Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma

Gynecologic Oncology 129 (2013) 63–68

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Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma☆ J. Alejandro Rauh-Hain a, Caroline C. Nitschmann a, b, Micheal J. Worley Jr. b, Leslie S. Bradford a, Ross S. Berkowitz b, John O. Schorge a, Susana M. Campos b, Marcela G. del Carmen a, Neil S. Horowitz b,⁎ a b

Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Division of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

H I G H L I G H T S ► In patients that have a recurrence and are treated with platinum chemotherapy, neoadjuvant chemotherapy increased the risk of platinum resistance. ► The timing of interval surgery should be based on the chemotherapy response, not in a fixed number of chemotherapy cycles.

a r t i c l e

i n f o

Article history: Received 12 November 2012 Accepted 11 January 2013 Available online 18 January 2013 Keywords: Ovarian cancer Platinum resistance Neoadjuvant chemotherapy

a b s t r a c t Objective. Primary debulking surgery (PDS) has historically been the standard treatment for advanced ovarian cancer. Recent data appear to support a paradigm shift toward neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) for a subset of women with advanced ovarian cancer. It remains unresolved whether NACT-IDS increases the risk of platinum resistance. We compared response to chemotherapy in patients that received NACT-IDS vs. PDS. Methods. From our Cancer Registry database we identified patients with stages IIIC and IV epithelial ovarian cancer who underwent treatment from January, 2005 to December, 2010. Standard univariate analyses were performed, as were multivariable analysis with logistic regression. The Kaplan–Meier method was used to generate survival data. Results. The study population consisted of 425 patients, 95 (22.3%) underwent NACT-IDS and 330 (77.6%) PDS. After the initial platinum-based chemotherapy, 42 (44.2%) women in the NACT-IDS group were considered to have platinum resistant disease, compared to 103 (31.2%) in the PDS group (P=0.01). When multivariate logistic regression was used to control for factors independently associated with platinum resistance, NACT-IDS was no longer associated with an initial increased risk. However, in women that had a recurrence and were retreated with platinum-based chemotherapy, 32 (88.8%) in the NACT-IDS group had developed a recurrence within six months and were considered platinum resistant, compared to 62 (55.3%) in the PDS (Pb 0.001). Conclusion. In women with EOC that have a recurrence and are treated again with platinum-based chemotherapy, NACT-IDS appears to increase the risk of platinum resistance. © 2013 Elsevier Inc. All rights reserved.

Introduction Worldwide, the estimated annual incidence of epithelial ovarian cancer (EOC) is 204,000 with 125,000 deaths [1]. EOC is associated with the highest case-fatality ratio of all gynecologic cancers, reflecting a propensity for early peritoneal dissemination, and advanced-stage disease at clinical diagnosis [2,3]. Primary debulking surgery (PDS) remains the standard of care in advanced EOC. Neoadjuvant chemotherapy with

☆ An abstract of this manuscript was accepted at the 14th Biennial Meeting of the International Gynecologic Cancer Society (IGCS), Vancouver, October, 2012. ⁎ Corresponding author at: Division of Gynecologic Oncology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. Fax: +1 617 738 5124. E-mail address: [email protected] (N.S. Horowitz). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.01.009

interval debulking surgery (NACT-IDS) is an alternative approach that has been advocated by some, especially for the treatment of stage IV ovarian cancer, for patients with heavy metastatic tumor load, or for patients in poor general condition [4,5]. Recently, the results of a large phase III trial reported that women with stages IIIC and IV EOC randomized to NACT-IDS had the same survival as women undergoing PDS followed by chemotherapy [6]. The theoretical advantages of surgical cytoreduction pertain to host factors, tumor vascular supply, and the prevention of chemotherapy resistance [7]. Poorly-vascularized tumor is removed and the remaining tumor is more susceptible to cytotoxic chemotherapy through improved perfusion. Another important consideration may be a change in cell cycle distribution with increased recruitment of cells into the active growth phase. This increased growth phase after cytoreduction

