- Email: [email protected]
Identification of prognostic factors after positive second-look surgery in epithelial ovarian carcinoma
Gynecologic Oncology 102 (2006) 8 – 14 www.elsevier.com/locate/ygyno
Identification of prognostic factors after positive second-look surgery in epithelial ovarian carcinoma Wayne A. McCreath a,1 , Eric L. Eisenhauer a , Nadeem R. Abu-Rustum a , Ennapadam S. Venkatraman b , Aileen Caceres c , Rachel Bier a , Jae Huh a , Jae Cho a , Richard R. Barakat a , Dennis S. Chi a,⁎ a b
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021, USA c Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA Received 22 June 2005 Available online 20 January 2006
Abstract Objective. The objective of this study was to identify independent prognostic factors for survival in patients with epithelial ovarian cancer who had persistent disease identified at second-look surgery. Methods. We performed a retrospective chart review of all patients with epithelial ovarian cancer who had positive findings at second-look surgery between June 1991 and June 2002. All patients achieved a complete clinical remission after a prescribed course of primary therapy. Survival was determined from the time of second-look surgery until last follow-up or death. Results. The study included a total of 262 patients, with a median age of 54 years (range, 22–80). Of the 262 patients, 166 (63%) had died of disease. Records of initial (salvage) treatment after the positive second-look surgery were available for 243 patients. Therapies included the following: intraperitoneal (IP) cisplatin, 71 (29%); IP cisplatin combined with a second drug, 53 (22%); IP therapy other than cisplatin, 29 (12%); intravenous (IV) chemotherapy, 50 (21%); IP and IV therapy, 35 (14%); and oral chemotherapy, 5 (2%). Of the 13 potential prognostic factors analyzed, only 2 factors emerged that, when combined, were significant—residual disease after primary surgery and size of persistent disease found at second-look surgery. Patients with ≤1 cm residual disease after primary surgery and microscopic disease at second-look surgery had significantly improved survival. Conclusion. In our analysis, the only prognostic factor for survival in patients with positive second-look procedures was a combination of residual disease after primary surgery and size of persistent disease identified at second-look surgery. No individual chemotherapy treatment imparted a survival advantage. Novel that therapeutic approaches are needed in this setting. © 2005 Elsevier Inc. All rights reserved. Keywords: Prognostic factors; Ovarian cancer; Second-look surgery
Introduction Second-look surgery (SLS) is the most reliable method for evaluating the status of ovarian cancer after primary treatment [1]. SLS can be used to detect occult residual disease in patients who have completed a prescribed course of primary chemo-
⁎ Corresponding author. Fax: +1 212 717 3214. E-mail address: [email protected] (D.S. Chi). 1 Currently at Crystal Run Healthcare Middletown, NY, USA. 0090-8258/$ - see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.11.040
therapy and are in a complete clinical remission. SLS is more specific and sensitive than non-invasive modalities [1,2]. Traditionally, second-look operations have helped to determine the patient's cancer status and to identify patients with persistent disease who may benefit from continued treatment. The value of the second-look operation is controversial because relapse rates continue to remain high (40–60%) even when the findings at surgery are negative. A lack of prospective data supporting its use still persists today [3–5]. At our institution, SLS has the added benefit of enabling adequate placement of an intraperitoneal (IP) port and catheter
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14 Table 1 Patient characteristics (n = 262) Variable Age (years) Median Range
Patients
%
54 22–80
Initial FIGO stage IIC IIIA IIIB IIIC IV Unstaged
1 4 17 210 29 1
b1 2 6 80 11 b1
Tumor grade G1 G2 G3 Not available
16 67 160 19
6 26 61 7
Tumor histology Serous Endometrioid Mixed Clear cell Mucinous Carcinosarcoma Other
164 34 25 9 3 1 26
63 13 9 3 1 b1 10
Ascites at primary surgery Yes No Not recorded
177 22 63
68 8 24
9
clinical remission was defined as return to CA-125 values b35 U/mL in patients with preoperative elevated CA-125 levels and no evidence of measurable disease by CT scan for those patients who had CT scans. Second-look operation was performed by laparoscopy and/or laparotomy. In patients with gross evidence of persistent disease, systematic biopsies were not routinely performed since only one positive biopsy was needed to define an SLS as positive. However, in patients with no evidence of gross disease, random biopsies were obtained from the bilateral diaphragms, bilateral paracolic gutters, bilateral pelvic sidewalls, anterior and posterior cul de sacs and any suspicious adhesions. Individual records were reviewed, and pertinent demographic, clinical, pathologic and follow-up information abstracted. Patients who had more than 100 cm3 of peritoneal fluid at the time of primary surgery were considered to be positive for ascites. Optimal primary cytoreduction was defined as ≤1 cm residual disease. Survival time was calculated in months from the SLS to death or to the date of last follow-up visit for those patients still alive. Survival curves were estimated using the Kaplan–Meier method [8]. Potential prognostic factors were tested by univariate analysis using the log-rank test for categorical factors and Cox's proportional hazards model for continuous factors [9]. Stepwise model selection methods were used for selecting factors included in the multivariate Cox proportional hazards model [10].
Results
CA-125 before primary surgery (U/mL) Median 871 Range 1–16,844 FIGO, International Federation of Gynecology and Obstetrics.
