1152

Secondary Cytoreductive Surgery for Patients with Relapsed Epithelial Ovarian Carcinoma: Who Benets?
Rong-Yu Zang, M.D., Ph.D.1 Zi-Ting Li, M.D.1 Jie Tang, M.D.1 Xi Cheng, M.D.1 Shu-Mo Cai, M.D.1 Zhi-Yi Zhang, M.D.1 Nelson N. Teng, M.D., Ph.D.2
1

BACKGROUND. This study was performed to address patient selection criteria and
the role of secondary cytoreductive surgery (SCR) in patients with epithelial ovarian carcinoma (EOC) who had relapsed tumors after a progression-free interval 3 months. METHODS. One hundred seventeen patients with relapsed EOC after a clinical complete remission duration 3 months who underwent SCR were entered on this prospective trial. Survival curves were generated using the KaplanMeier method, and statistical comparisons were performed using log-rank tests, logistic stepwise regression analyses, and a Cox stepwise regression model.

Department of Gynecologic Oncology, Cancer Hospital of Fudan University (formerly Shanghai Medical University), Shanghai, China. Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, California.

Supported in part by the New Star Project (Rong-Yu Zang) and by a grant from the Shanghai Health Bureau 99408 (Zi-Ting Li). The authors thank Yan Xing, Ph.D., at the M. D. Anderson Cancer Center for statistical assistance. Address for reprints: Rong-Yu Zang, M.D., Ph.D., Department of Gynecologic Oncology, Cancer Hospital of Fudan University, 399 Ling-Ling Road, Shanghai 200032, China; Fax: (011) 86 2164174774. Received September 16, 2003; revision received January 5, 2004; accepted January 6, 2004. 2004 American Cancer Society DOI 10.1002/cncr.20106

RESULTS. The median patient age at the time of relapse was 53 years (range, 20 78 years). The median survival was 22 months and the estimated 5-year survival rate for the entire cohort was 17.2%. Tumor was conned to a solitary site in 33 patients and to 2 sites in 84 patients. After they underwent SCR, 11 patients were rendered macroscopically disease free, 61 patients had residual disease that measured 1 cm in greatest dimension, and 45 patients had bulky intraabdominal residual disease. Survival was inuenced by the extent of relapse disease (solitary site vs. multiple sites; P 0.0001), the size of residual disease after SCR (0 cm vs. 1 cm [P 0.1211], 1 cm vs. 1 cm [P 0.0002], and 0 cm vs. 1 cm [P 0.0011]), Eastern Cooperative Oncology Group performance status (0 vs. 1 [P 0.134], 1 vs. 2 [P 0.007], and 0 vs. 2 [P 0.0012]), and the number of cycles of salvage chemotherapy (12 cycles vs. 35 cycles [P 0.0144]; 12 cycles vs. 6 cycles [P 0.0001]; and 35 cycles vs. 6 cycles [P 0.0009]). The outcome of SCR was inuenced by the extent of relapse disease (multiple sites [51.2%] vs. solitary sites [87.9%]; relative risk [RR] 9.1237; P 0.0002) and by the use of bowel resection (yes [60.9%] vs. no [37.5%]; RR 0.3828; P 0.0106). CONCLUSIONS. SCR was found to be safe for patients with relapsed EOC who achieved a clinical complete remission that lasted 3 months, with resectability similar to that of primary debulking surgery. Optimal surgical outcomes were achieved easily in patients who apparently had solitary tumor sites, with bowel resection making it possible to remove bulky tumors that involved the intestine. A survival benet was provided by optimal SCR, particularly when surgery was supported by multiple courses of salvage chemotherapy. Cancer 2004;100: 1152 61. 2004 American Cancer Society. KEYWORDS: ovarian carcinoma, relapse, surgery, secondary cytoreductive surgery.

varian carcinoma represents 25% of all malignancies of the female genital tract but is the most common cause of death among women who develop gynecologic malignancies. The majority (nearly 75%) of patients with epithelial ovarian carcinoma (EOC) have advanced-stage disease at the time of diagnosis. The 5-year survival rate for patients with all stages of EOC is 53% but falls to 20 31% for patients who present with advanced disease.13 Approximately 48

SCR and Relapsed EOC/Zang et al.

