- Email: [email protected]
Histopathology predicts clinical outcome in advanced epithelial ovarian cancer patients treated with neoadjuvant chemotherapy and debulking surgery
Gynecologic Oncology 131 (2013) 531–534
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Histopathology predicts clinical outcome in advanced epithelial ovarian cancer patients treated with neoadjuvant chemotherapy and debulking surgery Miho Muraji a, Tamotsu Sudo a,b,⁎, Shin-ichi Iwasaki a, Sayaka Ueno a, Senn Wakahashi a, Satoshi Yamaguchi a, Kiyoshi Fujiwara a, Ryuichiro Nishimura a a b
Department of Gynecologic Oncology, Hyogo Cancer Center, 13-70 Kita-Oji, Akashi 6738558, Japan Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji, Akashi 6738558, Japan
H I G H L I G H T S • We investigate the prognostic factors for advanced ovarian cancer patients treated with neoadjuvant chemotherapy followed by interval debulking surgery. • Patients received neoadjuvant chemotherapy every 3 weeks for three to four cycles, followed by interval debulking surgery. • The amount of residual disease, stage, and the presence of more viable disease in operative specimens are prognostic factors.
a r t i c l e
i n f o
Article history: Received 17 July 2013 Accepted 28 September 2013 Available online 4 October 2013 Keywords: Neoadjuvant chemotherapy Interval debulking surgery Advanced ovarian cancer Drug resistance Pathological evaluation
a b s t r a c t Objective. To analyze the factors prognostic of survival in patients with advanced epithelial ovarian cancer (EOC) treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery. Methods. Outcomes were retrospectively in patients with advanced EOC or peritoneal cancer who received neoadjuvant paclitaxel and carboplatin chemotherapy every 3 weeks for three to four cycles, followed by interval debulking surgery and three additional cycles of the same regimens from January 2001 to November 2010. Therapeutic response was assessed histopathologically as grade 0 to 3, based on the degree of disappearance of cancer cells, displacement by necrotic and fibrotic tissue, and tumor-induced inflammation. Factors prognostic of progression-free survival (PFS) and overall survival (OS) were calculated. Results. The 124 enrolled patients had a median age of 62 years (range, 35–79 years). Viable cancer cells were observed in specimens resected from 72 patients (58%) at interval debulking surgery after NAC. Multivariate analysis using the Cox proportional hazard model showed that advanced (stage IV) disease (hazard ratio [HR] = 1.94, p = 0.003), residual cancer at the end of surgery ≥1 cm (HR = 3.78, p b 0.001), and histological grade 0–1 (HR = 1.65, p = 0.03) were independent predictors of decreased OS. Grade 0–1 was also an independent predictor of increased risk of relapse within 6 months (odds ratio = 8.42, p = 0.003). Conclusions. Residual disease of ≥1 cm, advanced stage, and the presence of more viable disease in resected specimens are prognostic factors for survival in advanced EOC patients receiving NAC followed by interval debulking surgery. © 2013 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer is a gynecologic malignancy with a high mortality rate. In Japan, morbidity rates due to ovarian cancer have increased over the past decade. Approximately 70% of women with ovarian cancer are diagnosed at an advanced stage of disease, at which time they have already experienced peritoneal dissemination [1]. Primary debulking ⁎ Corresponding author at: Department of Gynecologic Oncology and Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji, Akashi 673-8558, Japan. Fax: +81 78 927 9511. E-mail address: [email protected] (T. Sudo). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.09.030
surgery (PDS) followed by platinum-based chemotherapy is the standard treatment for ovarian cancer patients, and complete debulking is the only factor significantly prognostic of survival [2–4]. However, complete resection is difficult for patients with massively disseminated tumors. Neoadjuvant chemotherapy (NAC) has been shown to benefit patients with advanced epithelial ovarian cancer (EOC). For example, a recent randomized trial, performed by the European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC), comparing PDS with NAC followed by interval debulking surgery, found that, although progression-free survival (PFS) and overall survival (OS) rates were similar in the two groups, adverse effect and mortality rates were significantly lower in the NAC
532
M. Muraji et al. / Gynecologic Oncology 131 (2013) 531–534
group [5]. Thus, NAC before radical surgery has become a primary treatment for patients with advanced EOC [6,7]. However, despite NAC being useful for patients in whom optimal debulking appears impossible, primary surgical cytoreduction should not be precluded by a lack of surgical skills and experience [8,9]. NAC in patients with large tumors may also lead to the development of drug resistance, resulting in shorter PFS and OS. Therefore, it is necessary to distinguish patients who can benefit from primary surgical cytoreduction with those who can benefit from NAC followed by interval debulking surgery. We have therefore analyzed the factors prognostic for OS and PFS in patients with advanced EOC treated with NAC followed by interval debulking surgery, and assessed the likelihood of developing drug resistance by histological assessment of surgical specimens after NAC. Materials and methods Patients with advanced stage EOC or peritoneal (FIGO Stage IIIc and IV) treated in the Department of Gynecologic Oncology at Hyogo Cancer Center from January 2001 to November 2010 were retrospectively analyzed. A total of 220 patients were clinically diagnosed with stage IIIc and IV EOC or peritoneal cancer by imaging modalities, including abdominal and pelvic computed tomography (CT) scan or magnetic resonance imaging (MRI). Primary EOC or peritoneal cancer was definitively diagnosed by examination of biopsy specimens removed during initial laparotomy or by cytologic assessment of ascites or pleural effusion if a biopsy specimen was not available. Primary surgical exploration or imaging modalities predicted that 168 of these patients could not achieve complete cytoreduction during debulking, and these patients were indicated for NAC. Forty-four patients