for additional consolidation or salvage IP chemotherapy [6,7]. We have previously demonstrated a survival advantage to IP consolidation chemotherapy compared with no therapy in patients with negative SLS [6]. Consequently, IP consolidation chemotherapy is currently our standard treatment for patients with negative second-look procedures. The management of patients with positive second-look procedures presents a more perplexing problem. Various treatments have been proposed, but a clearly superior approach has not emerged. The objective of this study was to compare the survival outcomes of the various salvage regimens used and to identify independent prognostic factors for survival in patients with epithelial ovarian carcinoma who have persistent disease identified at second-look operation. Methods After receiving Institutional Review Board approval, we used our Gynecology Service database to identify all patients with epithelial ovarian carcinoma who underwent SLS between June 1991 and June 2002. SLS was defined as a comprehensive surgical evaluation of disease status in patients with advanced ovarian cancer who achieved a complete clinical remission after primary cytoreductive surgery and platinum-based systemic chemotherapy. Complete
Patient characteristics and primary therapy A total of 262 patients were initially identified for this study. Patient characteristics are listed in Table 1. Their median age was 54 years (range, 22–80). The majority of patients initially presented with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC disease (210, 80%), grade 3 tumors (160, 61%), serous histology (164, 63%) and ascites (177, 68%). The preoperative serum CA-125 before primary surgery was recorded in 72 patients. The median was 871 U/ mL, with a range of 1–16,844 U/mL. Table 2 Outcome of primary therapy (n = 262) Variable
Patients
%
Initial evaluation Evaluated before primary surgery Referred after primary surgery
161 101
61 39
Residual disease after first surgery No gross visible ≤1 cm N1 cm Unknown
22 84 123 33
8 32 47 13
≥5 cycles of platinum-based chemotherapy Yes No Unknown
212 42* 8
81 16 3
Cycles needed to normalize CA-125 (n = 94) 1 2 3 4 5 6 7 Median cycles Range
17 20 29 12 9 6 1 3 1–7
18 21 31 13 10 6 1
10
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
The outcomes after primary therapy are shown in Table 2. The majority of patients (61%) had their primary surgery at our institution. Of the 229 cases whose residual disease status after primary surgery was known, 123 (54%) had residual disease N1 cm. The majority of patients (212, 81%) received ≥5 cycles of platinum-based chemotherapy after primary surgery. Forty-two patients (16%) were treated on an institutional stem cell protocol and received 6 total chemotherapy cycles, of which 4 were platinum-based. The number of cycles of chemotherapy administered prior to normalization of the serum CA-125 was known in 94 patients. In these 94 cases, the median number of cycles required to normalize the serum CA-125 after primary surgery was 3 (range, 1–7). Findings at second-look surgery The results of SLS are summarized in Table 3. A similar number of patients underwent SLS via laparoscopy and laparotomy. Findings at SLS revealed 84 cases (32%) with Table 3 Findings at SLS (n = 262) Variable
Patients
%
Second-look surgery Laparoscopy Laparotomy Both Unknown
122 120 19 1
46 46 7 b1
Findings at SLS Microscopically positive Grossly positive ≤1 cm Grossly positive N1 cm Grossly positive, no dimensions Unknown
84 136 37 2 3
32 52 14 1 1
Area of positive findings (n = 259) Peritoneal biopsy Peritoneal fluid Lymph nodes
237 75 29
92 29 11
IP port insertion Yes No
200 62
76 24
Disease progression after SLS Yes No Unknown
214 22 26
82 8 10
Diagnosis of progression after SLS (n = 214) CA-125 CT Scan Additional surgery Physical examination Unknown
109 79 11 2 13
51 37 5 1 6
Status NED AWD DOD
28 68 166
11 26 63
IP, intraperitoneal; CT, computed tomography; NED, no evidence of disease; AWD, alive with disease; DOD, dead of disease.
Table 4 Salvage chemotherapy regimens (n = 243) Regimens
IP CDDP only IP CDDP plus additional IP medication Gemcitabine Mitoxatrone Etoposide Monthly taxol Weekly taxol FUDR Monthly taxol and mitoxatrone Gemcitabine and FUDR IP Other Monthly taxol Weekly taxol CDBCA and etoposide Mitoxatrone FUDR FUDR/Leucovorin/Oxaliplatin IV only Monthly taxol Weekly taxol Doxil Topotecan Ifosfamide CDBDA and monthly taxol CDBDA and weekly taxol CDDP/Monthly taxol/Ifosfamide CDDP and monthly taxol CDBDA and CTX Monthly taxol/CTX/Mitoxantrone CDBDA/Weekly Taxol/Doxil/Gemcitabine Unknown IV and IP medications IP CDDP and IV monthly taxol IP CDDP and IV weekly taxol IP CDDP/IP mitoxantrone and IV monthly taxol IP DCCP/IP CDBCA and IV weekly taxol IP CDDP and IV CDDP/IV monthly taxol IP CDDP and IV doxil/IV gemcitabine IP monthly taxol and IV monthly taxol IP monthly taxol and IV weekly taxol IP CDBCA/IP etoposide and IV CDBDA Oral medications only Etoposide Capecitabine
Patients
Cycles
n
%
Median
Range
71 53 24 20 4 1 1 1 1 1 29 1 9 8 6 4 1 50 21 7 4 2 2 4 1 1 2 2 1 1 2 35 24
29 22 10 8 2 0.4 0.4 0.4 0.4 0.4 12 0.4 4 3 2 2 0.4 21 9 3 2 0.8 0.8 0.2 0.4 0.4 0.8 0.8 0.4 0.4 0.8 14 10
4
1–6
4 5 4 2 11 1 1 1
2–12 1–10 1–6 2 11 1 1 1
4 16 4.5/4.5 5 4.5 1
4 15–16 2–6/2–6 3–8 4–6 1
6 12 4 6 4.5 5.5/4.5 4/13 3/3/3 3/3.5 5.5/5.5 1/1/2 4/13/6/1 1/1
1–12 4–18 2–6 3–9 4–5 3–6/2–6 4,13 3,3,3 3–4/3–4 5–6 1/1/2 4/13/6/1 1/1
5/5
5
2
1
0.4 5/5/6
(1–6)/ 1–6) (1–4)/ (15–20) 5/5/6
1 1 1 1 1 1 5 4 1
0.4 0.4 0.4 0.4 0.4 0.4 2 2 0.4
4/15
2/3/15 1/2/1 6/4/7 1/2 5/2 2/4/4
2/3/15 1/2/1 6/4/7 1/2 5/2 2/4/4
4 3
(2–5) 3
CDDP, cisplatin; FUDR, fluorodeoxyuridine; CDBDA, carboplatin; IV, intravenous; IP, intraperitoneal; CTX, cyclophosphomide.
microscopically positive disease, 136 (52%) with grossly positive disease ≤1 cm and 37 (14%) with grossly positive disease N1 cm. Two patients (1%) had grossly positive disease; however, dimensions were not quantified. Second-look findings were not available for 3 cases (1%). Of the 39 patients with unquantified or grossly positive disease N1 cm, 18 (46%) underwent secondary cytoreduction at the time of second-look surgery. Persistent disease was found most commonly on peritoneal biopsies (237, 92%), with some patients having positive findings on numerous biopsies and/or areas.
