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Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma
YGYNO-976913; No. of pages: 7; 4C: Gynecologic Oncology xxx (2017) xxx–xxx
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Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma Koji Matsuo a,⁎, Malcolm S. Ross b, Mayu Yunokawa c, Marian S. Johnson d, Hiroko Machida a, Kohei Omatsu e, Merieme M. Klobocista f,1, Dwight D. Im g, Shinya Satoh h, Tsukasa Baba i, Yuji Ikeda j, Stephen H. Bush k, Kosei Hasegawa l, Erin A. Blake m, Munetaka Takekuma n, Masako Shida o, Masato Nishimura p, Sosuke Adachi q, Tanja Pejovic r, Satoshi Takeuchi s, Takuhei Yokoyama t, Yutaka Ueda u, Keita Iwasaki v, Takahito M. Miyake w, Shiori Yanai x, Tadayoshi Nagano y, Tadao Takano z, Mian M.K. Shahzad k, Frederick R. Ueland d, Joseph L. Kelley b, Lynda D. Roman a a
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, CA, USA Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Magee-Womens Hospital, University of Pittsburgh, PA, USA Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan d Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky, KY, USA e Department of Gynecology, Cancer Institute Hospital, Tokyo, Japan f Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Montefiore Medical Center, NY, USA g The Gynecologic Oncology Center, Mercy Medical Center, Baltimore, MD, USA h Department of Obstetrics and Gynecology, Tottori University, Tottori, Japan i Department of Obstetrics and Gynecology, Kyoto University, Kyoto, Japan j Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan k Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Moffitt Cancer Center, University of South Florida, FL, USA l Department of Obstetrics and Gynecology, Saitama Medical University International Medical Center, Saitama, Japan m Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado, CO, USA n Department of Obstetrics and Gynecology, Shizuoka Cancer Center, Shizuoka, Japan o Department of Obstetrics and Gynecology, Tokai University, Kanagawa, Japan p Department of Obstetrics and Gynecology, Tokushima University, Tokushima, Japan q Department of Obstetrics and Gynecology, Niigata University, Niigata, Japan r Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Oregon Health & Science University, OR, USA s Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan t Department of Obstetrics and Gynecology, Osaka Rosai Hospital, Osaka, Japan u Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan v Department of Obstetrics and Gynecology, Aichi Medical University, Aichi, Japan w Department of Obstetrics and Gynecology, Kawasaki Medical School, Okayama, Japan x Department of Obstetrics and Gynecology, Kurashiki Medical Center, Okayama, Japan y Department of Obstetrics and Gynecology, Kitano Hospital, Osaka, Japan z Department of Obstetrics and Gynecology, Tohoku University, Miyagi, Japan b c
H I G H L I G H T S • • • •
Survival after recurrence was examined in women with recurrent uterine carcinosarcoma. Salvage therapy with taxane/platinum (TP) regimen was compared to non-TP regimens. Survival after recurrence was higher in TP regimen compared to non-TP regimen. Longer disease-free interval was associated with TP response.
⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD 520, Los Angeles, CA 90033, USA. E-mail address: [email protected] (K. Matsuo). 1 Current affiliation: Division of Surgical Gynecologic Oncology, John Theurer Cancer Center, Hackensack University Medical Center, NJ, USA.
https://doi.org/10.1016/j.ygyno.2017.10.008 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
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a r t i c l e
i n f o
Article history: Received 26 August 2017 Received in revised form 3 October 2017 Accepted 4 October 2017 Available online xxxx Keywords: Uterine carcinosarcoma Recurrence Chemotherapy Taxane Platinum Survival outcome
a b s t r a c t Objective. To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. Methods. We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. Results. There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P b 0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P = 0.02). When stratified by disease-free interval, women with a disease-free interval ≥6 months who received a taxane/platinum doublet had a higher 2year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P = 0.002); conversely, in women with a disease-free interval b6 months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P = 0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P = 0.019). Conclusion. Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6 months. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Uterine carcinosarcoma is a high-grade endometrial cancer that has undergone an epithelial-mesenchymal transition with the sarcoma component arising from a dedifferentiated carcinoma component [1, 2]. The aggressiveness of uterine carcinosarcoma is clearly reflected in the considerably high incidence of disease recurrence after initial treatment. Nearly half of women with uterine carcinosarcoma experience a disease recurrence despite a comprehensive treatment approach [1,3]. Currently, there is no standard consensus for treatment strategy in women with recurrent uterine carcinosarcoma. The use of systemic chemotherapy plays a pivotal role in salvage therapy; more specific treatment considerations may be dependent on patient and tumor factors. Cisplatin, carboplatin, ifosfamide, and paclitaxel are all considered active agents for the treatment uterine carcinosarcoma [4]. One of the commonly used chemotherapy regimens for uterine carcinosarcoma is a paclitaxel with carboplatin doublet. Less toxicity, fewer adverse events, and ease of administration compared to other regimens such as an ifosfamide-based regimen make this a favorable option [1]. A combination regimen of paclitaxel with carboplatin has been reported to be effective for women with uterine carcinosarcoma in multiple clinical trials [5–8], with overall response rates ranging from 54% to 67%. These studies predominantly evaluated the effectiveness of this regimen in advanced stage disease via single arm cohorts; and recurrent disease accounting for only 17 to 57% of their study subjects [5–8]. Currently, there is no clinical trial reporting superiority of a taxane/platinum regimen over others in uterine carcinosarcoma. Given differences in tumor biology between primary and recurrent tumors, a study solely examining recurrent disease is useful in the management of uterine carcinosarcoma. The objective of the study was to examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. 2. Patients and methods 2.1. Systematic literature review We first performed a systematic literature search examining a public search engine PubMed/MEDLINE with the entry keywords “uterine carcinosarcoma” OR “malignant mixed müllerian tumor” AND “carboplatin”
AND “paclitaxel” limited to English literature (searched on July 24, 2017). We used the MOOSE guideline to summarize the search results [9]. There were 56 articles identified in the initial search (Fig. S1), with seven articles examining the efficacy of carboplatin and paclitaxel in advanced stage, persistent, and recurrent uterine carcinosarcoma (Table S1) [5–8,10–12]. We found no prior study comparing a taxane/ platinum regimen to other non-taxane/platinum regimens in a recurrent uterine carcinosarcoma population. 2.2. Study Eligibility We utilized a previously organized database for uterine carcinosarcoma [3,13–15]. In this retrospective cohort study, we collected consecutive cases of uterine carcinosarcoma anywhere it was available between 1993 and 2013 from 26 institutions in the United States and Japan. The database consisted of 906 women with stage I–IV uterine carcinosarcoma who underwent primary hysterectomy-based surgical staging. Institutional Review Board approval was obtained at each participating institution. We consulted the STROBE guidelines to outline the results of the cohort study [16]. Within this surgical database, women who had no residual disease at the time of initial hysterectomy-based surgical treatment and who eventually developed disease recurrence were included in our analysis of salvage chemotherapies. We excluded women with residual disease at surgical treatment because prognosis is distinctively different compared to those who had complete resection [3,17]. Among those who were eligible for analysis, characteristics and outcomes of women who received the first-line salvage chemotherapy with taxane/platinum doublet were compared to those who received other regimens. 2.3. Clinical information We examined information from the initial diagnosis of uterine carcinosarcoma and from the time of the first recurrence. Variables ascertained from the initial uterine carcinosarcoma diagnosis were country, ethnicity, cancer stage, histologic subtypes (carcinoma and sarcoma), surgery type and the extent of residual disease, type of postoperative chemotherapy (taxane/platinum versus others), and type of postoperative radiotherapy (whole pelvic irradiation versus others). Variables abstracted at the time of disease recurrence included age at recurrence, the histology type of the recurrence (carcinoma versus