were excluded because of disease progression during NAC; thus, a total of 124 patients were included in this study. These patients received three (n = 38) or four (n = 86) cycles of neoadjuvant paclitaxel (175 mg/m2, day 1) and carboplatin (area under the curve = 6, day 1) chemotherapy (TC) every 3 weeks, followed by interval debulking surgery and three cycles of adjuvant TC, regardless of their response to NAC. The total number of cycles of NAC given depends upon the stage of the disease and how well the patient tolerates chemotherapy. The study protocol was approved by our institutional review board. Factors prognostic of OS and PFS were assessed by univariate and multivariate analyses. Factors analyzed included age, stage, residual disease at the end of interval debulking surgery, responsiveness to chemotherapy, serum CA125 concentration before treatment, and cytology of ascites at interval debulking surgery. Residual disease at the end of interval debulking surgery was categorized as no macroscopic residual disease, residual disease of ≤1 cm, and residual disease of N 1 cm. Responsiveness to chemotherapy was classified into four grades, based on the degeneration of all resected specimens at the time of interval debulking surgery (Fig. 1). Tumors were assessed
A
B
pathologically by four gynecologic pathologists, blinded to surgical and clinical outcomes, and systematically re-reviewed in pathological conference. Histopathological criteria for assessing therapeutic response in patients with EOC have not yet been established. In locally advanced breast cancer, NAC is the standard care to reduce initially inoperable tumors, and many criteria related to therapeutic effects of NAC have been reported. In Japan, the Japanese criteria for breast cancer, using a 6-grade scale (Grade 0, 1a, 1b, 2a, 2b and 3), are generally used by pathologists and oncologists [10]. We modified these criteria and used a 4-grade scale to assess therapeutic response to NAC in patients with EOC. NAC was judged effectively if there was degeneration or disappearance of carcinoma cells, accompanied by necrosis, fibrosis, and/or tumor-induced inflammation. We reviewed pathology slides from resected tumors at the time of IDS and assessed the degree to which residual carcinoma cells did not show such changes. Grade 0 was defined as a lack of clinical response to NAC; Grade 1 as a mild response, with marked degenerative changes (necrosis, fibrosis, and tumor-induced inflammation), such that fewer than two-thirds of cancer cells were inviable; Grade 2 as a marked response, with degenerative change in more than two-thirds of cancer cells; and Grade 3 as no evidence of malignant disease in the primary tumor site or disseminated disease at surgical excision. Composition scoring was not included in the current investigation. PFS was calculated from the date of initial treatment of chemotherapy to the date of first disease relapse or progression. OS was calculated from the date of initial treatment to the date of death or the date of last examination. The effect of prognostic factors on OS and PFS was assessed in the 104 patients who underwent optimal surgery after NAC, defined as residual tumor b1 cm at the end of interval debulking surgery, by comparing PFS and OS in patients with histological Grades 0–1 and Grades 2–3. Logistic regression models were developed to assess the predictors of relapse within 6 months, indicative of platinum resistance, in these 104 patients. All statistical analyses were performed using IBM SPSS statistics software (version 20). Clinicopathological characteristics were compared using chi-square tests or Fisher's exact tests, if appropriate. Survival curves were determined using the Kaplan–Meier method and compared using the log-rank test. Multivariate Cox proportional hazard regression analysis was used to assess factors prognostic of OS and PFS.[11,12] All tests were two-sided and p-values of b0.05 were considered statistically significant. Results The characteristics of the 124 included patients are shown in Table 1. Median follow-up was 33 months (range, 3–143 months). Twenty-six (21%) patients had other histological diseases, because histological identification was difficult owing to cellular inflammation after NAC.
C
D
x20
x100
Fig. 1. Pathological features classified as Grades 0–3. A: Grade 0, showing a lack of clinical response to chemotherapy. B: Grade 1, showing a mild response to chemotherapy. A large amount of vacuolation can be seen in viable cancer cells. C: Grade 2, showing a marked response to chemotherapy. Fibrosis and inflammation with a few degenerated cancer cells can be seen. D: Grade 3, showing no evidence of malignant disease.
M. Muraji et al. / Gynecologic Oncology 131 (2013) 531–534
533
Surgery was optimal in 104 (83.9%) patients, defined as residual tumor b1 cm. Evaluation of the resected specimens showed histological Grade 0 or 1 in 72 (58.1%) patients, indicating poor responsiveness, with persisting disease after NAC. Furthermore, 43% of patients with no macroscopic residual disease had histological Grade 0 or 1 tumors. The number of courses of NAC did not affect histological grading (p = 0.438) (Supplementary Table 1) or OS (p=0.765) (Supplementary Fig. 1). Univariate analysis showed that tumor stage, optimal rate, cytology of ascites, and histological grade were significantly prognostic of OS (Table 2). Multivariate analysis, using a Cox proportional hazard model, showed that stage IV disease (hazard ratio [HR]= 1.94, p = 0.003), residual cancer of ≥1 cm (HR = 3.78, p b 0.001), and histological Grades 0–1 (HR = 1.65, p = 0.03) were independent predictors of reduced OS (Table 3). The impact of pathological analysis on PFS and OS among the 104 patients who underwent optimal surgery after NAC is shown in Fig. 2. Patients with Grades 2–3 had significantly superior PFS; OS tended to be superior, but this was not significant. To assess factors prognostic of platinum resistance among patients who underwent optimal surgery after NAC, logistic regression models were developed to examine the predictors of relapse within 6months after the last platinum-based chemotherapy (Table 4). Histological Grades 0–1 (odds ratio [OR] = 8.42, p = 0.003) and Stage IV (OR = 6.21.p = 0.003) were independent predictors of relapse within 6 months.
