Gynecologic Oncology 134 (2014) 468–472
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
A comparison of primary intraperitoneal chemotherapy to consolidation intraperitoneal chemotherapy in optimally resected advanced ovarian cancer☆ Rudy S. Suidan a, Caryn M. St. Clair a, Stephen J. Lee a, Joyce N. Barlin a, Kara C. Long Roche a, Edward J. Tanner a, Yukio Sonoda a,b, Richard R. Barakat a,b, Oliver Zivanovic a,b, Dennis S. Chi a,b,⁎ a b
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, New York, NY, USA
H I G H L I G H T S • Primary IV/IP chemotherapy was associated with improved overall survival compared to IV followed by consolidation IP chemotherapy. • No statistically significant difference in progression-free survival was noted between both treatment groups.
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Article history: Received 23 April 2014 Accepted 13 July 2014 Available online 17 July 2014 Keywords: Intraperitoneal chemotherapy Consolidation intraperitoneal chemotherapy Ovarian cancer Progression-free survival Overall survival
a b s t r a c t Objective. To compare survival outcomes for patients with advanced epithelial ovarian cancer (EOC) who received primary intravenous/intraperitoneal (IV/IP) chemotherapy to those who received IV followed by consolidation (treatment given to patients in remission) IP chemotherapy. Methods. Data were analyzed and compared for all patients with stage III–IV EOC who underwent optimal primary cytoreduction (residual disease ≤ 1 cm) followed by cisplatin-based consolidation IP chemotherapy (1/2001–12/2005) or primary IV/IP chemotherapy (1/2005–7/2011). Results. We identified 224 patients; 62 (28%) received IV followed by consolidation IP chemotherapy and 162 (72%) received primary IV/IP chemotherapy. The primary IP group had significantly more patients with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites. There were no differences in residual disease at the end of cytoreduction between both groups. The median progression-free survival (PFS) was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57–1.06; p = 0.11). The median overall survival (OS) was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38–0.83; p = 0.004). On multivariate analysis, after adjusting for confounders, the difference in PFS was not significant (HR 0.78; 95% CI, 0.56–1.11; p = 0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39–0.89; p = 0.01). Conclusions. In our study, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP chemotherapy in patients with optimally cytoreduced advanced EOC. © 2014 Elsevier Inc. All rights reserved.
Introduction Of the estimated 21,980 women diagnosed each year with primary epithelial ovarian, fallopian tube, or peritoneal carcinoma in the United States, the majority present with advanced-stage (International ☆ Presented at the 45th Annual Meeting of the Society of Gynecologic Oncologists, Tampa, FL, March 22–25, 2014. ⁎ Corresponding author at: Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, H-1304, New York, NY 10065, USA. Fax: +1 212 717 3095. E-mail address: [email protected] (D.S. Chi).
http://dx.doi.org/10.1016/j.ygyno.2014.07.090 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Federation of Gynecology and Obstetrics [FIGO] III/IV) disease [1]. Standard initial therapy for these patients consists of primary cytoreductive surgery followed by a combination of platinum and taxane-based chemotherapy [2,3]. The natural history of advanced epithelial ovarian cancer is one of clinical remission after initial therapy. However, long-term cure rates languish between 20 and 30%, and relapse occurs in most patients [3]. The majority of disease recurrences are confined to the peritoneal cavity [4–6]. Attempts to improve outcomes for this patient population have prompted the investigation of intraperitoneal (IP) chemotherapy as consolidation treatment after second-look surgery following the
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completion of adjuvant therapy. Multiple phase II trials have demonstrated a survival benefit for patients who received IP consolidation therapy after both negative second-look assessment (no residual disease) and in cases in which small-volume (≤ 1 cm) residual was found at second look [7–11]. Cisplatin was the most common agent assessed in these trials, alone or in combination with other agents. Investigators have also evaluated the role of IP chemotherapy in the primary setting after cytoreductive surgery. Three phase III trials in women with optimally debulked (≤ 1 cm residual) stage III ovarian cancer have shown a survival advantage for patients who received intravenous (IV)/IP chemotherapy compared to those who received IV therapy [12–14]. The most recent one, Gynecologic Oncology Group (GOG) study 172, demonstrated a dramatic 16-month overall survival (OS) benefit for the IP arm [14]. The regimens used in these trials were also cisplatin-based. At our institution, patients with advanced epithelial ovarian cancer who had primary debulking followed by IV chemotherapy were historically offered second-look surgery and consolidation treatment with IP chemotherapy if no or small-volume (≤ 1 cm) residual disease was found at second look [11]. All patients who were in clinical remission after adjuvant IV therapy, whether ‘high’ or ‘low risk’, were offered this treatment, except for those with poor performance status. With the publication of GOG 172, this management approach changed to giving IV/IP chemotherapy up-front after primary cytoreduction. There is a paucity of data in the literature comparing these two different treatment approaches. The purpose of this study was to compare survival outcomes for patients who received primary IV/IP chemotherapy to those who received IV followed by consolidation IP chemotherapy.