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
sarcoma), anatomical location of recurrent site (local versus distance), disease-free interval (b6, 6–11.9, and ≥12 months), the first-line salvage chemotherapy type (taxane/platinum versus others) and number of chemotherapy cycles (1–3, 4–6, and N 6 cycles), use of radiotherapy in the recurrent setting, and survival outcome including SAR. 2.4. Study Definition Cancer stage was re-classified based on the 2009 International Federation of Gynecology and Obstetrics system [18]. Carcinoma components and sarcoma components were grouped as described previously [3]. Disease-free interval was determined as the time interval between the date of hysterectomy and the date of the first recurrence. SAR was defined as the time interval between the date of the first recurrence and the date of death from uterine carcinosarcoma. Patients were censored if alive at the last follow-up or died of causes other than uterine carcinosarcoma. Local recurrence was defined as vaginal cuff and/or pelvic recurrence, and distant recurrence was defined as any recurrence other than local recurrence. 2.5. Statistical analysis The primary interest of analysis was to compare the SAR between women who received a taxane/platinum regimen for the first-line salvage chemotherapy to women who received other regimens. The secondary interest of analysis was to evaluate predictive factors for response to a taxane/platinum regimen. Continuous variables were assessed for distribution by the Kolmogorov–Smirnov test, expressed with mean (± standard deviation) or median (interquartile range) as appropriate. Statistical significance of continuous variables was assessed with Student t-test or Mann-Whitney U test as appropriate. Categorical variables were evaluated with chi-square test or Fisher exact test as appropriate. The Kaplan-Meier method was used to construct survival curves [19], and the statistical significance between the curves was examined by log-rank test for univariate analysis. We used a Cox proportional hazard regression model to identify the independent predictive factors for SAR on multivariate analysis [20]. In this model, we first entered the covariates with P b 0.10 on univariate analysis, and the least significant covariate was removed from the model until all the covariates remained significant (cutoff, P b 0.05) in the final model (conditional backward). The magnitude of the statistical significance was expressed with adjusted hazard ratio (HR) and 95% confidence interval (CI). In the multivariate model the variance inflation factor was determined among covariates entered in the analysis, and a value of 2 or greater was considered to indicate the presence of multicollinearity [21]. Over-adjustment was also assessed with ratio of interest per covariates in the model with a ratio of b 10 was considered over-adjustment. A P-value b0.05 was considered statistically significant (all, two-sided hypothesis), and Statistical Package for Social Science software (SPSS, version 12.0, Chicago, IL, USA) was used for all the analyses. 3. Results Among 906 women who underwent primary surgical treatment for uterine carcinosarcoma without neoadjuvant therapy, there were 873 women who had information regarding residual disease at time of initial surgery. Of these 873 women, 774 women had a complete surgical resection without residual disease. From this completely resected cohort, 326 women developed a disease recurrence. Information regarding salvage treatment was not available in 140 of the 326 women with a disease recurrence. Among 186 women with information on salvage treatment available, 32 women who had radiotherapy alone, two women who had surgery alone, two women who transferred care, and two women who opted for palliative care were excluded.
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Table 1 Patterns of the first-line salvage chemotherapy. Regimen type
Frequency
(%)
Taxane + platinum doublet Ifosamide-based Ifosfamide doublet Ifosfamide alone Other non-taxane/platinum Multi-agent Single agent
71 30 20 10 47 19 28
48.0% 20.3% 13.5% 6.8% 31.8% 12.8% 18.9%
Remaining 148 women with available information regarding salvage chemotherapy comprised of the study population. The first-line chemotherapy treatment regimens for recurrent uterine carcinosarcoma are shown in Table 1. There were 71 (48.0%) women who received a taxane/platinum doublet as the first-line salvage chemotherapy, with the remaining 77 (52.0%) women receiving other regimens. The most common chemotherapy regimen was carboplatin with paclitaxel (n = 64, 43.2%), followed by ifosfamide-based therapy administered in 30 (20.3%) women. Patient demographics at the initial uterine carcinosarcoma diagnosis are shown in Table 2. Stage distribution and histologic types at the initial diagnosis were similar between the taxane/platinum group and the other regimen group (both, P N 0.05). Across the two groups, the majority of recurrent uterine carcinosarcoma had high-grade carcinoma (79.7%) and homologous sarcoma (56.8%) at the initial diagnosis. At the initial diagnosis, 125 (84.5%) women underwent pelvic lymphadenectomy and 81 (54.7%) women underwent para-aortic lymphadenectomy. Women who did not receive postoperative chemotherapy after hysterectomy-based surgical treatment were more likely to receive a taxane/platinum regimen as the first-line salvage chemotherapy for recurrent disease compared to those who received a taxane/platinum regimen after the primary surgery (64.4% versus 36.7%, P = 0.018). Characteristics of recurrent uterine carcinosarcoma were compared between women who received a taxane/platinum regimen and those who received other regimens (Table 3). Age at recurrence, histology type at recurrence, and anatomical location of recurrent site were not Table 2 Patient demographics (at initial diagnosis). Characteristics
Taxane/platinum
Others
Number Country USA Japan Race White African Hispanic Asian Others Stage I II–IV Carcinoma component Low-grade High-grade Sarcoma component Homologous Heterologous Prior taxane/platinum* No Yes No prior chemotherapy Prior WPRT* No Yes
n = 71 (48.0%)
n = 77 (52.0%)
29 (40.3%) 42 (55.3%)
43 (59.7%) 34 (44.7%)
17 (36.2%) 10 (62.5%) 2 (40%) 42 (55.3%) 0
30 (63.8%) 6 (37.5%) 3 (60%) 34 (44.7%) 2 (100%)
29 (49.2%) 42 (47.2%)
30 (50.8%) 47 (52.8%)
17 (56.7%) 54 (45.8%)
13 (43.3%) 64 (54.2%)
43 (51.2%) 28 (43.8%)
41 (48.8%) 36 (56.3%)
20 (46.5%) 22 (36.7%) 29 (64.4%)
23 (53.5%) 38 (63.3%) 16 (35.6%)
53 (49.5%) 18 (43.9%)
54 (50.5%) 23 (56.1%)
P-value 0.07
0.11
0.87
0.31
0.41
0.018
0.59
Number (%) per row is shown. *Postoperative therapy at the initial diagnosis. Total number may not be 148 due missing information. Fisher exact test or chi-square test for Pvalues. Abbreviation: WPRT, whole pelvic radiotherapy.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
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K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Table 3 Patient demographics (at recurrence). Characteristics
Taxane/platinum
Others
Number Age at recurrence b 60 years ≥ 60 years Histology type at recurrence Carcinoma Sarcoma Carcinoma/sarcoma No tissue diagnosis Histology type at recurrence⁎ Carcinoma§ Sarcoma Location of recurrence Local alone Distant alone Local and distant Location of recurrence‡ Local alone Distant +/− local Disease-free interval b 6 months 6–11.9 months ≥ 12 months Chemotherapy cycle† ≤ 3 cycles 4–6 cycles N 6 cycles Radiotherapy for recurrence No Yes
n = 71 (48.0%) 66.1 (±10.7) 19 (50%) 52 (47.3%)
n = 77 (52.0%) 65.8 (±8.8) 19 (50%) 58 (52.7%)
11 (42.3%) 5 (55.6%) 6 (60%) 49 (47.6%)
15 (57.7%) 4 (44.4%) 4 (40%) 54 (52.4%)
17 (47.2%) 5 (55.6%)
19 (52.8%) 4 (44.4%)
16 (50%) 45 (50.6%) 9 (36%)
16 (50%) 44 (49.4%) 16 (64%)
16 (50%) 60 (52.6%)
16 (50%) 54 (47.4%)
13 (39.4%) 22 (39.3%) 36 (61.0%)
20 (60.6%) 34 (60.7%) 23 (39.0%)
20 (36.4%) 45 (67.2%) 5 (31.3%)
35 (63.6%) 22 (32.8%) 11 (68.8%)
53 (46.9%) 18 (51.4%)
60 (53.1%) 17 (52.0%)
P-value 0.89
0.77
0.72
0.42
0.84
0.035
0.001
0.70
Number (%) per row or mean (±SD) is shown. ⁎Analyzed only cases with known histology types. §Carcinoma alone or carcinoma and sarcoma. ‡Location was grouped based on presence of distant recurrence. †Cycles for recurrent disease. Total number may not be 148 due missing information. Fisher exact test, chi-square test, or Student t-test for P-values.