Table 2 Univariate analysis of prognostic factors for overall survival.
Discussion
factors prognostic of survival in advanced EOC patients after NAC, we included pathological grade, clinical stage, optimal rate, and cytology of ascites in a multivariate model. We found that pathological response to NAC, as well as clinical stage and residual disease, was significantly prognostic of OS, suggesting that pathological evaluation may be useful in predicting patients at risk of early recurrence. Ovarian cancer is one of the most sensitive of all solid tumors to cytotoxic chemotherapy, with over 80% of women showing a response to standard platinum and paclitaxel based treatment. Even if preoperative diagnostic imaging shows massive ascites and diffuse huge dissemination, these show a dramatic disappearance at interval debulking surgery after NAC. The EORTC–NCIC randomized trial showed that surgery was less extensive in patients who received NAC, with associated reductions in mortality and postoperative complication rates. Nevertheless, NAC did not extend OS, perhaps due to tumor development of drug resistance [8,20,21]. NAC followed by interval debulking surgery may increase platinum resistance in women who experience recurrence during adjuvant platinum-based chemotherapy [20]. Moreover, drug resistance after NAC and postoperative chemotherapy has been found to correlate with in vitro drug resistance [21]. We found that, among patients with residual disease of b 1 cm, the size of the viable tumor in the operative specimens was inversely correlated with PFS and OS. Using multivariate logistic regression to control for factors independently associated with platinum resistance, we found that Grades 0–1, defined as more than two-thirds of the residual tumor remaining in the operative specimens, were associated with an increased risk of
Maximal primary cytoreductive surgery is the standard treatment for patients with advanced EOC, with the amount of residual tumor associated with patient prognosis [13,14]. NAC has been introduced to treat patients unable to undergo complete resection during in PDS. The EORTC–NCIC randomized trial showed that a largest residual tumor less than 1 cm was achieved in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. However, NAC did not improve OS. Several recent reports have shown the significance of evaluating pathological responses of breast cancers to NAC [15–17]. Pathological response and molecular subtype have been considered predictors of patient prognosis and of response to molecular targeted therapy. Pathological assessment of 101 EOC patients after NAC found that a high pathological tumor response score was the only significant predictor of time to disease-related death [18]. Moreover, pathological features after NAC, such as fibrosis and necrosis, have been shown to affect outcomes in patients with EOC [19]. To identify Table 1 Patients' characteristics. N = 124 Median age (range) Stage IIIc IV Histology Serous Endometrioid Clear Mucinous Other Median CA125 (U/ml) (range) Optimal rate No residual cancer Residual cancer b1 cm Residual cancer ≥1 cm Cytology of ascites Negative Positive Histological analysis Grade 3 Grade 2 Grade 1 Grade 0
62 (35–79) 86 (69.4%) 38 (30.6%) 87 4 5 2 26 1415
(70.2%) (3.2%) (4.0%) (1.6%) (21%) (14–26190)
61(49.2%) 43 (34.7%) 20 (16.1%) 42 (33.9%) 82 (66.1%) 12 40 61 11
(9.7%) (32.2%) (49.2%) (8.9%)
Characteristics Age b50 50–70 70b Stage IIIc IV CA125 b1000 1000–3000 3000b Optimal rate No residual cancer Residual cancer b1 cm Residual cancer ≥1 cm Cytology of ascites Negative Positive Histological analysis Grade 3 Grade 2 Grade1 Grade 0
No.(%)
Median survival (month)
15 (12.1%) 87 (70.2%) 22 (17.7%)
36 42 41
0.355 0.267
86 (69.4%) 38 (30.6%)
48c 29
0.027
49 (39.5%) 41 (33.1%) 34 (27.4%)
41 45 33
0.220 0.741
61(49.2%) 43 (34.7%) 20 (16.1%)
54 38 15
0.103 b0.001
42 (33.9%) 82 (66.1%)
57 36
0.009
11 61 40 12
Undefined 42 37 28
0.087 0.010 0.001
(8.9%) (49.2%) (32.2%) (9.7%)
p
Table 3 Multivariate analysis of prognostic factors for overall survival. Factors Stage IIIc IV Optimal rate No residual cancer Residual cancer b1 cm Residual cancer N1 cm Cytology of ascites Negative Positive Histological analysis Grade 2–3 Grade 0–1
Hazard ratio
95% confidence interval
p
1 1.94
1.26–2.98
0.003
1 1.39 3.78
0.89–2.19 2.06–6.94
0.14 b0.001
1 1.14
0.71–1.82
0.56
1 1.65
1.04–2.59
0.03
534
M. Muraji et al. / Gynecologic Oncology 131 (2013) 531–534
1.0
0.8
grade 2-3 grade 0-1
0.6 0.4 P=0.024
0.2 0.0
Overall survival (%)
Progression free survival (%)
1.0
0.8
grade 2-3 grade 0-1
0.6 0.4
P=0.058
0.2 0.0
.00
20.00 40.00 60.00 80.00 100.00 120.00 140.00
month
.00
20.00
40.00
60.00
80.00 100.00 120.00 140.00
month
Fig. 2. Estimation of progression-free survival and overall survival according to pathological evaluation (Grades 0–1 vs Grades 2–3) among patients who received complete surgery after NAC, evaluated by log-rank tests.