(60 mg/m2) on day 8 [16]. Treatment modifications, dose reductions, and therapy discontinuation were at the discretion of the treating medical oncologist. Categorical variables were compared using Fisher's exact test or the χ2 test as applicable, and continuous variables were compared using the Mann–Whitney U test. All statistical tests were two-sided, with a p value of b 0.05 considered significant. The primary outcomes were progression-free survival (PFS) and OS. The date of progression was determined by computed tomography (CT) scan and/or CA-125 levels. When using CT imaging, the first appearance of one or more new lesions or increased size of existing lesions was considered as progression. When using CA-125 levels, the date of progression was defined as the first date of the initial CA-125 of greater than or equal to two times the nadir value or upper limit of normal, as applicable [17,18]. When a subsequent CT scan confirmed that the rise in CA-125 indicated progression, the date of progression was defined as the date of CA-125 rise. PFS was defined as the time interval from the date of primary debulking surgery to the date of disease progression, death, or last follow-up. OS was defined as the time interval from the date of primary debulking surgery to the date of death or last follow-up. The Kaplan–Meier method was used to estimate survival rates. Univariate analysis of all assessed categorical and continuous variables was performed for prognostic significance using the log-rank test and Cox proportional hazards model for significance, respectively. Differences in survival were calculated using the Cox proportional hazards model. Variables with a p value of b 0.05 on univariate analysis were then included in a multivariate Cox regression analysis. Statistical analysis was performed using SPSS 21.0 (IBM Corporation, Armonk, NY).
Patients and methods
Results
After obtaining institutional review board approval, we identified all patients at our institution with FIGO stage III–IV epithelial ovarian, fallopian tube, or peritoneal cancer who underwent optimal primary cytoreduction (≤1 cm residual disease) followed by IP chemotherapy between January 2001 and July 2011. Eligible patients were classified into two groups. The consolidation IP group consisted of all patients who received IV followed by cisplatin-based consolidation IP chemotherapy from January 2001 to December 2005. The primary IP group consisted of all patients who received cisplatin-based primary IV/IP chemotherapy from January 2005 to July 2011. We chose to start our data collection from 2001 onwards as that was the time period when our institution began incorporating extensive upper abdominal surgery into the primary cytoreductive effort, which led to an improvement in optimal debulking rates and survival outcomes [15]. The year 2005 was a period of transition in which some patients received IP therapy in the primary setting and others received consolidation therapy. Individual records for all patients were retrospectively reviewed, and demographic, clinical, chemotherapeutic, and survival data were recorded. Clinical data abstracted included: age, body mass index, FIGO stage, primary disease site, tumor grade, histology, preoperative platelet count, preoperative albumin, American Society of Anesthesiologists (ASA) class, preoperative CA-125, volume of ascites, and presence of gross residual disease after cytoreductive surgery. Chemotherapy data included: number of IP cycles administered, number of IV cycles administered, and details of the chemotherapy regimens. After debulking surgery and the completion of 6 cycles of IV chemotherapy, patients in the consolidation group underwent second-look surgery and were administered an additional 3–5 cycles of consolidation IP therapy if no or small-volume residual disease was found at second look (based on phase II data [7–11]). IP cisplatin was given at a dose of 75 mg/m2. For patients in the primary IP group, IV/IP therapy was initiated after cytoreduction, with the intent to administer 6 cycles. A modified GOG 172 outpatient regimen has been used at our institution since 2005, and is administered as follows: IV paclitaxel (135 mg/m2) over 3 h on day 1, IP cisplatin (75 mg/m2) on day 2, and IP paclitaxel
Two hundred twenty-four patients were included over the study period. Sixty-two patients (28%) received IV followed by consolidation IP chemotherapy, and 162 patients (72%) received primary IV/IP chemotherapy (Table 1). Patient and tumor characteristics are shown in Table 2. The primary IP group had significantly more women with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites at presentation. There were no differences in residual disease at the end of debulking surgery between both groups. Patients who received primary IP therapy had a significantly greater median number of IP cycles administered, while patients who received consolidation IP therapy had a significantly greater median number of IV and total (IV + IP) chemotherapy cycles administered (Table 1). At the time of second-look surgery for women in the consolidation IP group, 33 patients (53%) had no residual disease at the beginning of surgery, 9 (15%) had microscopic disease noted on biopsy only with no gross evidence of disease, and 19 (31%) had gross ≤1 cm residual (1 patient did not have second-look surgery). Among the 19 patients Table 1 Intraperitoneal chemotherapy regimens. Chemotherapy regimen Consolidation IP regimen IV paclitaxel 175 mg/m2 on day 1 IV carboplatin AUC = 6 on day 1 (Every 21 days for 6 cycles) Followed by second-look surgery and if no or small-volume (≤1 cm) residual disease found: IP cisplatin 75 mg/m2 (Every 28 days for 3–5 cycles) Primary IP regimen IV paclitaxel 135 mg/m2 over 3 h on day 1 IP cisplatin 75 mg/m2 on day 2 IP paclitaxel 60 mg/m2 on day 8 (Every 21 days for 6 cycles) IP, intraperitoneal; IV, intravenous; AUC, area under the curve.
