Doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, or doxorubicin alone as a first‐line treatment for advanced leiomyosarcoma: A propensity score matching analysis from the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group

Abstract

BACKGROUND:The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first-line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) sites. METHODS: The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval-censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent. RESULTS: Three hundred three patients from 18 EORTC-STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score-matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval [CI], 5.2-9.7 months), 8.2 months (95% CI, 5.2-10.1 months), and 4.8 months (95% CI, 2.3-6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio [HR], 0.72; 95% CI, 0.52-0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9-47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7-33.4 months; HR, 0.65; 95% CI, 0.40-1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0-36.3 months; HR, 0.66; 95% CI, 0.43-0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS. CONCLUSIONS: This is the largest retrospective study of first-line treatment for advanced leiomyosarcoma. In the propensity score-matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials. Cancer 2020;126:2637-2647.

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

“…Top1 inhibitors’ camptothecin derivatives used are irinotecan (colorectal [ 169 ], pancreatic (in combination) [ 170 ], and small cell lung cancers (in clinical trials and in combination) [ 171 , 172 ]), and topotecan (ovarian [ 173 , 174 ], cervical [ 175 ], and small cell lung cancers [ 176 ]). Top2 anticancer drugs commonly used are from the anthracycline group such as doxorubicin (acute leukemia [ 177 ], lymphomas [ 178 ], sarcomas [ 179 , 180 ], and solid tumors [ 181 ]), epirubicin (breast cancer [ 182 ]), valrubicin (bladder cancer [ 183 ]), and idarubicin (acute myeloid leukemia [ 184 ]), from the anthracenedione classes: mitoxantron and pixantron (lymphoma, [ 185 , 186 , 187 ]), and from the epipodopodophyllotoxins group such as etoposide (testicular [ 188 ] and small cell lung cancers [ 189 ]) and teniposide (brain [ 190 ] and small cell lung [ 191 ] cancers, acute lymphocytic leukemia [ 192 ]). Only a few numbers of Top1 inhibitors are in clinical trials including the promising indenoisoquinoline derivatives LMP400 (Indotecan), LMP776 (Indimitecan) (phase I), and LMP744 examined in a phase I study on lymphoma in dogs [ 193 ].…”

Neoadjuvant Treatment Options in Soft Tissue Sarcomas

“…More intensive CHT increases the risk of serious adverse events without providing significant benefit. Given the limited role of ifosfamide in leiomyosarcoma, doxorubicin+dacarbazine may be an alternative, less toxic treatment option in this group of patients [58]. Other treatment regimens cannot be recommended outside clinical trials.…”

Impact of Chemotherapy in the Adjuvant Setting of Early Stage Uterine Leiomyosarcoma: A Systematic Review and Updated Meta-Analysis

“…Uterine leiomyosarcoma (uLMS) is a rare tumor accounting for approximately 2% of all uterine malignancies and 65% of all uterine sarcomas, with an estimated incidence of 0.60 per 100.000 women/year [ 1 , 2 , 3 , 4 , 5 ]. Currently, uLMSs are staged in accordance with the Federation of Gynecology and Obstetrics (FIGO) 2009 staging system, which does not include tumor grading [ 6 , 7 ] ( Table 1 ).…”

“…Total hysterectomy represents the therapeutic mainstay for localized disease [ 2 , 3 ] and, although there are no available data indicating that oophorectomy improves survival outcomes, bilateral salpingo–oophorectomy is considered a reasonable option in perimenopausal and postmenopausal women [ 8 , 9 ]. However, despite radical surgery, the risk of recurrence remains high, ranging between 50% and 70% [ 10 ] and to date, age, tumor stage and tumor size are recognized as prognostic factors [ 9 , 11 , 12 ] in resected uLMS.…”

“…However, despite radical surgery, the risk of recurrence remains high, ranging between 50% and 70% [ 10 ] and to date, age, tumor stage and tumor size are recognized as prognostic factors [ 9 , 11 , 12 ] in resected uLMS. Additional prognostic factors are represented by tumor morcellation [ 13 , 14 , 15 ], extrauterine spread, mitotic index and tumor grade, although the prognostic value of tumor grade in uLMS remains controversial and it is not commonly applied to the staging procedures [ 3 ].…”