1153

50% of women with EOC ultimately will develop a recurrent tumor and will require further treatment.3 The unfavorable prognosis and diminished survival of patients who do not achieve complete remission with induction chemotherapy or who develop recurrent tumors after achieving a prior response and controversy regarding the management of recurrent EOC have led to the application of numerous active agents in the second-line setting.4 6 Despite the introduction of new chemotherapeutic agents and the development of novel combinations, a review of clinical outcomes in patients with recurrent EOC concluded that there has been little change in response duration and survival during the past 2 decades. Strategies designed to improve these results continue to be investigated.3 Randomized investigations examining the role of primary cytoreductive surgery are lacking, and it is impossible to conduct such a trial. However, more recently, a meta-analysis summarizing data from 1989 to 1998 revealed that, during the platinum era, maximal cytoreduction, rather than the dose intensity of platinum compound administered, was one of the most powerful determinants of cohort survival among patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III or Stage IV EOC. The authors of that study believed that consistently referring patients with apparent advanced EOC to expert centers for primary surgery may be the best means currently available for improving overall survival.7 The situation is not as encouraging for patients who require secondary cytoreductive surgery (SCR). In 1983, Berek et al. were the rst investigators to demonstrate that patients with recurrent EOC beneted from optimal SCR.8 Six years later, however, a widely quoted report from the M. D. Anderson Cancer Center on a review of patients who had recurrent disease did not nd any signicant survival benet from SCR. Those authors stated that, in the absence of efcacious second-line medical therapy, the value of secondary tumor-reductive surgery for recurrent EOC was limited.9 However, Janicke et al.10 and other investigators11,12 reported that a survival benet was provided by successful secondary debulking surgery. Recent observations also indicate that SCR is feasible, well tolerated, and associated with signicant prolongation of survival in selected patients with recurrent EOC.1317 However, that opinion is not unanimous, and numerous issues remain: 1) Patients with recurrent EOC are highly selected for secondary surgery and, to date, there are no standard selection criteria; 2) the SCR surgical technique is more complicated compared with primary surgery, and the SCR approach is restricted to a few large institutions; 3) retrospective reviews are not convincing enough to advocate SCR as

a standard approach for the treatment of patients with recurrent EOC, and no gold standard trials have been performed to date; and 4) conversely, salvage chemotherapy is conducted easily with fewer restrictions on the physician. Even so, inspired by the encouraging results available and our experience in a retrospective study, we conducted this prospective trial to address the following questions: When they develop recurrent EOC, 1) which patients are suitable candidates for secondary cytoreductive surgery; and 2) which patients may benet most from SCR?

MATERIALS AND METHODS

Eligibility Criteria
Patients with EOC in this prospective trial had undergone primary cytoreductive surgery followed by platinum-based chemotherapy. They had established relapse, which was dened as tumor recurrence after a progression-free interval (PFI) 3 months. This clinical setting was categorized as relapse, as distinguished from the conventional concept of recurrence, which was dened as tumor recurrence after a PFI 6 months after completing primary therapy. Other criteria for inclusion were 1) a rising CA 125 level and/or radiographic or physical ndings suggestive of relapse; 2) evaluation of disease status within 2 weeks before enrolling onto the trial; 3) an estimated survival 3 months; 4) the absence of hepatic parenchyma metastasis; 5) a surgical objective to remove all visible lesions in the pelvis and/or the abdomen; 6) patient consent to undergo secondary surgery; 7) an Eastern Cooperative Oncology Group (ECOG) performance status 2; and 8) the absence of medical contradictions to an extensive surgical procedure.

Denitions
Response to salvage chemotherapy after SCR was assessed before each cycle for disease measurable on physical examination and as appropriate for tumors measured on medical imaging. Chest X-rays were repeated as necessary to monitor tumor response. A complete remission was dened as the disappearance of all measurable and assessable disease for at least 4 weeks. A partial response required a reduction in tumor burden 50% that lasted 4 weeks and no appearance of new lesions. A responder was dened as any patient who exhibited a complete or partial response. For patients who underwent optimal cytoreduction, response was dened as the disappearance of all macroscopic disease for at least 4 weeks; for patients who underwent complete SCR, a responder was dened as a patient without any tumor for at least 8 weeks. All measurable disease sites were assessed us-

1154

CANCER March 15, 2004 / Volume 100 / Number 6

ing the same techniques that were used to measure disease sites at baseline. Compared with platinum-based, rst-line chemotherapy, second-line chemotherapy was dened as chemotherapy that included one of the following drugs or their combinations: topotecan, gemcitabine, etoposide, ifosfamide, docetaxel, hydroxycamptothecine (HCPT), vinorelbine (NVB), or hexamethylmelamine. For economic reasons, in China, paclitaxel cannot be used in the primary setting; therefore, it also is considered a second-line agent.3,15,18

chemotherapy. Some patients with localized recurrences also received external beam radiation therapy. Among 11 patients who underwent complete SCR, 6 patients were treated with second-line salvage chemotherapy. Platinum-based salvage chemotherapy was administered in 5 patients who were sensitive to platinum-based chemotherapy in primary therapy.