associated with use of taxane/platinum regimen (all, P N 0.05). Across the groups, carcinoma component was the most common histology type in the recurrent sites (carcinoma alone 57.8%, carcinoma with sarcoma 22.2%, and sarcoma alone 20%). Disease-free interval was significantly correlated with a taxane/platinum regimen use, and women who had a disease-free interval ≥12 months (61.0%) were more likely to receive this regimen compared to those who had a shorter interval (39.3% for 6–11.9 months, and 39.4% for b6 months, P = 0.035). Women who received a taxane/platinum regimen were more likely to have received 4–6 cycles of the first-line salvage chemotherapy (67.2% versus 32.8%, P = 0.001). On survival analysis, 90 (60.8%) women died of uterine carcinosarcoma, including 36 (50.7%) deaths in the taxane/platinum group and 54 (70.1%) deaths in the other regimen group. The median time to death due to uterine carcinosarcoma after the first recurrence was 10.1 months. In the 58 (39.2%) women alive at the last follow-up visit, the median follow-up time after the first recurrence was 24 months. Disease-free interval was not associated with patterns of recurrence (P = 0.79). On univariate analysis women who received a taxane/platinum doublet had superior SAR compared to women who received non-taxane/ platinum regimens (2-year SAR rate 55.5% versus 34.8%, median SAR time 72.4 versus 12.0 months, HR 0.49, 95% CI 0.32 to 0.75, P b 0.001; Fig. 1A). When cases were grouped based on the use of a multi-agent regimen, the taxane/platinum group had a higher 2-year SAR compared to the non-taxane/platinum multi-agent group (55.5% versus 36.6%. P = 0.007: Fig. 1B). Among women who received non-taxane/platinum regimens, 2-year SAR rates were similar between the monotherapy group and the multi-agent group (32.6% versus 36.6%, P = 0.99: Fig. 1B). Results of univariate analysis for other covariates are shown in Table S2. Disease-free interval (2-year SAR rates, 19.3% for b 6 months,
39.1% for 6–11.9 months, and 62.3% for ≥12 months, P b 0.001) and administered chemotherapy cycles for recurrent disease (22.2% for ≤ 3 cycles, 59.4% for 4–6 cycles, and 81.0% for N6 cycles, P b 0.001) were significantly associated with SAR. Local recurrence alone was associated with longer SAR compared to distant recurrence but it did not reach statistical significance (2-year rates, local alone 59.7%, distant alone 42.9%, and both local and distant 31.8%, P = 0.09). Prior chemotherapy status was not associated with SAR (2-year rates, 47.5% for no prior chemotherapy, 47.7% for prior taxane/platinum regimen, and 39.8% for prior other regimens, P = 0.67). On multivariate analysis (Table 4), use of a taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-HR 0.56, 95% CI 0.35 to 0.91, P = 0.02). Additionally, anatomical recurrence site (local/distant versus local alone, adjusted-HR 3.22, 95% CI 1.58 to 6.56), disease-free interval (≥ 12 versus b 6 months, adjusted-HR 0.36, 95% CI 0.19 to 0.68), and number of chemotherapy cycles (N 6 versus ≤ 3 cycles, adjusted-HR 0.18, 95% CI 0.07 to 0.47; and 4–6 versus ≤ 3 cycles, adjusted-HR 0.37, 95% CI 0.23 to 0.59) remained independent prognostic factors for SAR (all, P b 0.05). A sensitivity analysis was performed to examine the predictive factors for response to the taxane/platinum regimen (Table 5). Prior taxane/platinum use (2-year SAR rate, 62.1% versus 39.7%, P = 0.019), absence of prior whole pelvic irradiation (52.2% versus 31.6%, P = 0.004), distant recurrence (54.6% versus 26.8%, P = 0.001), and disease-free interval ≥6 months (61.9% versus 40.0%, P = 0.002) were statistically associated with improved SAR with taxane/platinum regimen as the first-line salvage chemotherapy. SAR was extremely poor among cases with disease-free interval b 6 months regardless of chemotherapy types (20.5% versus 18.4%, P = 0.61). Presence of carcinoma at the recurrent site was associated with high taxane/platinum response but it did not reach statistical significance (66.5% versus 45.2%, P = 0.06) whereas presence of sarcoma was not (P = 0.29). In another sensitivity analysis, the effectiveness of a platinum agent as salvage chemotherapy for recurrent uterine carcinosarcoma was examined among women with a prior use of platinum agent as their initial postoperative chemotherapy (n = 49). SAR was examined based on the duration of disease-free interval. Women with disease-free interval ≥ 12 months had a significantly high 2-year SAR rate compared to those who had disease-free interval b6 months (67.7% versus 14.3%, HR 0.18, 95% CI 0.07 to 0.49, P = 0.001). The 2-year SAR rate of the 6– 12 months disease-free interval group was higher compared to the b6 months group but it did not demonstrate statistical significance (26.0% versus 14.3%, HR 0.64, 95% CI 0.25 to 1.65, P = 0.36). 4. Discussion In this study, women who received a taxane/platinum doublet as the first-line salvage chemotherapy for recurrent uterine carcinosarcoma had better survival compared to those who received other regimens. Moreover, there were certain patient and tumor factors that may possibly predict a taxane/platinum treatment response. The role and utility of a taxane/platinum regimen in the setting of disease recurrence merits further discussion. There are several biologically plausible reasons why a taxane/platinum doublet would be an effective regimen in recurrent uterine carcinosarcoma. Uterine carcinosarcoma is recognized to originate from endometrial carcinoma and a taxane/platinum regimen is known to be effective for high-risk endometrial carcinoma [22]. It is typically the carcinoma but not the sarcoma component of uterine carcinosarcoma that recurs and metastasizes [3]. Our study confirmed this, with a majority carcinoma component seen in 80% of the recurrent sites. Additionally this study showed that the presence of a carcinoma at the recurrent site was associated with a higher taxane/platinum response compared to other regimens, whereas presence of sarcoma did not impact taxane/platinum response.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
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Fig. 1. Survival curves based on salvage chemotherapy types. Log-rank test for P-values. Survival time after the first recurrence is shown based on the type of first-line salvage chemotherapy: (A) taxane/platinum versus non-taxane/platinum, and (B) taxane/platinum, non-taxane/platinum (monotherapy), and non-taxane/platinum (multi-agents).