n 62
162
470
R.S. Suidan et al. / Gynecologic Oncology 134 (2014) 468–472
Table 2 Patient and tumor characteristics (N = 224). Characteristic
Consolidation IP n = 62
Primary IP n = 162
Median age (range)
59.6 yrs (25–78) 25.1 kg/m2 (19.1–39.2)
59 yrs (23–83) 25.5 kg/m2 (18.3–54.6)
1 (2%) 2 (3%) 56 (90%) 3 (5%)
8 (5%) 7 (4%) 129 (80%) 18 (11%)
0.35
51 (82%) 3 (5%) 8 (13%)
115 (71%) 28 (17%) 19 (12%)
0.04
3 (5%) 58 (95%)
8 (5%) 154 (95%)
0.99
53 (85%) 0 (0%) 1 (2%) 8 (13%) 367 K/μl (204–1067) 4.1 g/dl (2.7–4.8) 798 U/ml (9–29,797)
152 (94%) 3 (2%) 2 (1%) 5 (3%) 322 K/μl (146–1150) 4.2 g/dl (2.6–4.8) 301 U/ml (9–24,500)
0.03
3 (5%) 46 (77%) 11 (18%)
9 (6%) 99 (61%) 54 (33%)
0.08
12 (19%) 16 (26%) 28 (45%) 6 (10%)
76 (47%) 31 (19%) 40 (25%) 15 (9%)
0.001
34 (55%) 28 (45%) 3 (1–5) 6 (3–9) 9 (7–13)
100 (62%) 62 (38%) 5 (1–6) 0 (0–7) 6 (4–8)
0.37
Median BMI (range) FIGO stage IIIA IIIB IIIC IV Primary disease site Ovary Fallopian tube Peritoneum Tumor grade* 1 2/3 Histology Serous Clear cell Endometrioid Mixed/other Median preoperative platelet count (range) Median preoperative albumin (range)† Median preoperative CA-125 (range)‡ ASA class§ 1 2 3 Ascites None 1–1000 1001–5000 N5000 Residual disease None ≤1 cm Median IP chemotherapy cycles, (range) Median IV chemotherapy cycles (with no IP), (range) Median total chemotherapy cycles (IP + IV), (range)
p 0.75 0.77
Primary IP Consolidation IP Multivariate p=0.17
0.01 0.2 0.007
b0.001 b0.001 b0.001
Fig. 1. Progression-free survival: consolidation intraperitoneal vs primary intraperitoneal chemotherapy.
the difference in PFS was not significant (HR 0.78; 95% CI, 0.56–1.11; p = 0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39–0.89; p = 0.01). Multivariate models for PFS and OS are shown in Tables 3 and 4. A sensitivity analysis was performed excluding patients with stage IV cancer. Consistent with our primary analysis, the median PFS after adjusting for confounders was greater for the primary IP group, but this did not reach statistical significance (24.2 months vs 21.8 months; HR 0.82; 95% CI, 0.58–1.15; p = 0.24). The median OS was significantly greater for the primary IP group (80.2 months vs 57.9 months; HR 0.61; 95% CI, 0.4–0.93; p = 0.02). Patients who received IV followed by consolidation IP chemotherapy comprised 35% (66/187) of optimally debulked patients from 2001 to 2005: 62 patients received cisplatin-based IP consolidation (included in our study as the consolidation IP group), 4 received noncisplatin based IP consolidation (not included in any analysis), and 121 did not get IP consolidation. After adjusting for confounders, patients
IP, intraperitoneal; IV, intravenous; BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; ASA, American Society of Anesthesiologists. Data missing for: *one, †eight, ‡ten, and §two patients.
with gross residual disease at the initiation of second-look surgery, 8 had all tumor nodules excised, while 11 had representative biopsies taken with ≤1 cm residual disease left at completion. No second-look surgery was performed for women in the primary IP group as that was not part of the standard management for these patients. Median follow-up was 50 months (range, 9–141) for the entire cohort, 58 months (range, 10–141) for the consolidation IP group, and 49 months (range, 9–102) for the primary IP group. The median PFS was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57–1.06; p = 0.11) (Fig. 1). The median OS was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38–0.83; p = 0.004) (Fig. 2). On univariate analysis, factors that were significantly associated with PFS were histology (p b 0.001), preoperative CA-125 (log transformation) (p = 0.04), and residual disease (p = 0.007). Factors that were significantly associated with OS were histology (p b 0.001), preoperative platelet count (log transformation) (p = 0.02), and residual disease (p = 0.02). On multivariate analysis, after adjusting for confounders,
Primary IP
Consolidation IP Multivariate p=0.01
Fig. 2. Overall survival: consolidation intraperitoneal vs primary intraperitoneal chemotherapy.
R.S. Suidan et al. / Gynecologic Oncology 134 (2014) 468–472 Table 3 Multivariate analysis for progression-free survival. Factor
N
Hazard Ratio (95% CI)
p
Primary IP chemotherapy Consolidation IP chemotherapy Preoperative CA-125 (log) Histology Serous Clear cell Endometrioid Mixed/other Residual disease None ≤1 cm
156 58 214
0.78 (0.56–1.11) Reference 1.07 (0.97–1.18)
0.17
195 3 3 13
Reference 11.62 (3.54–38.14) 0.33 (0.05–2.38) 0.85 (0.45–1.61)
127 87
0.77 (0.56–1.06) Reference
0.2
b0.001 0.27 0.62 0.11
IP, Intraperitoneal Patients with missing CA-125 excluded (10 patients).
who received cisplatin-based IP consolidation had a nonsignificantly greater median PFS compared to patients who did not get IP consolidation (19.7 months vs 16 months; HR 0.94; 95% CI 0.67–1.31; p = 0.7), and a nonsignificantly greater median OS (57.5 months vs 50.3 months; HR 0.97; 95% CI 0.7–1.35; p = 0.85). On the other hand, patients who received primary IV/IP therapy comprised 62% (204/328) of optimally debulked patients from 2005 to 7/2011: 162 received cisplatin-based IV/ IP therapy (included in our study as the primary IP group), 42 received an alternate IV/IP regimen, and 124 did not get IV/IP therapy. In the recurrent setting, the consolidation IP group was treated with one of 14 chemotherapy regimens, while the primary IP group was treated with one of 15 regimens. The most common regimens (all IV) used in both groups were: doxorubicin, carboplatin/doxorubicin, carboplatin/gemcitabine, and carboplatin/paclitaxel. Among the patients in the consolidation IP group who recurred, 60% (32/53) were treated with one of those four regimens, compared to 70% (85/120) of those in the primary IP group who recurred (p = 0.24).
