Multimodality Treatment of Desmoplastic Small Round Cell Tumor: Chemotherapy and Complete Cytoreductive Surgery Improve Patient Survival

Abstract

Purpose: Desmoplastic small round cell tumor (DSRCT), which harbors EWSR1-WT1 t(11;22)(p13:q12) chromosomal translocation, is an aggressive malignancy that typically presents as intra-abdominal sarcomatosis in young males. Given its rarity, optimal treatment has not been defined.Experimental Design: We conducted a retrospective study of 187 patients with DSRCT treated at MD Anderson Cancer Center over 2 decades. Univariate and multivariate regression analyses were performed. We determined whether chemotherapy, complete cytoreductive surgery (CCS), hyperthermic intraperitoneal cisplatin (HIPEC), and/or whole abdominal radiation (WART) improve overall survival (OS) in patients with DSRCT. Critically, because our institutional practice limits HIPEC and WART to patients with less extensive, potentially resectable disease that had benefited from neoadjuvant chemotherapy, a time-variant analysis was performed to evaluate those adjunct treatment modalities.Results: The pre-2003 5-year OS rate of 5% has substantially improved to 25% with the advent of newer chemotherapies and better surgical and radiotherapy techniques (HR, 0.47; 95% CI, 0.29-0.75). Chemotherapy response (log rank P = 0.004) and CCS (log rank P < 0.0001) were associated with improved survival. Although WART and HIPEC lacked statistical significance, our study was not powered to detect their potential impact upon OS.Conclusions: Improved 3- and 5-year OS were observed following multidisciplinary treatment that includes Ewing sarcoma (ES)-based chemotherapy and complete tumor cytoreductive surgery, but few if any patients are cured. Prospective randomized studies will be required to prove whether HIPEC or WART are important. In the meantime, chemotherapy and CCS remain the cornerstone of treatment and provide a solid foundation to evaluate new biologically targeted therapies. Clin Cancer Res; 24(19); 4865-73. ©2018 AACR.

Figure 1. Chemotherapy impact upon OS in DSRCT patients

(A) Overall survival for all patients according to treatment era (before 2003, after 2003, and both). (B) Overall survival in patients who achieved clinical benefit or had progressive disease to their initial chemotherapy regimen. (C) Stratification of overall survival by RECIST response to the first chemotherapy regimen each patient received, and (D) Survival effect resulting from standard 3-week chemotherapy treatment vs. dose-dense treatment, when the traditional neoadjuvant VAC/IE regimen was provided. PD = partial disease; SD = stable disease; PR = partial response; CR = complete response.

Figure 2. Chemotherapy patterns in DSRCT patients

(A) The initial chemotherapy regimens used to treat DSRCT patients. (B) Chemotherapy administration in relation to surgery: included neoadjuvant (87.3%), adjuvant (6.6%), or salvage (6.1%) treatments. (C) Dosing interval in DSRCT patients. 72.7% of the patients received standard therapy every 3 weeks and 27.3% received dense therapy every two weeks. (D) Second-line chemotherapy treatment regimens used in DSRCT patients. (E) Organ sites involved among the 114 patients who presented with metastases at the time of diagnosis. P6 = 7 cycles of IE/VDC (Ifosfamide, Etoposide, Vincristine, Adriamycin, and Cytoxan); BEP = bleomycin, etoposide, and cisplatin; VAI = Vincristine, actinomycin & ifosfamide; VAC/IE = Vincristine, Adriamycin, Cyclophosphamide, Ifosfamide and Etoposide; Cy = cyclophosphamide; Topo = topotecan; HD ifos = high dose ifosfamide; Tem = temozolomide; Irino = irinotecan; Vcr = vincristine; N = number of metastatic sites.

Figure 3. Impact upon OS by surgery, HIPEC, radiation, and WART

(A) Overall survival in patients who underwent complete cytoreductive surgery (CCS). (B) Overall survival benefit of CCS in patients who achieved clinical benefit from their first neoadjuvant chemotherapy regimen. (C) Overall survival in patients that underwent CCS +/− HIPEC (D) Overall survival in patients who received radiation at some time during their clinical care. (E) The overall survival effect of whole abdominal radiotherapy (WART), which was almost always provided 6–8 weeks following CCS.

Figure 4. Revised DSRCT Treatment algorithm adapted by MDACC

The diagnosis of DSRCT is confirmed using immunohistochemistry and/or cytology, and the staging workup is completed. All patients receive neoadjuvant chemotherapy, usually six cycles of the current standard-of-care for ES. Clinical response is assessed with PET/CT every two cycles and the small minority that fail to respond to chemotherapy are transitioned to second-line regimens. Patients that harbor extra-peritoneal disease (EPD) after 6 neoadjuvant chemotherapy cycles are considered poor surgical candidates and continue with chemotherapy. Those lacking EPD proceed to complete cytoreductive surgery (CCS), with the aim of removing all measurable disease. In light the current study findings, we recommend HIPEC only in conjunction with an ongoing clinical study. Whole abdominopelvic intensity-modulated radiotherapy (WART), if provided, is also given as part of a prospective clinical trial designed to assess disease-free survival and intra-abdominal recurrence-free survival. Adjuvant chemotherapy with temozolomide/irinotecan or other agents are provided and oligo-metastatic sites are treated, when needed, using radiofrequency ablation or stereotactic radiation. VAC/IE = Vincristine, Adriamycin, Cyclophosphamide, Ifosfamide and Etoposide; VAI = Vincristine, actinomycin & ifosfamide; VIDE = Vincristine, Adriamycin, Ifosfamide and Etoposide; P6 = 7 cycles of IE/VDC (Ifosfamide, Etoposide, Vincristine, Adriamycin, and Cytoxan); LN = lymph nodes; HIPEC = hyperthermic peritoneal perfusion of chemotherapy; IGF-1R = insulin-like growth factor receptor 1; mTOR = mammalian target of Rapamycin.