Table 4 Multivariate analysis of factors associated with relapse within 6 month after last chemotherapy in patients with optimal surgery after NAC. Factors Stage IIIc IV Cytology of ascites Negative Positive Histological analysis Grade 2–3 Grade 0–1
Odds ratio
95% confidence interval
p
1 6.21
1.86–20.7
0.003
1 1.69
0.45–6.38
0.44
1 8.42
2.11–33.6
0.003
platinum resistance. Of patients with residual disease of b1 cm, 61.5% had positive ascites. Engraftment of viable residual disease, with acquired platinum resistance, can lead to early recurrence. Moreover, patients with a poor pathological score after interval debulking surgery should be treated with drug regimens other than platinum based chemotherapy. In conclusion, we found that advanced tumor stage, residual disease of ≥1 cm, and the presence of more viable disease in operative specimens were prognostic of poor survival in patients with EOC who received NAC followed by interval debulking surgery. Pathological assessment of operative specimens in patients who undergo optimal interval debulking surgery is useful in predicting patients' survival. In addition, the presence of viable disease in surgical specimens appears to increase the risk of platinum resistance, shortening OS. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2013.09.030. Conflict of interest statement The authors declare that there are no conflicts of interest.
Acknowledgment We thank Ms Ushio and Ms Kinoshita for their excellent technical assistance.
References [1] Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2006;95:S161–92.
[2] 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;20:1248–59. [3] Chi DS, Eisenhauer EL, Lang J, Huh J, Haddad L, Abu-Rustum NR, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 2006;103:559–64. [4] du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO). Cancer 2009;115:1234–44. [5] Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53. [6] Cornelis S, Van Calster B, Amant F, Leunen K, van der Zee AG, Vergote I. Role of neoadjuvant chemotherapy in the management of stage IIIC-IV ovarian cancer: survey results from the members of the European Society of Gynecological Oncology. Int J Gynecol Cancer 2012;22:407–16. [7] Vergote I, Tropé CG, Amant F, Ehlen T, Reed NS, Casado A. Neoadjuvant chemotherapy is the better treatment option in some patients with stage IIIc to IV ovarian cancer. J Clin Oncol 2011;29:4076–8. [8] Chi DS, Musa F, Dao F, Zivanovic O, Sonoda Y, Leitao MM, et al. An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical timeperiod as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy(NACT). Gynecol Oncol 2012;124:10–4. [9] Vergote I, du Bois A, Amant F, Heitz F, Leunen K, Harter P. Neoadjuvant chemotherapy in advanced ovarian cancer: on what do we agree and disagree? Gynecol Oncol 2013;128:6–11. [10] Kurosumi M, Akashi-Tanaka S, Akiyama F, Komoike Y, Mukai H, Nakamura S, et al. Histopathological criteria for assessment of therapeutic response in breast cancer. (2007 version). Breast Cancer 2008;15:5–7. [11] Cox D. Regression models and life tables. J R Stat Soc 1972;34:187–220. [12] Kaplan E, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457–81. [13] Randall TC, Rubin SC. Cytoreductive surgery for ovarian cancer. Surg Clin North Am 2001;81:871–83. [14] Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8. [15] Kurosumi M. Significance and problems in evaluations of pathological responses to neoadjuvant therapy for breast cancer. Breast Cancer 2006;13:254–9. [16] Kim SI, Sohn J, Koo JS, Park SH, Park HS, Park BW. Molecular subtypes and tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Oncology 2010;79:324–30. [17] Spanheimer PM, Carr JC, Thomas A, Sugg SL, Scott-Conner CE, Liao J, et al. The response to neoadjuvant chemotherapy predicts clinical outcome and increases breast conservation in advanced breast cancer. Am J Surg 2013;30:13–5. [18] Le T, Williams K, Senterman M, Hopkins L, Faught W, Fung-Kee-Fung M. Histopathologic assessment of chemotherapy effects in epithelial ovarian cancerpatients treated with neoadjuvant chemotherapy and delayed primary surgical debulking. Gynecol Oncol 2007;106:160–3. [19] Samrao D, Wang D, Ough F, Lin YG, Liu S, Menesses T, et al. Histologic parameters predictive of disease outcome in women with advanced stage ovarian carcinoma treated with neoadjuvant chemotherapy. Transl Oncol 2012;5:469–74. [20] Rauh-Hain JA, Nitschmann CC, Worley Jr MJ, Bradford LS, Berkowitz RS, Schorge JO, et al. Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma. Gynecol Oncol 2013;129:63–8. [21] Matsuo K, Eno ML, Im DD, Rosenshein NB. Chemotherapy time interval and development of platinum and taxane resistance in ovarian, fallopian, and peritoneal carcinomas. Arch Gynecol Obstet 2010;281:325–8.