In summary, it is speculated that distant recurrences are more likely to consist of the carcinoma component and have a more of a tendency to respond to taxane/platinum chemotherapy as opposed to other regimens. However, histologic evaluation from the recurrent site was performed in only 28.5% of cases. Therefore, while we demonstrated hypothetical causality between histology type and taxane/platinum response, this small sample size weakens the reliability of our interpretation and further study is warranted to prove and validate this association. Our study found that prior treatment modalities such as taxane/platinum use as well as the absence of prior pelvic irradiation were associated with taxane/platinum response in the recurrent setting (Table 5). While limited in the interpretation due to small sample size, it is speculated that these prior adjuvant treatments after surgery may impact recurrence patterns, resulting in different responses to salvage therapy [3, 13]. However, although it did not show statistical significance, differences in 2-year SAR rates were clinically meaningful among women who did not receive prior taxane/platinum regimen (47.1% versus 33.8% P = 0.14) or who did receive prior whole pelvic radiotherapy (64.4% versus 42.4%, P = 0.09). It is likely that this may be due to a type II error reflecting the limited sample size to perform this sensitivity analysis. In this study a longer disease-free interval was associated with higher taxane/platinum response. Because a platinum compound is an important backbone in this regimen, we also examined the response to a platinum agent based on disease-free interval among women who had a prior platinum treatment. In this internal validation analysis, longer disease-free interval was consistently associated with a response to platinum in the salvage setting. Platinum-free interval is a known tumor factor affecting the response to platinum retreatment in other types of gynecologic malignancy [23–25], which may provide additional plausibility to our results. This study has a number of strengths. To our knowledge this is likely the first study examining the effectiveness of a taxane/platinum doublet compared to a non-taxane/platinum regimen in women with recurrent uterine carcinosarcoma as described above. The study population is homogenous in that we only examined recurrent disease among women who had a complete resection at the initial surgery. Moreover, the sample size is relatively large when compared to previous studies of recurrent uterine carcinosarcoma. Lastly, we examined salient clinicopathological variables at the time of the first recurrence of the disease including metastatic patterns and histology type at recurrence sites. This study also has a number of limitations. First, it is a retrospective analysis and thus there may be missing confounding factors in the analysis. For example, we do not know how the chemotherapy
regimen was chosen as the salvage therapy per care providers. However, our statistics clearly demonstrated that care providers prefer to choose a taxane/platinum doublet over other regimens for women with recurrent uterine carcinosarcoma when disease-free interval was one year or longer, implying that platinum sensitivity may play a factor in selecting this regimen. It is speculated that women with recurrent uterine carcinosarcoma are likely to be elderly with multiple medical comorbidities and therefore care providers may prefer a regimen with less toxicity such as taxane/platinum agent over ifosfamide-based regimen [1]. Patient performance status at recurrence and toxicity profile related to salvage chemotherapy are important determinants in chemotherapy selection, but unfortunately these data were not available for analysis. Additionally, there were multiple chemotherapy regimens identified in the study population making regimen-specific comparisons difficult to conduct. Furthermore, we analyzed only SAR as a surrogate marker for treatment response of the first-line chemotherapy regimen, and the exact progression-free interval for the first-line salvage chemotherapy as well as strict treatment response per the RECIST criteria were not available in this surgical database [26]. Sample size may not be adequate to demonstrate statistical significance in sensitivity analyses for predictors of taxane/platinum response. Finally, there were many cases with recurrence where information on salvage therapy was not available.
Table 4 Multivariate analysis for survival after recurrence. Characteristics Recurrent site Local alone Distant alone Local/distant DFI duration b 6 months 6–11.9 months ≥ 12 months Salvage chemotherapy Non-taxane/platinum Taxane/platinum Chemotherapy cycle ≤ 3 cycles 4–6 cycles N 6 cycles
2-yr (%)
Adjusted-HR (95% CI)
59.7% 42.9% 31.8%
1 1.47 (0.83–2.63) 3.22 (1.58–6.56)
19.3% 39.1% 62.3%
1 0.89 (0.51–1.56) 0.36 (0.19–0.68)
34.8% 55.5%
1 0.56 (0.35–0.91)
22.2% 59.4% 81.0%
1 0.37 (0.23–0.59) 0.18 (0.07–0.47)
P-value 0.004 0.19 0.001 0.001 0.69 0.002
0.02 b0.001 b0.001 b0.001
A Cox proportional hazard regression model (conditional backward) for multivariate analysis. Only the significant covariates in the final model are listed. Abbreviations: 2-yr (%), 2year survival after recurrence rate; DFI, disease-free interval; HR, hazard ratio; and CI, confidence interval.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
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Table 5 Predictors of taxane/platinum response. Characteristic Carcinoma at recurrence Others Taxane/platinum Distant recurrence (–) Others Taxane/platinum DFI b6 months Others Taxane/platinum Prior WPRT (–) Others Taxane/platinum Prior taxane/platinum (–) Others Taxane/platinum
2-yr (%)
HR (95% CI)
P-value
45.2% 66.5%
1 0.43 (0.18–1.07)
0.06
55.9% 63.9%
1 0.50 (0.19–1.33)
0.16
18.4% 20.5%
1 0.80 (0.33–1.90)
0.61
31.6% 52.2%
1 0.49 (0.30–0.79)
0.004
33.8% 47.1%
1 0.57 (0.27–1.20)
0.14
Characteristic Sarcoma at recurrence Others Taxane/platinum Distant recurrence (+) Others Taxane/platinum DFS ≥6 months Others Taxane/platinum Prior WPRT (+) Others Taxane/platinum Prior Taxane/platinum (+) Others Taxane/platinum
2-yr (%)
HR (95% CI)
P-value
44.0% 68.6%
1 0.53 (0.16–1.74)
0.29
26.8% 54.6%
1 0.45 (0.28–0.72)
0.001
40.0% 61.9%
1 0.46 (0.28–0.75)
0.002
42.4% 64.4%
1 0.48 (0.20–1.12)
0.09
39.7% 62.1%
1 0.40 (0.18–0.86)
0.019
Unadjusted Cox proportional hazard regression models for P-values. Abbreviations: 2-yr (%), 2-year survival rate after recurrence; HR, hazard ratio; CI, confidence interval; DFI, diseasefree interval; and WPRT, whole pelvic radiotherapy.
Given the relatively limited sample size in this study, the lack of recurrence information may impact the results and is a recognized study limitation. There is a phase III randomized clinical trial comparing a carboplatin and paclitaxel regimen to an ifosfamide and paclitaxel regimen for ovarian and uterine carcinosarcomas (GOG-261) [27]. Patient accrual has been completed, and we are currently awaiting the results. As the inclusion criteria of the trial included recurrent uterine carcinosarcoma, this trial is expected to address the utility of taxane/platinum doublet in recurrent uterine carcinosarcoma. Compared to other treatment regimens, women with recurrent uterine carcinosarcoma who receive taxane/platinum doublet chemotherapy appear to have improved survival, particularly those with longer disease-free interval. This study provides insight into both clinical and histologic factors that can predict treatment response for recurrent uterine carcinosarcoma. If feasible and safe, tumor biopsy from the site of recurrence may predict improved SAR from a taxane/platinum regimen if the presence of a carcinoma component is confirmed. Even in patients with a prior adjuvant taxane/platinum treatment readministration of this regimen would be reasonable if disease-free interval is six months or longer. Further study is warranted to determine the effective chemotherapeutic agents for recurrent uterine carcinosarcoma with short disease-free interval. Financial Support Ensign Endowment for Gynecologic Cancer Research (K.M.) Disclosure statement There is no conflict of interest for any authors in this study. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ygyno.2017.10.008. References [1] L.A. Cantrell, S.V. Blank, L.R. Duska, Uterine carcinosarcoma: a review of the literature, Gynecol. Oncol. 137 (2015) 581–588. [2] S. Zhao, S. Bellone, S. Lopez, D. Thakral, C. Schwab, D.P. English, J. Black, E. Cocco, J. Choi, L. Zammataro, F. Predolini, E. Bonazzoli, M. Bi, N. Buza, P. Hui, S. Wong, M. Abu-Khalaf, A. Ravaggi, E. Bignotti, E. Bandiera, C. Romani, P. Todeschini, R. Tassi, L. Zanotti, F. Odicino, S. Pecorelli, C. Donzelli, L. Ardighieri, F. Facchetti, M. Falchetti, D.A. Silasi, E. Ratner, M. Azodi, P.E. Schwartz, S. Mane, R. Angioli, C. Terranova, C.M. Quick, B. Edraki, K. Bilguvar, M. Lee, M. Choi, A.L. Stiegler, T.J. Boggon, J. Schlessinger, R.P. Lifton, A.D. Santin, Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition, Proc. Natl. Acad. Sci. U. S. A. 113 (2016) 12238–12243.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma Koji Matsuo a,⁎, Malcolm S. Ross b, Mayu Yunokawa c, Marian S. Johnson d, Hiroko Machida a, Kohei Omatsu e, Merieme M. Klobocista f,1, Dwight D. Im g, Shinya Satoh h, Tsukasa Baba i, Yuji Ikeda j, Stephen H. Bush k, Kosei Hasegawa l, Erin A. Blake m, Munetaka Takekuma n, Masako Shida o, Masato Nishimura p, Sosuke Adachi q, Tanja Pejovic r, Satoshi Takeuchi s, Takuhei Yokoyama t, Yutaka Ueda u, Keita Iwasaki v, Takahito M. Miyake w, Shiori Yanai x, Tadayoshi Nagano y, Tadao Takano z, Mian M.K. Shahzad k, Frederick R. Ueland d, Joseph L. Kelley b, Lynda D. Roman a a