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14 Table 5 Univariate analysis of potential prognostic factors for overall survival
11
Table 6 Median survival by residual disease after primary surgery and findings at SLS
Potential prognostic factor
P value
Age FIGO stage Tumor grade Tumor histology (serous vs. others) Preoperative serum CA-125 before primary surgery Ascites at primary surgery Residual disease after primary surgery (≤1 cm vs. N1 cm) Number of chemotherapy cycles to normalize serum CA-125 Type of second-look surgery Findings at second-look surgery Area of positive findings Secondary cytoreduction at second-look surgery (yes vs. no) Type of salvage therapy after second-look surgery
0.02 0.41 0.01 0.02 0.20 0.01 0.04 0.11 0.68 0.06 0.17 0.61 0.11
FIGO, International Federation of Gynecology and Obstetrics.
Two hundred (76%) of the 262 patients had an IP port and catheter inserted at the time of SLS. After a median follow-up period of 40 months, 214 (82%) of the patients had disease progression after their SLS. Progression was most commonly diagnosed (109/214, 51%) by a rising serum CA-125. Salvage chemotherapy regimens Table 4 summarizes the salvage chemotherapy regimens used after SLS. The various regimens used were divided into 6 categories—IP cisplatin alone, 71 (29%); IP cisplatin combined with a second drug, 53 (22%); IP therapy other than cisplatin, 29 (12%); intravenous (IV) chemotherapy only, 50 (21%); IV and IP therapy, 35 (14%); and oral chemotherapy, 5 (2%). The treatment after SLS was unknown in 19 patients. Toxicities of the various salvage IP and systemic chemotherapy regimens were not evaluated in this study.
Residual after primary surgery
Second look findings
Number of patients
Median survival P (years) value
Optimal
Microscopic disease Microscopic disease Gross disease Gross disease
31
5.9
0.01
44
3.4
NS
75 75
3.1 2.1
NS NS
Suboptimal Optimal Suboptimal NS, not significant.
Prognostic factors After a median follow-up of 40 months, 166 (63%) of the 262 patients had died of disease, 68 (26%) were alive with disease, and 28 (11%) showed no evidence of disease. Of the 13 potential prognostic factors analyzed on univariate analysis, 5 were found to be significant—age, tumor grade, histology, the presence of ascites at primary surgery and residual disease after primary cytoreduction (Table 5). The amount of disease found at second-look surgery was of borderline significance and was included in the multivariate model. On multivariate analysis, only 2 factors emerged that when combined were statistically significant—residual disease after primary surgery and size of persistent disease found at SLS. Patients who had an optimal primary cytoreductive procedure and were subsequently found to have microscopic disease at SLS had significantly improved survival (Fig. 1). As shown in Table 6, the median survival was 5.9 years in this group compared with 2.1–3.4 years for those patients who had suboptimal primary surgery and/or grossly visible disease identified at SLS (P = 0.01).
Fig. 1. Residual disease and second-look laparotomy findings.
12
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
Fig. 2. Type of salvage therapy. Salvage therapies: 1, IP cisplatin; 2, IP cisplatin and second drug; 3, IP not cisplatin; 4, IV chemotherapy; 5, IP and IV chemotherapy.
Fig. 2 shows the survival curves based on the type of salvage therapy for 5 of the 6 salvage regimens. Oral chemotherapy was not analyzed due to the small patient numbers. None of the 5 specific treatments proved to be associated with a significant survival advantage. Intraperitoneal cisplatin combined with a second intraperitoneal drug had the longest median survival of 4 years. However, the improved survival associated with this combination intraperitoneal regimen did not reach statistical significance when compared to the other 4 regimens (Table 7). Discussion In 1998, Barakat and colleagues published our institutional experience with IP consolidation platinum-based chemotherapy for patients with negative SLS [6]. Disease-free survival for patients who received consolidation chemotherapy after negative SLS was significantly improved in patients who received IP chemotherapy compared with patients who declined consolidation therapy in the same time period. This
Table 7 Median survival by salvage treatment regimen Regimen
Salvage therapy
Number of patients
Median survival (years)
P value
1 2
IP cisplatin IP cisplatin and second drug IP not cisplatin IV chemotherapy IP and IV chemotherapy
42 34
3.2 4.0
NS NS
21 30
3.9 2.7
NS NS
24
3.0
NS
3 4 5
IP, intraperitoneal; IV, intravenous; NS, not significant.
