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.
mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
Everolimus contains a 2-hydroxethyl substitution at position 40 of the rapamycin structure. Like rapamycin, it forms a complex with FKB12, which then binds with mTOR to inhibit downstream signaling. Everolimus is administered by mouth and is well tolerated, with only mild to moderate adverse reactions. Temsirolimus, an ester of rapamycin, is available as an intravenous (IV) or oral formulation. Adverse effects that are unique to the IV formulation include rare, acute hypersensitivity reactions during the infusion. AP23573, which is a nonprodrug rapamycin analog, is also available in an oral or IV form. This compound has been studied most extensively in patients with solid tumors, especially sarcomas; and there have been fewer studies in hematological malignancies.
Neuroendocrine tumors of the gastrointestinal tract
Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner in Endocrine Surgery, 2017
Targeted therapies against VEGF receptors, for example, the tyrosine kinase inhibitor sunitinib, and mTOR, e.g., everolimus, have been shown to be active against pancreatic NETs in pivotal Phase III trials. In a placebo-controlled randomized controlled trial in 171 patients with advanced and nonresectable pancreatic NETs, sunitinib therapy was shown to double median progression-free survival from 5.5 months to 11.4 months compared with placebo. Overall survival was improved, with the hazard ratio for death estimated at 0.41 (95% confidence interval 0.19–0.89) for sunitinib therapy. The main adverse effects were diarrhea, nausea and vomiting, tiredness, hypertension, and neutropenia [29]. The RADIANT-3 Phase III randomized controlled trial showed that everolimus was also capable of doubling median progression-free survival from 4.6 months to 11.0 months in patients with progressive and metastatic pancreatic NETs. However, no benefit in overall survival was noted. The most common adverse effects noted were stomatitis/aphthous ulceration, rash, diarrhea, fatigue, neutropenia, and an increased rate of infections (unsurprising, as everolimus is also an immunosuppressant). Everolimus also induces some metabolic adverse effects: hypertriglyceridemia and diabetes mellitus. The metabolic effects are controllable with insulin and hypolipidemic treatment, and sometimes advantageous in the case of metastatic insulinomas. Lastly, everolimus is associated with pneumonitis, interstitial lung disease, and sometimes lung fibrosis. This class of adverse effects can be serious and may require steroid treatment to suppress them, and often represents a dose-limiting adverse effect [30].
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
Everolimus, a 40-O-(2-hydroxyethyl) derivative of rapamycin, was granted FDA approval in 2019 for the treatment of advanced postmenopausal HR+/HER2− breast cancer in women, pancreatic-derived progressive neuroendocrine tumours, renal vascular smooth muscle lipoma, RCC, and other indications225. In phase II randomised trial, everolimus plus letrozole was used to treat women with advanced premenopausal breast cancer who were HR+/HER2−. Patients in the everolimus plus letrozole group received longer median PFS than those in the letrozole alone group (19.4 months vs. 12.9 months), indicating that the combination was beneficial226. Similarly, everolimus combined with an aromatase inhibitor (AI) has shown promising therapeutic activity in patients suffering from breast cancer. The median PFS in the everolimus plus AI group and the AI monotherapy group was 11.0 months and 7.2 months respectively, with ORRs of 22.4% and 19.2% respectively227. When everolimus was combined with bevacizumab to treat patients with the RCC form of metastatic cancer, the median PFS was 13.7 months with an ORR of 35%. The combination’s robust activity supports this regimen as the standard choice for patients with RCC228. Overall, everolimus has displayed considerable potential in various cancer treatments, and the efficacy of different combination regimens of everolimus is currently being further explored.
From clinical trials to clinical practice: the use of everolimus and exemestane in the treatment of hormone receptor-positive metastatic breast cancer: real-world data
Published in Journal of Chemotherapy, 2022
Hikmat Abdel-Razeq, Baha' Sharaf, Hazem Abdulelah, Nayef Abdel-Razeq, Mourad Salam, Bayan Inserat, Rayan Bater
Numerous studies had demonstrated the synergistic anticancer activity of everolimus when combined with ET in mBC. A phase 2 randomized study that involved 111 post-menopausal women with HR-positive mBC previously treated with aromatase inhibitors showed that the combination of everolimus and tamoxifen was associated with significantly improved PFS compared to tamoxifen alone (8.6 vs. 4.5 months; p = 0.002) [19]. More recently, the efficacy of everolimus combined with exemestane was demonstrated in the BOLERO-2 trial with significant PFS improvement [19]. However, the lack of overall survival (OS) advantage [20] and the relatively high incidence of adverse events; some were serious enough to interrupt or permanently stop the drug, had resulted in the reluctance in adopting the drug in routine clinical practice. Prior to the recent introduction of CDK4/6 inhibitor [21, 22], everolimus, combined with exemestane, was among few available treatment options for such patients.
Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence
Published in Expert Opinion on Pharmacotherapy, 2018
Lingaku Lee, Tetsuhide Ito, Robert T. Jensen
In recent guidelines, everolimus is generally recommended as second-line therapy behind SSAs [201–203,207–209], because of the low toxicity with high tolerability of SSAs treatment [165]. At present, everolimus is one of the most frequently used second-line treatments in patients presenting clinically significant tumor burden and disease progression on SSAs. Other competing therapeutic agents including sunitinib for panNETs, PRRT, chemotherapy, and liver-directed therapy for panNETs and other NETs, may also be indicated in these settings [201–203,207–209]. Of these, the recent approval of PRRT is most likely to change everolimus’s order in the antitumor therapeutic approach. PRRT results in a longer PFS than everolimus, is well tolerated by patients, a significant percentage of patients show a cytotoxic effect with reduced tumor burden [26,27], and thus it will likely have a significant impact on the use of cytostatic agents including everolimus and sunitinib, especially in patients with aggressive tumors. Severe AE/toxicity of PRRT is reported to be low (1–2%) (leukemia, myeloproliferative effects) [26,27,213]. With PRRT’s general availability and use in all groups of NETs, AE/toxicity will be better defined, and this could play a role in its general use and the position of everolimus in the treatment sequence. It should be noted that most guidelines have not reflected the recent availability of PRRT, shown in the NETTER-1 trial and other recent studies [202,203,209,210].
Related Knowledge Centers
- Immunosuppression
- Restenosis
- Medication
- Transplant Rejection
- Organ Transplantation
- Targeted Therapy
- Drug-Eluting Stent
- Sirolimus
- Mtor
- Tuberous Sclerosis