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Histopathology predicts clinical outcome in advanced epithelial ovarian cancer patients treated with neoadjuvant chemotherapy and debulking surgery Miho Muraji a, Tamotsu Sudo a,b,⁎, Shin-ichi Iwasaki a, Sayaka Ueno a, Senn Wakahashi a, Satoshi Yamaguchi a, Kiyoshi Fujiwara a, Ryuichiro Nishimura a a b
Department of Gynecologic Oncology, Hyogo Cancer Center, 13-70 Kita-Oji, Akashi 6738558, Japan Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji, Akashi 6738558, Japan
H I G H L I G H T S • We investigate the prognostic factors for advanced ovarian cancer patients treated with neoadjuvant chemotherapy followed by interval debulking surgery. • Patients received neoadjuvant chemotherapy every 3 weeks for three to four cycles, followed by interval debulking surgery. • The amount of residual disease, stage, and the presence of more viable disease in operative specimens are prognostic factors.
a r t i c l e
i n f o
Article history: Received 17 July 2013 Accepted 28 September 2013 Available online 4 October 2013 Keywords: Neoadjuvant chemotherapy Interval debulking surgery Advanced ovarian cancer Drug resistance Pathological evaluation
a b s t r a c t Objective. To analyze the factors prognostic of survival in patients with advanced epithelial ovarian cancer (EOC) treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery. Methods. Outcomes were retrospectively in patients with advanced EOC or peritoneal cancer who received neoadjuvant paclitaxel and carboplatin chemotherapy every 3 weeks for three to four cycles, followed by interval debulking surgery and three additional cycles of the same regimens from January 2001 to November 2010. Therapeutic response was assessed histopathologically as grade 0 to 3, based on the degree of disappearance of cancer cells, displacement by necrotic and fibrotic tissue, and tumor-induced inflammation. Factors prognostic of progression-free survival (PFS) and overall survival (OS) were calculated. Results. The 124 enrolled patients had a median age of 62 years (range, 35–79 years). Viable cancer cells were observed in specimens resected from 72 patients (58%) at interval debulking surgery after NAC. Multivariate analysis using the Cox proportional hazard model showed that advanced (stage IV) disease (hazard ratio [HR] = 1.94, p = 0.003), residual cancer at the end of surgery ≥1 cm (HR = 3.78, p b 0.001), and histological grade 0–1 (HR = 1.65, p = 0.03) were independent predictors of decreased OS. Grade 0–1 was also an independent predictor of increased risk of relapse within 6 months (odds ratio = 8.42, p = 0.003). Conclusions. Residual disease of ≥1 cm, advanced stage, and the presence of more viable disease in resected specimens are prognostic factors for survival in advanced EOC patients receiving NAC followed by interval debulking surgery. © 2013 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer is a gynecologic malignancy with a high mortality rate. In Japan, morbidity rates due to ovarian cancer have increased over the past decade. Approximately 70% of women with ovarian cancer are diagnosed at an advanced stage of disease, at which time they have already experienced peritoneal dissemination [1]. Primary debulking ⁎ Corresponding author at: Department of Gynecologic Oncology and Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji, Akashi 673-8558, Japan. Fax: +81 78 927 9511. E-mail address: [email protected] (T. Sudo). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.09.030
surgery (PDS) followed by platinum-based chemotherapy is the standard treatment for ovarian cancer patients, and complete debulking is the only factor significantly prognostic of survival [2–4]. However, complete resection is difficult for patients with massively disseminated tumors. Neoadjuvant chemotherapy (NAC) has been shown to benefit patients with advanced epithelial ovarian cancer (EOC). For example, a recent randomized trial, performed by the European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC), comparing PDS with NAC followed by interval debulking surgery, found that, although progression-free survival (PFS) and overall survival (OS) rates were similar in the two groups, adverse effect and mortality rates were significantly lower in the NAC
532
M. Muraji et al. / Gynecologic Oncology 131 (2013) 531–534
group [5]. Thus, NAC before radical surgery has become a primary treatment for patients with advanced EOC [6,7]. However, despite NAC being useful for patients in whom optimal debulking appears impossible, primary surgical cytoreduction should not be precluded by a lack of surgical skills and experience [8,9]. NAC in patients with large tumors may also lead to the development of drug resistance, resulting in shorter PFS and OS. Therefore, it is necessary to distinguish patients who can benefit from primary surgical cytoreduction with those who can benefit from NAC followed by interval debulking surgery. We have therefore analyzed the factors prognostic for OS and PFS in patients with advanced EOC treated with NAC followed by interval debulking surgery, and assessed the likelihood of developing drug resistance by histological assessment of surgical specimens after NAC. Materials and methods Patients with advanced stage EOC or peritoneal (FIGO Stage IIIc and IV) treated in the Department of Gynecologic Oncology at Hyogo Cancer Center from January 2001 to November 2010 were retrospectively analyzed. A total of 220 patients were clinically diagnosed with stage IIIc and IV EOC or peritoneal cancer by imaging modalities, including abdominal and pelvic computed tomography (CT) scan or magnetic resonance imaging (MRI). Primary EOC or peritoneal cancer was definitively diagnosed by examination of biopsy specimens removed during initial laparotomy or by cytologic assessment of ascites or pleural effusion if a biopsy specimen was not available. Primary surgical exploration or imaging modalities predicted that 168 of these patients could not achieve complete cytoreduction during debulking, and these patients were indicated for NAC. Forty-four patients were excluded because of disease progression during NAC; thus, a total of 124 patients were included in