disease-free survival advantage occurred in spite of the fact that risk factors for recurrence, such as high tumor grade and stage, were greater in the group of patients who received consolidation IP therapy. Based on these data, this consolidation approach is our current standard of care for patients who have a negative SLS. To date, the optimal management of patients with positive SLS has been elusive. In a subsequent study, Barakat and investigators demonstrated that survival after SLS and IP chemotherapy strongly correlated with the amount of disease found at SLS [7]. The median survival for those patients with a negative SLS was 8.7 years, with incremental decreases down to 1.2 years for those patients found to have N1 cm disease at the time of SLS. This study illustrated the strong prognostic value of the findings at SLS. However, since all patients received IP chemotherapy, the survival of other salvage therapies could not be analyzed. The current study was performed with the understanding that patients who have positive SLS have a worse prognosis than those with negative SLS, but with the potential to identify a promising approach for further investigation in this complex patient population. In this patient group, the only factor found to have significant prognostic value was the combination of optimal cytoreduction at primary surgery and microscopically persistent disease at SLS. These results are consistent with the numerous reports of the powerful prognostic importance of optimal primary cytoreduction and suggest that extensive surgery at primary debulking is warranted and justified prior to the initiation of chemotherapy [11–13]. The finding of decreased survival for patients who had suboptimal primary cytoreduction with microscopic disease at SLS compared with those with optimal primary cytoreduction with microscopic disease at SLS could be explained by differences in innate tumor biology. However, given that both groups of patients had
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
complete clinical responses to chemotherapy preceding the SLS, another reasonable explanation is that the tumor control obtained with chemotherapy is more durable after an optimal primary cytoreduction than a suboptimal one. These results parallel those reported by Rubin and associates in a prior analysis of second-look laparotomy (SLL) in patients from our institution [14]. In this series, all 91 patients had negative findings at second-look laparotomy; however, the amount of residual tumor after primary cytoreduction was found to be a significant predictor of recurrence. In a more recent study, Dowdy and colleagues reported on the long-term follow-up of 150 patients with ovarian cancer who had positive SLL [15]. Of the 150 patients, 145 were followed until death; the 5 other surviving patients had longterm follow-up with a median of 15.4 years. Patients with microscopic disease or those with ≤1 cm who were cytoreduced to microscopic disease had a significantly better survival than those with ≤1 cm disease who were not cytoreduced to microscopic residual and those found to have N1 cm disease, regardless of whether they underwent cytoreduction at SLL or not. The authors stated that cytoreduction at SLS was associated with a survival benefit only if microscopic residual disease was achieved in patients who started with b1 cm of disease. Cytoreduction did not improve survival in patients with N1 cm disease even if microscopic residual was achieved. The salvage therapies used after SLL in this study were intraperitoneal P32, whole-abdominal radiation, and systemic platinum-based chemotherapy. None of these approaches was found to have a significant beneficial effect on survival. Similarly, in our series, when comparing the various salvage regimens used, we did not identify one specific chemotherapy regimen that was associated with a significant survival advantage. However, 84% of patients (203/243) received IP chemotherapy as salvage therapy, and, in 69% of the patients (167/243), the salvage treatment was platinum-based IP therapy. With only 40 patients receiving non-IP salvage therapy, there may have been too few patients to adequately compare to those receiving IP salvage therapy, and specifically platinum-based IP salvage therapy. Though not statistically valid, the median survivals of 2.7–4.0 years attained with the predominantly platinum-based IP approach in our study compare favorably to the 1.0–3.3 year median survivals utilizing a predominantly radiation and systemic chemotherapeutic approach reported by Dowdy and colleagues [15]. Similarly, poor results with salvage radiation and systemic chemotherapy have been reported by others [16,17]. In the subgroup of 39 patients with unquantified or N1 cm disease found at SLS, 18 (46%) had secondary cytoreduction performed. Patients who underwent secondary cytoreduction had improved median survival (3.3 vs. 1.8 years, P = 0.03) compared to those in the subgroup who did not. However, secondary cytoreduction at SLS was not found to be a significant prognostic factor in the analysis of the entire 262patient cohort. This was most likely due to the low number of patients who were found to have N1 cm disease (37, 14%) and the even smaller number of patients who underwent cytoreduction. As secondary cytoreduction was not a main focus of this
13
study, the selection criteria used to determine which patients had attempted cytoreduction could not be determined nor were the factors that made secondary cytoreduction possible in these patients. Although cytoreduction is not the primary purpose of SLS, select patients found to have resectable disease at SLS may benefit from cytoreduction, as previously described [18]. The findings of our study demonstrate the durable prognostic value of optimal primary cytoreduction. No specific salvage chemotherapy regimen was associated with a survival advantage in patients who had tumor present at SLS. Novel therapeutic approaches are needed in this setting. However, the outcomes of patients receiving IP chemotherapy in this study compare favorably to other studied therapies in the literature. Given these findings, in combination with the prospective, randomized trials demonstrating the survival benefit of IP chemotherapy in the primary treatment setting, IP chemotherapy is a reasonable approach for patients who have not received prior IP treatment and are found to have microscopic or b1 cm disease, or can be further cytoreduced, at the time of SLS [19–21]. References [1] Morrow CP. An opinion in support of second-look surgery in ovarian cancer. Gynecol Oncol 2000;79:341–3. [2] Rose PG, Faulhaber P, Miraldi F, Abdul-Karim FW. Positive emission tomography for evaluating a complete clinical response in patients with ovarian or peritoneal carcinoma: correlation with second-look laparotomy. Gynecol Oncol 2001;82:17–21. [3] Podratz KC, Cliby WA. Second-look surgery in the management of epithelial ovarian carcinoma. Gynecol Oncol 1994;55:S128–33. [4] Greer BE, Bundy BN, Ozols RF, et al. Implications of second-look laparotomy (SLL) in the context of Gynecologic Oncology Group (GOG) protocol 158: a non-randomized comparison using an explanatory analysis. Gynecol Oncol 2003;88:156–7. [5] Cannistra SA. Cancer of the ovary. N Engl J Med 2004;351:2519–29. [6] Barakat RR, Almadrones L, Venkatraman ES, et al. A phase II trial of intraperitoneal cisplatin and etoposide as consolidation therapy in patients with stage II–IV epithelial ovarian cancer following negative surgical assessment. Gynecol Oncol 1998;69:17–22. [7] Barakat RR, Sabatini P, Bhaskaran D, et al. Intraperitoneal chemotherapy for ovarian carcinoma: results of long-term follow-up. J Clin Oncol 2002;20:694–8. [8] Kaplan EL, Meier P. Nonparametric estimator from incomplete observations. J Am Stat Assoc 1958;53:457–81. [9] Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–70. [10] Cox DR. Regression models and life tables. J R Stat Soc, B 1972;34: 187–220. [11] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59. [12] Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390–6. [13] Chi DS, Franklin CC, Levine DA, et al. Improved optimal cytoreduction rates for stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancer: a change in surgical approach. Gynecol Oncol 2004; 94:650–4. [14] Rubin SC, Randall TC, Armstrong KA, Chi DS, Hoskins WJ. Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings. Obstet Gynecol 1999;93:21–4.
14
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
[15] Dowdy SC, Constantinou CL, Hartmann LC, et al. Long-term follow-up of women with ovarian cancer after positive second-look laparotomy. Gynecol Oncol 2003;91:563–8. [16] MacGibbon A, Bucci J, MacLeod C, et al. Whole abdominal radiotherapy following second-look laparotomy for ovarian carcinoma. Gynecol Oncol 1999;75:62–7. [17] Bertucci F, Viens P, Delpero JR, et al. High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results. Bone Marrow Transplant 2000;26:61–7. [18] Hoskins WJ, Rubin SC, Dulaney E, et al. Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma. Gynecol Oncol 1989;34: 365–71.
[19] Alberts DS, Liu PY, Hannigan EV, 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. [20] Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:1001–7. [21] Armstrong DK, Bundy BN, Baergen R, et al. Randomized phase III study of intravenous (IV) paclitaxel, intraperitoneal (IP) cisplatin and IP paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group trial. Proc Am Soc Clin Oncol 2002;12:201a.
