Chemotherapy

A randomized study (NCT00061984) assessed whether dose intensification of doxorubicin and ifosfamide improved the survival of patients with advanced soft tissue sarcoma compared with doxorubicin alone.[11][Level of evidence A1] In this study, patients were randomly assigned to receive doxorubicin (n = 228) or doxorubicin and ifosfamide (n = 227). The median follow-up was 56 months (interquartile range [IQR], 31–77 months) in the doxorubicin-only group and 59 months (IQR, 36–72 months) in the combination group.

A randomized study (NCT00061984) assessed whether dose intensification of doxorubicin and ifosfamide improved the survival of patients with advanced soft tissue sarcoma compared with doxorubicin alone.[11][Level of evidence A1] In this study, patients were randomly assigned to receive doxorubicin (n = 228) or doxorubicin and ifosfamide (n = 227). The median follow-up was 56 months (interquartile range [IQR], 31–77 months) in the doxorubicin-only group and 59 months (IQR, 36–72 months) in the combination group.

There was no significant difference in OS between groups: the median OS was 12.8 months (95.5% confidence interval [CI], 10.5–14.3) in the doxorubicin-alone group versus 14.3 months (range, 12.5–16.5) in the doxorubicin and ifosfamide group (hazard ratio [HR], 0.83; 95.5% CI, 0.67–1.03; stratified log-rank test P = .076).

A randomized study (NCT00061984) assessed whether dose intensification of doxorubicin and ifosfamide improved the survival of patients with advanced soft tissue sarcoma compared with doxorubicin alone.[11][Level of evidence A1] In this study, patients were randomly assigned to receive doxorubicin (n = 228) or doxorubicin and ifosfamide (n = 227). The median follow-up was 56 months (interquartile range [IQR], 31–77 months) in the doxorubicin-only group and 59 months (IQR, 36–72 months) in the combination group.

Median PFS was significantly higher for the doxorubicin and ifosfamide group (7.4 months; 95% CI, 6.6–8.3) than for the doxorubicin-alone group (4.6 months; range, 2.9–5.6 ) (HR, 0.74; 95% CI, 0.60–0.90; stratified log-rank test P = .003).

A randomized study (NCT00061984) assessed whether dose intensification of doxorubicin and ifosfamide improved the survival of patients with advanced soft tissue sarcoma compared with doxorubicin alone.[11][Level of evidence A1] In this study, patients were randomly assigned to receive doxorubicin (n = 228) or doxorubicin and ifosfamide (n = 227). The median follow-up was 56 months (interquartile range [IQR], 31–77 months) in the doxorubicin-only group and 59 months (IQR, 36–72 months) in the combination group.

More patients in the doxorubicin and ifosfamide group had an overall response (60 of 227 patients [26%]) than did patients in the doxorubicin-alone group (31 of 228 patients [14%]) (P < .0006).

A randomized study (NCT00061984) assessed whether dose intensification of doxorubicin and ifosfamide improved the survival of patients with advanced soft tissue sarcoma compared with doxorubicin alone.[11][Level of evidence A1] In this study, patients were randomly assigned to receive doxorubicin (n = 228) or doxorubicin and ifosfamide (n = 227). The median follow-up was 56 months (interquartile range [IQR], 31–77 months) in the doxorubicin-only group and 59 months (IQR, 36–72 months) in the combination group.

The most common grade 3 and 4 toxic effects were all more common with doxorubicin and ifosfamide (n = 224) than with doxorubicin alone (n = 223), and included leukopenia (43% vs. 18%), neutropenia (42% vs. 37%), febrile neutropenia (46% vs. 13%), anemia (35% vs. 5%), and thrombocytopenia (33% vs. <1%).

