The study is designed as a two arm open label randomized phase iii superiority trial with an observation only control arm, Regimen ii, and experimental arm of multi-agent chemotherapy (Regimen i, 4 cycles of gemcitabine and docetaxel followed by 4 cycles of doxorubicin). The design will provide a direct assessment of the null hypothesis that multi-agent adjuvant chemotherapy offers no increase in survival when compared with observation until recurrence.
Randomization will be stratified by country of treating site.
Patients diagnosed with high grade uterine LMS and who have had a hysterectomy will be randomized into one of the two management arms:
ReGiMen i: Patients randomly assigned to Regimen i will be treated as follows:
Gemcitabine 900 mg/m2 iV over 90 minutes on days 1 and 8
Docetaxel 75 mg/m2 iV day 8 (pre-medication dexamethasone 4-8 mg p.o. bid for 3 days, starting 12-24 hours prior to docetaxel)
(Gemcitabine is administered prior to docetaxel on day 8)
Filgrastim (GCSF) 5 micrograms/kg (may round to nearest vial size of 300 micrograms or 480 micrograms) subcutaneously days 9-15 or pegfilgrastim 6 mg subcutaneously day 9 or 10
each cycle is 21 days
Treat for 4 cycles
Repeat CT chest/abdomen/pelvis (or CT chest + MRi abdomen/pelvis) imaging after 4 cycles (no sooner than 3 months from start of study treatment, but no later than 4 months from start of study treatment) of gemcitabine plus docetaxel to confirm continued no evidence of disease (neD).
if no evidence of disease (neD), no sooner than 3 weeks, but no longer than 8 weeks from cycle 4 day 1 of gemcitabine/docetaxel start:
Doxorubicin 60 mg/m2 iV every 21 days for 4 cycles (use of central venous catheter access recommended, but not required).
Filgrastim (GCSF) 5 micrograms/kg (may round to nearest vial size of 300 micrograms or 480 micrograms) subcutaneously days 2-8 or pegfilgrastim 6 mg subcutaneously day 2 or 3 is oPTionaL.
noTe: Patients who are found, after enrollment, to have a cardiac ejection fraction of [Less Than]50% or below institutional normal limits will conclude their adjuvant chemotherapy at the completion of 4 cycles of gemcitabine + docetaxel. They will noT receive any doxorubicin. They will remain on STuDY and proceed with follow-up as detailed for all patients assigned to Regimen i.
Follow patients for recurrence by physical examination and CT chest/abdomen/pelvis (or CT chest +MRi abdomen/pelvis) every 4 months from study entry until 3 years out from the start of study treatment, then every 6 months for the next 2 years. There is a maximum of 5 years of imaging for initial recurrence.
ReGiMen ii: observation only
Rn (nurse) or MD (physician) telephone call every 3-4 weeks for approximately 24 weeks to document patient-reported toxicities or adverse events (see Section 7.1, Regimen ii table).
CT chest/abdomen/pelvis (or CT chest +MRi abdomen/pelvis) imaging after 3 to 4 months from study entry to confirm continued no evidence of disease.
Continue with observation if there is no evidence of disease.
Follow patients for recurrence by physical examination and CT chest/abdomen/pelvis (or CT chest +MRi abdomen/pelvis) imaging every 4 months from study entry until 3 years out from the start of study treatment, then every 6 months for the next 2 years. There is a maximum of 5 years of imaging for detection of first recurrence.
3.11 Patients with high risk uterine LMS, FIGO stage I (confined to corpus +/- cervix). Patients with known uterine serosa involvement are not eligible. Patients should have had, at least, a complete hysterectomy (including removal of the cervix). Bilateral salpingo-oophorectomy is not required.
3.111 Institutional pathology review calls the uterine leiomyosarcoma
* high grade.
3.112 Additionally, if the pathology report indicates a mitotic rate, the mitotic rate should be greater than or equal to 5 mitoses/10 high power field.
All patients must be no longer than 12 weeks (3 months) from surgical resection of cancer at the time of enrollment on study. If a patient requires a second operation to complete her surgery, i.e. trachelectomy to remove the cervix and/or BSO, the 12 weeks may be counted from the time of the second operation.
3.12 All patients must have no evidence of persistent or metastatic disease as documented by a post-resection CT of the chest/abdomen/pelvis or by CT chest + MRI abdomen/pelvis. The post-resection imaging studies should be performed within 4 weeks of registration on study.
3.13 Patients must have adequate:
3.131 Bone marrow function: Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (ANC 1.5 x 109/liter (L).
Platelets greater than or equal to100,000/mcl (Platelets 100 x 109/L). Hemoglobin greater than 8.0 g/dl (= 80 g/L; or 4.9 mmol/L).
3.132 Renal function: creatinine less than or equal to 1.5 x institutional upper limit normal (ULN.)
3.133 Hepatic function: Bilirubin within normal range. SGOT (AST), SGPT (ALT), and alkaline phosphatase less than or equal to 2.5 x ULN.
Patients with a history of Gilbert[Single Quote]s syndrome may be eligible provided total bilirubin is less than or equal to 1.5 x ULN and the AST, ALT, Alkaline phosphatase meet the criteria detailed.
3.134 Neurologic function: Neuropathy (sensory and motor) less than or equal to CTCAE grade 1.
3.14 Patients with GOG performance status of 0 or 1; ECOG performance status of 0 or,1; or KPS >= 80%.
3.15 Patients who have met the pre-entry requirements specified in Section 7.0.
3.16 Patients must have signed an approved informed consent.
3.17 Patients participating through U.S. sites must sign an approved and authorization permitting release of personal health information.
3.18 Patients must be a minimum of 18 years of age.
3.19 Patients should be free of active infection requiring antibiotics (with the exception of an uncomplicated UTI).