this study. These patients received three (n = 38) or four (n = 86) cycles of neoadjuvant paclitaxel (175 mg/m2, day 1) and carboplatin (area under the curve = 6, day 1) chemotherapy (TC) every 3 weeks, followed by interval debulking surgery and three cycles of adjuvant TC, regardless of their response to NAC. The total number of cycles of NAC given depends upon the stage of the disease and how well the patient tolerates chemotherapy. The study protocol was approved by our institutional review board. Factors prognostic of OS and PFS were assessed by univariate and multivariate analyses. Factors analyzed included age, stage, residual disease at the end of interval debulking surgery, responsiveness to chemotherapy, serum CA125 concentration before treatment, and cytology of ascites at interval debulking surgery. Residual disease at the end of interval debulking surgery was categorized as no macroscopic residual disease, residual disease of ≤1 cm, and residual disease of N 1 cm. Responsiveness to chemotherapy was classified into four grades, based on the degeneration of all resected specimens at the time of interval debulking surgery (Fig. 1). Tumors were assessed
A
B
pathologically by four gynecologic pathologists, blinded to surgical and clinical outcomes, and systematically re-reviewed in pathological conference. Histopathological criteria for assessing therapeutic response in patients with EOC have not yet been established. In locally advanced breast cancer, NAC is the standard care to reduce initially inoperable tumors, and many criteria related to therapeutic effects of NAC have been reported. In Japan, the Japanese criteria for breast cancer, using a 6-grade scale (Grade 0, 1a, 1b, 2a, 2b and 3), are generally used by pathologists and oncologists [10]. We modified these criteria and used a 4-grade scale to assess therapeutic response to NAC in patients with EOC. NAC was judged effectively if there was degeneration or disappearance of carcinoma cells, accompanied by necrosis, fibrosis, and/or tumor-induced inflammation. We reviewed pathology slides from resected tumors at the time of IDS and assessed the degree to which residual carcinoma cells did not show such changes. Grade 0 was defined as a lack of clinical response to NAC; Grade 1 as a mild response, with marked degenerative changes (necrosis, fibrosis, and tumor-induced inflammation), such that fewer than two-thirds of cancer cells were inviable; Grade 2 as a marked response, with degenerative change in more than two-thirds of cancer cells; and Grade 3 as no evidence of malignant disease in the primary tumor site or disseminated disease at surgical excision. Composition scoring was not included in the current investigation. PFS was calculated from the date of initial treatment of chemotherapy to the date of first disease relapse or progression. OS was calculated from the date of initial treatment to the date of death or the date of last examination. The effect of prognostic factors on OS and PFS was assessed in the 104 patients who underwent optimal surgery after NAC, defined as residual tumor b1 cm at the end of interval debulking surgery, by comparing PFS and OS in patients with histological Grades 0–1 and Grades 2–3. Logistic regression models were developed to assess the predictors of relapse within 6 months, indicative of platinum resistance, in these 104 patients. All statistical analyses were performed using IBM SPSS statistics software (version 20). Clinicopathological characteristics were compared using chi-square tests or Fisher's exact tests, if appropriate. Survival curves were determined using the Kaplan–Meier method and compared using the log-rank test. Multivariate Cox proportional hazard regression analysis was used to assess factors prognostic of OS and PFS.[11,12] All tests were two-sided and p-values of b0.05 were considered statistically significant. Results The characteristics of the 124 included patients are shown in Table 1. Median follow-up was 33 months (range, 3–143 months). Twenty-six (21%) patients had other histological diseases, because histological identification was difficult owing to cellular inflammation after NAC.
C
D
x20
x100
Fig. 1. Pathological features classified as Grades 0–3. A: Grade 0, showing a lack of clinical response to chemotherapy. B: Grade 1, showing a mild response to chemotherapy. A large amount of vacuolation can be seen in viable cancer cells. C: Grade 2, showing a marked response to chemotherapy. Fibrosis and inflammation with a few degenerated cancer cells can be seen. D: Grade 3, showing no evidence of malignant disease.
M. Muraji et al. / Gynecologic Oncology 131 (2013) 531–534
533
Surgery was optimal in 104 (83.9%) patients, defined as residual tumor b1 cm. Evaluation of the resected specimens showed histological Grade 0 or 1 in 72 (58.1%) patients, indicating poor responsiveness, with persisting disease after NAC. Furthermore, 43% of patients with no macroscopic residual disease had histological Grade 0 or 1 tumors. The number of courses of NAC did not affect histological grading (p = 0.438) (Supplementary Table 1) or OS (p=0.765) (Supplementary Fig. 1). Univariate analysis showed that tumor stage, optimal rate, cytology of ascites, and histological grade were significantly prognostic of OS (Table 2). Multivariate analysis, using a Cox proportional hazard model, showed that stage IV disease (hazard ratio [HR]= 1.94, p = 0.003), residual cancer of ≥1 cm (HR = 3.78, p b 0.001), and histological Grades 0–1 (HR = 1.65, p = 0.03) were independent predictors of reduced OS (Table 3). The impact of pathological analysis on PFS and OS among the 104 patients who underwent optimal surgery after NAC is shown in Fig. 2. Patients with Grades 2–3 had significantly superior PFS; OS tended to be superior, but this was not significant. To assess factors prognostic of platinum resistance among patients who underwent optimal surgery after NAC, logistic regression models were developed to examine the predictors of relapse within 6months after the last platinum-based chemotherapy (Table 4). Histological Grades 0–1 (odds ratio [OR] = 8.42, p = 0.003) and Stage IV (OR = 6.21.p = 0.003) were independent predictors of relapse within 6 months.
