Adjuvant gemcitabine plus docetaxel for completely

resected stage I-IV high grade uterine leiomyosarcoma: results

of a phase II trialMartee L. Hensley, Nicole Ishill, Robert Soslow, Nadeem Abu-Rustum, Paul Sabbatini, Jason Konner, William Tew, David

Spriggs, Carol A. Aghajanian

Memorial Sloan-Kettering Cancer Center, New York, NY

RATIONALE• 2-year progression-free survival (PFS) is

estimated at 20-40% for women with completely resected HGuLMS

• Recurrence rates estimated at 50-80%

• No prospective trials have adequately assessed adjuvant systemic therapy for high-risk disease

RATIONALE

• Fixed dose-rate gemcitabine + docetaxel achieves high response rates in metastatic HGuLMS, even as 2nd or 3rd line therapy

• Need to determine whether 2-year PFS with adjuvant chemotherapy for HGuLMS is sufficiently promising to warrant study in a prospective, randomized phase III trial

Gemcitabine-Docetaxel in advanced uterine LMS

Objective RR Median duration of response

Range, months

MSKCC phase II

40% 7 months 4 - 45

GOG, second line

27% 9+ months 3.1 – 24.5+

GOG, first line

36% 6+ months 2.1 - 33.4+

Hensley, JCO 2002; Hensley Gyn Onc 2008; Hensley Gyn Onc 2008

Background: historical PFS for uLMSReference-Intervention

Recurrence rate

Patient details

% recurrence at 2-3 years

Comments

Kushner, Gyn Oncol 2000

Retrospective

Ifos 4.5 gm

13 ut sarc pts

6 LMS pts

5/6 (83%) LMS pts recurred

4 pts stage I/II

2 pts stage III/IV

70% recurrence at 2y among stage I LMS pts

Omura, GOG, J Clin Oncol 1985

Dox 60mg/m2 x 8 v. observation

Dox 44% (11/25 LMS)

Obs 61% (14/23 LMS)

All stage I/II (no data on grade, mitotic rate)

40% recurrence at 2y (for combined MMT and LMS pts)

•RT allowed, but no difference in recurrence rates•No CT imaging required

Gaducci, Gyn Onc 1996

Retrospective, some patients received adjuvant chemo, some RT, some no adjuvant

No adjuvant Rx 25/64 (39%)

Chemo 4/9 (44%)

RT 5/15 (33%)

126 LMS pts

90 pts with stage I, II

60% recurrence at 2 y

(35/90 pts recurred, at median of 16 mo)

2-year DFS by mitotic rate

5-10 80%

10-19 60%

>20 25%

Major, GOG, Cancer 1993

Retrospective study to determine prognostic factors

71% among the 59 LMS pts

59 pts (83% stage I, 17% II)

69% recurrence at 3y

3-y PFS by mitotic rate

<10 100%

10-20 39%

>20 21%

Reference-Intervention

Recurrence rate

Patient Details

Recurrence rate at 2-3 y

Comments

Dinh, Gyn Onc 2004

Retrospective9/11 stage I, II, IIIA-serosa only LMS pts recurred (82%)

med PFS 17 mo, range 3-30 mo

81% recurrence at 2 for all 27 pts

•Trend for poorer survival with higher mitotic rate

Giuntoli, Gyn Onc 2003

Retrospective•17% received adjuvant RT•16% received adjuvant chemo

208 LMS patients

60% recurrence at 2y for subset of 62 patients (68% of whom were stage I or II)

Case-control analysis for RT (n=31) v. no RT (n=31, matched for age, stage) showed no difference in PFS or OS

Pautier, Cancer 2000

Retrospective•15% received chemo•26% received RT•10% received both

157 uterine sarcomas

78 LMS pts

75% recurrence at 3y among 78 LMS (73% of whom were stage I or II)

Stage and mitotic rate were prognostic for LMS

Wu, Gyn Oncol, 2006

Retrospective12/41 (29%) stage I recurred

51 LMS •41 stage I•7 stage III•3 stage IV

33% recurrence at 3 y

Approx 75% at 3 years among 41 stage 1 pts

•9/41 stage I pts received adj chemo—11% recurred•31/41 stage I had no adjuvant chemo—36% recurred

Reference-Intervention

Recurrence rate

Patient Details Recurrence rate at 3-5 y

Comments

Odunsi, Int J Gyn Cancer, 2004

CYVADIC adjuvant chemo

8/24 (33%) recurred

Stage I uterine sarcomas (n=24)•11 LMS•8 MMT•3 ESS

35% recurrence at 5 y

•Prospective phase II

Pautier, Int J Gyn Cancer, 2004

dox-cis-ifos x 3, then RT

5/13 (38%) LMS recurred

18 uterine sarcoma pts•16/18 stage I-II•13/18 had LMS

24% recurrence at 3-Y for chemo-RT pts

57% recurrence at 3y for RT only

Case-control study, with controls, matched on stage, age, histology, surgery

Small studies of adjuvant chemotherapy

OBJECTIVES

Primary: • determine whether treatment with adjuvant fixed-

dose-rate gemcitabine plus docetaxel following complete resection of stage I-IV high grade uterine LMS is associated with a >40% PFS at 2 years

