist. Am J Hematol 2000; 65:25 – 9. [25] Funk EM, Schlimok G, Ehret W, Witte J. The current status of vaccination and antibiotic prophylaxis in splenectomy. Chirung 1997;68:586 – 90. [26] Kyaw MH, Holmes EM, Chalmers J, Jones IG, Campbell H. A survey of vaccine coverage and antibiotic prophylaxis in splenectomised patients in Scotland. J Clin Pathol 2002;55:472 – 4. [27] 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. [28] Le T, Krepart GV, Lotocki RJ, Heywood MS. Does debulking surgery improve survival in biologically aggressive ovarian cancer. Gynecol Oncol 1997;67:208 – 14. [29] Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction for ovarian cancer. Is there a correlation with ‘‘biological aggressiveness’’ and survival? Gynecol Oncol 2001;82:435 – 41. [30] Chen LM, Leuchter RS, Lagasse LD, Karlan BY. Splenectomy and surgical cytoreduction for ovarian cancer. Gynecol Oncol 2000;77:362 – 8. [31] Sonnendecker EW, Guidozzi F, Margolius KA. Splenectomy during primary cytoreductive surgery for ovarian cancer. Gynecol Oncol 1989;35:301 – 6. [32] Scarabelli C, Campagnutta E, Zarelli A, De Piero G, Volpe R, Coran F. Splenectomy in cytoreductive surgery in ovarian cancer. Minerva Ginecol 1993;45:19 – 25. [33] Gemignani ML, Chi DS, Gurin CC, Curtin JP, Barakat RR. Splenectomy in recurrent epithelial ovarian cancer. Gynecol Oncol 1999;72:407 – 10. [34] Farias-Eisner R, Braly P, Berek JS. Solitary recurrent metastasis of epithelial ovarian cancer in the spleen. Gynecol Oncol 1993;48:338 – 41. [35] Ayhan A, Al RA, Baykal C, Demirtas E, Ayhan A, Yuce K. The influence of splenic metastases on survival in FIGO stage IIIC epithelial ovarian cancer. Int J Gynecol Cancer 2004;14:51 – 6. [36] Eisenkop SM, Spirtos NM. What are the current surgical objectives, strategies, and technical capabilities of gynecologic oncologists treating advanced epithelial ovarian cancer? Gynecol Oncol 2001;82: 489 – 97. [37] Sitzman FC. Contraindications and complications in vaccinations. Wien Med Wochenschr 1987;137:564 – 8. [38] Morrow CP, Curtin JP. Surgery for ovarian neoplasia. Gynecologic cancer surgery. New York’ Churchill Livingstone; 1996.