Statistical Considerations
One hundred twenty-three eligible patients were targeted over a 4-year enrollment period with an additional 1-year of follow-up before the nal analysis. Survival was measured from the day of either secondary surgery or chemotherapy before secondary surgery. Data were analyzed using SPSS soft package for Windows (version 9.0; SPSS Inc., Chicago, IL). The median follow-up was 16 months (range, 5 84 months). Survival was compared using a time-toevent methodology. Life tables and the KaplanMeier method were used to obtain estimates of survival and median survival, respectively. Survival curves were generated using the KaplanMeier method and were compared using the log-rank test. This prospective study was initiated to determine the ability to surgically eliminate all visible disease in patients with relapsed EOC and the associated impact on survival. Apart from SCR, other treatment approaches, such as salvage chemotherapy and radiotherapy, may affect the survival. Therefore, when a Cox stepwise regression model is established, every variant that may have an effect on survival should be considered and entered into multivariate analysis. Factors that have an impact on the outcome of SCR, the efcacy of second-line chemotherapy, and performance status after surgery were examined using logistic stepwise regression analysis. The results of the Cox and logistic model analyses were reported with relative risks (RR) and 95% condence intervals. P 0.05 was considered signicant in these analyses.

Treatment Approaches
Chest X-rays and ultrasonic or computed tomography scans or magnetic resonance images of the pelvis and abdomen were obtained to evaluate disease status. Serum CA 125 levels were determined every week after relapse was conrmed. Patients had mechanical and antibiotic bowel preparation prior to surgery whenever possible. The resectability of relapsed lesions was assessed before surgery by two senior gynecologic surgeons, but surgical cytoreduction was discontinued if disease was encountered that could not be removed with existing techniques. Cytoreductive surgery was dened as optimal if the greatest dimension of the largest residual tumor measured 1 cm and suboptimal if it measured 1 cm. After they recovered from surgery, patients received individualized salvage therapy based on initial treatment, response to prior chemotherapy, PFI, surgical ndings, surgical outcome, and anticipated ability to tolerate the toxicity of salvage chemotherapy. All patients received either intraperitoneal or intravenous salvage chemotherapy, and 73 patients (62.4%) received 17 cycles of platinum-based intraperitoneal chemotherapy, which was repeated every week. Seventy-nine patients (67.5%) received 1 combinations of intravenous second-line salvage chemotherapy. Among them, 43 patients (36.8%) were treated with paclitaxel, 15 patients (12.8%) were treated with etoposide, 14 patients (12%) were treated with topotecan, 7 patients (6.0%) were treated with gemcitabine, 6 patients (5.1%) were treated with ifosfamide, 5 patients (4.3%) were treated with platin-docetaxel therapy, 4 patients (3.4%) were treated with HCPT, 4 patients (3.4%) were treated with NVB, and 2 patients (1.7%) were treated with hexamethylmelamine. Regarding the efciency of second-line chemotherapy, all 79 patients were evaluated for response: Seven patients (8.9%) achieved a clinical complete response, and 49 patients (62%) achieved a partial clinical response. Other than second-line agents, 38 patients (32.5%) were treated with platinum-based salvage

RESULTS
Patient Characteristics
This trial, which was conducted at Cancer Hospital of Fudan University, opened in January 1998 and was closed to patient accrual in December 2001. Follow-up was available through December 2002. In all, 117 patients were entered. The median age at the time patients underwent secondary surgery was 53 years (range, 20 78 years). The median PFI was 15.4 months. The distributions of preoperative and postoperative factors in this cohort of patients are shown in Table 1. Forty-six women (39.3%) received some salvage chemotherapy before undergoing secondary surgery,

SCR and Relapsed EOC/Zang et al. TABLE 1 Patient Characteristics

Characteristic Age (yrs) 65 65 FIGO stage (1989) Stage I Stage II Stage III Stage IV Histology Serous Mucinous Adenocarcinoma Endometrioid Clear cell Mixed Other Grade Grade 1 Grade 2 Grade 3 Residual disease after primary surgery 1 cm 1 cm PFI (mos) 312 1323 24 Recurrent ascites No Yes Extent of relapsed disease Solitary Multiple Chemotherapy cycles before SCR 0 28 ECOG performance status 0 1 2 Bowel resection or colostomy No Yes Residual disease after SCR 0 cm 1 cm 1 cm Second-line chemotherapy No Yes Efcacious second-line chemotherapy No/not treated Yes Cycles of salvage chemotherapy after SCR 12 35 6 Pelvic radiation No Yes Total No. of patients No. of deaths Median survival (mos)