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may thereby render these cells more susceptible to chemotherapeutic agents [8]. Finally, chemotherapeutic agents exert their maximum effect on smaller, actively proliferating tumors; thus cytoreductive surgery employed before systemic therapy results in improved chemotherapy response rates [9,10]. In contrast, the use of NACT-IDS may increase the risk of developing drug resistance, by exposing large tumor volumes to chemotherapy. Consequently, the potential advantages of NACT-IDS have to be balanced against the risk of the emergence of drug-resistant cell clones. The purpose of the present study was to retrospectively compare platinum resistance in patients with advanced stage EOC who underwent PDS followed by adjuvant platinum-based chemotherapy, to those who received NACT-IDS.

Materials and methods An institutional review board-approved retrospective analysis of the Cancer Registry database at the Massachusetts General Hospital and Brigham and Women's Hospital was performed. Patients with epithelial ovarian carcinoma, primary peritoneal carcinoma, or fallopian-tube carcinoma with International Federation of Gynecology and Obstetrics (FIGO) stages IIIC and IV who underwent initial surgical management and treatment at the two participating institutions, between January 1, 2005 and December 31, 2010, were identified from the tumor registry database. All surgical procedures were performed by gynecologic oncology faculty, with an intent to achieve optimal cytoreduction. Optimal cytoreduction was defined as less than or equal to 1 cm maximal diameter of the largest residual tumor nodule at the completion of the primary operation. Chemotherapy was largely platinum and paclitaxel based and reflected standard protocols used during the study period. Patients were excluded from the study for the following: histology consistent with borderline cancer, surgical exploration at another institution, incomplete clinico-pathologic data, World Health Organization (WHO) performance status of >2 [11], serious disabling diseases that would contraindicate primary cytoreductive surgery or platinumbased chemotherapy. Once patients were identified, individual subject data were collected retrospectively from inpatient and clinical records. The decision to perform PDS vs. NACT-IDS and the initial chemotherapy regimens, as well as those at the time of recurrence, was based on the attending physician's judgment. In general, NACT-IDS was reserved for with stage IV ovarian cancer, for patients with heavy metastatic tumor load, or for patients in poor general condition. Upper abdomen surgical procedures were defined as splenectomy, pancreatectomy, gall bladder resection, liver resection, and diaphragmatic resection. Diagnosis of recurrence was identified with use of CA 125 values, radiological studies, pathology, and operative reports. Although CA 125 values and operative findings from second look surgeries were reviewed, recurrence was not included until there was evidence of disease on imaging or surgical pathology. Response to chemotherapy was assessed according to WHO criteria in all patients with measurable disease [8]. Complete response (CR) was defined as complete disappearance of all target or non-target lesions and/or normalization of the serum CA-125 level to 35 U/mL or less. Partial response (PR) was defined as 30% or greater decrease in the sum of the longest diameter of all target lesions, persistence of non-target lesions, and/or maintenance of serum CA-125 levels greater than 35 U/mL after an initial 50% or greater decrease. Progressive disease (PD) was defined as 20% or greater increase in the sum of the longest diameter of target lesions, the appearance of new lesions, and/or unequivocal progression of existing non-target lesions. CT scan results, if applicable, superseded serum CA-125 levels in determining response. Patients were noted to have platinum-sensitive disease if disease relapsed more than six months after completing prior platinum therapy, were noted to have platinum-resistant disease if relapse occurred within six months of prior platinum therapy, and platinum-refractory disease if disease progressed or was stable during platinum therapy [12,13].

