Published prospective trials addressing the efficacy of chemotherapeutic and investigational agents in advanced, persistent, or recurrent ECS
| Author, year | Identification number | Design | Setting | N | Treatment arm(s) | Results | Conclusion |
| First-line chemotherapy | |||||||
| Sutton et al, 198976 | – | Open-label, multicenter, single-arm, phase II trial | Metastatic or recurrent uterine MMT, no prior CHT | 28 | Ifosfamide 1.5 g/mq d1–5 q28, until PD or unacceptable toxicity | ORR: 32% DCR: 68% | Ifosfamide is an unusually active drug in patients with advanced or recurrent mixed Müllerian tumors of the uterus. Studies with combination regimens incorporating ifosfamide are warranted |
| Thigpenet al, 199177 | – | Open-label, multicenter, single-arm, phase II trial | Metastatic or recurrent uterine sarcomas, no prior CHT | 96 (23 ECS) | Cisplatin 50 mg/mq q21, until PD or unacceptable toxicity | ORR: 19% DCR: 70% | Cisplatin has definite activity for patients with mixed mesodermal sarcomas who have not received prior CHT |
| Sutton et al, 200078 | GOG-108 | Open-label, multicenter, single-arm, phase III RCT | Advanced, persistent, or recurrent ECS, no prior CHT | 194 |
| PFS: 6 vs 4 months (RR=0.73; 95% upper confidence limit, 0.94; p=0.02). OS: 9.4 vs 7.6 months (RR=0.80, 95% upper confidence limit, 1.03; p=0.07). ORR: 54% vs 36% | The addition of cisplatin to ifosfamide appears to offer a small improvement in PFS, but the added toxicity may not justify use of this combination |
| Van Rijswijk et al, 200379 | EORTC 55923 | Open-label, multicenter, single-arm, phase II trial | Advanced or metastatic ECS, no prior RT or CHT | 41 (22 ECS) | Cisplatin 50 mg/mq IV+ifosfamide 5 g/mq IV+mesna 5 g/mq IV+doxorubicin 45 mg/mq IV | ORR: 56% DCR: 72% OS: 26 months (for all 41 patients) | The results of this study are in line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. Considering the observed toxicities, alternative platinum-based regimens with more favorable toxicity profiles should be explored |
| Ramondetta et al, 200380 | – | Open-label, multicenter, single-arm, phase II trial | Uterine MMMT, no prior CHT | 16 | Cisplatin 75 mg/mq+ifosfamide 1.2 mg/mq+mesna 240 mg/mq q28 | ORR: 33.3% DCR: 50% | The combination of cisplatin, ifosfamide, and mesna in patients with MMMT had moderate activity, but the high toxicity and short response duration suggest that this regiment is disappointing |
| Sutton et al, 200581 | GOG-117 | Open-label, multicenter, single-arm, phase II trial | Adjuvant treatment after surgery for stage I–II ECS | 65 | Ifosfamide 1.5 g/mq IV d1–5 q21+cisplatin 20 mg/mq IV q21, for three cycles | 2-year PFS: 69% 2-year OS: 82% 5-year OS: 62% 7-year PFS: 54% 7-year OS: 52% | Adjuvant ifosfamide and cisplatin after primary surgery for stage I–II ECS of the uterus is tolerable |
| Homesley et al, 200782 | NCT00003128 GOG-161 | Multicentric, phase III RCT | Advanced, persistent, or recurrent ECS, no prior CHT | 179 |
| PFS: 5.8 vs 3.6 months (HR=0.71, 95% CI 0.51 to 0.97; p=0.03) OS: 13.5 vs 8.4 months (HR=0.69, 95% CI 0.49 to 0.97; p=0.03). ORR 45% vs 29% DCR: 67% vs 46% | Survival rates were significantly improved with the combination ifosfamide/paclitaxel, and toxicities were as expected and manageable |
| Powell et al, 201083 | NCT00112489 GOG-232B | Open-label, multicenter, single-arm, phase II trial | Advanced, persistent, or recurrent, no prior CHT | 46 | Paclitaxel 175 mg/mq IV+CBDCA AUC 6 q21, until PD or unacceptable toxicity | ORR: 54% (CR: 13%; PR 41%) DCR: 67% PFS: 7.6 months OS: 14.7 months | Paclitaxel plus carboplatin demonstrates antitumor activity against ECS with acceptable toxicity |