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13]

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13]

The median OS was significantly higher in the doxorubicin-plus-trabectedin group (33 months), compared with the doxorubicin-alone group (24 months) (HR, 0.65; 95% CI, 0.44–0.95). The 24-month OS rate was 68% (95% CI, 57%–78%) in the combination group and 49% (95% CI, 38%–60%) in the doxorubicin-alone group.[13][Level of evidence A1]

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13]

The median PFS was significantly higher in the doxorubicin-plus-trabectedin group (12 months), compared with the doxorubicin-alone group (6 months) (HR, 0.37; 95% CI, 0.26–0.53). The 24-month PFS rate was 30% (95% CI, 21%–42%) in the combination group and 3% (95% CI, 1%–9%) in the doxorubicin-alone group.[13][Level of evidence A1]

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13]

There are some important caveats to consider:

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13] › There are some important caveats to consider:

Only patients in the doxorubicin-plus-trabectedin group without progression after six cycles were eligible to receive maintenance trabectedin. The median number of maintenance cycles of trabectedin received was 10.5. However, a total of 17 patients (23%) in the combination group did not receive maintenance therapy.

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13] › There are some important caveats to consider:

In the doxorubicin-alone group, 22% of patients had disease progression during the first six cycles. In the same group, 37% of patients received trabectedin as their second-line treatment, and 23% of patients received trabectedin as third-line therapy or beyond.

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13] › There are some important caveats to consider:

Surgery was performed in 20% of patients in the combination group and 8% of patients in the doxorubicin-alone group. This treatment could bias PFS and OS results.

A randomized, open-label, phase III trial (LMS-04 [NCT02997358]) evaluated the combination of doxorubicin and trabectedin compared with doxorubicin alone for treatment-naïve patients with metastatic and unresectable leiomyosarcoma. Patients were randomly assigned to receive either doxorubicin (at a 20% dose reduction, or 60 mg/m2) with trabectedin (at a 27% dose reduction, or 1.1 mg/m2) for up to six cycles, followed by maintenance trabectedin (at the same dose) or doxorubicin alone (at a standard dose of 75 mg/m2) for up to six cycles. Surgery was allowed in both arms for nonprogressive residual lesions after the completion of six cycles, if judged to be beneficial. A total of 150 patients were enrolled (67 with uterine leiomyosarcoma, 83 with soft tissue leiomyosarcoma); 74 patients received doxorubicin and trabectedin, and 76 patients received doxorubicin alone. The median follow-up was 55 months (IQR, 49–63 months).[13]

Grade 3 and 4 adverse events, including neutropenia, anemia, thrombocytopenia, and febrile neutropenia, were more common in the doxorubicin-plus-trabectedin group (97%) than in the doxorubicin-alone group (56%) (P < .001). In addition, grade 3 and 4 liver toxicity was more common in the combination group (46%), compared with the doxorubicin-alone group (3%).

A randomized phase II study of 122 patients with soft tissue sarcoma reported the following results:[5][Level of evidence B3]

A randomized phase II study of 122 patients with soft tissue sarcoma reported the following results:[5][Level of evidence B3]

The objective response rate was 16% in the gemcitabine and docetaxel group versus 8% in the gemcitabine-alone group.

A randomized phase II study of 122 patients with soft tissue sarcoma reported the following results:[5][Level of evidence B3]

Median PFS was 6.2 months in the gemcitabine and docetaxel group versus 3.0 months in the gemcitabine-alone group.

A randomized phase II study of 122 patients with soft tissue sarcoma reported the following results:[5][Level of evidence B3]

Median OS was 17.9 months in the gemcitabine and docetaxel group versus 11.5 months in the gemcitabine-alone group.

In a retrospective series of 133 patients, gemcitabine and docetaxel showed activity in patients with leiomyosarcoma as well as other histologies with an overall response rate of 18.4%.[15]

The GeDDis trial (ISRCTN07742377) randomly assigned 257 previously untreated patients to receive either gemcitabine and docetaxel or doxorubicin alone.[14]

The GeDDis trial (ISRCTN07742377) randomly assigned 257 previously untreated patients to receive either gemcitabine and docetaxel or doxorubicin alone.[14]

The PFS rate at 24 weeks (46% in both groups) and the primary end point (median PFS, 23.3 weeks vs. 23.7 weeks) were identical in both groups.

The GeDDis trial (ISRCTN07742377) randomly assigned 257 previously untreated patients to receive either gemcitabine and docetaxel or doxorubicin alone.[14]

This study may have been limited by the relatively low dose of gemcitabine used (675 mg/m2 on days 1 and 8 instead of 900 mg/m2 as in previous trials).