Statistical analysis Continuous variables were evaluated by Student's t test or Wilcoxon–Mann–Whitney test, as appropriate. Categorical variables were evaluated by chi square test or Fisher's exact test as appropriate for category size. Standard univariate analyses were performed, as were multivariable analysis with logistic regression to control for potential confounding variables. Survival estimates were plotted utilizing the Kaplan–Meier method. The log-rank test was utilized to statistically quantify these survival differences on univariate analysis. Multivariate analyses were performed with a Cox proportional regression method. For continuous variables, the cutoff level chosen was their median value, unless otherwise specified. Length of survival was calculated from the date of initial surgery to the date of death in patients that underwent PDS, and from the date of initial diagnosis to the date of death in patients that underwent NACT-IDS. Surviving patients were censored at the date of last contact. All statistical tests were 2 sided and differences were considered statistically significant at P b 0.05. Statistical analyses including Kaplan–Meier curves were plotted using SPSS statistical software (version 16.0, SPSS, Inc., Chicago, IL). All other data analyses were performed with Stata statistical software (version 9.2, Stata Corp LP, College Station, TX). Results Preliminary review identified 504 patients with histologically proven stages IIIC and IV EOC who underwent surgery and received chemotherapy between January 1, 2005 and December 31, 2010. Seventy-nine patients were excluded from the final analysis: seven patients did not receive platinum-based chemotherapy, 49 patients were initially treated at outside hospitals, 16 patients were lost to follow-up, and seven were excluded because the patients underwent an interval cytoreduction after an initial attempt of primary cytoreduction that was suboptimal. The final study group therefore consisted of 425 women with stages IIIC and IV EOC. 95 (22.3%) women underwent NACT-IDS and 330 (77.6%) PDS. In the NACT-IDS group, only patients that had a confirmed diagnosis of EOC after interval debulking surgery were included in the study. Table 1 summarizes the demographic and clinical characteristics of the study population. Patients that underwent NACT-IDS had mean age of 65 years old compared to 61 years old in the PDS group (P = 0.001). NACT-IDS patients had a higher rate of stage IV disease (53.7% vs. 21%; P b 0.001). CA-125 at diagnosis was not significantly different between the groups (1893 U/mL vs. 1673 U/mL; P = 0.7). The rate of optimal debulking to ≤1 cm residual disease was significantly higher in NACT-IDS compared to PDS patients (91.5% vs. 82.7%; P = 0.04). In addition, the rate of complete resection to no residual disease was significantly higher in patients with NACT-IDS compared to PDS (43.1% vs. 26%; P = 0.01). Patients that underwent NACT-IDS had a lower rate of bowel surgery and upper abdominal surgical procedures. The use platinum and paclitaxel chemotherapy was similar between the groups (97.8% vs. 95.4%; P = 0.2). Patients in the NACT-IDS group more frequently received greater than six cycles of first line chemotherapy (43.1 vs. 10.6; P b 0.001). The median number of NAC cycles administered was 3, with the range of cycles given between 1 and 9. At the end of all therapy response to chemotherapy was analyzed. In the NACT-IDS group, none of the patients experienced PD while on platinum and taxane based chemotherapy; 79 patients (83.2%) had a CR, and 16 patients (16.8%) had a PR. Therefore, the overall response rate was 100% in the NACT-IDS group. The overall response rate in the PDS group was 97.8%, including 278 patients (84.2%) who had a CR (P=0.2). At 6 months from the completion of the initial platinum-based chemotherapy, 42 (44.2%) of the women in the NACT-IDS group had developed a recurrence and were considered to have platinum resistant disease, compared to 103 (31.2%) in the PDS (P =0.01). Variables

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Table 1 Demographic and clinical characteristics of the study population.

Age (years) Histology [N (%)] Serous Endometrioid Mucinous Clear cell Transitional cell Mixed Carcinosarcoma Unknown Stage [N (%)] III IV Grade [N (%)] 1 2 3 Unknown CA-125 U/mL Optimal cytoreduction b1 cm [N (%)] Complete resection to no residual disease [N (%)] Bowel surgery [N (%)] Upper abdominal surgical procedures [N (%)] Post-operative chemotherapy (platinum and taxol) [N (%)] Received >6 cycles of chemotherapy [N (%)] Received b6 cycles of chemotherapy [N (%)] Intraperitoneal chemotherapy Frontline bevacizumab b 6 cycles Consolidation with bevacizumab

PDS (N = 330)

NACT-IDS (N = 95)

61 (±10)

65 (±10)