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, CA, USA Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Magee-Womens Hospital, University of Pittsburgh, PA, USA Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan d Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky, KY, USA e Department of Gynecology, Cancer Institute Hospital, Tokyo, Japan f Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Montefiore Medical Center, NY, USA g The Gynecologic Oncology Center, Mercy Medical Center, Baltimore, MD, USA h Department of Obstetrics and Gynecology, Tottori University, Tottori, Japan i Department of Obstetrics and Gynecology, Kyoto University, Kyoto, Japan j Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan k Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Moffitt Cancer Center, University of South Florida, FL, USA l Department of Obstetrics and Gynecology, Saitama Medical University International Medical Center, Saitama, Japan m Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado, CO, USA n Department of Obstetrics and Gynecology, Shizuoka Cancer Center, Shizuoka, Japan o Department of Obstetrics and Gynecology, Tokai University, Kanagawa, Japan p Department of Obstetrics and Gynecology, Tokushima University, Tokushima, Japan q Department of Obstetrics and Gynecology, Niigata University, Niigata, Japan r Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Oregon Health & Science University, OR, USA s Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan t Department of Obstetrics and Gynecology, Osaka Rosai Hospital, Osaka, Japan u Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan v Department of Obstetrics and Gynecology, Aichi Medical University, Aichi, Japan w Department of Obstetrics and Gynecology, Kawasaki Medical School, Okayama, Japan x Department of Obstetrics and Gynecology, Kurashiki Medical Center, Okayama, Japan y Department of Obstetrics and Gynecology, Kitano Hospital, Osaka, Japan z Department of Obstetrics and Gynecology, Tohoku University, Miyagi, Japan b c
H I G H L I G H T S • • • •
Survival after recurrence was examined in women with recurrent uterine carcinosarcoma. Salvage therapy with taxane/platinum (TP) regimen was compared to non-TP regimens. Survival after recurrence was higher in TP regimen compared to non-TP regimen. Longer disease-free interval was associated with TP response.
⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD 520, Los Angeles, CA 90033, USA. E-mail address: [email protected] (K. Matsuo). 1 Current affiliation: Division of Surgical Gynecologic Oncology, John Theurer Cancer Center, Hackensack University Medical Center, NJ, USA.
https://doi.org/10.1016/j.ygyno.2017.10.008 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
2
K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
a r t i c l e
i n f o
Article history: Received 26 August 2017 Received in revised form 3 October 2017 Accepted 4 October 2017 Available online xxxx Keywords: Uterine carcinosarcoma Recurrence Chemotherapy Taxane Platinum Survival outcome
a b s t r a c t Objective. To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. Methods. We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. Results. There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P b 0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P = 0.02). When stratified by disease-free interval, women with a disease-free interval ≥6 months who received a taxane/platinum doublet had a higher 2year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P = 0.002); conversely, in women with a disease-free interval b6 months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P = 0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P = 0.019). Conclusion. Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6 months. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Uterine carcinosarcoma is a high-grade endometrial cancer that has undergone an epithelial-mesenchymal transition with the sarcoma component arising from a dedifferentiated carcinoma component [1, 2]. The aggressiveness of uterine carcinosarcoma is clearly reflected in the considerably high incidence of disease recurrence after initial treatment. Nearly half of women with uterine carcinosarcoma experience a disease recurrence despite a comprehensive treatment approach [1,3]. Currently, there is no standard consensus for treatment strategy in women with recurrent uterine carcinosarcoma. The use of systemic chemotherapy plays a pivotal role in salvage therapy; more specific treatment considerations may be dependent on patient and tumor factors. Cisplatin, carboplatin, ifosfamide, and paclitaxel are all considered active agents for the treatment uterine carcinosarcoma [4]. One of the commonly used chemotherapy regimens for uterine carcinosarcoma is a paclitaxel with carboplatin doublet. Less toxicity, fewer adverse events, and ease of administration compared to other regimens such as an ifosfamide-based regimen make this a favorable option [1]. A combination regimen of paclitaxel with carboplatin has been reported to be effective for women with uterine carcinosarcoma in multiple clinical trials [5–8], with overall response rates ranging from 54% to 67%. These studies predominantly evaluated the effectiveness of this regimen in advanced stage disease via single arm cohorts; and recurrent disease accounting for only 17 to 57% of their study subjects [5–8]. Currently, there is no clinical trial reporting superiority of a taxane/platinum regimen over others in uterine carcinosarcoma. Given differences in tumor biology between primary and recurrent tumors, a study solely examining recurrent disease is useful in the management of uterine carcinosarcoma. The objective of the study was to examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. 2. Patients and methods 2.1. Systematic literature review We first performed a systematic literature search examining a public search engine PubMed/MEDLINE with the entry keywords “uterine carcinosarcoma” OR “malignant mixed müllerian tumor” AND “carboplatin”
AND “paclitaxel” limited to English literature (searched on July 24, 2017). We used the MOOSE guideline to summarize the search results [9]. There were 56 articles identified in the initial search (Fig. S1), with seven articles examining the efficacy of carboplatin and paclitaxel in advanced stage, persistent, and recurrent uterine carcinosarcoma (Table S1) [5–8,10–12]. We found no prior study comparing a taxane/ platinum regimen to other non-taxane/platinum regimens in a recurrent uterine carcinosarcoma population. 2.2. Study Eligibility We utilized a previously organized database for uterine carcinosarcoma [3,13–15]. In this retrospective cohort study, we collected consecutive cases of uterine carcinosarcoma anywhere it was available between 1993 and 2013 from 26 institutions in the United States and Japan. The database consisted of 906 women with stage I–IV uterine carcinosarcoma who underwent primary hysterectomy-based surgical staging. Institutional Review Board approval was obtained at each participating institution. We consulted the STROBE guidelines to outline the results of the cohort study [16]. Within this surgical database, women who had no residual disease at the time of initial hysterectomy-based surgical treatment and who eventually developed disease recurrence were included in our analysis of salvage chemotherapies. We excluded women with residual disease at surgical treatment because prognosis is distinctively different compared to those who had complete resection [3,17]. Among those who were eligible for analysis, characteristics and outcomes of women who received the first-line salvage chemotherapy with taxane/platinum doublet were compared to those who received other regimens. 2.3. Clinical information We examined information from the initial diagnosis of uterine carcinosarcoma and from the time of the first recurrence. Variables ascertained from the initial uterine carcinosarcoma diagnosis were country, ethnicity, cancer stage, histologic subtypes (carcinoma and sarcoma), surgery type and the extent of residual disease, type of postoperative chemotherapy (taxane/platinum versus others), and type of postoperative radiotherapy (whole pelvic irradiation versus others). Variables abstracted at the time of disease recurrence included age at recurrence, the histology type of the recurrence (carcinoma versus