Discussion Three phase III trials in women with optimally debulked stage III ovarian cancer have shown a survival advantage for patients who received primary IV/IP chemotherapy compared to those who received IV therapy [12–14]. This led to a change in our institution's treatment approach for this patient population, which shifted from administering IP chemotherapy as consolidation to giving it up-front after cytoreductive surgery. In our analysis, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP therapy in patients with optimally cytoreduced advanced epithelial ovarian cancer. Our study compares the outcomes of these two management strategies at the same institution. Given the significant survival benefits reported in the randomized trials evaluating primary IV/IP therapy [13,14,19], it is unlikely that a phase III trial will be conducted comparing the two treatment approaches. The IV/IP regimen used Table 4 Multivariate analysis for overall survival. Factor
N
Hazard ratio (95% CI)
Primary IP chemotherapy Consolidation IP chemotherapy Preoperative platelet count (log) Histology Serous Clear cell Endometrioid Mixed/other Residual disease None ≤1 cm
162 62 224
0.59 (0.39–0.89) Reference 1.67 (0.91–3.06)
205 3 3 13
Reference 63.23 (16.41–243.64) 1.3 (0.18–9.45) 1.15 (0.54–2.43)
134 90
0.78 (0.52–1.17) Reference
IP, intraperitoneal.
p 0.01 0.1
b0.001 0.79 0.72 0.23
471
in the primary IP group is a modified GOG 172 regimen that is administered on an outpatient basis. This regimen has been shown to have similar survival outcomes to those reported in GOG 172, albeit with improved toxicity, tolerability, and the convenience of outpatient treatment [16]. We chose to include patients with stage IV disease, which we feel increases the generalizability of our results. Although the phase III GOG trials evaluating primary IV/IP chemotherapy only included patients with stage III ovarian cancer [12–14], several centers and providers consider that the benefits of IV/IP therapy should be offered to certain patients with optimally cytoreduced stage IV disease [20,21]. At our institution, IV/IP therapy is sometimes considered for select patients with stage IV cancer who are optimally debulked and who have resected supradiaphragmatic lymph nodes, pleural disease, isolated cutaneous or liver metastasis, or a malignant pleural effusion, and no residual extraperitoneal disease postoperatively. Consolidation IP therapy has also been considered in the past for patients with stage IV disease who had similar characteristics [7,11]. We did, however, assess the survival outcomes between the two management approaches after excluding patients with stage IV cancer (n = 21), and there was no change in the results. There are limitations in comparing the two groups in our study. Patients in the primary IP group were treated in a different time period (2005–2011) than those in the consolidation IP group (2001–2005), and it is possible that subsequent therapies may have contributed to the difference in OS seen. We addressed this by evaluating the salvage regimens used in both arms of the study at recurrence. Both groups had access to a similar number of chemotherapeutic treatments (14 vs 15), with the majority of patients in each group (60% vs 70%) receiving one of four commonly used regimens. Another potential weakness is selection bias, as the majority of patients who had optimal cytoreduction after 2005 received primary IV/IP therapy (62%), compared to 35% of those in the previous time period receiving consolidation IP therapy. Some women with no clinical evidence of disease after primary IV chemotherapy declined further surgery and IP chemotherapy, which may have excluded patients with the best outcomes during that era. On the other hand, the performance status of patients deemed eligible by providers for second-look surgery may be higher than that of an unselected cohort. At the same time, women who progressed on primary IV chemotherapy would not have had a second-look surgery and subsequent IP consolidation, which may have excluded patients with the worst outcomes. In order to address this issue, we compared the survival outcomes of patients who received consolidation IP therapy to those who did not from 2001 to 2005. The consolidation IP group had nonsignificantly greater median PFS and OS, which we feel minimizes selection bias as a limitation. In our study, patients who received consolidation IP chemotherapy had a greater median preoperative platelet count, CA-125, and ascites, while the patients who received primary IV/IP therapy had a greater proportion of serous tumors. There were no differences in residual disease at the end of cytoreductive surgery. We attempted to account for the heterogeneity between the two groups by adjusting for significant prognostic factors in our multivariate survival analysis, the results of which were consistent with the primary analysis. Our data show an approximately 21-month OS benefit for the primary IP group (78.8 months vs 57.5 months) and an approximately 4-month PFS benefit for the same group (23.7 months vs 19.7 months). The difference in OS was statistically significant, while the difference in PFS was not. While the previously described limitations may explain this discrepancy, this could also be related to the sample size of our consolidation IP group (62 patients). It is possible that a larger patient cohort may have been needed to show a statistically significant PFS difference, which was not needed to show an OS benefit, as the difference in survival between both groups was striking. Nevertheless, this assertion cannot be supported with the current analysis. Including patients who received consolidation IP chemotherapy prior to 2001 may have addressed this matter. We chose not to because of the surgical
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paradigm shift that occurred at our institution during that time period, in which a more comprehensive cytoreduction of upper abdominal disease was performed. Patients prior to that year did not have extensive upper abdominal procedures incorporated into the debulking effort, and had lower overall optimal cytoreduction rates and decreased PFS and OS [15]. Including those patients would have biased the results in favor of the primary IP group. In our study, primary IV/IP therapy in patients with advanced epithelial ovarian cancer was associated with improved OS compared to IV followed by consolidation IP treatment. This suggests that decreasing the time period between primary debulking and the administration of IP chemotherapy may potentially lead to improved survival outcomes, taking into account all the limitations of a retrospective analysis. The benefit observed with the difference in the timing of administration is hypothesis generating and should be explored further. Future randomized trials should consider the evaluation of IP chemotherapy at the time of surgery or soon after cytoreduction. Conflict of interest statement There are no conflicts to disclose.