Identification of prognostic factors after positive second-look surgery in epithelial ovarian carcinoma Wayne A. McCreath a,1 , Eric L. Eisenhauer a , Nadeem R. Abu-Rustum a , Ennapadam S. Venkatraman b , Aileen Caceres c , Rachel Bier a , Jae Huh a , Jae Cho a , Richard R. Barakat a , Dennis S. Chi a,⁎ a b
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021, USA c Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA Received 22 June 2005 Available online 20 January 2006
Abstract Objective. The objective of this study was to identify independent prognostic factors for survival in patients with epithelial ovarian cancer who had persistent disease identified at second-look surgery. Methods. We performed a retrospective chart review of all patients with epithelial ovarian cancer who had positive findings at second-look surgery between June 1991 and June 2002. All patients achieved a complete clinical remission after a prescribed course of primary therapy. Survival was determined from the time of second-look surgery until last follow-up or death. Results. The study included a total of 262 patients, with a median age of 54 years (range, 22–80). Of the 262 patients, 166 (63%) had died of disease. Records of initial (salvage) treatment after the positive second-look surgery were available for 243 patients. Therapies included the following: intraperitoneal (IP) cisplatin, 71 (29%); IP cisplatin combined with a second drug, 53 (22%); IP therapy other than cisplatin, 29 (12%); intravenous (IV) chemotherapy, 50 (21%); IP and IV therapy, 35 (14%); and oral chemotherapy, 5 (2%). Of the 13 potential prognostic factors analyzed, only 2 factors emerged that, when combined, were significant—residual disease after primary surgery and size of persistent disease found at second-look surgery. Patients with ≤1 cm residual disease after primary surgery and microscopic disease at second-look surgery had significantly improved survival. Conclusion. In our analysis, the only prognostic factor for survival in patients with positive second-look procedures was a combination of residual disease after primary surgery and size of persistent disease identified at second-look surgery. No individual chemotherapy treatment imparted a survival advantage. Novel that therapeutic approaches are needed in this setting. © 2005 Elsevier Inc. All rights reserved. Keywords: Prognostic factors; Ovarian cancer; Second-look surgery
Introduction Second-look surgery (SLS) is the most reliable method for evaluating the status of ovarian cancer after primary treatment [1]. SLS can be used to detect occult residual disease in patients who have completed a prescribed course of primary chemo-
⁎ Corresponding author. Fax: +1 212 717 3214. E-mail address: [email protected] (D.S. Chi). 1 Currently at Crystal Run Healthcare Middletown, NY, USA. 0090-8258/$ - see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.11.040
therapy and are in a complete clinical remission. SLS is more specific and sensitive than non-invasive modalities [1,2]. Traditionally, second-look operations have helped to determine the patient's cancer status and to identify patients with persistent disease who may benefit from continued treatment. The value of the second-look operation is controversial because relapse rates continue to remain high (40–60%) even when the findings at surgery are negative. A lack of prospective data supporting its use still persists today [3–5]. At our institution, SLS has the added benefit of enabling adequate placement of an intraperitoneal (IP) port and catheter
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14 Table 1 Patient characteristics (n = 262) Variable Age (years) Median Range
Patients
%
54 22–80
Initial FIGO stage IIC IIIA IIIB IIIC IV Unstaged
1 4 17 210 29 1
b1 2 6 80 11 b1
Tumor grade G1 G2 G3 Not available
16 67 160 19
6 26 61 7
Tumor histology Serous Endometrioid Mixed Clear cell Mucinous Carcinosarcoma Other
164 34 25 9 3 1 26
63 13 9 3 1 b1 10
Ascites at primary surgery Yes No Not recorded
177 22 63
68 8 24
9
clinical remission was defined as return to CA-125 values b35 U/mL in patients with preoperative elevated CA-125 levels and no evidence of measurable disease by CT scan for those patients who had CT scans. Second-look operation was performed by laparoscopy and/or laparotomy. In patients with gross evidence of persistent disease, systematic biopsies were not routinely performed since only one positive biopsy was needed to define an SLS as positive. However, in patients with no evidence of gross disease, random biopsies were obtained from the bilateral diaphragms, bilateral paracolic gutters, bilateral pelvic sidewalls, anterior and posterior cul de sacs and any suspicious adhesions. Individual records were reviewed, and pertinent demographic, clinical, pathologic and follow-up information abstracted. Patients who had more than 100 cm3 of peritoneal fluid at the time of primary surgery were considered to be positive for ascites. Optimal primary cytoreduction was defined as ≤1 cm residual disease. Survival time was calculated in months from the SLS to death or to the date of last follow-up visit for those patients still alive. Survival curves were estimated using the Kaplan–Meier method [8]. Potential prognostic factors were tested by univariate analysis using the log-rank test for categorical factors and Cox's proportional hazards model for continuous factors [9]. Stepwise model selection methods were used for selecting factors included in the multivariate Cox proportional hazards model [10].
Results
CA-125 before primary surgery (U/mL) Median 871 Range 1–16,844 FIGO, International Federation of Gynecology and Obstetrics.