Secondary:• assess tolerability of 4 cycles fixed-dose-rate gemcitabine plus docetaxel in an adjuvant treatment population

Study Schema

Confirm histology: high-grade uterine LMS, stage I, II, III, or IV, completely resected

Confirm No Evidence of Disease (NED) by CT C/A/P and physical examination

CT scan and Physical Exam every 3 months

Gemcitabine 900mg/m2 over 90 minutes days 1 and 8 + Docetaxel 75mg/m2 d8, with GCSF or Neulasta day 9, every 3

weeks for 4 cycles

ELIGIBILITY CRITERIA

Pathologically confirmed uterine LMS, stage I, II, III, or IV, completely resected

No prior chemotherapy for LMS; no prior gemcitabine or docetaxel

Age > 18 y; KPS > 80%

Adequate organ function and bone marrow reserve

No prior radiation therapy (RT) to abdomen or whole pelvis

No other cancer present within the past 3 years

No neuropathy greater than grade 1

PATIENT CHARACTERISTICSTotal # patients enrolled 25

Median age (range) 49 (37-73)

Number of patients evaluable for PFS endpoint23

1-never treated1-ineligible

FIGO Stage I or II uterine LMS (all high grade) 18 (78%)

FIGO stage III or IV uterine LMS (all completely resected, high grade)

5 (22%)

Median uterine tumor size, stage I and II patients

10 cm (6-28 cm)

Median LMS tumor mitotic rate per 10 hpf (range)

20 (5-60)

GRADE 3/4 TOXICITIESToxicity

(N = 92 cycles)Grade 3 Grade 4

Neutropenia 2/23 (8.7%) 0

Febrile neutropenia 2/23 (8.7%) 0

Anemia 2/23 (8.7%) 0

Thrombocytopenia 1/23 (4.3%) 0

Hyperglycemia 2/23 (8.7%) 0

Pulmonary toxicity 2/23 (8.7%) 0

Diarrhea 1/23 (4.3%) 0

All patients completed all 4 cycles of planned therapy

Progression-free survival

% of patients progression-free at 2 years

All patients (n=23)

45%Stage I or II uterine LMS (n=18)

59%

Median follow-up for all patients = 49 monthsMedian follow-up for Stage I, II patients = 40 months

Median PFS-all patients = 13 mo

Median PFS-Stage I and II = 39 mo

Median Overall survival- all patients = not yet reached (> 45 mo)

Median Overall survival- Stage I, II patients = not reached (>60 months)

Sites of 1st Recurrence

Lung Pelvis Lung + Pelvis

Stage I, II patients

3/18 (16%) 2/18 (11%) 3/18 (16%)

All patients

3/23 (13%) 5/23 (22%) 5/23 (22%)

CONCLUSIONS

•Patients treated with adjuvant fixed-dose-rate gemcitabine + docetaxel for completely resected stage I-IV high-grade LMS had 2 year PFS of 45%

•Patients with stage I or II disease had 2 and 3-y PFS of 59%

•2 year PFS appears superior to historical rates of 20-40% PFS at 2 years.

•Median OS for all patients is not yet reached—exceeds 45 months

•Assessment of adjuvant Gem-Doce therapy in high-risk stage I and II uterine LMS is warranted

REFERENCES

• Omura, J Clin Oncol 3: 1240-1245, 1985• Major, Cancer 71: 1702-1709, 1993.• Gaducci, Gyn Oncol 62: 25-32, 1996.• Kushner, Gyn Oncol 78: 221-227, 2000.• Pautier, Cancer 88: 1425-1431. 2000.• Hensley, J Clin Oncol 20: 2824-2831, 2002.• Hensley, Gyn Oncol 109: 323-328, 2008• Hensley, Gyn Oncol 109: 329-324, 2008.• Giuntoli, Gyn Oncol 89: 460-469, 2003.• Pautier, Int J Gyn Cancer 14: 1112-1117, 2004.• Dinh, Gyn Oncol 92: 648-652, 2004.• Wu, Gyn Oncol 100: 166-172, 2006.

Acknowledgments

• Carol Aghajanian, MD• David Spriggs, MD• GMO physicians and

care team• MSO physicians• Robert Soslow, MD• Kathy Appollo, RN• GOG Uterine Corpus

and DTC committees

• Laurence Baker, MD and SARC leadership

• CTOS leadership• MSKCC patients and

GOG patients and physicians