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
sarcoma), anatomical location of recurrent site (local versus distance), disease-free interval (b6, 6–11.9, and ≥12 months), the first-line salvage chemotherapy type (taxane/platinum versus others) and number of chemotherapy cycles (1–3, 4–6, and N 6 cycles), use of radiotherapy in the recurrent setting, and survival outcome including SAR. 2.4. Study Definition Cancer stage was re-classified based on the 2009 International Federation of Gynecology and Obstetrics system [18]. Carcinoma components and sarcoma components were grouped as described previously [3]. Disease-free interval was determined as the time interval between the date of hysterectomy and the date of the first recurrence. SAR was defined as the time interval between the date of the first recurrence and the date of death from uterine carcinosarcoma. Patients were censored if alive at the last follow-up or died of causes other than uterine carcinosarcoma. Local recurrence was defined as vaginal cuff and/or pelvic recurrence, and distant recurrence was defined as any recurrence other than local recurrence. 2.5. Statistical analysis The primary interest of analysis was to compare the SAR between women who received a taxane/platinum regimen for the first-line salvage chemotherapy to women who received other regimens. The secondary interest of analysis was to evaluate predictive factors for response to a taxane/platinum regimen. Continuous variables were assessed for distribution by the Kolmogorov–Smirnov test, expressed with mean (± standard deviation) or median (interquartile range) as appropriate. Statistical significance of continuous variables was assessed with Student t-test or Mann-Whitney U test as appropriate. Categorical variables were evaluated with chi-square test or Fisher exact test as appropriate. The Kaplan-Meier method was used to construct survival curves [19], and the statistical significance between the curves was examined by log-rank test for univariate analysis. We used a Cox proportional hazard regression model to identify the independent predictive factors for SAR on multivariate analysis [20]. In this model, we first entered the covariates with P b 0.10 on univariate analysis, and the least significant covariate was removed from the model until all the covariates remained significant (cutoff, P b 0.05) in the final model (conditional backward). The magnitude of the statistical significance was expressed with adjusted hazard ratio (HR) and 95% confidence interval (CI). In the multivariate model the variance inflation factor was determined among covariates entered in the analysis, and a value of 2 or greater was considered to indicate the presence of multicollinearity [21]. Over-adjustment was also assessed with ratio of interest per covariates in the model with a ratio of b 10 was considered over-adjustment. A P-value b0.05 was considered statistically significant (all, two-sided hypothesis), and Statistical Package for Social Science software (SPSS, version 12.0, Chicago, IL, USA) was used for all the analyses. 3. Results Among 906 women who underwent primary surgical treatment for uterine carcinosarcoma without neoadjuvant therapy, there were 873 women who had information regarding residual disease at time of initial surgery. Of these 873 women, 774 women had a complete surgical resection without residual disease. From this completely resected cohort, 326 women developed a disease recurrence. Information regarding salvage treatment was not available in 140 of the 326 women with a disease recurrence. Among 186 women with information on salvage treatment available, 32 women who had radiotherapy alone, two women who had surgery alone, two women who transferred care, and two women who opted for palliative care were excluded.
3
Table 1 Patterns of the first-line salvage chemotherapy. Regimen type
Frequency
(%)
Taxane + platinum doublet Ifosamide-based Ifosfamide doublet Ifosfamide alone Other non-taxane/platinum Multi-agent Single agent
71 30 20 10 47 19 28
48.0% 20.3% 13.5% 6.8% 31.8% 12.8% 18.9%
Remaining 148 women with available information regarding salvage chemotherapy comprised of the study population. The first-line chemotherapy treatment regimens for recurrent uterine carcinosarcoma are shown in Table 1. There were 71 (48.0%) women who received a taxane/platinum doublet as the first-line salvage chemotherapy, with the remaining 77 (52.0%) women receiving other regimens. The most common chemotherapy regimen was carboplatin with paclitaxel (n = 64, 43.2%), followed by ifosfamide-based therapy administered in 30 (20.3%) women. Patient demographics at the initial uterine carcinosarcoma diagnosis are shown in Table 2. Stage distribution and histologic types at the initial diagnosis were similar between the taxane/platinum group and the other regimen group (both, P N 0.05). Across the two groups, the majority of recurrent uterine carcinosarcoma had high-grade carcinoma (79.7%) and homologous sarcoma (56.8%) at the initial diagnosis. At the initial diagnosis, 125 (84.5%) women underwent pelvic lymphadenectomy and 81 (54.7%) women underwent para-aortic lymphadenectomy. Women who did not receive postoperative chemotherapy after hysterectomy-based surgical treatment were more likely to receive a taxane/platinum regimen as the first-line salvage chemotherapy for recurrent disease compared to those who received a taxane/platinum regimen after the primary surgery (64.4% versus 36.7%, P = 0.018). Characteristics of recurrent uterine carcinosarcoma were compared between women who received a taxane/platinum regimen and those who received other regimens (Table 3). Age at recurrence, histology type at recurrence, and anatomical location of recurrent site were not Table 2 Patient demographics (at initial diagnosis). Characteristics
Taxane/platinum
Others
Number Country USA Japan Race White African Hispanic Asian Others Stage I II–IV Carcinoma component Low-grade High-grade Sarcoma component Homologous Heterologous Prior taxane/platinum* No Yes No prior chemotherapy Prior WPRT* No Yes
n = 71 (48.0%)
n = 77 (52.0%)
29 (40.3%) 42 (55.3%)
43 (59.7%) 34 (44.7%)
17 (36.2%) 10 (62.5%) 2 (40%) 42 (55.3%) 0
30 (63.8%) 6 (37.5%) 3 (60%) 34 (44.7%) 2 (100%)
29 (49.2%) 42 (47.2%)
30 (50.8%) 47 (52.8%)
17 (56.7%) 54 (45.8%)
13 (43.3%) 64 (54.2%)
43 (51.2%) 28 (43.8%)
41 (48.8%) 36 (56.3%)
20 (46.5%) 22 (36.7%) 29 (64.4%)
23 (53.5%) 38 (63.3%) 16 (35.6%)
53 (49.5%) 18 (43.9%)
54 (50.5%) 23 (56.1%)
P-value 0.07
0.11
0.87
0.31
0.41
0.018
0.59
Number (%) per row is shown. *Postoperative therapy at the initial diagnosis. Total number may not be 148 due missing information. Fisher exact test or chi-square test for Pvalues. Abbreviation: WPRT, whole pelvic radiotherapy.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
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K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Table 3 Patient demographics (at recurrence). Characteristics
Taxane/platinum
Others
Number Age at recurrence b 60 years ≥ 60 years Histology type at recurrence Carcinoma Sarcoma Carcinoma/sarcoma No tissue diagnosis Histology type at recurrence⁎ Carcinoma§ Sarcoma Location of recurrence Local alone Distant alone Local and distant Location of recurrence‡ Local alone Distant +/− local Disease-free interval b 6 months 6–11.9 months ≥ 12 months Chemotherapy cycle† ≤ 3 cycles 4–6 cycles N 6 cycles Radiotherapy for recurrence No Yes
n = 71 (48.0%) 66.1 (±10.7) 19 (50%) 52 (47.3%)
n = 77 (52.0%) 65.8 (±8.8) 19 (50%) 58 (52.7%)
11 (42.3%) 5 (55.6%) 6 (60%) 49 (47.6%)
15 (57.7%) 4 (44.4%) 4 (40%) 54 (52.4%)
17 (47.2%) 5 (55.6%)
19 (52.8%) 4 (44.4%)
16 (50%) 45 (50.6%) 9 (36%)
16 (50%) 44 (49.4%) 16 (64%)
16 (50%) 60 (52.6%)
16 (50%) 54 (47.4%)
13 (39.4%) 22 (39.3%) 36 (61.0%)
20 (60.6%) 34 (60.7%) 23 (39.0%)
20 (36.4%) 45 (67.2%) 5 (31.3%)
35 (63.6%) 22 (32.8%) 11 (68.8%)
53 (46.9%) 18 (51.4%)
60 (53.1%) 17 (52.0%)
P-value 0.89
0.77
0.72
0.42
0.84
0.035
0.001
0.70
Number (%) per row or mean (±SD) is shown. ⁎Analyzed only cases with known histology types. §Carcinoma alone or carcinoma and sarcoma. ‡Location was grouped based on presence of distant recurrence. †Cycles for recurrent disease. Total number may not be 148 due missing information. Fisher exact test, chi-square test, or Student t-test for P-values.
