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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Everolimus (AfinitorTM) (Figure 6.95) is approved for the treatment of neuroendocrine tumors of pancreatic and gastrointestinal origin, advanced breast cancer after endocrine therapy, and advanced renal cell carcinoma after previous treatment when the disease has progressed despite treatment with VEGF therapies. It is also still used as an immunosuppressive therapy for liver and kidney transplants.
Soft Tissue Sarcomas
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Thomas F. DeLaney, David C. Harmon, Karol Sikora, Francis J. Hornicek
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
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
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.
Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms
Published in Acta Oncologica, 2021
Eva Tiensuu Janson, Ulrich Knigge, Gitte Dam, Birgitte Federspiel, Henning Grønbaek, Peter Stålberg, Seppo W. Langer, Andreas Kjaer, Johanna Arola, Camilla Schalin-Jäntti, Anders Sundin, Staffan Welin, Espen Thiis-Evensen, Halfdan Sorbye
Everolimus, a specific inhibitor of the mTOR pathway, has demonstrated efficacy in NET patients. The RADIANT 3 study [38] including panNET patients, showed a significantly longer median PFS for everolimus of 11.4 vs. 5.4 months for placebo. In the RADIANT 4 study that included GI- and lung-NET patients, median PFS was significantly longer for the treatment arm compared to placebo (11.0 vs. 3.9 months) for the whole group, but for SI-NETs there was no difference [39, 40]. The main side effects of everolimus are stomatitis, rash, diarrhoea, hyperglycaemia, fatigue and infections. Dose reduction or temporary interruptions are frequently needed. A serious side effect is non-infectious pneumonitis. Everolimus is recommended for progressing panNET. Its exact place in the treatment of SI-NETs has still to be clarified [39,40].
Safety, efficacy, and tolerability of systemic therapies in male breast cancer: are there sex-specific differences?
Published in Expert Opinion on Drug Safety, 2020
Siddhartha Yadav, Karthik V. Giridhar, Jodi Taraba, Roberto Leon-Ferre, Kathryn J. Ruddy
Everolimus, an mTOR inhibitor, in combination with exemestane has demonstrated improvement in progression-free survival of approximately 5 months in women with ER positive breast cancer whose disease is resistant to non-steroidal AIs. In two case reports, the combination of everolimus and tamoxifen or exemestane was noted to be effective in MBC [13,14]. As discussed previously, it is advisable to add GNRHa when using the exemestane and everolimus combination in men. Common toxicities associated with everolimus include stomatitis, rash, fatigue, diarrhea and are seen in approximately one-third of patients. In advanced nonfunctional neuroendocrine tumors, everolimus treatment appeared to be more effective in women compared to men in sub-group analysis, but a differential response to toxicity was not reported [15].
Long-term use of mTORC1 inhibitors in tuberous sclerosis complex associated neurological aspects
Published in Expert Opinion on Orphan Drugs, 2020
Romina Moavero, Paolo Curatolo
Drug treatment with Everolimus usually requires therapeutic drug monitoring, which should be repeated at every dosage change and also every time a concomitant medication dosage is modified. Previous studies suggest that blood levels should be kept between 5 and 15 ng/mL [17,18]. Table 1 reports recommended starting dosage according to the age range of the patient and keeping in mind that the usual starting dose is 5 mg/m2 but it might be adjusted according to age, comedication, and even to the target manifestation. The technical sheet of Everolimus suggests that the initial dosage for epilepsy in children under 6 years should be 6 mg/m2 (9 mg/m2 if coadministration of CYP3A4/PgP inducers), while for older children the initial dosage should be 5 mg/m2 (8 mg/m2 if coadministration of CYP3A4/PgP inducers). For SEGA the recommended dosages are 7 mg/m2 for children 1–3 years and 4.5 mg/m2 for children >3 years.