Soft tissue sarcomas
Pat Price, Karol Sikora in Treatment of Cancer, 2014
Although the foregoing generalizations apply to most STSs, different histologic subtypes of sarcomas display their own patterns of chemosensitivity.450 Myxoid/round cell liposarcomas appear sensitive to doxorubicin and to trabectedin.451 Synovial sarcoma has a strong dose response to ifosfamide.440 Non-uterine leiomyosarcomas appear to have lower response rates to doxorubicin and ifosfamide, but may respond to Trabectedin.452 Angiosarcomas are almost unique in being sensitive to paclitaxel.453 Rhabdomyosarcoma, desmoplastic small round cell tumors and peripheral neuroectodermal tumours respond to combinations that include ifosfamide, etoposide, vincristine, doxorubicin, dactinomycin cyclophosphamide and topotecan/irinotecan.454,455 Sunitinib has proven useful against solitary fibrous tumor/haemangiopericytoma, alveolar soft part sarcoma, and clear cell sarcoma.456 Sirolimus has activity against tumors with perivascular epithelioid cell differentiation.457 Imatinib can help in metastatic dermatofibroma protuberans.458 Cediranib is effective against alveolar soft part sarcoma.459 Crizotinib is active against ALK translocated inflammatory myofibroblastic tumour.460 Bevacizumab with temozolamide has been employed for solitary fibrous tumour.461
Soft Tissue Sarcomas
Pat Price, Karol Sikora in Treatment of Cancer, 2020
Although the foregoing generalizations apply to most STSs, different histologic subtypes of sarcomas display their own patterns of chemosensitivity. Myxoid/round cell liposarcomas appear sensitive to doxorubicin and to trabectedin. Synovial sarcoma has a strong dose response to ifosfamide. Non-uterine leiomyosarcomas appear to have lower response rates to doxorubicin and ifosfamide, but may respond to trabectedin. Angiosarcomas are almost unique in being sensitive to paclitaxel. Rhabdomyosarcoma, desmoplastic small round cell tumors, and peripheral neuroectodermal tumors respond to combinations that include ifosfamide, etoposide, vincristine, doxorubicin, dactinomycin cyclophosphamide, and topotecan/irinotecan. Sunitinib has proven useful against solitary fibrous tumor/hemangiopericytoma, alveolar soft part sarcoma, and clear cell sarcoma. Everolimus has activity against tumors with perivascular epithelioid cell differentiation. Imatinib can help in metastatic dermatofibroma protuberans. Cediranib is effective against alveolar soft part sarcoma. Crizotinib is active against ALK translocated inflammatory myofibroblastic tumor. Bevacizumab with temozolomide has been employed for solitary fibrous tumor.
BRCA Mutation and PARP Inhibitors
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Cediranib, the small molecule inhibitor of VEGF 1/2/3 has been shown to produce responses in patients with recurrent ovarian cancer [78]. In preclinical models, PARP inhibition has been shown to inhibit angiogenesis in vivo; PARP-1 knockout mice have decreased in vivo angiogenesis when compared to wild-type animals [120]. Also, there is limited overlapping toxicity between PARP inhibitors and VEGF inhibitors, prompting investigation of this combination in clinical trials. The phase 1 study combining olaparib and cediranib in recurrent ovarian cancer and triple-negative breast cancer demonstrated manageable toxicities for the combination, with promising activity in ovarian cancer but not in breast cancer [73]. A follow-up phase 2 trial enrolled 90 eligible patients with recurrent ovarian cancer who were randomized to receive either olaparib alone at 400 mg twice daily or olaparib 200 mg twice daily with cediranib 30 mg daily. The combination demonstrated a significant improvement in median PFS (17.7 months) when compared to olaparib alone (9.0 months). However, the combination did cause more grade 3 toxicity than the single agent (70% vs. 11%), primarily hypertension, fatigue, and diarrhea [72].
State of the art and up-and-coming angiogenesis inhibitors for ovarian cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Nilanchali Singh, Daniyah Badrun, Prafull Ghatage
Though various trials with cediranib in different cancers have produced disappointing results, its activity in ovarian cancer is promising. ICON6 trial was a randomized phase III double-blind, placebo-controlled trial [34]. It included 156 women with platinum-sensitive relapsed ovarian cancer. Cediranib plus standard chemotherapy at the time of first relapse in patients with platinum-sensitive disease was tested. There were three arms, first one in which patients received 3-weekly platinum-based chemotherapy and daily placebo for six cycles followed by daily placebo for 18 months from randomization; in second one they received the same chemotherapy with cediranib 20 mg daily during chemotherapy followed by daily placebo for 18 months; and third arm received chemotherapy with cediranib 20 mg daily during chemotherapy and after chemotherapy for 18 months. The patients enrolled in cediranib maintenance arm experienced longer PFS (HR = 0.57, p = 0.024) and longer OS (HR = 0.70, p = 0.042) as compared to those treated with chemotherapy alone. Addition of cediranib, therefore, leads to improvement in progression-free survival, although it is associated with added toxic effects like diarrhea, neutropenia, hypertension, and voice changes.
Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?
Published in Expert Opinion on Drug Discovery, 2021
Indole-based hybrids viz. Dacinostat (LAQ824) has been approved for treating prostate and breast cancer while Panobinostat (LBH-589) is marketed drug for treatment of multiple myeloma. Quisinostat (JNJ-26,481,585), an indole-hydroxamic acid hybrid, is orally bioavailable, second-generation inhibitor of HDAC with potential antineoplastic activity. Cediranib is the VEGF2 tyrosine kinase inhibitor that inhibits endothelial cell function and growth of human renal tumor xenografts. Anlotinib (AL3818) is at clinical trial stage as a kinase inhibitor of receptor tyrosine targeting VEGFRs, specially for VEGFR2 and VEGFR3 with potential antineoplastic and antiangiogenic activities, see Figure 6 and Table 6.
Pharmacotherapeutic treatment options for recurrent epithelial ovarian cancer
Published in Expert Opinion on Pharmacotherapy, 2023
Nilanchali Singh, Aarthi S Jayraj, Avir Sarkar, Trishala Mohan, Amlin Shukla, Prafull Ghatage
ICON 6 was an international, three-arm, double-blind, placebo-controlled randomized trial in which an oral anti-angiogenic VEGFR 1–3 and c-kit receptor inhibitor, cediranib, was studied in 456 women with platinum-sensitive ROC. The study participants were randomized to receive chemotherapy with placebo followed by maintenance placebo (arm A), chemotherapy with cediranib followed by maintenance placebo (arm B), or chemotherapy with cediranib followed by cediranib (arm C). The trial was originally designed to recruit 2000 patients, However, AstraZeneca stopped manufacturing cediranib in October 2011, leading to stoppage of trial after enrollment of 456 patients. At a median follow up of 19.5 months, median PFS was 8.7 months in arm A as compared to 9.9 months in arm B and 11 months in arm C (hazard ratio arm A vs arm C 0.56, 95% CI: 0 .44–0 · 72, p < 0.0001). Side effects such as hypertension, neutropenia, and voice changes lead to discontinuation of cediranib in 32% patients during the chemotherapy phase, prior to disease progression [48]. A final update of survival analysis was published in February 2021 when 90% of trial participants had died at a median follow-up period of 25.6 months. It was seen that concurrent and maintenance cediranib (arm C) showed improved PFS outcomes compared to arms A and B. The median OS in arm A was 19.9 months compared to 27.3 months in arm C (HR 0.86, 95% CI of 0.67–1.11, p = 0.24). The relative reduction in risk of death was 14% [49].
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