associated with use of taxane/platinum regimen (all, P N 0.05). Across the groups, carcinoma component was the most common histology type in the recurrent sites (carcinoma alone 57.8%, carcinoma with sarcoma 22.2%, and sarcoma alone 20%). Disease-free interval was significantly correlated with a taxane/platinum regimen use, and women who had a disease-free interval ≥12 months (61.0%) were more likely to receive this regimen compared to those who had a shorter interval (39.3% for 6–11.9 months, and 39.4% for b6 months, P = 0.035). Women who received a taxane/platinum regimen were more likely to have received 4–6 cycles of the first-line salvage chemotherapy (67.2% versus 32.8%, P = 0.001). On survival analysis, 90 (60.8%) women died of uterine carcinosarcoma, including 36 (50.7%) deaths in the taxane/platinum group and 54 (70.1%) deaths in the other regimen group. The median time to death due to uterine carcinosarcoma after the first recurrence was 10.1 months. In the 58 (39.2%) women alive at the last follow-up visit, the median follow-up time after the first recurrence was 24 months. Disease-free interval was not associated with patterns of recurrence (P = 0.79). On univariate analysis women who received a taxane/platinum doublet had superior SAR compared to women who received non-taxane/ platinum regimens (2-year SAR rate 55.5% versus 34.8%, median SAR time 72.4 versus 12.0 months, HR 0.49, 95% CI 0.32 to 0.75, P b 0.001; Fig. 1A). When cases were grouped based on the use of a multi-agent regimen, the taxane/platinum group had a higher 2-year SAR compared to the non-taxane/platinum multi-agent group (55.5% versus 36.6%. P = 0.007: Fig. 1B). Among women who received non-taxane/platinum regimens, 2-year SAR rates were similar between the monotherapy group and the multi-agent group (32.6% versus 36.6%, P = 0.99: Fig. 1B). Results of univariate analysis for other covariates are shown in Table S2. Disease-free interval (2-year SAR rates, 19.3% for b 6 months,
39.1% for 6–11.9 months, and 62.3% for ≥12 months, P b 0.001) and administered chemotherapy cycles for recurrent disease (22.2% for ≤ 3 cycles, 59.4% for 4–6 cycles, and 81.0% for N6 cycles, P b 0.001) were significantly associated with SAR. Local recurrence alone was associated with longer SAR compared to distant recurrence but it did not reach statistical significance (2-year rates, local alone 59.7%, distant alone 42.9%, and both local and distant 31.8%, P = 0.09). Prior chemotherapy status was not associated with SAR (2-year rates, 47.5% for no prior chemotherapy, 47.7% for prior taxane/platinum regimen, and 39.8% for prior other regimens, P = 0.67). On multivariate analysis (Table 4), use of a taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-HR 0.56, 95% CI 0.35 to 0.91, P = 0.02). Additionally, anatomical recurrence site (local/distant versus local alone, adjusted-HR 3.22, 95% CI 1.58 to 6.56), disease-free interval (≥ 12 versus b 6 months, adjusted-HR 0.36, 95% CI 0.19 to 0.68), and number of chemotherapy cycles (N 6 versus ≤ 3 cycles, adjusted-HR 0.18, 95% CI 0.07 to 0.47; and 4–6 versus ≤ 3 cycles, adjusted-HR 0.37, 95% CI 0.23 to 0.59) remained independent prognostic factors for SAR (all, P b 0.05). A sensitivity analysis was performed to examine the predictive factors for response to the taxane/platinum regimen (Table 5). Prior taxane/platinum use (2-year SAR rate, 62.1% versus 39.7%, P = 0.019), absence of prior whole pelvic irradiation (52.2% versus 31.6%, P = 0.004), distant recurrence (54.6% versus 26.8%, P = 0.001), and disease-free interval ≥6 months (61.9% versus 40.0%, P = 0.002) were statistically associated with improved SAR with taxane/platinum regimen as the first-line salvage chemotherapy. SAR was extremely poor among cases with disease-free interval b 6 months regardless of chemotherapy types (20.5% versus 18.4%, P = 0.61). Presence of carcinoma at the recurrent site was associated with high taxane/platinum response but it did not reach statistical significance (66.5% versus 45.2%, P = 0.06) whereas presence of sarcoma was not (P = 0.29). In another sensitivity analysis, the effectiveness of a platinum agent as salvage chemotherapy for recurrent uterine carcinosarcoma was examined among women with a prior use of platinum agent as their initial postoperative chemotherapy (n = 49). SAR was examined based on the duration of disease-free interval. Women with disease-free interval ≥ 12 months had a significantly high 2-year SAR rate compared to those who had disease-free interval b6 months (67.7% versus 14.3%, HR 0.18, 95% CI 0.07 to 0.49, P = 0.001). The 2-year SAR rate of the 6– 12 months disease-free interval group was higher compared to the b6 months group but it did not demonstrate statistical significance (26.0% versus 14.3%, HR 0.64, 95% CI 0.25 to 1.65, P = 0.36). 4. Discussion In this study, women who received a taxane/platinum doublet as the first-line salvage chemotherapy for recurrent uterine carcinosarcoma had better survival compared to those who received other regimens. Moreover, there were certain patient and tumor factors that may possibly predict a taxane/platinum treatment response. The role and utility of a taxane/platinum regimen in the setting of disease recurrence merits further discussion. There are several biologically plausible reasons why a taxane/platinum doublet would be an effective regimen in recurrent uterine carcinosarcoma. Uterine carcinosarcoma is recognized to originate from endometrial carcinoma and a taxane/platinum regimen is known to be effective for high-risk endometrial carcinoma [22]. It is typically the carcinoma but not the sarcoma component of uterine carcinosarcoma that recurs and metastasizes [3]. Our study confirmed this, with a majority carcinoma component seen in 80% of the recurrent sites. Additionally this study showed that the presence of a carcinoma at the recurrent site was associated with a higher taxane/platinum response compared to other regimens, whereas presence of sarcoma did not impact taxane/platinum response.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
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Fig. 1. Survival curves based on salvage chemotherapy types. Log-rank test for P-values. Survival time after the first recurrence is shown based on the type of first-line salvage chemotherapy: (A) taxane/platinum versus non-taxane/platinum, and (B) taxane/platinum, non-taxane/platinum (monotherapy), and non-taxane/platinum (multi-agents).