P 0.001

222 (67.3) 16 (4.8) 5 (1.6) 13 (3.9) 5 (1.6) 35 (10.6) 23 (6.9) 11(3.3)

68 (71.5) 3 (3.1) 2 (2.2) 3 (3.1) 2 (2.2) 9 (9.5) 3 (3.1) 5 (5.3)

0.03

261 (79) 69 (21)

44 (46.3) 51 (53.7)

b0.001

14 (4.2) 21 (6.4) 293 (88.8) 2 (0.6) 1673 ± 8095 273 (82.7) 86 (26) 138 (41.8%) 55 (16.7) 315 (95.4) 35 (10.6) 23 (6.9) 98 (29.6) 14 (4.2) 32 (9.6)

2 (2.1) 6 (6.3) 86 (90.5) 1 (1.1) 1893 ± 2157 87 (91.5) 41 (43.1) 24 (25.2) 11 (11.5) 93 (97.8) 41 (43.1) 2 (2.1) 7 (7.3) 0 3 (3.1)

0.8

0.7 0.03 0.01 0.003 0.05 0.2 b0.001 0.07 b0.001 0.04 0.04

PDS: Primary debulking surgery; NACT-IDS: Neoadjuvant chemotherapy and interval debulking surgery. Values for continuous measurements are means, unless otherwise specified.

associated with platinum resistance included advanced age, NACT-IDS, stage, sub-optimal cytoreduction, intravenous vs. intraperitoneal chemotherapy, and more than six initial cycles of platinum-based chemotherapy (Table 2). Frontline bevacizumab was not associated with a

decreased risk of platinum resistance. When multivariate logistic regression was used to control for factors previously identified to be independently associated with platinum resistance, NACT-IDS was no longer associated with an increased risk of platinum resistance (Table 3).

Table 2 Univariate analysis for platinum resistance. Entire study population (N = 425). OR

95% CI

P

NACT-IDS Age (b62 years old vs. ≥62 years old) Stage (III vs. IV) Optimal cytoreduction Platinum and paclitaxel Intraperitoneal chemotherapy Total initial cycles of platinum based chemotherapy (≤6 vs. >6 cycles) Bevacizumab treatment

1.3 1.5 3.1 0.2 0.4 0.2 2.7 0.6

(1.09–2.7) (1.03–2.3) (2.03–4.9) (0.1–0.4) (0.1–0.9) (0.1–0.4) (1.6–4.5) (0.3–1.2)

0.01 0.03 b0.001 b0.001 0.03 b0.001 b0.001 0.2

NACT-IDS Age (b62 years old vs. ≥62 years old) Stage (III vs. IV) Optimal cytoreduction Platinum and paclitaxel Intraperitoneal chemotherapy Total initial cycles of platinum based chemotherapy (≤6 vs. >6 cycles) Bevacizumab treatment

Only patients that responded to initial chemotherapy (N = 414). 1.8 (1.1–2.9) 1.4 (0.9–2.1) 3.1 (2.01–4.9) 0.2 (0.1–0.4) 0.3 (0.1–1.1) 0.2 (0.1–0.4) 2.9 (1.7–4.9) 0.6 (0.3–1.3)

NACT-IDS Age (b62 years old vs. ≥62 years old) Stage (III vs. IV) Optimal cytoreduction Platinum and paclitaxel Intraperitoneal chemotherapy Total initial cycles of platinum based chemotherapy (≤6 vs. >6 cycles) Bevacizumab treatment

Only patients that received four or more cycles of NACT (N = 44) and all patients that underwent PDS (N = 330). 1.6 (0.8–3.1) 0.1 1.5 (0.9–2.3) 0.06 3.2 (2.01–5.3) b0.001 0.2 (0.1–0.3) b0.001 0.4 (0.1–1.1) 0.09 0.2 (0.1–0.4) b0.001 2.5 (1.4–4.4) 0.001 0.7 (0.3–1.4) 0.3

PDS: Primary debulking surgery; NACT-IDS: Neoadjuvant chemotherapy and interval debulking surgery.