Funding This study was supported by the Roy M. Speer Foundation. References [1] Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. [2] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47:159–66. [3] Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194–200. [4] Tay EH, Grant PT, Gebski V, Hacker NF. Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Obstet Gynecol 2002;99:1008–13. [5] Rubin SC, Hoskins WJ, Saigo PE, Chapman D, Hakes TB, Markman M, et al. Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy. Gynecol Oncol 1991;42:137–41. [6] Verheijen RH, Massuger LF, Benigno BB, Epenetos AA, Lopes A, Soper JT, et al. Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 2006;24:571–8.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
A comparison of primary intraperitoneal chemotherapy to consolidation intraperitoneal chemotherapy in optimally resected advanced ovarian cancer☆ Rudy S. Suidan a, Caryn M. St. Clair a, Stephen J. Lee a, Joyce N. Barlin a, Kara C. Long Roche a, Edward J. Tanner a, Yukio Sonoda a,b, Richard R. Barakat a,b, Oliver Zivanovic a,b, Dennis S. Chi a,b,⁎ a b
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, New York, NY, USA
H I G H L I G H T S • Primary IV/IP chemotherapy was associated with improved overall survival compared to IV followed by consolidation IP chemotherapy. • No statistically significant difference in progression-free survival was noted between both treatment groups.
a r t i c l e
i n f o
Article history: Received 23 April 2014 Accepted 13 July 2014 Available online 17 July 2014 Keywords: Intraperitoneal chemotherapy Consolidation intraperitoneal chemotherapy Ovarian cancer Progression-free survival Overall survival
a b s t r a c t Objective. To compare survival outcomes for patients with advanced epithelial ovarian cancer (EOC) who received primary intravenous/intraperitoneal (IV/IP) chemotherapy to those who received IV followed by consolidation (treatment given to patients in remission) IP chemotherapy. Methods. Data were analyzed and compared for all patients with stage III–IV EOC who underwent optimal primary cytoreduction (residual disease ≤ 1 cm) followed by cisplatin-based consolidation IP chemotherapy (1/2001–12/2005) or primary IV/IP chemotherapy (1/2005–7/2011). Results. We identified 224 patients; 62 (28%) received IV followed by consolidation IP chemotherapy and 162 (72%) received primary IV/IP chemotherapy. The primary IP group had significantly more patients with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites. There were no differences in residual disease at the end of cytoreduction between both groups. The median progression-free survival (PFS) was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57–1.06; p = 0.11). The median overall survival (OS) was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38–0.83; p = 0.004). On multivariate analysis, after adjusting for confounders, the difference in PFS was not significant (HR 0.78; 95% CI, 0.56–1.11; p = 0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39–0.89; p = 0.01). Conclusions. In our study, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP chemotherapy in patients with optimally cytoreduced advanced EOC. © 2014 Elsevier Inc. All rights reserved.
Introduction Of the estimated 21,980 women diagnosed each year with primary epithelial ovarian, fallopian tube, or peritoneal carcinoma in the United States, the majority present with advanced-stage (International ☆ Presented at the 45th Annual Meeting of the Society of Gynecologic Oncologists, Tampa, FL, March 22–25, 2014. ⁎ Corresponding author at: Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, H-1304, New York, NY 10065, USA. Fax: +1 212 717 3095. E-mail address: [email protected] (D.S. Chi).
http://dx.doi.org/10.1016/j.ygyno.2014.07.090 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Federation of Gynecology and Obstetrics [FIGO] III/IV) disease [1]. Standard initial therapy for these patients consists of primary cytoreductive surgery followed by a combination of platinum and taxane-based chemotherapy [2,3]. The natural history of advanced epithelial ovarian cancer is one of clinical remission after initial therapy. However, long-term cure rates languish between 20 and 30%, and relapse occurs in most patients [3]. The majority of disease recurrences are confined to the peritoneal cavity [4–6]. Attempts to improve outcomes for this patient population have prompted the investigation of intraperitoneal (IP) chemotherapy as consolidation treatment after second-look surgery following the
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completion of adjuvant therapy. Multiple phase II trials have demonstrated a survival benefit for patients who received IP consolidation therapy after both negative second-look assessment (no residual disease) and in cases in which small-volume (≤ 1 cm) residual was found at second look [7–11]. Cisplatin was the most common agent assessed in these trials, alone or in combination with other agents. Investigators have also evaluated the role of IP chemotherapy in the primary setting after cytoreductive surgery. Three phase III trials in women with optimally debulked (≤ 1 cm residual) stage III ovarian cancer have shown a survival advantage for patients who received intravenous (IV)/IP chemotherapy compared to those who received IV therapy [12–14]. The most recent one, Gynecologic Oncology Group (GOG) study 172, demonstrated a dramatic 16-month overall survival (OS) benefit for the IP arm [14]. The regimens used in these trials were also cisplatin-based. At our institution, patients with advanced epithelial ovarian cancer who had primary debulking followed by IV chemotherapy were historically offered second-look surgery and consolidation treatment with IP chemotherapy if no or small-volume (≤ 1 cm) residual disease was found at second look [11]. All patients who were in clinical remission after adjuvant IV therapy, whether ‘high’ or ‘low risk’, were offered this treatment, except for those with poor performance status. With the publication of GOG 172, this management approach changed to giving IV/IP chemotherapy up-front after primary cytoreduction. There is a paucity of data in the literature comparing these two different treatment approaches. The purpose of this study was to compare survival outcomes for patients who received primary IV/IP chemotherapy to those who received IV followed by consolidation IP chemotherapy.