In summary, it is speculated that distant recurrences are more likely to consist of the carcinoma component and have a more of a tendency to respond to taxane/platinum chemotherapy as opposed to other regimens. However, histologic evaluation from the recurrent site was performed in only 28.5% of cases. Therefore, while we demonstrated hypothetical causality between histology type and taxane/platinum response, this small sample size weakens the reliability of our interpretation and further study is warranted to prove and validate this association. Our study found that prior treatment modalities such as taxane/platinum use as well as the absence of prior pelvic irradiation were associated with taxane/platinum response in the recurrent setting (Table 5). While limited in the interpretation due to small sample size, it is speculated that these prior adjuvant treatments after surgery may impact recurrence patterns, resulting in different responses to salvage therapy [3, 13]. However, although it did not show statistical significance, differences in 2-year SAR rates were clinically meaningful among women who did not receive prior taxane/platinum regimen (47.1% versus 33.8% P = 0.14) or who did receive prior whole pelvic radiotherapy (64.4% versus 42.4%, P = 0.09). It is likely that this may be due to a type II error reflecting the limited sample size to perform this sensitivity analysis. In this study a longer disease-free interval was associated with higher taxane/platinum response. Because a platinum compound is an important backbone in this regimen, we also examined the response to a platinum agent based on disease-free interval among women who had a prior platinum treatment. In this internal validation analysis, longer disease-free interval was consistently associated with a response to platinum in the salvage setting. Platinum-free interval is a known tumor factor affecting the response to platinum retreatment in other types of gynecologic malignancy [23–25], which may provide additional plausibility to our results. This study has a number of strengths. To our knowledge this is likely the first study examining the effectiveness of a taxane/platinum doublet compared to a non-taxane/platinum regimen in women with recurrent uterine carcinosarcoma as described above. The study population is homogenous in that we only examined recurrent disease among women who had a complete resection at the initial surgery. Moreover, the sample size is relatively large when compared to previous studies of recurrent uterine carcinosarcoma. Lastly, we examined salient clinicopathological variables at the time of the first recurrence of the disease including metastatic patterns and histology type at recurrence sites. This study also has a number of limitations. First, it is a retrospective analysis and thus there may be missing confounding factors in the analysis. For example, we do not know how the chemotherapy
regimen was chosen as the salvage therapy per care providers. However, our statistics clearly demonstrated that care providers prefer to choose a taxane/platinum doublet over other regimens for women with recurrent uterine carcinosarcoma when disease-free interval was one year or longer, implying that platinum sensitivity may play a factor in selecting this regimen. It is speculated that women with recurrent uterine carcinosarcoma are likely to be elderly with multiple medical comorbidities and therefore care providers may prefer a regimen with less toxicity such as taxane/platinum agent over ifosfamide-based regimen [1]. Patient performance status at recurrence and toxicity profile related to salvage chemotherapy are important determinants in chemotherapy selection, but unfortunately these data were not available for analysis. Additionally, there were multiple chemotherapy regimens identified in the study population making regimen-specific comparisons difficult to conduct. Furthermore, we analyzed only SAR as a surrogate marker for treatment response of the first-line chemotherapy regimen, and the exact progression-free interval for the first-line salvage chemotherapy as well as strict treatment response per the RECIST criteria were not available in this surgical database [26]. Sample size may not be adequate to demonstrate statistical significance in sensitivity analyses for predictors of taxane/platinum response. Finally, there were many cases with recurrence where information on salvage therapy was not available.
Table 4 Multivariate analysis for survival after recurrence. Characteristics Recurrent site Local alone Distant alone Local/distant DFI duration b 6 months 6–11.9 months ≥ 12 months Salvage chemotherapy Non-taxane/platinum Taxane/platinum Chemotherapy cycle ≤ 3 cycles 4–6 cycles N 6 cycles
2-yr (%)
Adjusted-HR (95% CI)
59.7% 42.9% 31.8%
1 1.47 (0.83–2.63) 3.22 (1.58–6.56)
19.3% 39.1% 62.3%
1 0.89 (0.51–1.56) 0.36 (0.19–0.68)
34.8% 55.5%
1 0.56 (0.35–0.91)
22.2% 59.4% 81.0%
1 0.37 (0.23–0.59) 0.18 (0.07–0.47)
P-value 0.004 0.19 0.001 0.001 0.69 0.002
0.02 b0.001 b0.001 b0.001
A Cox proportional hazard regression model (conditional backward) for multivariate analysis. Only the significant covariates in the final model are listed. Abbreviations: 2-yr (%), 2year survival after recurrence rate; DFI, disease-free interval; HR, hazard ratio; and CI, confidence interval.
Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008
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K. Matsuo et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Table 5 Predictors of taxane/platinum response. Characteristic Carcinoma at recurrence Others Taxane/platinum Distant recurrence (–) Others Taxane/platinum DFI b6 months Others Taxane/platinum Prior WPRT (–) Others Taxane/platinum Prior taxane/platinum (–) Others Taxane/platinum
2-yr (%)
HR (95% CI)
P-value
45.2% 66.5%
1 0.43 (0.18–1.07)
0.06
55.9% 63.9%
1 0.50 (0.19–1.33)
0.16
18.4% 20.5%
1 0.80 (0.33–1.90)
0.61
31.6% 52.2%
1 0.49 (0.30–0.79)
0.004
33.8% 47.1%
1 0.57 (0.27–1.20)
0.14
Characteristic Sarcoma at recurrence Others Taxane/platinum Distant recurrence (+) Others Taxane/platinum DFS ≥6 months Others Taxane/platinum Prior WPRT (+) Others Taxane/platinum Prior Taxane/platinum (+) Others Taxane/platinum
2-yr (%)
HR (95% CI)
P-value
44.0% 68.6%
1 0.53 (0.16–1.74)
0.29
26.8% 54.6%
1 0.45 (0.28–0.72)
0.001
40.0% 61.9%
1 0.46 (0.28–0.75)
0.002
42.4% 64.4%
1 0.48 (0.20–1.12)
0.09
39.7% 62.1%
1 0.40 (0.18–0.86)
0.019
Unadjusted Cox proportional hazard regression models for P-values. Abbreviations: 2-yr (%), 2-year survival rate after recurrence; HR, hazard ratio; CI, confidence interval; DFI, diseasefree interval; and WPRT, whole pelvic radiotherapy.
Given the relatively limited sample size in this study, the lack of recurrence information may impact the results and is a recognized study limitation. There is a phase III randomized clinical trial comparing a carboplatin and paclitaxel regimen to an ifosfamide and paclitaxel regimen for ovarian and uterine carcinosarcomas (GOG-261) [27]. Patient accrual has been completed, and we are currently awaiting the results. As the inclusion criteria of the trial included recurrent uterine carcinosarcoma, this trial is expected to address the utility of taxane/platinum doublet in recurrent uterine carcinosarcoma. Compared to other treatment regimens, women with recurrent uterine carcinosarcoma who receive taxane/platinum doublet chemotherapy appear to have improved survival, particularly those with longer disease-free interval. This study provides insight into both clinical and histologic factors that can predict treatment response for recurrent uterine carcinosarcoma. If feasible and safe, tumor biopsy from the site of recurrence may predict improved SAR from a taxane/platinum regimen if the presence of a carcinoma component is confirmed. Even in patients with a prior adjuvant taxane/platinum treatment readministration of this regimen would be reasonable if disease-free interval is six months or longer. Further study is warranted to determine the effective chemotherapeutic agents for recurrent uterine carcinosarcoma with short disease-free interval. Financial Support Ensign Endowment for Gynecologic Cancer Research (K.M.) Disclosure statement There is no conflict of interest for any authors in this study. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ygyno.2017.10.008. References [1] L.A. Cantrell, S.V. Blank, L.R. Duska, Uterine carcinosarcoma: a review of the literature, Gynecol. Oncol. 137 (2015) 581–588. [2] S. Zhao, S. Bellone, S. Lopez, D. Thakral, C. Schwab, D.P. English, J. Black, E. Cocco, J. Choi, L. Zammataro, F. Predolini, E. Bonazzoli, M. Bi, N. Buza, P. Hui, S. Wong, M. Abu-Khalaf, A. Ravaggi, E. Bignotti, E. Bandiera, C. Romani, P. Todeschini, R. Tassi, L. Zanotti, F. Odicino, S. Pecorelli, C. Donzelli, L. Ardighieri, F. Facchetti, M. Falchetti, D.A. Silasi, E. Ratner, M. Azodi, P.E. Schwartz, S. Mane, R. Angioli, C. Terranova, C.M. Quick, B. Edraki, K. Bilguvar, M. Lee, M. Choi, A.L. Stiegler, T.J. Boggon, J. Schlessinger, R.P. Lifton, A.D. Santin, Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition, Proc. Natl. Acad. Sci. U. S. A. 113 (2016) 12238–12243.
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Please cite this article as: K. Matsuo, et al., Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.10.008