0.009 0.07 b0.001 b0.001 0.06 b0.001 b0.001 0.2

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Table 3 Multivariate logistic regression for platinum resistance. Entire study population (N = 425). OR

95% CI

P

NACT-IDS Age (b62 years old vs. ≥62 years old) Stage (III vs. IV) Optimal cytoreduction Platinum and paclitaxel Intraperitoneal chemotherapy Total initial cycles of platinum based chemotherapy (≤6 vs. >6 cycles)

1.1 1.3 2.5 0.2 0.4 0.6 1.8

(0.6–1.9) (0.8–2.2) (1.5–4.2) (0.1–0.5) (0.1–1.2) (0.2–0.8) (1.06–3.3)

0.7 0.1 b0.001 b0.001 0.1 0.1 0.03

NACT-IDS Age (b62 years old vs. ≥62 years old) Stage (III vs. IV) Optimal cytoreduction Platinum and paclitaxel Intraperitoneal chemotherapy Total initial cycles of platinum based chemotherapy (≤6 vs. >6 cycles)

Only patients that responded to initial chemotherapy (N = 414). 1.1 (0.6–2) 1.3 (0.8–2) 2.5 (1.5–4.2) 0.3 (0.1–0.5) 0.4 (0.1–1.3) 0.6 (0.3–1.2) 1.9 (1.1–3.5)

NACT-IDS Age (b62 years old vs. ≥62 years old) Stage (III vs. IV) Optimal cytoreduction Platinum and paclitaxel Intraperitoneal chemotherapy Total initial cycles of platinum based chemotherapy (≤6 vs. >6 cycles)

Only patients that received four or more cycles of NACT (N = 44) and all patients that underwent PDS (N = 330). 0.7 (0.3–1.7) 0.5 1.4 (0.8–2.3) 0.1 2.5 (1.4–4.4) 0.001 0.2 (0.1–0.5) b0.001 0.5 (0.1–1.7) 0.3 0.5 (0.3–1.1) 0.1 1.8 (0.9–3.6) 0.06

0.6 0.2 b0.001 b0.001 0.1 0.2 0.02

PDS: Primary debulking surgery; NACT-IDS: Neoadjuvant chemotherapy and interval debulking surgery.

Stage, sub-optimal cytoreduction, and more than six initial cycles of platinum-based chemotherapy were the only variables associated to platinum resistance in the multivariate analysis. When patients with platinum refractory disease were excluded from the analysis, variables associated with platinum resistance included NACT-IDS, stage, sub-optimal cytoreduction, intravenous vs. intraperitoneal chemotherapy, and more than six initial cycles of platinum-based chemotherapy (Table 2). Again, in the multivariate logistic regression NACT-IDS was no longer associated with an increased risk of platinum resistance (Table 3). Similarly, when the patients that received four or more cycles of NACT were analyzed separately and compared to PDS, variables associated with platinum resistance included stage, suboptimal cytoreduction, intravenous vs. intraperitoneal chemotherapy, and more than six initial cycles of platinum-based chemotherapy (Table 2). In multivariate logistic regression analysis, NACT-IDS was not associated with an increased risk of platinum resistance (Table 3). Table 4 delineates the first line of treatment regimen received by the patients with recurrent EOC. There was no difference in the rate of platinum-based chemotherapy used as first line treatment of recurrence between NACT-IDS and PDS (54.3% vs. 43.8%; P= 0.9). In addition, there was not a significant difference in the rate of secondary cytoreduction between the groups (4.9% vs. 9.6%; P =0.2). Response to treatment was analyzed in the 148 patients that received platinum-based chemotherapy at the time of their first recurrence. In the NACT-IDS group, 10 patients (27.7%) had a CR, 19 patients (52.7%) had a PR, and 7 (19.4%) had progression of disease. Therefore, the overall response rate to platinum-based chemotherapy was 80.4% in the recurrence setting in the NACT-IDS group; compared to an overall response rate of 85% in the PDS group, including 43 patients (37.7%) who had a CR, 54 (47.3%) who had a PR, 14 (12.3%) had progression of disease, and in three (2.7%) patients the response was unknown (P =0.3). At 6 months from the completion of platinum-based chemotherapy for recurrent disease, 32 (88.8%) of the women in the NACT-IDS group had developed a recurrence and were considered platinum resistant, compared to 62 (55.3%) in the PDS (Pb 0.001). Variables associated with platinum resistance after the first recurrence included advanced age, NACT-IDS, stage III vs. IV, intravenous vs. intraperitoneal chemotherapy.