1155

P valuea NS

107 10 13 31 66 7 61 6 11 21 10 3 5 7 65 45 78 39 48 44 25 94 23 33 84 71 46 23 62 32 8 109 11 61 45 38 79 61 56 16 52 49 85 32 117

63 9 7 15 45 5 36 5 9 9 8 1 4 2 43 27 45 27 34 27 11 52 20 11 61 45 27 11 37 24 7 65 3 33 36 25 47 43 29 14 36 22 56 16 72

21.0 27.0 NS 26.5 27.5 20.0 16.0 25.0 10.0 16.0 26.5 14.5 25.5 15.5 25.0 20.0 21.5 NS 26.0 20.0 0.0382 18.0 26.0 40.0 0.003 25.5 17.5 0.0001 b 16.5 NS 21.0 23.0 0.001 40.5 24.5 15.0 NS 7.0 22.0 0.0001 b 26.0 14.5 NS 14.5 25.0 0.0027 14.5 26.5 0.0001 9.0 15.5 30.0 0.0165 19.0 26.5 22.0 0.017 Reference 0.0507 NS NS 0.0181 NS NS NS

FIGO: International Federation of Gynecology and Obstetrics; NS: no statistical signicance; PFI: progression-free interval; ECOG: Eastern Cooperative Oncology Group; SCR: secondary cytoreductive surgery. a Log-rank test. b The median survival was not reached.

1156

CANCER March 15, 2004 / Volume 100 / Number 6 TABLE 2 Life Table of Factors that Determined Survival after Relapse
Survival rate (%) Factor Extent of relapsed disease Solitary Multiple lesions Residual disease 0 cm 1 cm 1 cm ECOG performance status before surgery 0 1 2 Salvage chemotherapy cycles after SCR 12 35 6 Total 2 yrs 3 yrs 5 yrs

and 71 women (60.7%) underwent SCR before they were treated with any salvage chemotherapy. Among the patients who were treated with salvage chemotherapy before undergoing SCR, 38 patients had multiple relapsed lesions, and 8 patients had a solitary focus. At secondary surgery, it was found that tumor was conned to a solitary site in 33 patients (28.2%) and to 2 sites in 84 patients (71.8%). Of the 117 patients who underwent secondary surgery, 11 patients (9.4%) were rendered macroscopically disease free, 61 patients (52.1%) had residual disease that measured 1 cm in greatest dimension, and 45 patients (38.5%) had bulky intraabdominal residual disease. Optimal SCR was achieved in 29 of 33 patients (9 patients with microscopic residual disease and 20 patients with macroscopic residual disease; 87.9%) with a solitary focus and in 43 of 84 patients (51.2%) with multiple lesions (P 0.0002). To achieve optimal surgical results, many surgical approaches have been used, as described previously.15 One hundred three patients (88%) underwent bowel resection, including 64 patients (54.7%) who underwent small bowel resection, 22 patients (18.8%) who underwent modied posterior pelvic exenteration, and 17 patients (14.5%) who underwent large bowel resection. Sixty-four patients (54.7%) underwent peritoneal implantation ablation, 25 patients (21.4%) underwent retroperitoneal lymphadenectomy, 11 patients (9.4%) underwent excision of retained omental tissue, 3 patients (2.6%) underwent splenectomy, 1 patient underwent a distal pancreatectomy en bloc with splenectomy, and 1 patient each (0.9%) underwent partial liver resection and urinary tract resection. Among the patients with unresectable disease, 3 patients (2.6%) underwent open and close procedures, and 6 patients (5.1%) underwent palliative colostomy: To eliminate selection bias, those 9 patients were entered into the survival analyses. The median blood loss was 300 mL (range, 20 1500 mL). The median operative time was 150 minutes (range, 30 420 minutes). No patients suffered from mortality after surgery. Nine patients (7.7%) experienced complications, such as ileus (6 patients; 5.1%), cutaneous wound infection (2 patients; 1.7%), and stula (1 patient; 0.9%). One patient with a stula required surgery, and the other patients were treated medically with success.

76.1 35.9 79.0 55.2 30.4 62.5 51.6 27.9 10.8 39.3 69.1 48.0

59.8 16.3 61.4 39.9 8.9 50.0 30.4 7.0 10.8 19.7 46.7 29.4

49.8 5.4 61.4 21.1 4.5 41.7 12.2 0.0 0.0 8.4 30.2 17.2

ECOG: Eastern Cooperative Oncology Group; SCR: secondary cytoreductive surgery.

