|Ahead of print
Adjuvant chemotherapy in uterine carcinosarcoma: Comparison of a doublet and a triplet chemotherapeutic regimen
Udip Maheshwari1, Suhas K Rajappa2, Vineet Talwar1, Varun Goel1, Prasanta K Dash1, Manish Sharma1, Pankaj Goyal1, Parveen Jain1, Venkata P B Koyyala1, Dinesh C Doval1
1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
2 Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
|Date of Submission||16-Jan-2019|
|Date of Decision||24-Apr-2019|
|Date of Acceptance||28-Apr-2019|
|Date of Web Publication||27-Jan-2021|
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi
Source of Support: None, Conflict of Interest: None
Background: Uterine carcinosarcoma (UCS) is a rare and aggressive malignancy, and there are no existing standard guidelines for adjuvant therapy. Doublet chemotherapy regimens are most favored in adjuvant setting; however, given the early chances of distant recurrences, does a triple-drug adjuvant chemotherapy improve disease-free survival (DFS), remains to be seen. Our aim of the study is to compare and review different adjuvant regimens used in UCS.
Methods: Retrospective chart analysis included 37 optimally staged UCS patients. Each of them had either received paclitaxel plus carboplatin (PC) or paclitaxel, ifosfamide, and cisplatin (TIP). A toxicity analysis was charted as per common terminology criteria for adverse events (CTCAE) 4 criteria. A survival analysis was done by the Kaplan-Meier method, and log-rank test was used for comparison of two variables.
Results: Incidence of UCS was 4.1% and mean age (standard deviation) was 58.73 ± 6.3 (range 42 - 71) years. TIP and PC chemotherapies were given to 22 and 15 patients, respectively. Five-year DFS and overall survival for TIP versus PC were 38.2% versus 35.9% (P = 0.118) and 49% versus 50.3% (P = 0.306), respectively, and for Stage I, II versus Stage III was 78.8% versus 12.7%(P = 0.001) and 92.3% versus 34.2% (P = 0.002), respectively. However, in advanced disease (Stage III), there is a trend toward DFS advantage of triple-drug adjuvant regimen (Hazards ratio (HR) = 0.35, 95% confidence interval (CI) = 0.12–1.07). Grade 3 and 4 toxicities were seen in 54.5% patients of TIP chemotherapy group and in 13.3% patients of the PC chemotherapy (P = 0.012).
Conclusion: Triple-drug adjuvant chemotherapy (TIP) confers no survival advantage over doublet chemotherapy (PC), and in turn, increases the grade 3/4 toxicity in the adjuvant setting of optimally staged UCS patients.
Keywords: Adjuvant chemotherapy, carboplatin, carcinosarcoma, ifosfamide, paclitaxelKey Message Triple-drug ifosfamide based adjuvant chemotherapy confers no survival advantage over doublet chemotherapy and in turn, increases the grade 3/4 toxicity in optimally staged uterine carcinosarcoma patients.
|How to cite this URL:|
Maheshwari U, Rajappa SK, Talwar V, Goel V, Dash PK, Sharma M, Goyal P, Jain P, B Koyyala VP, Doval DC. Adjuvant chemotherapy in uterine carcinosarcoma: Comparison of a doublet and a triplet chemotherapeutic regimen. Indian J Cancer [Epub ahead of print] [cited 2021 Feb 25]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=308043
| » Introduction|| |
Uterine carcinosarcoma (UCS) is a rare malignancy accounting for 1–3% of all uterine cancer., It is an aggressive biphasic tumor composed of both epithelial as well as mesenchymal elements.,,Initially, carcinosarcomas were classified with sarcomas and were managed in accordance with sarcoma protocols. However, with the advent of newer molecular studies, it is now evident that carcinosarcomas of the uterus are monoclonal and they de-differentiate from epithelial components leading to their classification with uterine carcinomas.,,, Uterine malignancies are known to present in early stages and constitute 40% to 60% of the total cases., In spite the early presentation, UCS is an aggressive malignancy with dismal 5-year survival rates, ranging from 33–39% for all stages, and 50% or less for early stages., Surgery forms the mainstay of treatment in early stage disease, but postoperative chemotherapy forms an integral part of management with the rationale that distant recurrences occur very commonly even in early-stages of UCS. Many authors have proven the effectiveness of adjuvant chemotherapy in early stage UCS and have suggested a survival advantage for postoperative chemotherapy and chemoradiotherapy.,, However, there is no consensus on the optimal mode of postoperative radiotherapy as pelvic radiotherapy has not shown any survival advantage., Platinum, taxane, and ifosfamide form the backbone of adjuvant chemotherapy, and multiple trials have observed survival advantage for doublet chemotherapy.,,,Triplet chemotherapeutic regimen has been used in the advanced setting to increase the response rates. In the present study, we have retrospectively analyzed and compared two standard chemotherapeutic regimens in the adjuvant setting in patients with UCS.