| Aghajanian et al, 201284 | NCT00687687 GOG-232C | Open-label, multicenter, single-arm, phase II trial | Advanced, persistent, or recurrent ECS, no prior CHT | 17 | PTX 175 mg/q IV+CBDCA (AUC 6) IV d1w21+iniparib 4 mg/kg IV twice weekly beginning on day 1, until PD or unacceptable toxicity | ORR: 23.5% DCR: 58.9% PFS: 3.8 months OS: 11.3 months | Iniparib plus PTX and CBDCA did not show significant activity to warrant further study |
| Powell et al, 202275 | NCT00954174 GOG-261 | Multicentric, phase III, non-inferiority RCT | Newly diagnosed stage I–IV or recurrent chemotherapy-naïve ECS | 449 |
| PFS: 16 vs 12 months (HR=0.73, 95% CI 0.58 to 0.93; p<0.01) OS: 37 vs 29 months (HR=0.87, 90% CI 0.70 to 1.075; p<0.01) | PC was not inferior to the active regimen PI and should be standard treatment for ECS |
| Further lines chemotherapy | |||||||
| Curtin et al, 200185 | – | Open-label, multicenter, single-arm, phase II trial | Persistent or recurrent ECS | 44 | Paclitaxel 135 or 170 mg/mq | ORR: 18.2% | Paclitaxel had moderate activity in ECS patients |
| Miller et al, 200586 | NCT00003156 GOG-130D | Open-label, multicenter, single-arm, phase II trial | Advanced or recurrent ECS, 0–1 prior CHT lines | 48 | Topotecan 1.5 mg/mq IV QD d1–5 q21, until PD or unacceptable toxicity | ORR: 10% (all CR) SD: 27% | Topotecan does not appear to have major activity in patients with advanced or recurrent ECS |
| Yi-Shin Kuo et al, 200687 | NCT00006005 | Open-label, multicenter, single-arm, phase II trial | Recurrent or persistent gynecologic sarcomas or carcinosarcomas | 17 | Thalidomide 200 mg PO QD (escalated by 100–200 mg every 7 to 14 days), until PD or unacceptable toxicity | PFS: 1.84 months OS: 6.64 months | Thalidomide has no activity in patients with advanced or recurrent gynecologic sarcomas and was not well-tolerated |
| Miller et al, 201088 | NCT00114218 GOG-130E | Open label, multicenter, single-arm, phase II trial | Recurrent ECS, one prior CHT | 24 | Gemcitabine 600 mg/mq+docetaxel 35 mg/mq IV d1,8,15 q28, until PD or unacceptable toxicity | ORR: 8.3% (all PR) PFS: 1.8 months; OS: 4.9 months | Docetaxel/gemcitabine is not active in patients with recurrent ECS as second-line CHT |
| McMeekin et al, 201289 | NCT00025506 GOG-230B | Open-label, multicenter, single-arm, phase II trial | Recurrent or persistent ECS, up to two prior CHT lines | 45 | Starting dose of 200 mg thalidomide PO QD that was increased by 200 mg every 2 weeks to a target dose of 1000 mg QD, until PD or unacceptable toxicity | PFS6: 18% PFS: 1.9 months; OS: 5.9 months | Treatment with thalidomide met the protocol-specified goal of prolonging PFS6. However, based on results with newer agents, the activity was insufficient to support further investigation |
| Harter et al, 201690 | NCT0081594 AGO-GYN 7 | Open-label, multicentric, single-arm, phase II trial | Newly diagnosed or recurrent gynecologic sarcoma or carcinosarcoma, 0–1 prior CHT lines | 40 (20 ECS) | Pegylated liposomal doxorubicin (40 mg/mq) and carboplatin (AUC 6) q28 | ORR: 33.3% 1 year PFS: 32.5% 1 year OS: 77.0% | The combination of carboplatin and pegylated liposomal doxorubicin is feasible and has activity. |
| Novel therapeutic agents | |||||||
| George et al, 200991 | NCT00474994 | Open-label, multicenter, single-arm, phase II trial | Advanced non-GIST soft tissue sarcomas | 48 | Sunitinib 37.5 mg PO QD, until PD or unacceptable toxicity | Metabolic PR: 48% Metabolic SD: 52% | Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma |
| Nimeiri et al, 201092 | NCT00238121 NCI-2009–00068 | Open-label, multicenter, single-arm, phase II trial | Advanced or recurrent ECS, 0–1 prior CHT lines | 16 | Sorafenib 400 mg PO twice daily, until PD or unacceptable toxicity | ORR: 0% SD: 25%. PFS6: 13%; OS: 5.0 months | Sorafenib had minimal activity in ECS patients |