Initial optimal cytoreduction, more than six initial cycles of platinumbased chemotherapy, and frontline bevacizumab were not associated with an increased risk. When multivariate logistic regression was used to control for factors previously identified to be independently associated with platinum resistance in the recurrent setting, NACT-IDS was the only factor associated with an increased risk of platinum resistance (OR 4.06; 95% CI 1.2–13.1; P=0.01). Survival analysis Median follow-up was 28 months (range, 1–83 months). Patients were analyzed according to treatment group. The median disease free survival (DFS) for NACT-IDS was 13 months (95% CI, 11 to 14 months) compared to 16 months (95% CI, 14 to 18 months) in the PDS group (P = 0.03). Overall survival (OS) was also significantly Table 4 First line of treatment regimen received by the patients with recurrent cancer. Chemotherapy [N (%)]

PDS (N = 260)

NACT-IDS (N = 81)

None Single agent carboplatinum Carboplatinum and paclitaxel Carboplatinum and doxil Carboplatinum and gemcitabine Carboplatinum, gemcitabine, iniparib Carboplatinum and pralatrexate Any combination with carboplatinum Cyclophosphamide Liposomal doxorubicin Single agent gemcitabine Single agent paclitaxel Single agent topotecan Single agent bevacizumab Clinical trial Radiotherapy only Ablation only Unknown

18 (6.9) 14 (5.3) 15 (5.7) 16 (6.1) 37 (14.2) 25 (9.6) 5 (1.9) 112 (43) 9 (3.4) 55 (21.1) 7 (2.6) 7 (2.6) 7 (2.6) 4 (1.5) 57 (21.9) 6 (2.3) 5 (1.9) 3 (1.1)

7 (8.6) 5 (6.1) 5 (6.1) 6 (7.4) 15 (18.5) 5 (6.1) 0 36 (44.4) 2 (2.4) 22 (27.1) 3 (3.7) 10 (12.3) 3 (3.7) 0 8 (9.8) 0 1 (1.2) 1 (1.2)

Patients might be included in more than one category.

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decreased in NACT-IDS, with a median OS of 42 months (95% CI, 35 to 48 months) compared to 67 months (95% CI, 49 to 71 months) in the PDS group (P = 0.002) (Table 5). In the Cox regression analysis, optimal cytoreduction (P =0.01), platinum and paclitaxel based chemotherapy (P = 0.004), and intraperitoneal chemotherapy (P = 0.001) were independently associated with survival. Age (P = 0.5), NACT-IDS (P = 0.07), and stage (P = 0.07), failed to show statistical significance (Table 6). When the 44 patients that received four or more cycles of NACT were analyzed separately and compared to women that underwent PDS, the median DFS for NACT-IDS was 15 months (95% CI, 14 to 18 months) compared to 15 months (95% CI, 10 to 21 months) in the PDS group (P = 0.7). Overall survival (OS) was not significantly decreased in NACT-IDS, with a median OS of 46 months (95% CI, 37 to 53 months) compared to 67 months (95% CI, 49 to 71 months) in the PDS group (P =0.2). In the Cox regression analysis, optimal cytoreduction (P = 0.01), platinum and paclitaxel based chemotherapy (P = 0.04), and intraperitoneal chemotherapy (P = 0.001) were independently associated with survival. Age (P = 0.4), NACT-IDS (P = 0.7), and stage (P = 0.1) failed to show statistical significance. Conclusion Surgical staging and optimal tumor cytoreduction followed by platinum-based chemotherapy is the standard of care in the management of EOC and results in improved patient survival [14]. NACT-IDS has been explored as a management strategy in several settings. Various justifications can be provided to support this approach, including a reduction in morbidity associated with subsequent surgery and optimizing the probability of obtaining complete cytoreduction in a patient with very advanced disease. Although the recent randomized trial by Vergote et al. showed equivalent survivals for NACT-IDS and PDS, others have shown this survival to be inferior when compared to PDS [15]. Though difficult to make cross study comparisons, the major differences in survival between NACT-IDS and PDS were in OS not in PFS. This, along with the overall lower than expected survival shown by Vergote et al., raises the question of whether or not NACT-IDS induces/increases the risk of platinum resistant disease. To date there has been limited data published regarding this possibility [15], therefore, this investigation was undertaken. EOC has been recognized to be one of the most biologically sensitive solid cancers to cytotoxic chemotherapeutic agents, with responses expected in over 80% of women who receive standard platinum and paclitaxel based treatment. Unfortunately, more than 75% of clinically complete responders develop recurrent disease [16]. Those who relapse