Survival
The median survival for the entire cohort was 22 months, and the estimated 5-year survival rate was 17.2%. Table 2 summarizes the stratied life table for

2-year, 3-year, and 5-year survival. Log-rank analysis revealed that the factors extent of relapse disease, residual disease after SCR, ECOG performance status, salvage chemotherapy after SCR, PFI, radiotherapy after SCR, histology, ascites at recurrence, and response to second-line salvage chemotherapy inuenced the probability of survival (Table 1). The factors age at relapse, tumor grade, ascites before primary surgery, residual disease after primary surgery, FIGO stage, salvage chemotherapy before SCR, retroperitoneal lymphadenectomy, bowel resection, intraperitoneal chemotherapy after SCR, and whether second-line salvage chemotherapy was used after SCR did not appear to inuence the probability of survival. Table 3 provides a summary of the factors that inuenced survival, as identied in the Cox stepwise regression analysis. Solitary focus, optimal SCR, an ECOG performance status of 0 1, and greater than six cycles of salvage chemotherapy after SCR were identied in the rst, second, third, and fourth steps, respectively, and patients with those factors experienced prolonged survival (Figs. 1 4). KaplanMeier tests revealed that, compared with patients who had a PFI of 312 months or 1323 months, patients who had a PFI 24 months experienced longer survival (312 months vs. 1323 months: chi-square 0.81 [P 0.3676]; 1323 months vs. 24 months: chi-square 4.12 [P 0.0424]; and 312 months vs. 24 months: chi-square 6.01 [P 0.0142]), but multivariate analysis suggested that PFI did not inuence prognosis (Tables 1 and 3). Patients who were treated with radiotherapy after SCR

SCR and Relapsed EOC/Zang et al. TABLE 3 Factors that Affected Survival after Relapse: Determined by Cox Stepwise Regression Model
95% CI Factor Extent of relapsed disease Residual disease ECOG performance status Salvage chemotherapy post-SCR Beta coefcient 1.1183 0.4944 0.5482 0.1471 SE 0.3579 0.234 0.1914 0.0375 Wald chi-square 9.7641 4.4659 8.2061 15.3665 P value 0.0018 0.0346 0.0042 0.0001 Relative risk 3.0598 1.6396 1.7302 0.8632 Lower 1.5172 1.0365 1.189 0.802

1157

Upper 6.1707 2.5934 2.5176 0.9291

SE: standard error; 95% CI: 95% condence interval; ECOG: Eastern Cooperative Oncology Group; SCR: secondary cytoreductive surgery.

FIGURE 1.

Survival of patients with relapsed epithelial ovarian carcinoma (chi-square 17.72; P 0.0001). Dashed line: patients with multiple lesions; solid line: patients with solitary lesions.

FIGURE 2. Survival according to the size of residual disease after patients

underwent secondary cytoreductive surgery for epithelial ovarian carcinoma (0 cm vs. 1 cm: chi-square 2.4 [P 0.1211]; 1 cm vs. 1 cm: chi-square 13.55 [P 0.0002]; and 0 cm vs. 1 cm: chi-square 10.59 [P 0.0011]). Triangles: no residual disease; crosses: residual disease measuring 1 cm in greatest dimension; plus signs: residual disease measuring 1 cm in greatest dimension.

experienced lengthened survival (chi-square 5.75; P 0.0165), although further analysis did not support the nding that this encouraging treatment approach was an independent determinant of prognosis. Further analyses were performed to identify the correlation between optimal SCR and efcacious second-line salvage chemotherapy. Among the patients who underwent optimal SCR, the median survivals of patients who were treated with efcacious second-line chemotherapy and patients who received either nonefcacious or no second-line chemotherapy were 38.7 months and 20.0 months, respectively (closely approximating statistical signicance: chi-square 2.95; P 0.0856).

DISCUSSION
SCR: the Best Choice for Patients with A Solitary Relapse
With regard to SCR, patients with EOC are grouped into four clinical settings.18 Issues for debate are fewer in the settings of interval cytoreductive surgery, debulking surgery at second-look laparotomy, and sur-

gery for progressive disease compared with the issues raised by SCR for recurrent disease, because it remains uncertain which patients with recurrent EOC are suitable for such surgery. A large series of 106 patients reported by Eisenkop et al.14 stated that complete cytoreduction was possible for the majority of patients with recurrent EOC and maximized survival if it was undertaken before salvage chemotherapy. The median survival in that study was 44.4 months for patients who had no visible residual disease after SCR compared with 19.3 months for patients who had any macroscopic residual disease (P 0.007). More recently, an experience from the M. D. Anderson Cancer Center indicated that SCR for patients with recurrent ovarian carcinoma at an apparently solitary intraabdominal site resulted in optimal residual tumor in a high proportion of patients. In that study, SCR was found to be optimal in 18 of 25 patients (72%). The