for additional consolidation or salvage IP chemotherapy [6,7]. We have previously demonstrated a survival advantage to IP consolidation chemotherapy compared with no therapy in patients with negative SLS [6]. Consequently, IP consolidation chemotherapy is currently our standard treatment for patients with negative second-look procedures. The management of patients with positive second-look procedures presents a more perplexing problem. Various treatments have been proposed, but a clearly superior approach has not emerged. The objective of this study was to compare the survival outcomes of the various salvage regimens used and to identify independent prognostic factors for survival in patients with epithelial ovarian carcinoma who have persistent disease identified at second-look operation. Methods After receiving Institutional Review Board approval, we used our Gynecology Service database to identify all patients with epithelial ovarian carcinoma who underwent SLS between June 1991 and June 2002. SLS was defined as a comprehensive surgical evaluation of disease status in patients with advanced ovarian cancer who achieved a complete clinical remission after primary cytoreductive surgery and platinum-based systemic chemotherapy. Complete
Patient characteristics and primary therapy A total of 262 patients were initially identified for this study. Patient characteristics are listed in Table 1. Their median age was 54 years (range, 22–80). The majority of patients initially presented with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC disease (210, 80%), grade 3 tumors (160, 61%), serous histology (164, 63%) and ascites (177, 68%). The preoperative serum CA-125 before primary surgery was recorded in 72 patients. The median was 871 U/ mL, with a range of 1–16,844 U/mL. Table 2 Outcome of primary therapy (n = 262) Variable
Patients
%
Initial evaluation Evaluated before primary surgery Referred after primary surgery
161 101
61 39
Residual disease after first surgery No gross visible ≤1 cm N1 cm Unknown
22 84 123 33
8 32 47 13
≥5 cycles of platinum-based chemotherapy Yes No Unknown
212 42* 8
81 16 3
Cycles needed to normalize CA-125 (n = 94) 1 2 3 4 5 6 7 Median cycles Range
17 20 29 12 9 6 1 3 1–7
18 21 31 13 10 6 1
10
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
The outcomes after primary therapy are shown in Table 2. The majority of patients (61%) had their primary surgery at our institution. Of the 229 cases whose residual disease status after primary surgery was known, 123 (54%) had residual disease N1 cm. The majority of patients (212, 81%) received ≥5 cycles of platinum-based chemotherapy after primary surgery. Forty-two patients (16%) were treated on an institutional stem cell protocol and received 6 total chemotherapy cycles, of which 4 were platinum-based. The number of cycles of chemotherapy administered prior to normalization of the serum CA-125 was known in 94 patients. In these 94 cases, the median number of cycles required to normalize the serum CA-125 after primary surgery was 3 (range, 1–7). Findings at second-look surgery The results of SLS are summarized in Table 3. A similar number of patients underwent SLS via laparoscopy and laparotomy. Findings at SLS revealed 84 cases (32%) with Table 3 Findings at SLS (n = 262) Variable
Patients
%
Second-look surgery Laparoscopy Laparotomy Both Unknown
122 120 19 1
46 46 7 b1
Findings at SLS Microscopically positive Grossly positive ≤1 cm Grossly positive N1 cm Grossly positive, no dimensions Unknown
84 136 37 2 3
32 52 14 1 1
Area of positive findings (n = 259) Peritoneal biopsy Peritoneal fluid Lymph nodes
237 75 29
92 29 11
IP port insertion Yes No
200 62
76 24
Disease progression after SLS Yes No Unknown
214 22 26
82 8 10
Diagnosis of progression after SLS (n = 214) CA-125 CT Scan Additional surgery Physical examination Unknown
109 79 11 2 13
51 37 5 1 6
Status NED AWD DOD
28 68 166
11 26 63
IP, intraperitoneal; CT, computed tomography; NED, no evidence of disease; AWD, alive with disease; DOD, dead of disease.
Table 4 Salvage chemotherapy regimens (n = 243) Regimens
IP CDDP only IP CDDP plus additional IP medication Gemcitabine Mitoxatrone Etoposide Monthly taxol Weekly taxol FUDR Monthly taxol and mitoxatrone Gemcitabine and FUDR IP Other Monthly taxol Weekly taxol CDBCA and etoposide Mitoxatrone FUDR FUDR/Leucovorin/Oxaliplatin IV only Monthly taxol Weekly taxol Doxil Topotecan Ifosfamide CDBDA and monthly taxol CDBDA and weekly taxol CDDP/Monthly taxol/Ifosfamide CDDP and monthly taxol CDBDA and CTX Monthly taxol/CTX/Mitoxantrone CDBDA/Weekly Taxol/Doxil/Gemcitabine Unknown IV and IP medications IP CDDP and IV monthly taxol IP CDDP and IV weekly taxol IP CDDP/IP mitoxantrone and IV monthly taxol IP DCCP/IP CDBCA and IV weekly taxol IP CDDP and IV CDDP/IV monthly taxol IP CDDP and IV doxil/IV gemcitabine IP monthly taxol and IV monthly taxol IP monthly taxol and IV weekly taxol IP CDBCA/IP etoposide and IV CDBDA Oral medications only Etoposide Capecitabine
Patients
Cycles
n
%
Median
Range
71 53 24 20 4 1 1 1 1 1 29 1 9 8 6 4 1 50 21 7 4 2 2 4 1 1 2 2 1 1 2 35 24
29 22 10 8 2 0.4 0.4 0.4 0.4 0.4 12 0.4 4 3 2 2 0.4 21 9 3 2 0.8 0.8 0.2 0.4 0.4 0.8 0.8 0.4 0.4 0.8 14 10
4
1–6
4 5 4 2 11 1 1 1
2–12 1–10 1–6 2 11 1 1 1
4 16 4.5/4.5 5 4.5 1
4 15–16 2–6/2–6 3–8 4–6 1
6 12 4 6 4.5 5.5/4.5 4/13 3/3/3 3/3.5 5.5/5.5 1/1/2 4/13/6/1 1/1
1–12 4–18 2–6 3–9 4–5 3–6/2–6 4,13 3,3,3 3–4/3–4 5–6 1/1/2 4/13/6/1 1/1
5/5
5
2
1
0.4 5/5/6
(1–6)/ 1–6) (1–4)/ (15–20) 5/5/6
1 1 1 1 1 1 5 4 1
0.4 0.4 0.4 0.4 0.4 0.4 2 2 0.4
4/15
2/3/15 1/2/1 6/4/7 1/2 5/2 2/4/4
2/3/15 1/2/1 6/4/7 1/2 5/2 2/4/4
4 3
(2–5) 3
CDDP, cisplatin; FUDR, fluorodeoxyuridine; CDBDA, carboplatin; IV, intravenous; IP, intraperitoneal; CTX, cyclophosphomide.
microscopically positive disease, 136 (52%) with grossly positive disease ≤1 cm and 37 (14%) with grossly positive disease N1 cm. Two patients (1%) had grossly positive disease; however, dimensions were not quantified. Second-look findings were not available for 3 cases (1%). Of the 39 patients with unquantified or grossly positive disease N1 cm, 18 (46%) underwent secondary cytoreduction at the time of second-look surgery. Persistent disease was found most commonly on peritoneal biopsies (237, 92%), with some patients having positive findings on numerous biopsies and/or areas.