Table 2 Univariate analysis of prognostic factors for overall survival.
Discussion
factors prognostic of survival in advanced EOC patients after NAC, we included pathological grade, clinical stage, optimal rate, and cytology of ascites in a multivariate model. We found that pathological response to NAC, as well as clinical stage and residual disease, was significantly prognostic of OS, suggesting that pathological evaluation may be useful in predicting patients at risk of early recurrence. Ovarian cancer is one of the most sensitive of all solid tumors to cytotoxic chemotherapy, with over 80% of women showing a response to standard platinum and paclitaxel based treatment. Even if preoperative diagnostic imaging shows massive ascites and diffuse huge dissemination, these show a dramatic disappearance at interval debulking surgery after NAC. The EORTC–NCIC randomized trial showed that surgery was less extensive in patients who received NAC, with associated reductions in mortality and postoperative complication rates. Nevertheless, NAC did not extend OS, perhaps due to tumor development of drug resistance [8,20,21]. NAC followed by interval debulking surgery may increase platinum resistance in women who experience recurrence during adjuvant platinum-based chemotherapy [20]. Moreover, drug resistance after NAC and postoperative chemotherapy has been found to correlate with in vitro drug resistance [21]. We found that, among patients with residual disease of b 1 cm, the size of the viable tumor in the operative specimens was inversely correlated with PFS and OS. Using multivariate logistic regression to control for factors independently associated with platinum resistance, we found that Grades 0–1, defined as more than two-thirds of the residual tumor remaining in the operative specimens, were associated with an increased risk of
Maximal primary cytoreductive surgery is the standard treatment for patients with advanced EOC, with the amount of residual tumor associated with patient prognosis [13,14]. NAC has been introduced to treat patients unable to undergo complete resection during in PDS. The EORTC–NCIC randomized trial showed that a largest residual tumor less than 1 cm was achieved in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. However, NAC did not improve OS. Several recent reports have shown the significance of evaluating pathological responses of breast cancers to NAC [15–17]. Pathological response and molecular subtype have been considered predictors of patient prognosis and of response to molecular targeted therapy. Pathological assessment of 101 EOC patients after NAC found that a high pathological tumor response score was the only significant predictor of time to disease-related death [18]. Moreover, pathological features after NAC, such as fibrosis and necrosis, have been shown to affect outcomes in patients with EOC [19]. To identify Table 1 Patients' characteristics. N = 124 Median age (range) Stage IIIc IV Histology Serous Endometrioid Clear Mucinous Other Median CA125 (U/ml) (range) Optimal rate No residual cancer Residual cancer b1 cm Residual cancer ≥1 cm Cytology of ascites Negative Positive Histological analysis Grade 3 Grade 2 Grade 1 Grade 0
62 (35–79) 86 (69.4%) 38 (30.6%) 87 4 5 2 26 1415
(70.2%) (3.2%) (4.0%) (1.6%) (21%) (14–26190)
61(49.2%) 43 (34.7%) 20 (16.1%) 42 (33.9%) 82 (66.1%) 12 40 61 11
(9.7%) (32.2%) (49.2%) (8.9%)
Characteristics Age b50 50–70 70b Stage IIIc IV CA125 b1000 1000–3000 3000b Optimal rate No residual cancer Residual cancer b1 cm Residual cancer ≥1 cm Cytology of ascites Negative Positive Histological analysis Grade 3 Grade 2 Grade1 Grade 0
No.(%)
Median survival (month)
15 (12.1%) 87 (70.2%) 22 (17.7%)
36 42 41
0.355 0.267
86 (69.4%) 38 (30.6%)
48c 29
0.027
49 (39.5%) 41 (33.1%) 34 (27.4%)
41 45 33
0.220 0.741
61(49.2%) 43 (34.7%) 20 (16.1%)
54 38 15
0.103 b0.001
42 (33.9%) 82 (66.1%)
57 36
0.009
11 61 40 12
Undefined 42 37 28
0.087 0.010 0.001
(8.9%) (49.2%) (32.2%) (9.7%)
p
Table 3 Multivariate analysis of prognostic factors for overall survival. Factors Stage IIIc IV Optimal rate No residual cancer Residual cancer b1 cm Residual cancer N1 cm Cytology of ascites Negative Positive Histological analysis Grade 2–3 Grade 0–1
Hazard ratio
95% confidence interval
p
1 1.94
1.26–2.98
0.003
1 1.39 3.78
0.89–2.19 2.06–6.94
0.14 b0.001
1 1.14
0.71–1.82
0.56
1 1.65
1.04–2.59
0.03
534
M. Muraji et al. / Gynecologic Oncology 131 (2013) 531–534
1.0
0.8
grade 2-3 grade 0-1
0.6 0.4 P=0.024
0.2 0.0
Overall survival (%)
Progression free survival (%)
1.0
0.8
grade 2-3 grade 0-1
0.6 0.4
P=0.058
0.2 0.0
.00
20.00 40.00 60.00 80.00 100.00 120.00 140.00
month
.00
20.00
40.00
60.00
80.00 100.00 120.00 140.00
month
Fig. 2. Estimation of progression-free survival and overall survival according to pathological evaluation (Grades 0–1 vs Grades 2–3) among patients who received complete surgery after NAC, evaluated by log-rank tests.