| » Methods|| |
Retrospective chart analysis of pathologically confirmed cases of UCS registered during the time period of 2010–2017 was performed at a tertiary care center in northern India. Data were extracted from electronic medical records. Patients who were adequately surgically staged received adjuvant chemotherapy with or without radiotherapy and with a minimum follow-up of 12 months were included. Total 62 patients of UCS were identified out of which only 37 patients meeting the inclusion criteria were considered for analysis, whereas 19 patients had inoperable disease at presentation and 6 patients defaulted treatment. All selected patients had either received paclitaxel (135 mg/m2 D1), ifosfamide (1 gm/m2 D1–D5), and cisplatin (20 mg/m2 D1–D5) (TIP) based triple-drug chemotherapy or paclitaxel (175 mg/m2) plus carboplatin (Area under the curve (AUC) = 5) (PC) based doublet chemotherapy in the adjuvant setting. Patients who were not fit for chemotherapy or who refused chemotherapy and the patients who defaulted treatment were all excluded from the analysis. Toxicities were recorded in accordance to CTCAE criteria. Patients were followed up every 3 months for the first 2 years and then every 6 months for the next 3 years. Ultrasonography of abdomen and CA-125 levels were formed at each follow-up. As it was a retrospective study, the institutional review board (IRB) of our institution gave a waiver of consent.
Descriptive summaries were presented in mean ± standard deviation or median, range as per the distribution of data. Frequencies and percentages are given for categorical variables. Two-sample proportion Z-test was performed using MedCalc software. The survival analysis was performed using the Kaplan-Meier method and log-rank test was used to compare the difference in survival between two factors. The Cox regression analysis was used to calculate the hazards ratio (HR) for disease-free survival (DFS) and overall survival (OS). P value of <0.05 was considered as statistically significant. IBM SPSS Statistics for Windows (Version 25.0. Armonk, NY: IBM Corp) was used for statistical analysis.
| » Results|| |
Out of 1,503 uterine cancer patients, 62 (4.1%) patients of UCS were identified during the study period; however, only 37 patients met the eligibility criteria of the study. The mean age standard deviation (SD) of the cohort was 58.73 ± 6.3 (range 42 - 71) years, with 20/37 (54.05%) patients being ≥60 years. Distribution of clinical and pathologic parameters in the whole cohort has been represented in [Table 1]. There were 43.2% (16/37) patients who presented with Stage I and II and 56.7% patients had presented with Stage III disease. Stage-wise distribution has been presented in [Table 1]. The median follow-up time for the whole cohort was 55 months (range 29.3–80.6). The survival analysis has been represented in [Table 2]. Five-year disease-free survival (DFS) and overall survival (OS) for the whole cohort was 37.4% and 56.8%, respectively and median DFS being 39.5 months. On comparison, the difference in survival between the two chemotherapeutic groups was non-significant. Five-year DFS and OS for TIP versus PC was 38.2% versus 35.9% (P = 0.118) and 49% versus 50.3% (P = 0.306), respectively [Figure 1]. On Cox regression analysis, HR for DFS and OS for TIP with PC as reference were 0.5 (95% confidence interval (CI) = 0.2–1.25), P = 0.126 and 0.58 (95% CI 0.2–1.62), P = 0.312, respectively. DFS and OS for Stage I, II versus Stage III were 78.8% versus 12.7% (P = 0.001) and 92.3% versus 34.2% (P = 0.002), respectively [Figure 2], and on Cox regression, HR for DFS was 12.7 (95% CI 1.66–97.7), P = 0.014. In a subset analysis of advanced Stage III patients, there is a trend toward DFS advantage of a triple-drug regimen over doublet with HR of 0.35, (95% CI 0.12–1.07) and 3-year DFS of 41.7% versus 22.2% (P = 0.055) [Figure 3]. Grade 3 and 4 toxicities were seen in 12/22 (54.5%) patients in TIP chemotherapy group as opposed to 2/15 (13.3%) in the PC chemotherapy group (P = 0.012). All patients in this study completed a total of 6 cycles of chemotherapy.