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14 Table 5 Univariate analysis of potential prognostic factors for overall survival
11
Table 6 Median survival by residual disease after primary surgery and findings at SLS
Potential prognostic factor
P value
Age FIGO stage Tumor grade Tumor histology (serous vs. others) Preoperative serum CA-125 before primary surgery Ascites at primary surgery Residual disease after primary surgery (≤1 cm vs. N1 cm) Number of chemotherapy cycles to normalize serum CA-125 Type of second-look surgery Findings at second-look surgery Area of positive findings Secondary cytoreduction at second-look surgery (yes vs. no) Type of salvage therapy after second-look surgery
0.02 0.41 0.01 0.02 0.20 0.01 0.04 0.11 0.68 0.06 0.17 0.61 0.11
FIGO, International Federation of Gynecology and Obstetrics.
Two hundred (76%) of the 262 patients had an IP port and catheter inserted at the time of SLS. After a median follow-up period of 40 months, 214 (82%) of the patients had disease progression after their SLS. Progression was most commonly diagnosed (109/214, 51%) by a rising serum CA-125. Salvage chemotherapy regimens Table 4 summarizes the salvage chemotherapy regimens used after SLS. The various regimens used were divided into 6 categories—IP cisplatin alone, 71 (29%); IP cisplatin combined with a second drug, 53 (22%); IP therapy other than cisplatin, 29 (12%); intravenous (IV) chemotherapy only, 50 (21%); IV and IP therapy, 35 (14%); and oral chemotherapy, 5 (2%). The treatment after SLS was unknown in 19 patients. Toxicities of the various salvage IP and systemic chemotherapy regimens were not evaluated in this study.
Residual after primary surgery
Second look findings
Number of patients
Median survival P (years) value
Optimal
Microscopic disease Microscopic disease Gross disease Gross disease
31
5.9
0.01
44
3.4
NS
75 75
3.1 2.1
NS NS
Suboptimal Optimal Suboptimal NS, not significant.
Prognostic factors After a median follow-up of 40 months, 166 (63%) of the 262 patients had died of disease, 68 (26%) were alive with disease, and 28 (11%) showed no evidence of disease. Of the 13 potential prognostic factors analyzed on univariate analysis, 5 were found to be significant—age, tumor grade, histology, the presence of ascites at primary surgery and residual disease after primary cytoreduction (Table 5). The amount of disease found at second-look surgery was of borderline significance and was included in the multivariate model. On multivariate analysis, only 2 factors emerged that when combined were statistically significant—residual disease after primary surgery and size of persistent disease found at SLS. Patients who had an optimal primary cytoreductive procedure and were subsequently found to have microscopic disease at SLS had significantly improved survival (Fig. 1). As shown in Table 6, the median survival was 5.9 years in this group compared with 2.1–3.4 years for those patients who had suboptimal primary surgery and/or grossly visible disease identified at SLS (P = 0.01).
Fig. 1. Residual disease and second-look laparotomy findings.
12
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
Fig. 2. Type of salvage therapy. Salvage therapies: 1, IP cisplatin; 2, IP cisplatin and second drug; 3, IP not cisplatin; 4, IV chemotherapy; 5, IP and IV chemotherapy.
Fig. 2 shows the survival curves based on the type of salvage therapy for 5 of the 6 salvage regimens. Oral chemotherapy was not analyzed due to the small patient numbers. None of the 5 specific treatments proved to be associated with a significant survival advantage. Intraperitoneal cisplatin combined with a second intraperitoneal drug had the longest median survival of 4 years. However, the improved survival associated with this combination intraperitoneal regimen did not reach statistical significance when compared to the other 4 regimens (Table 7). Discussion In 1998, Barakat and colleagues published our institutional experience with IP consolidation platinum-based chemotherapy for patients with negative SLS [6]. Disease-free survival for patients who received consolidation chemotherapy after negative SLS was significantly improved in patients who received IP chemotherapy compared with patients who declined consolidation therapy in the same time period. This
Table 7 Median survival by salvage treatment regimen Regimen
Salvage therapy
Number of patients
Median survival (years)
P value
1 2
IP cisplatin IP cisplatin and second drug IP not cisplatin IV chemotherapy IP and IV chemotherapy
42 34
3.2 4.0
NS NS
21 30
3.9 2.7
NS NS
24
3.0
NS
3 4 5
IP, intraperitoneal; IV, intravenous; NS, not significant.
disease-free survival advantage occurred in spite of the fact that risk factors for recurrence, such as high tumor grade and stage, were greater in the group of patients who received consolidation IP therapy. Based on these data, this consolidation approach is our current standard of care for patients who have a negative SLS. To date, the optimal management of patients with positive SLS has been elusive. In a subsequent study, Barakat and investigators demonstrated that survival after SLS and IP chemotherapy strongly correlated with the amount of disease found at SLS [7]. The median survival for those patients with a negative SLS was 8.7 years, with incremental decreases down to 1.2 years for those patients found to have N1 cm disease at the time of SLS. This study illustrated the strong prognostic value of the findings at SLS. However, since all patients received IP chemotherapy, the survival of other salvage therapies could not be analyzed. The current study was performed with the understanding that patients who have positive SLS have a worse prognosis than those with negative SLS, but with the potential to identify a promising approach for further investigation in this complex patient population. In this patient group, the only factor found to have significant prognostic value was the combination of optimal cytoreduction at primary surgery and microscopically persistent disease at SLS. These results are consistent with the numerous reports of the powerful prognostic importance of optimal primary cytoreduction and suggest that extensive surgery at primary debulking is warranted and justified prior to the initiation of chemotherapy [11–13]. The finding of decreased survival for patients who had suboptimal primary cytoreduction with microscopic disease at SLS compared with those with optimal primary cytoreduction with microscopic disease at SLS could be explained by differences in innate tumor biology. However, given that both groups of patients had
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