Table 4 Multivariate analysis of factors associated with relapse within 6 month after last chemotherapy in patients with optimal surgery after NAC. Factors Stage IIIc IV Cytology of ascites Negative Positive Histological analysis Grade 2–3 Grade 0–1
Odds ratio
95% confidence interval
p
1 6.21
1.86–20.7
0.003
1 1.69
0.45–6.38
0.44
1 8.42
2.11–33.6
0.003
platinum resistance. Of patients with residual disease of b1 cm, 61.5% had positive ascites. Engraftment of viable residual disease, with acquired platinum resistance, can lead to early recurrence. Moreover, patients with a poor pathological score after interval debulking surgery should be treated with drug regimens other than platinum based chemotherapy. In conclusion, we found that advanced tumor stage, residual disease of ≥1 cm, and the presence of more viable disease in operative specimens were prognostic of poor survival in patients with EOC who received NAC followed by interval debulking surgery. Pathological assessment of operative specimens in patients who undergo optimal interval debulking surgery is useful in predicting patients' survival. In addition, the presence of viable disease in surgical specimens appears to increase the risk of platinum resistance, shortening OS. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2013.09.030. Conflict of interest statement The authors declare that there are no conflicts of interest.
Acknowledgment We thank Ms Ushio and Ms Kinoshita for their excellent technical assistance.
References [1] Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2006;95:S161–92.
[2] 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;20:1248–59. [3] Chi DS, Eisenhauer EL, Lang J, Huh J, Haddad L, Abu-Rustum NR, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 2006;103:559–64. [4] du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO). Cancer 2009;115:1234–44. [5] Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53. [6] Cornelis S, Van Calster B, Amant F, Leunen K, van der Zee AG, Vergote I. Role of neoadjuvant chemotherapy in the management of stage IIIC-IV ovarian cancer: survey results from the members of the European Society of Gynecological Oncology. Int J Gynecol Cancer 2012;22:407–16. [7] Vergote I, Tropé CG, Amant F, Ehlen T, Reed NS, Casado A. Neoadjuvant chemotherapy is the better treatment option in some patients with stage IIIc to IV ovarian cancer. J Clin Oncol 2011;29:4076–8. [8] Chi DS, Musa F, Dao F, Zivanovic O, Sonoda Y, Leitao MM, et al. An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical timeperiod as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy(NACT). Gynecol Oncol 2012;124:10–4. [9] Vergote I, du Bois A, Amant F, Heitz F, Leunen K, Harter P. Neoadjuvant chemotherapy in advanced ovarian cancer: on what do we agree and disagree? Gynecol Oncol 2013;128:6–11. [10] Kurosumi M, Akashi-Tanaka S, Akiyama F, Komoike Y, Mukai H, Nakamura S, et al. Histopathological criteria for assessment of therapeutic response in breast cancer. (2007 version). Breast Cancer 2008;15:5–7. [11] Cox D. Regression models and life tables. J R Stat Soc 1972;34:187–220. [12] Kaplan E, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457–81. [13] Randall TC, Rubin SC. Cytoreductive surgery for ovarian cancer. Surg Clin North Am 2001;81:871–83. [14] Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8. [15] Kurosumi M. Significance and problems in evaluations of pathological responses to neoadjuvant therapy for breast cancer. Breast Cancer 2006;13:254–9. [16] Kim SI, Sohn J, Koo JS, Park SH, Park HS, Park BW. Molecular subtypes and tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Oncology 2010;79:324–30. [17] Spanheimer PM, Carr JC, Thomas A, Sugg SL, Scott-Conner CE, Liao J, et al. The response to neoadjuvant chemotherapy predicts clinical outcome and increases breast conservation in advanced breast cancer. Am J Surg 2013;30:13–5. [18] Le T, Williams K, Senterman M, Hopkins L, Faught W, Fung-Kee-Fung M. Histopathologic assessment of chemotherapy effects in epithelial ovarian cancerpatients treated with neoadjuvant chemotherapy and delayed primary surgical debulking. Gynecol Oncol 2007;106:160–3. [19] Samrao D, Wang D, Ough F, Lin YG, Liu S, Menesses T, et al. Histologic parameters predictive of disease outcome in women with advanced stage ovarian carcinoma treated with neoadjuvant chemotherapy. Transl Oncol 2012;5:469–74. [20] Rauh-Hain JA, Nitschmann CC, Worley Jr MJ, Bradford LS, Berkowitz RS, Schorge JO, et al. Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma. Gynecol Oncol 2013;129:63–8. [21] Matsuo K, Eno ML, Im DD, Rosenshein NB. Chemotherapy time interval and development of platinum and taxane resistance in ovarian, fallopian, and peritoneal carcinomas. Arch Gynecol Obstet 2010;281:325–8.