1158

CANCER March 15, 2004 / Volume 100 / Number 6

FIGURE 3. Survival by Eastern Cooperative Oncology Group (ECOG) performance status before patients underwent secondary cytoreductive surgery for epithelial ovarian carcinoma. There was a signicant difference between patients who had an ECOG performance status of 0 (triangles), 1 (crosses), and 2 (plus signs), with a median survival of 40.5 months, 24.5 months, and 15 months, respectively (ECOG 0 vs. ECOG 1: chi-square 2.25 [P 0.134]; ECOG 1 vs. ECOG 2: chi-square 7.28; [P 0.007]; and ECOG 0 vs. ECOG 2: chi-square 10.57 [P 0.0012]).
median survival was 56.9 months for patients who underwent optimal SCR and 25.1 months for patients who underwent suboptimal SCR.16 The eligible patients were too few to reach a level of statistically signicant difference, but a latent survival benet may exist. In the current report, the resectability rate was 87.9% in patients with a solitary focus and 51.2% in patients with multiple lesions; that is, patients with solitary lesions achieved optimal surgical outcomes more easily. Furthermore, survival assessments conrmed a statistically signicant advantage for patients who had a solitary site of relapse, with a 5-year survival rate of 49.8% compared with 5.4% in patients who had multiple sites of relapse (P 0.0001). To our surprise, when this factor was considered in the Cox stepwise regression model together with other variants that may inuence survival, the extent of relapsed disease presented at the rst step as the strongest determinant of survival, which may indicate that SCR is the best approach currently available for patients who have a solitary site of relapse. No investigators to date have advocated the use of SCR in the treatment of patients who have a PFI between 3 months and 6 months, because those patients are platinum nonresponders who remain a treatment dilemma.14,17,19 Little progress has been made in salvage second-line chemotherapy for these patients; however, it is our understanding that they are quite different from patients who experience no remission at all during front-line chemotherapy. In particular,

FIGURE 4. Survival by chemotherapy after patients underwent secondary cytoreductive surgery for epithelial ovarian carcinoma. The median survival of patients who received 12 cycles of chemotherapy, 35 cycles of chemotherapy, or 6 cycles of chemotherapy were 9.0 months, 15.5 months, and 30.0 months, respectively, and there were signicant difference between them (12 cycles vs. 35 cycles: chi-square 5.98; [P 0.0144]; 12 cycles vs. 6 cycles: chi-square 30.76 [P 0.0001]; and 35 cycles vs. 6 cycles: chi-square 10.98 [P 0.0009]). Triangles: 6 cycles; crosses: 35 cycles; plus signs: 12 cycles.
patients with residual disease measuring 1 cm who achieve complete remission that lasts from 3 months to 6 months are for the most part platinum responders, and should not be classied with platinum resistance, but they will respond less to salvage chemotherapy compared with patients who have a PFI 6 months after completing front-line chemotherapy. To maximize the population who may benet from SCR (in addition to patients with a PFI 6 months after completing rst-line chemotherapy), patients with a remission duration of 3 6 months who developed relapsed disease also were included in this trial. There was no marked difference in survival between patients with PFI of 312 months and patients with a PFI of 1323 months. However, there was a statistically signicant, positive correlation between the percentage of optimal SCR and median survival. Seventy-two of 117 patients (61.5%) who underwent optimal cytoreduction achieved a median survival 26.5 months compared with 14.5 months in patients who underwent suboptimal surgery (P 0.0001). This correlation remained signicant after controlling for all other variables, whereas PFI was not found to be an independent determinant of survival (Table 3). This compelling evidence indicates that patients with who had a PFI of 3 6 months and a PFI 6 months may be treated safely with surgery and may have a survival advantage with optimal SCR. Compared with earlier

SCR and Relapsed EOC/Zang et al. TABLE 4 Clinical Variants that Inuenced the Outcome of Secondary Surgical Cytoreduction
95% CI Factor Extent of relapsed diseasea Bowel resection Constant Beta coefcient 2.2109 0.9602 3.1691 SE 0.5967 0.3759 1.1304 Wald chi-square 13.7303 6.5229 7.8603 P value 0.0002 0.0106 0.0051 Relative risk 9.1237 0.3828 Lower 2.8333 0.1832

1159

Upper 29.3797 0.7999

SE: standard error; 95% CI: 95% condence interval. a Relapse was dened as tumor recurrence after a progression-free interval (PFI) 3 months, as distinguished the from conventional concept of a recurrence, with a PFI 6 months after the completion of primary therapy.

studies, to our knowledge, no other trial to date has advocated considering these patients for secondary surgery.