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within 6 months of completing initial treatment typically have response rates to secondary treatment of less than 20% and, therefore, are classified as being platinum resistant. Patients who relapse more than 12 months are termed platinum sensitive, and more than 60% respond to platinum-based chemotherapy. Patients who relapse between 6 and 12 months are classified as being partially platinum sensitive, and around 30% of these patients will respond to a second use of platinum [17]. It is also well established that the statistical likelihood that such a secondary response will increase as the duration of the period between the completion of the prior therapy and planned initiation of the second-line approach lengthens [18]. Resistance to platinum alone or in combination is multifactorial. Several studies have attempted to clarify the mechanisms behind resistance to platinum-based chemotherapy, whether intrinsic, as observed in colorectal, prostate, breast or lung cancer, or acquired during treatment. At present, numerous molecular pathways are known to be involved in drug resistance. Among such pathways, increased DNA repair and enhanced drug efflux and/or inactivation play an important role in platinum resistance and may also be instrumental in predicting patient prognosis in a clinical setting [19,20]. A better understanding of the mechanisms and the risk factors associated to platinum resistance is needed for the development of drugs and better treatment strategies that could circumvent resistance mechanisms. Goldie and Coldman [10] demonstrated that the rate of development of tumor resistance was related to the size of the tumor. According to their hypothesis, the larger the tumor, the greater the population of potentially drug resistant cancer cells. By this rationale, the use of NACT-IDS may increase the risk of acquiring drug resistance, by exposure to chemotherapy while tumor volume is still high. In the present study we employed commonly accepted criteria to assess chemotherapy response and platinum resistance, and we found that during the first line of treatment, when multivariate logistic regression was used to control for factors independently associated with platinum resistance, NACT-IDS did not appeared to be associated with an increased risk of platinum resistance. However, when response to treatment was analyzed in the 148 patients retreated with platinum-based chemotherapy at first recurrence, those initially treated with NACT exhibited a higher rate of progression while on therapy (19.4% vs. 12.3%) and where more likely have platinum resistant disease (interval to second recurrenceb 6 months) (88.8% vs. 55.3%). We found our results interesting in light of previous evidence supporting the concept of a higher risk of platinum resistance with NACT. Matsuo et al. [21] evaluated in vitro drug resistance assays after exposure to NACT-IDS and PDS in epithelial ovarian, fallopian, and primary peritoneal carcinomas. There were 277 cases that underwent

Table 5 Univariate survival analysis. Median DFS Neoadjuvant chemotherapy No Yes Age b62 years old ≥62 years old Stage III IV Optimal cytoreduction Yes No Platinum and paclitaxel Yes No Intraperitoneal chemotherapy Yes No

95% CI

P

Median OS

95% CI

67 42

(49–71) (35–48)

0.03 16 13

(14–18) (11–14)

16 14

(13–18) (12–15)

0.002

0.3

0.01 Not reached 51

(41–62)

62 41

(52–69) (35–47)

59 35

(49–68) (27–43)

58 22

(51–66) (14–31)

b0.001 17 11

(14–19) (10–13)

16 9

(14–18) (7–12)

15 11

(13–16) (1–21)

20 14

(15–25) (12–15)

P

b0.001

b0.001

0.001

b0.001

0.02

b0.001

0.03 Not reached 49

(42–56)

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Table 6 Multivariate Cox proportional hazards model for overall mortality.