(60 mg/m2) on day 8 [16]. Treatment modifications, dose reductions, and therapy discontinuation were at the discretion of the treating medical oncologist. Categorical variables were compared using Fisher's exact test or the χ2 test as applicable, and continuous variables were compared using the Mann–Whitney U test. All statistical tests were two-sided, with a p value of b 0.05 considered significant. The primary outcomes were progression-free survival (PFS) and OS. The date of progression was determined by computed tomography (CT) scan and/or CA-125 levels. When using CT imaging, the first appearance of one or more new lesions or increased size of existing lesions was considered as progression. When using CA-125 levels, the date of progression was defined as the first date of the initial CA-125 of greater than or equal to two times the nadir value or upper limit of normal, as applicable [17,18]. When a subsequent CT scan confirmed that the rise in CA-125 indicated progression, the date of progression was defined as the date of CA-125 rise. PFS was defined as the time interval from the date of primary debulking surgery to the date of disease progression, death, or last follow-up. OS was defined as the time interval from the date of primary debulking surgery to the date of death or last follow-up. The Kaplan–Meier method was used to estimate survival rates. Univariate analysis of all assessed categorical and continuous variables was performed for prognostic significance using the log-rank test and Cox proportional hazards model for significance, respectively. Differences in survival were calculated using the Cox proportional hazards model. Variables with a p value of b 0.05 on univariate analysis were then included in a multivariate Cox regression analysis. Statistical analysis was performed using SPSS 21.0 (IBM Corporation, Armonk, NY).
Patients and methods
Results
After obtaining institutional review board approval, we identified all patients at our institution with FIGO stage III–IV epithelial ovarian, fallopian tube, or peritoneal cancer who underwent optimal primary cytoreduction (≤1 cm residual disease) followed by IP chemotherapy between January 2001 and July 2011. Eligible patients were classified into two groups. The consolidation IP group consisted of all patients who received IV followed by cisplatin-based consolidation IP chemotherapy from January 2001 to December 2005. The primary IP group consisted of all patients who received cisplatin-based primary IV/IP chemotherapy from January 2005 to July 2011. We chose to start our data collection from 2001 onwards as that was the time period when our institution began incorporating extensive upper abdominal surgery into the primary cytoreductive effort, which led to an improvement in optimal debulking rates and survival outcomes [15]. The year 2005 was a period of transition in which some patients received IP therapy in the primary setting and others received consolidation therapy. Individual records for all patients were retrospectively reviewed, and demographic, clinical, chemotherapeutic, and survival data were recorded. Clinical data abstracted included: age, body mass index, FIGO stage, primary disease site, tumor grade, histology, preoperative platelet count, preoperative albumin, American Society of Anesthesiologists (ASA) class, preoperative CA-125, volume of ascites, and presence of gross residual disease after cytoreductive surgery. Chemotherapy data included: number of IP cycles administered, number of IV cycles administered, and details of the chemotherapy regimens. After debulking surgery and the completion of 6 cycles of IV chemotherapy, patients in the consolidation group underwent second-look surgery and were administered an additional 3–5 cycles of consolidation IP therapy if no or small-volume residual disease was found at second look (based on phase II data [7–11]). IP cisplatin was given at a dose of 75 mg/m2. For patients in the primary IP group, IV/IP therapy was initiated after cytoreduction, with the intent to administer 6 cycles. A modified GOG 172 outpatient regimen has been used at our institution since 2005, and is administered as follows: IV paclitaxel (135 mg/m2) over 3 h on day 1, IP cisplatin (75 mg/m2) on day 2, and IP paclitaxel
Two hundred twenty-four patients were included over the study period. Sixty-two patients (28%) received IV followed by consolidation IP chemotherapy, and 162 patients (72%) received primary IV/IP chemotherapy (Table 1). Patient and tumor characteristics are shown in Table 2. The primary IP group had significantly more women with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites at presentation. There were no differences in residual disease at the end of debulking surgery between both groups. Patients who received primary IP therapy had a significantly greater median number of IP cycles administered, while patients who received consolidation IP therapy had a significantly greater median number of IV and total (IV + IP) chemotherapy cycles administered (Table 1). At the time of second-look surgery for women in the consolidation IP group, 33 patients (53%) had no residual disease at the beginning of surgery, 9 (15%) had microscopic disease noted on biopsy only with no gross evidence of disease, and 19 (31%) had gross ≤1 cm residual (1 patient did not have second-look surgery). Among the 19 patients Table 1 Intraperitoneal chemotherapy regimens. Chemotherapy regimen Consolidation IP regimen IV paclitaxel 175 mg/m2 on day 1 IV carboplatin AUC = 6 on day 1 (Every 21 days for 6 cycles) Followed by second-look surgery and if no or small-volume (≤1 cm) residual disease found: IP cisplatin 75 mg/m2 (Every 28 days for 3–5 cycles) Primary IP regimen IV paclitaxel 135 mg/m2 over 3 h on day 1 IP cisplatin 75 mg/m2 on day 2 IP paclitaxel 60 mg/m2 on day 8 (Every 21 days for 6 cycles) IP, intraperitoneal; IV, intravenous; AUC, area under the curve.