Surgical Techniques of SCR and Outcome Determinants

Secondary tumor resection is possible technically in a signicant proportion of patients who have tumors that are eradicated by primary surgery and rst-line chemotherapy. In published series, the technical success rates of SCR vary widely, from 37 47%8,10,12 to 83%,14 although the latter rate lacks credibility. The SCR procedures include enterolysis, visualization of all peritoneal surface, examination and removal of multiple histologic specimens, and intraperitoneal or retroperitoneal tumor resection. The techniques used in abdominal, urologic, and gynecologic surgery, such as bowel resection, modied posterior pelvic exenteration, systematic retroperitoneal lymphadenectomy, colostomy, splenectomy, distal pancreatectomy en bloc with splenectomy, partial liver resection, and urinary tract resection, are applied in secondary surgery. On condition that the retroperitoneal cavity is not opened at primary surgery, even if bulky retroperitoneal lymph nodes may adhere to critical retroperitoneal structures, they are removable with meticulous dissection because they rarely invade completely into a vessel wall. Virtually all pelvic pathology is removable by en bloc resection of retained reproductive organs, with a retroperitoneal approach used for pelvic peritoneum and rectosigmoid colon. Preoperative imaging studies did not appear to predict unresectable disease. Bulky disease that involved the mesentery and underlying structures, a large volume of ascites with a prohibitive number of intestinal serosal implants resulting in small-volume residual miliary disease, and the whole length of the small bowel en bloc resulting in tumor-wrapped intestine most often precluded any meaningful cytoreductive effort. With currently available surgical techniques, SCR

can be accomplished with signicant but acceptable morbidity. The mortality risk is negligible. We determined that only 7.7% of patients experienced some degree of morbidity, which was lower compared with 24 63% of patients reported in the literature.8,10,14 No postoperative mortality occurred, but the rate reported in the literature is approximately 1.9%.14 In the current study, we identied other factors that inuenced the outcome of patients who underwent SCR. The variant multiple relapse lesions was a very unfavorable factor (RR 9.1237). In addition, although there was no positive correlation between bowel resection and survival, bowel resection is an ideal approach to resect all bulky tumors that involve the intestine (RR 0.3828) (Table 4). It is interesting to note that another study at the Memorial Sloan-Kettering Cancer Center showed that 71% of patients with tumor-induced bowel obstruction who underwent palliative surgery had successful palliation (the ability to tolerate a regular or low-residue diet at least 60 days postoperatively), and 79% of patients were able to tolerate salvage chemotherapy.20 Those observations did not address tumor resectability, but the favorable results strongly indicate that curative bowel resection may be more efcacious compared with palliation in the treatment of patients with recurrent EOC. We believe these ndings will greatly encourage gynecologic surgeons to train and improve their bowel resection techniques.

Issues for Debate

In this era of advanced medical technology, relapsed EOC continues to be a therapeutic dilemma. Patients with relapsed EOC frequently respond to second-line treatments, but the impact on survival remains uncertain.21 Therefore, it is of paramount importance for all clinicians to recognize that the primary objective of front-line therapy is to maximize the PFI. Conversely, once tumors recur, the primary objective of salvage therapy is to maximize survival and quality of life.

1160

CANCER March 15, 2004 / Volume 100 / Number 6

Between salvage chemotherapy and SCR there is not a better choice, and there are no data that are convincing enough to advocate SCR as a routine procedure. However, with these objectives in mind, we can offer patients a variety of different modalities to control disease, including SCR, second-line chemotherapy, hormone therapy, and immunotherapy.22,23 It is increasingly apparent that a secondary surgical approach can be used safely and efcaciously and confers a survival advantage. Therefore, it is not surprising that, in the current series, when controlling for factors in multivariant analysis, optimal SCR as well as multiple courses of salvage chemotherapy were found to improve survival signicantly in patients with relapsed EOC. With respect to second-line salvage chemotherapy, the current study showed that the 2 curves clearly separated within 3 years, but they converged after 3 years (data not shown). The currently available second-line agents are less successful in prolonging longterm survival, which is one reason why the overall prognosis of patients with advanced EOC remains pessimistic. Major strategies that include the following four steps are being tested in current clinical trials in an effort to improve the survival of patients with advanced EOC. The rst step, which is of fundamental importance, is maximizing the possibility of cytoreduction at primary surgery. Enhancement of sensitivity to chemotherapy, yet unproven, may be the greatest benet of bulky tumor resection. The second step is the development of more effective combination chemotherapy regimens that not only increase the overall response rate but also lead to an increased duration of response (remission inducement). The third step is the development of effective maintenance therapies that prevent or delay recurrences in patients who achieve a complete remission after standard chemotherapy (remission consolidation). The fourth step is establishing multidisciplinary treatments that include SCR and second-line chemotherapy.

optimal SCR, particularly when it is supported by multiple courses of salvage chemotherapy.