complete clinical responses to chemotherapy preceding the SLS, another reasonable explanation is that the tumor control obtained with chemotherapy is more durable after an optimal primary cytoreduction than a suboptimal one. These results parallel those reported by Rubin and associates in a prior analysis of second-look laparotomy (SLL) in patients from our institution [14]. In this series, all 91 patients had negative findings at second-look laparotomy; however, the amount of residual tumor after primary cytoreduction was found to be a significant predictor of recurrence. In a more recent study, Dowdy and colleagues reported on the long-term follow-up of 150 patients with ovarian cancer who had positive SLL [15]. Of the 150 patients, 145 were followed until death; the 5 other surviving patients had longterm follow-up with a median of 15.4 years. Patients with microscopic disease or those with ≤1 cm who were cytoreduced to microscopic disease had a significantly better survival than those with ≤1 cm disease who were not cytoreduced to microscopic residual and those found to have N1 cm disease, regardless of whether they underwent cytoreduction at SLL or not. The authors stated that cytoreduction at SLS was associated with a survival benefit only if microscopic residual disease was achieved in patients who started with b1 cm of disease. Cytoreduction did not improve survival in patients with N1 cm disease even if microscopic residual was achieved. The salvage therapies used after SLL in this study were intraperitoneal P32, whole-abdominal radiation, and systemic platinum-based chemotherapy. None of these approaches was found to have a significant beneficial effect on survival. Similarly, in our series, when comparing the various salvage regimens used, we did not identify one specific chemotherapy regimen that was associated with a significant survival advantage. However, 84% of patients (203/243) received IP chemotherapy as salvage therapy, and, in 69% of the patients (167/243), the salvage treatment was platinum-based IP therapy. With only 40 patients receiving non-IP salvage therapy, there may have been too few patients to adequately compare to those receiving IP salvage therapy, and specifically platinum-based IP salvage therapy. Though not statistically valid, the median survivals of 2.7–4.0 years attained with the predominantly platinum-based IP approach in our study compare favorably to the 1.0–3.3 year median survivals utilizing a predominantly radiation and systemic chemotherapeutic approach reported by Dowdy and colleagues [15]. Similarly, poor results with salvage radiation and systemic chemotherapy have been reported by others [16,17]. In the subgroup of 39 patients with unquantified or N1 cm disease found at SLS, 18 (46%) had secondary cytoreduction performed. Patients who underwent secondary cytoreduction had improved median survival (3.3 vs. 1.8 years, P = 0.03) compared to those in the subgroup who did not. However, secondary cytoreduction at SLS was not found to be a significant prognostic factor in the analysis of the entire 262patient cohort. This was most likely due to the low number of patients who were found to have N1 cm disease (37, 14%) and the even smaller number of patients who underwent cytoreduction. As secondary cytoreduction was not a main focus of this
13
study, the selection criteria used to determine which patients had attempted cytoreduction could not be determined nor were the factors that made secondary cytoreduction possible in these patients. Although cytoreduction is not the primary purpose of SLS, select patients found to have resectable disease at SLS may benefit from cytoreduction, as previously described [18]. The findings of our study demonstrate the durable prognostic value of optimal primary cytoreduction. No specific salvage chemotherapy regimen was associated with a survival advantage in patients who had tumor present at SLS. Novel therapeutic approaches are needed in this setting. However, the outcomes of patients receiving IP chemotherapy in this study compare favorably to other studied therapies in the literature. Given these findings, in combination with the prospective, randomized trials demonstrating the survival benefit of IP chemotherapy in the primary treatment setting, IP chemotherapy is a reasonable approach for patients who have not received prior IP treatment and are found to have microscopic or b1 cm disease, or can be further cytoreduced, at the time of SLS [19–21]. References [1] Morrow CP. An opinion in support of second-look surgery in ovarian cancer. Gynecol Oncol 2000;79:341–3. [2] Rose PG, Faulhaber P, Miraldi F, Abdul-Karim FW. Positive emission tomography for evaluating a complete clinical response in patients with ovarian or peritoneal carcinoma: correlation with second-look laparotomy. Gynecol Oncol 2001;82:17–21. [3] Podratz KC, Cliby WA. Second-look surgery in the management of epithelial ovarian carcinoma. Gynecol Oncol 1994;55:S128–33. [4] Greer BE, Bundy BN, Ozols RF, et al. Implications of second-look laparotomy (SLL) in the context of Gynecologic Oncology Group (GOG) protocol 158: a non-randomized comparison using an explanatory analysis. Gynecol Oncol 2003;88:156–7. [5] Cannistra SA. Cancer of the ovary. N Engl J Med 2004;351:2519–29. [6] Barakat RR, Almadrones L, Venkatraman ES, et al. A phase II trial of intraperitoneal cisplatin and etoposide as consolidation therapy in patients with stage II–IV epithelial ovarian cancer following negative surgical assessment. Gynecol Oncol 1998;69:17–22. [7] Barakat RR, Sabatini P, Bhaskaran D, et al. Intraperitoneal chemotherapy for ovarian carcinoma: results of long-term follow-up. J Clin Oncol 2002;20:694–8. [8] Kaplan EL, Meier P. Nonparametric estimator from incomplete observations. J Am Stat Assoc 1958;53:457–81. [9] Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–70. [10] Cox DR. Regression models and life tables. J R Stat Soc, B 1972;34: 187–220. [11] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59. [12] Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390–6. [13] Chi DS, Franklin CC, Levine DA, et al. Improved optimal cytoreduction rates for stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancer: a change in surgical approach. Gynecol Oncol 2004; 94:650–4. [14] Rubin SC, Randall TC, Armstrong KA, Chi DS, Hoskins WJ. Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings. Obstet Gynecol 1999;93:21–4.
14
W.A. McCreath et al. / Gynecologic Oncology 102 (2006) 8–14
[15] Dowdy SC, Constantinou CL, Hartmann LC, et al. Long-term follow-up of women with ovarian cancer after positive second-look laparotomy. Gynecol Oncol 2003;91:563–8. [16] MacGibbon A, Bucci J, MacLeod C, et al. Whole abdominal radiotherapy following second-look laparotomy for ovarian carcinoma. Gynecol Oncol 1999;75:62–7. [17] Bertucci F, Viens P, Delpero JR, et al. High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results. Bone Marrow Transplant 2000;26:61–7. [18] Hoskins WJ, Rubin SC, Dulaney E, et al. Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma. Gynecol Oncol 1989;34: 365–71.
[19] Alberts DS, Liu PY, Hannigan EV, 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. [20] Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:1001–7. [21] Armstrong DK, Bundy BN, Baergen R, et al. Randomized phase III study of intravenous (IV) paclitaxel, intraperitoneal (IP) cisplatin and IP paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group trial. Proc Am Soc Clin Oncol 2002;12:201a.