n 62
162
470
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Table 2 Patient and tumor characteristics (N = 224). Characteristic
Consolidation IP n = 62
Primary IP n = 162
Median age (range)
59.6 yrs (25–78) 25.1 kg/m2 (19.1–39.2)
59 yrs (23–83) 25.5 kg/m2 (18.3–54.6)
1 (2%) 2 (3%) 56 (90%) 3 (5%)
8 (5%) 7 (4%) 129 (80%) 18 (11%)
0.35
51 (82%) 3 (5%) 8 (13%)
115 (71%) 28 (17%) 19 (12%)
0.04
3 (5%) 58 (95%)
8 (5%) 154 (95%)
0.99
53 (85%) 0 (0%) 1 (2%) 8 (13%) 367 K/μl (204–1067) 4.1 g/dl (2.7–4.8) 798 U/ml (9–29,797)
152 (94%) 3 (2%) 2 (1%) 5 (3%) 322 K/μl (146–1150) 4.2 g/dl (2.6–4.8) 301 U/ml (9–24,500)
0.03
3 (5%) 46 (77%) 11 (18%)
9 (6%) 99 (61%) 54 (33%)
0.08
12 (19%) 16 (26%) 28 (45%) 6 (10%)
76 (47%) 31 (19%) 40 (25%) 15 (9%)
0.001
34 (55%) 28 (45%) 3 (1–5) 6 (3–9) 9 (7–13)
100 (62%) 62 (38%) 5 (1–6) 0 (0–7) 6 (4–8)
0.37
Median BMI (range) FIGO stage IIIA IIIB IIIC IV Primary disease site Ovary Fallopian tube Peritoneum Tumor grade* 1 2/3 Histology Serous Clear cell Endometrioid Mixed/other Median preoperative platelet count (range) Median preoperative albumin (range)† Median preoperative CA-125 (range)‡ ASA class§ 1 2 3 Ascites None 1–1000 1001–5000 N5000 Residual disease None ≤1 cm Median IP chemotherapy cycles, (range) Median IV chemotherapy cycles (with no IP), (range) Median total chemotherapy cycles (IP + IV), (range)
p 0.75 0.77
Primary IP Consolidation IP Multivariate p=0.17
0.01 0.2 0.007
b0.001 b0.001 b0.001
Fig. 1. Progression-free survival: consolidation intraperitoneal vs primary intraperitoneal chemotherapy.
the difference in PFS was not significant (HR 0.78; 95% CI, 0.56–1.11; p = 0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39–0.89; p = 0.01). Multivariate models for PFS and OS are shown in Tables 3 and 4. A sensitivity analysis was performed excluding patients with stage IV cancer. Consistent with our primary analysis, the median PFS after adjusting for confounders was greater for the primary IP group, but this did not reach statistical significance (24.2 months vs 21.8 months; HR 0.82; 95% CI, 0.58–1.15; p = 0.24). The median OS was significantly greater for the primary IP group (80.2 months vs 57.9 months; HR 0.61; 95% CI, 0.4–0.93; p = 0.02). Patients who received IV followed by consolidation IP chemotherapy comprised 35% (66/187) of optimally debulked patients from 2001 to 2005: 62 patients received cisplatin-based IP consolidation (included in our study as the consolidation IP group), 4 received noncisplatin based IP consolidation (not included in any analysis), and 121 did not get IP consolidation. After adjusting for confounders, patients
IP, intraperitoneal; IV, intravenous; BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; ASA, American Society of Anesthesiologists. Data missing for: *one, †eight, ‡ten, and §two patients.
with gross residual disease at the initiation of second-look surgery, 8 had all tumor nodules excised, while 11 had representative biopsies taken with ≤1 cm residual disease left at completion. No second-look surgery was performed for women in the primary IP group as that was not part of the standard management for these patients. Median follow-up was 50 months (range, 9–141) for the entire cohort, 58 months (range, 10–141) for the consolidation IP group, and 49 months (range, 9–102) for the primary IP group. The median PFS was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57–1.06; p = 0.11) (Fig. 1). The median OS was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38–0.83; p = 0.004) (Fig. 2). On univariate analysis, factors that were significantly associated with PFS were histology (p b 0.001), preoperative CA-125 (log transformation) (p = 0.04), and residual disease (p = 0.007). Factors that were significantly associated with OS were histology (p b 0.001), preoperative platelet count (log transformation) (p = 0.02), and residual disease (p = 0.02). On multivariate analysis, after adjusting for confounders,
Primary IP
Consolidation IP Multivariate p=0.01
Fig. 2. Overall survival: consolidation intraperitoneal vs primary intraperitoneal chemotherapy.
R.S. Suidan et al. / Gynecologic Oncology 134 (2014) 468–472 Table 3 Multivariate analysis for progression-free survival. Factor
N
Hazard Ratio (95% CI)
p
Primary IP chemotherapy Consolidation IP chemotherapy Preoperative CA-125 (log) Histology Serous Clear cell Endometrioid Mixed/other Residual disease None ≤1 cm
156 58 214
0.78 (0.56–1.11) Reference 1.07 (0.97–1.18)
0.17
195 3 3 13
Reference 11.62 (3.54–38.14) 0.33 (0.05–2.38) 0.85 (0.45–1.61)
127 87
0.77 (0.56–1.06) Reference
0.2
b0.001 0.27 0.62 0.11
IP, Intraperitoneal Patients with missing CA-125 excluded (10 patients).
who received cisplatin-based IP consolidation had a nonsignificantly greater median PFS compared to patients who did not get IP consolidation (19.7 months vs 16 months; HR 0.94; 95% CI 0.67–1.31; p = 0.7), and a nonsignificantly greater median OS (57.5 months vs 50.3 months; HR 0.97; 95% CI 0.7–1.35; p = 0.85). On the other hand, patients who received primary IV/IP therapy comprised 62% (204/328) of optimally debulked patients from 2005 to 7/2011: 162 received cisplatin-based IV/ IP therapy (included in our study as the primary IP group), 42 received an alternate IV/IP regimen, and 124 did not get IV/IP therapy. In the recurrent setting, the consolidation IP group was treated with one of 14 chemotherapy regimens, while the primary IP group was treated with one of 15 regimens. The most common regimens (all IV) used in both groups were: doxorubicin, carboplatin/doxorubicin, carboplatin/gemcitabine, and carboplatin/paclitaxel. Among the patients in the consolidation IP group who recurred, 60% (32/53) were treated with one of those four regimens, compared to 70% (85/120) of those in the primary IP group who recurred (p = 0.24).