REFERENCES
1. 2. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:526. Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: Vincent T, DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology, 5th edition. Philadelphia: Lippincott-Raven Publishers, 1997:14271539. Zang RY, Li ZT, Zhang ZY, Cai SM. Surgery and salvage chemotherapy for Chinese women with recurrent advanced epithelial ovarian carcinoma: a retrospective case-control study. Int J Gynecol Cancer. 2003;13:419 427. Markman M, Hall J, Spitz D, et al. Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol. 2002;20:23652369. Hanjani P, Nolte S, Shahin MS. Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer. Gynecol Oncol. 2002;85:278 284. Cantu MG, Buda A, Parma G, et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to rst-line platinum-based regimens. J Clin Oncol. 2002;20:12321237. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, 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 1259. Berek JS, Hacker NF, LaGasse LD, Nieberg RK, Elashoff RM. Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet Gynecol. 1983;61:189 193. Morris M, Gershenson DM, Wharton JT, Copeland LJ, Edwards CL, Stringer CA. Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol. 1989;34: 334 338. Janicke F, Holscher M, Kuhn W, et al. Radical surgical procedure improves survival time in patients with recurrent ovarian cancer. Cancer. 1992;70:2129 2136. Segna RA, Dottino PR, Mandeli JP, et al. Secondary cytoreduction for ovarian cancer following cisplatin therapy. J Clin Oncol. 1993;11:434 439. Vaccarello I, Rubin SC, Vlamis V, et al. cytoreductive surgery in ovarian carcinoma patients with a documented previously complete surgical response. Gynecol Oncol. 1995;57: 61 65. Eisenkop SM, Friedman RL, Wang H. Secondary cytoreduction for recurrent ovarian cancer. A prospective study. Cancer. 1995;76:1606 1614. Eisenkop SM, Firedman RL, Spirtos NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma. Cancer. 2000;88:144153. Zang RY, Zhang ZY, Li ZT, et al. Effect of cytoreductive surgery on survival of patients with recurrent epithelial ovarian cancer. J Surg Oncol. 2000;75:26 30. Munkarah A, Levenback C, Wolf JK, et al. Secondary cytoreductive surgery for localized intra-abdominal recurrences in epithelial ovarian cancer. Gynecol Oncol. 2001;81:237241. Scarabelli C, Gallo A, Carbone A. Secondary cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma. Gynecol Oncol. 2001;83:504 512.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

Conclusions
SCR is feasible and efcacious in patients with relapsed EOC and a good performance status who achieve a clinical complete remission that lasts 3 months; and, in selected patients, the resectability approximates that of primary debulking surgery. Optimal surgical outcomes are achieved easily in patients with apparent solitary tumor sites. Bowel resection is one valid approach to removing bulky tumors that involve the intestine. A survival benet is provided by

14.

15.

16.

17.

SCR and Relapsed EOC/Zang et al.

18. Zang RY, Zhang ZY, Li ZT, et al. Impact of secondary cytoreductive surgery on survival of patients with advanced epithelial ovarian cancer. Eur J Surg Oncol. 2000; 26:798 804. 19. Bristow RE, Lagasse LD, Karlan BY. Secondary surgery cytoreduction for advanced epithelial ovarian cancer. Patient selection and review of the literature. Cancer. 1996;78:20492062. 20. Pothuri B, Vaidya A, Aghajanian C, Venkatraman E, Barakat RR, Chi DS. Palliative surgery for bowel obstruction in re-

1161

current ovarian cancer: an updated series. Gynecol Oncol. 2003;89:306 313. 21. Ozols RF. Future directions in the treatment of ovarian cancer. Semin Oncol. 2002;29(1 Suppl 1):32 42. 22. Ozols RF. The current role of gemcitabine in ovarian cancer. Semin Oncol. 2001;28(2 Suppl 7):18 24. 23. Salom E, Almeida Z, Mirhashemi R. Management of recurrent ovarian cancer: evidence-based decisions. Curr Opin Oncol. 2002;14:519 527.