|Figure 1: Kaplan-Meier analysis of (A) Disease-free survival (DFS) and (B) Overall Survival (OS) w.r.t. chemotherapy groups. *TIP – Paclitaxel, Ifosfamide, and Cisplatin, *PC - Paclitaxel and Carboplatin|
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|Figure 2: Kaplan-Meier analysis of (C) Disease-free survival (DFS), and (D) Overall Survival (OS) w.r.t. Stage. *TIP – Paclitaxel, Ifosfamide, and Cisplatin, *PC - Paclitaxel and Carboplatin|
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|Figure 3: Kaplan-Meier curves for disease-free survival (DFS) of patients with advanced disease w.r.t chemotherapy. *PC–Paclitaxel and carboplatin, TIP–Paclitaxel, Ifosfamide, and Cisplatin|
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| » Discussion|| |
Adjuvant therapy in UCS, even in early stages, confers survival advantage as more than half of these patients are prone to recur. However, there is no consensus on the optimal adjuvant treatment. Many clinicians have adopted the approach of surgical staging/cytoreductive surgery followed by adjuvant chemotherapy with or without pelvic irradiation. In most studies, it has been observed that adjuvant pelvic irradiation reduces the local recurrence rate but has no effect on survival., Similar results were observed in a randomized phase 3 trial by European organisation for research and treatment of cancer (EORTC), where 91 patients were randomized to observation or pelvic radiation, and no benefit of pelvic radiation was observed on DFS and OS. Matsuo et al. in their review have observed a distant recurrence rate of 37.9% in Stage I UCS and that adjuvant chemotherapy reduces the distant recurrences and improves survival. The survival advantage of adjuvant chemotherapy of early stages has been observed by Cantrell et al. in their study of early stage UCS.Thus, there is a general consensus that adjuvant chemotherapy should be offered to all UCS patients including the early stages. Chemotherapy use in carcinosarcoma started with the use of single-agent drugs in the metastatic setting, with ifosfamide having the best response rates of 36%, followed by cisplatinand paclitaxel with response rate of 18% for each. Combination chemotherapy with cisplatin and ifosfamide was associated with improved response rates along with increased toxicity without any significant increment in OS. In contrast, a study by Homesley et al. demonstrated a survival advantage of combination chemotherapy with paclitaxel and ifosfamide.PC-based chemotherapy has been used in advanced setting in various studies with response rates ranging from 50% to 60%., The present literature strongly supports the use of chemotherapy in advanced and metastatic UCS. However, there are limited studies that report significant advantage for chemotherapy in the adjuvant setting. One of the studies by Sutton et al. observed a clinical benefit of adding adjuvant cisplatin and ifosfamide-based chemotherapy in Stage I and II UCS and observed a 5-year OS of 62%, which is similar to what is observed in the present study (56.8%) [Table 2]. However, in the present study, more than half of the patients had Stage III disease and only 1 patient died in Stage I and II subgroup (1/16). A Japanese multi-institutional phase II study of 51 completely resected UCS patients, evaluated PC-based adjuvant chemotherapy and they observed 4-year progression-free survival (PFS) and OS of 67.9% and 76%, respectively. In the present study, 5-year DFS and OS of 35.9% and 50.3% has been observed for the patients receiving PC, corroborating with the results of the Japanese study [Figure 1] and [Figure 2]. Three-drug combination including liposomal doxorubicin has been tried in various studies with response rates ranging from 50% to 60%., However, the EORTC group in their phase II study have observed significantly increased toxicity with three-drug combination (ifosfamide, cisplatin, and liposomal doxorubicin) and have recommended to use alternative regimens. TIP based three-drug regimen has been used by Kosmas et al. in their study of advanced carcinosarcomas of uterus and adnexa, and they concluded that it has a good response rate of 67.5% with manageable toxicity profile. To our knowledge, TIP-based chemotherapy has shown the best response rates in the advanced stage however, it has never been used in the adjuvant setting in patients with UCS. In this study, we retrospectively compared completely resected Stage I to III UCS receiving either PC or TIP regimen, which to best of our knowledge has not been reported in any study evaluating UCS. In the present study, it is observed that intensification of therapy with three-drug regimen does not significantly affect the DFS or the OS, however, it does increase the grade 3/4 toxicities significantly (P = 0.012). A subset analysis does show a numerical DFS advantage for triple-drug (TIP) regimen in patients with advanced stage UCS (Stage III) [Figure 3], but further studies are required to confirm this observation.
| » Conclusion|| |
UCS is a rare malignancy with significantly poor survival, especially in the advanced stage. Intensification of adjuvant therapy with three-drug regimen in light of increased distant recurrences does not affect the survival and increases toxicity. Because of the rarity of this tumor, there is scarcity of prospective randomized data. However, randomized studies are required to observe differences between adjuvant chemotherapy with a doublet or a triplet chemotherapy regimen. As of now, we suggest that PC is a well tolerated and efficacious regimen in the adjuvant setting in patients with UCS.
Gayatri Vishwakarma for helping with statistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]