Discussion Three phase III trials in women with optimally debulked stage III ovarian cancer have shown a survival advantage for patients who received primary IV/IP chemotherapy compared to those who received IV therapy [12–14]. This led to a change in our institution's treatment approach for this patient population, which shifted from administering IP chemotherapy as consolidation to giving it up-front after cytoreductive surgery. In our analysis, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP therapy in patients with optimally cytoreduced advanced epithelial ovarian cancer. Our study compares the outcomes of these two management strategies at the same institution. Given the significant survival benefits reported in the randomized trials evaluating primary IV/IP therapy [13,14,19], it is unlikely that a phase III trial will be conducted comparing the two treatment approaches. The IV/IP regimen used Table 4 Multivariate analysis for overall survival. Factor
N
Hazard ratio (95% CI)
Primary IP chemotherapy Consolidation IP chemotherapy Preoperative platelet count (log) Histology Serous Clear cell Endometrioid Mixed/other Residual disease None ≤1 cm
162 62 224
0.59 (0.39–0.89) Reference 1.67 (0.91–3.06)
205 3 3 13
Reference 63.23 (16.41–243.64) 1.3 (0.18–9.45) 1.15 (0.54–2.43)
134 90
0.78 (0.52–1.17) Reference
IP, intraperitoneal.
p 0.01 0.1
b0.001 0.79 0.72 0.23
471
in the primary IP group is a modified GOG 172 regimen that is administered on an outpatient basis. This regimen has been shown to have similar survival outcomes to those reported in GOG 172, albeit with improved toxicity, tolerability, and the convenience of outpatient treatment [16]. We chose to include patients with stage IV disease, which we feel increases the generalizability of our results. Although the phase III GOG trials evaluating primary IV/IP chemotherapy only included patients with stage III ovarian cancer [12–14], several centers and providers consider that the benefits of IV/IP therapy should be offered to certain patients with optimally cytoreduced stage IV disease [20,21]. At our institution, IV/IP therapy is sometimes considered for select patients with stage IV cancer who are optimally debulked and who have resected supradiaphragmatic lymph nodes, pleural disease, isolated cutaneous or liver metastasis, or a malignant pleural effusion, and no residual extraperitoneal disease postoperatively. Consolidation IP therapy has also been considered in the past for patients with stage IV disease who had similar characteristics [7,11]. We did, however, assess the survival outcomes between the two management approaches after excluding patients with stage IV cancer (n = 21), and there was no change in the results. There are limitations in comparing the two groups in our study. Patients in the primary IP group were treated in a different time period (2005–2011) than those in the consolidation IP group (2001–2005), and it is possible that subsequent therapies may have contributed to the difference in OS seen. We addressed this by evaluating the salvage regimens used in both arms of the study at recurrence. Both groups had access to a similar number of chemotherapeutic treatments (14 vs 15), with the majority of patients in each group (60% vs 70%) receiving one of four commonly used regimens. Another potential weakness is selection bias, as the majority of patients who had optimal cytoreduction after 2005 received primary IV/IP therapy (62%), compared to 35% of those in the previous time period receiving consolidation IP therapy. Some women with no clinical evidence of disease after primary IV chemotherapy declined further surgery and IP chemotherapy, which may have excluded patients with the best outcomes during that era. On the other hand, the performance status of patients deemed eligible by providers for second-look surgery may be higher than that of an unselected cohort. At the same time, women who progressed on primary IV chemotherapy would not have had a second-look surgery and subsequent IP consolidation, which may have excluded patients with the worst outcomes. In order to address this issue, we compared the survival outcomes of patients who received consolidation IP therapy to those who did not from 2001 to 2005. The consolidation IP group had nonsignificantly greater median PFS and OS, which we feel minimizes selection bias as a limitation. In our study, patients who received consolidation IP chemotherapy had a greater median preoperative platelet count, CA-125, and ascites, while the patients who received primary IV/IP therapy had a greater proportion of serous tumors. There were no differences in residual disease at the end of cytoreductive surgery. We attempted to account for the heterogeneity between the two groups by adjusting for significant prognostic factors in our multivariate survival analysis, the results of which were consistent with the primary analysis. Our data show an approximately 21-month OS benefit for the primary IP group (78.8 months vs 57.5 months) and an approximately 4-month PFS benefit for the same group (23.7 months vs 19.7 months). The difference in OS was statistically significant, while the difference in PFS was not. While the previously described limitations may explain this discrepancy, this could also be related to the sample size of our consolidation IP group (62 patients). It is possible that a larger patient cohort may have been needed to show a statistically significant PFS difference, which was not needed to show an OS benefit, as the difference in survival between both groups was striking. Nevertheless, this assertion cannot be supported with the current analysis. Including patients who received consolidation IP chemotherapy prior to 2001 may have addressed this matter. We chose not to because of the surgical
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paradigm shift that occurred at our institution during that time period, in which a more comprehensive cytoreduction of upper abdominal disease was performed. Patients prior to that year did not have extensive upper abdominal procedures incorporated into the debulking effort, and had lower overall optimal cytoreduction rates and decreased PFS and OS [15]. Including those patients would have biased the results in favor of the primary IP group. In our study, primary IV/IP therapy in patients with advanced epithelial ovarian cancer was associated with improved OS compared to IV followed by consolidation IP treatment. This suggests that decreasing the time period between primary debulking and the administration of IP chemotherapy may potentially lead to improved survival outcomes, taking into account all the limitations of a retrospective analysis. The benefit observed with the difference in the timing of administration is hypothesis generating and should be explored further. Future randomized trials should consider the evaluation of IP chemotherapy at the time of surgery or soon after cytoreduction. Conflict of interest statement There are no conflicts to disclose.
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