| Huh et al, 201093 | NCT00075400 GOG-230C | Open-label, multicentric, single-arm, phase II trial | Recurrent or persistent ECS, up to two prior CHT lines | 23 | Imatinib mesylate 600 mg PO QD, until PD or unacceptable toxicity | PFS6: 4.3% | Imatinib mesylate was generally well tolerated but had minimal activity as a single agent in unscreened patients |
| Mackay et al, 201294 | – | Multi-institutional non-randomized phase II trial | Recurrent or metastatic uterine carcinosarcomas and leiomyosarcoma, ≤2 prior lines of CHT | 22 | Aflibercept 4 mg/kg IV d 1q14, until PD or unacceptable toxicity | Two (9%) patients had SD, one lasting >24 weeks Median TTP was 1.6 months (95% CI 1.1 to 1.7) No PR | Single=agent aflibercept has minimal activity in women with carcinosarcoma |
| Alvarez et al, 201395 | NCT01010126 NCI-2012–02086 | Open-label, multicenter, single-arm, two-stage, phase II trial | Recurrent or persistent EC, up to two prior CHT lines | 49 (5 ECS) | Bevacizumab 10 mg/kg IV every other week+temsirolimus 25 mg IV weekly | ORR: 24.5% PFS6: 46.9% PFS: 5.6 months OS: 16.9 months | Combination of temsirolimus and bevacizumab is deemed active in recurrent or persistent EC. However, this treatment was associated with significant toxicity |
| Castonguay et al, 201496 | NCT00478426 NCI-2009–00210 | Open-label, multicenter, single-arm, two-stage, phase II trial | Recurrent/metastatic EC or ECS, no more than one prior CHT line | 33 | Sunitinib 50 mg PO QD (4 weeks on–2 weeks off schedule) | No responses or SD seen among the 3 patients with ECS. | Sunitinib showed promising activity in women with recurrent EC, but no activity was seen against ECS |
| Campos et al, 201497 | NCT01247571 GOG-230D | Open-label, multicentric, single-arm, phase II trial | Recurrent or persistent ECS, up to two prior CHT lines | 19 | Pazopanib 800 mg PO QD, until PD or unacceptable toxicity | ORR: 0% PFS6: 15.8% PFS: 2.0 months OS: 8.7 months | Pazopanib demonstrated minimal activity as a second- or third-line treatment for advanced ECS |
| McCourt et al, 201798 | NCT01168232 GOG-130F | Open-label, multicentric, single-arm, phase II trial | Recurrent or persistent ECS, up to two prior CHT lines | 34 | Ixabepilone 40 mg/mq IV d1q21, until PD or unacceptable toxicity | ORR: 11.8% (all PR) PFS: 1.7 months OS: 7.7 months PFS6: 20.6% | Single-agent ixabepilone showed modest but insufficient clinical activity within the investigated study cohort |
| Dhani et al, 202099 | NCT01935934 NCI-2013–00890 | Open-label, multicenter, single-arm, phase II trial | Recurrent or metastatic EC, 1–2 prior CHT lines | 102 (19 ECS) | Cabozantinib s-malate 60 mg PO QD, until PD or unacceptable toxicity | ORR: 6% 12 weeks PFS: 47% | Cabozantinib has activity in serous and endometrioid histology EC. |
| Rubinstein et al, 2020100 | NCT02549989 | Open-label, multicentric, single-arm, phase II trial | Recurrent or persistent EC | 28 | LY3023414 200 mg PO twice daily | ORR: 16% CBR: was 28% PFS: 2.5 months OS: 9.2 months | In patients with heavily pre-treated advanced EC prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile |
.AUC, area under curve; CBDCA, carboplatin; CBR, clinical benefit rate; CHT, chemotherapy; CI, confidence interval; CR, complete response; DCR, disease control rate; EC, endometrial cancer; ECS, endometrial carcinosarcoma; GIST, gastrointestinal stromal tumor; HR, hazard ratio; IV, intravenous; MMMT, malignant mixed Müllerian tumor; ORR, objective response rate; OS, overall survival; PC, carboplatin/paclitaxel; PD, progressive disease; PFS, progression-free survival; PFS6, progression-free survival at 6 months; PI, carboplatin/ifosfamide; PI3K, phosphoinositide 3-kinase; PO, per os; PR, partial response; PTX, paclitaxel; QD, quoque die; RCT, randomized clinical trial; RR, response rate; SD, stable disease; TTP, time to progression.