Neoadjuvant chemotherapy Age (b62 years old vs. ≥62 years old) Stage (III vs. IV) Optimal cytoreduction Platinum and paclitaxel Intraperitoneal chemotherapy

HR

95% CI

P

1.4 1.1 1.3 0.6 0.3 0.4

(0.9–2.09) (0.8–1.5) (0.9–1.9) (0.4–0.9) (0.2–0.7) (0.2–0.7)

0.07 0.5 0.07 0.01 0.004 0.001

PDS and 14 cases of NACT-IDS. NACT-IDS displayed an increased proportion of drug resistance assay results to platinum agents compared to PDS. There were no differences in the proportion of drug resistance assay to taxanes between the two groups. The authors concluded that platinum resistance was common after NACT-IDS. Selection of resistant tumor cells may be more significant when more chemotherapy cycles are used prior to interval cytoreduction [8]. This is important because disparities exist as to how many cycles of NACT should be given prior to interval cytoreduction, ranging from three to six or more. In the meta-analysis by Bristow and Chi [22], each incremental increase in pre-operative chemotherapy cycles was associated with a decrease in median survival time of 4.1 months. In the current study, patients that received four or more cycles of NACT did not show an increased risk of platinum resistance or worse survival. This discrepancy may be explained by the small number of women in our cohort treated with >4 cycles of NACT and the different statistical methods employed by Bristow et al. On the other hand, our findings are supported by a meta-analysis by Kang and Nam [23] that showed that the number of NACT cycles did not influence survival in their review of 21 studies published between 1989 and 2008. Based on this data and the findings of our retrospective study, it may be better to base the timing of interval surgery on the clinical and biological response to chemotherapy, rather than a fixed number of chemotherapy cycles. The present study is one of the largest retrospective series of patients to explore the risk of platinum resistance in advanced stage EOC. The strengths of this study lie in the number of patients with bulky abdominal disease treated at two large academic institutions. All the patients in this series had their tumors similarly comprehensively staged or cytoreduced, and histologically confirmed by a dedicated gynecologic pathologist. Second, our study has the advantage that its time period encompasses the last five years, during which most patients were treated with platinum and taxane containing regimens and aggressive upper abdominal procedures were employed to achieve optimal/complete cytoreduction. Finally, this is the first study that compares a clinical response to platinum-based chemotherapy between PDS and NACT-IDS. There are several limitations to this current study that must be considered in interpreting the data. This is a retrospective study, the limitations imposed by these attributes have to be borne in mind when interpreting or using the findings. Selection bias is especially important in studies analyzing NACT-IDS. The retrospective nature of the study had limited ability to reliably determine performance status, as well as how women were determined to undergo PDS vs. NACT-IDS. In addition, our Tumor Registry database provides no information regarding subsequent care at non-affiliated institutions. Information regarding post-surgical follow-up care was limited to information obtained from our institution's electronic medical records. Lastly, a standardized protocol to monitor chemotherapy response was not used in these patients thus potentially introducing leadtime bias, nor was our study designed to control for various second and further-line treatment regimens, which may have the ultimate impact on overall survival.

In conclusion, our study adds to the growing body of data demonstrating that advanced stage and sub-optimal cytoreduction are associated with platinum resistance. In addition, in women with EOC that have a recurrence and are treated again with platinum-based chemotherapy, NACT-IDS appears to increase the risk of platinum resistant which may explain the inferior overall survival reported by some for this management paradigm. Currently the optimal scenario for NACT-IDS has yet to be defined. As others have noted, prospective clinical trials are necessary to ultimately answer these questions. Until then, results from retrospective series are helpful in informing management strategies. Conflict of interest statement The authors declare that there are no conflicts of interest.

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