Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study.
OBJECTIVE
To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.


BACKGROUND
Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.


METHODS
We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.


RESULTS
There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.


CONCLUSIONS
Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.
University of Chicago, Chicago, IL 60637, United States. Electronic address: gfleming@medicine.bsd.uchicago.edu.
Gini F
GF
Fleming
Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
Virginia L
VL
Filiaci
Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
Brandon
B
Marzullo
Hershey Medical Center, Medical Center of Pennsylvania State University, Hershey, PA 17033, United States.
Richard J
RJ
Zaino
University of Colorado Cancer Center - Anschutz Cancer Pavilion, Aurora, CO 80045, United States.
Susan A
SA
Davidson
Stony Brook University Hospital, Stony Brook, NY 11794, United States.
Michael
M
Pearl
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, United States.
Vicky
V
Makker
Memorial Medical Center, Savannah, GA 31404, United States.
James J
JJ
Burke
UMass Memorial Medical Center, Worcester, MA 01605, United States.
Susan L
SL
Zweizig
UNC-Chapel Hill, Chapel Hill, NC 27599, United States.
Linda
L
Van Le
Hanjani Institute for Gynecologic Oncology, Abington, PA 19001, United States.
Parviz
P
Hanjani
Gynecologic Oncology of West Michigan, Grand Rapids, MI 49546, United States.
Gordon
G
Downey
University of Oklahoma, Oklahoma City, OK 73190, United States.
Joan L
JL
Walker
University of Iowa Hospitals and Clinics, Iowa City, IA 52242, United States.
Henry D
HD
Reyes
University of Iowa Hospitals and Clinics, Iowa City, IA 52242, United States.
Kimberly K
KK
Leslie
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019290:Megestrol Acetate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects
D013629:Tamoxifen; C401859:temsirolimus; D019290:Megestrol Acetate; D020123:Sirolimus
Endometrial cancer; Hormonal therapy; Megestrol acetate; Tamoxifen; Temsirolimus