011
IMPACT OF TUMOR MORCELLATION ON THE
NATURAL HISTORY OF UTERINE
LEIOMYOSARCOMA (ULMS)
César Serrano, MD1; Titilope Oduyebo2; Judith Manola3;
Yang Feng3; Michael G. Muto2; Suzanne George4
1Pathology Deparment, Brigham and Women's Hospital/
Harvard Medical School, Boston, MA, USA; 2Division of
Gynecologic Oncology, Brigham and Women's Hospital/
Harvard Medical School, Boston, MA, USA; 3Department
of Biostatistics and Computational Biology, Dana-Farber
Cancer Institute/Harvard Medical School, Boston, MA,
USA; 4Center for Sarcoma and Bone Oncology,
Dana-Farber Cancer Institute/Harvard Medical School,
Boston, MA, USA
Objective: ULMS is often diagnosed after surgery for
presumed fibroids. There is no preoperative diagnostic
modality that reliably differentiates ULMS from leiomyoma.
Increasing use of minimally invasive surgical approaches
results in inadvertently morcellated ULMS. We aim to assess
the impact of morcellation in patients with early stage
ULMS compared to ULMS surgically resected with total
abdominal hysterectomy (TAH).
Methods: All patients (pts) with ULMS seen at our institution
from 2007 to 2012 were reviewed. Pts with surgically
resectable ULMS at presentation and adequate followup
were included. Demographics and outcomes were
retrospectively compared between pts who underwent
morcellation or TAH as first surgery. Descriptive statistics
and Kaplan-Meier plots were used to characterize pts and
outcomes. Proportional hazards models were constructed
to identify factors associated with recurrence-free (RFS)
and overall survival. A one-sided mid-p test was used to
explore differences in incidence rates (IR) per person-year
(PY) of follow-up between the groups.
Results: 68 pts with surgically resectable ULMS were
identified, 16 (24%) had morcellation and 52 (76%)
had TAH. Pts who underwent morcellation tended to be
younger (mean age 48 vs 55), and less likely to undergo
oophorectomy (6%vs 75%). Recurrences, IR, and RFS,
are shown in Table 1. Pattern of recurrence differed based
on initial surgery: 100% peritoneal recurrences in the
morcellated group, vs 38% in the TAH group, (Fisher's
101
exact p=0.001). Median time to recurrence following
morcellation was significantly shorter when compared to
recurrences post TAH (11 mos vs 31 mos, Wald p = 0.03).
On univariate analysis, type of surgery, grade, size on
preoperative imaging and mitotic rate were prognostic for
RFS. After adjusting for size and mitotic rate in a multivariable
model, morcellation remained a significant adverse
prognostic factor for recurrence (adjusted hazard ratio 2.13,
95% CI 1.09 - 7.00, p=0.03). Median survival is 5 years and
does not differ by surgery type (logrank p=0.99).
Conclusion: Tumor morcellation of uterine LMS was associated
with increased risk of recurrence, shortened time
to recurrence and a marked increased risk of peritoneal
recurrence when compared to ULMS removed by TAH as
first surgery. Improved pre-operative techniques to identify
patients at high risk for sarcoma prior to presumed leiomyoma
resection are needed to reduce the risk of inadvertent
tumor morcellation.
Paper 012
LMS-02: A PHASE II SINGLE-ARM MULTICENTER
STUDY OF TRABECTEDIN IN COMBINATION WITH
DOXORUBICIN AS FIRST LINE TREATMENT OF
METASTATIC AND/OR LOCALLY ADVANCED
LEIOMYOSARCOMA OF UTERINE (U-LMS) OR
SOFT-TISSUE (ST-LMS) ORIGIN: RESULTS FROM
BOTH COHORTS, FOR THE FRENCH SARCOMA
GROUP (FSG)
Florence Duffaud, MD, PhD1; Christine Chevreau2;
Nicolas Penel, MD PhD3; Axel Le Cesne5;
Cécile Guillemet6; Corinne Delcambre4; Anne Floquet9;
Didier Cupissol7; Annie Rey8; Patricia Pautier5
1Medical Oncology, CHU La Timone, Marseille, France;
2Medical Oncology, Centre Claudius Regaud, Toulouse,
France; 3Medical Oncology, Centre Oscar Lambret, Lille,
France; 4Medical Oncology, Centre F Baclesse, Caen,
France; 5Medical Oncology, Institut Gustave Roussy,
Villejuif, France; 6Medical Oncology, Centre Henri
Becquerel, Rouen, France; 7Medical Oncology, Centre
Valdorelle, Montpellier, France; 8Statistics Unit, Institut
Gustave Roussy, Villejuif, France; 9Oncology, Institut
Bergonie, Bordeaux, France
Objective: Leiomyosarcoma (LMS) are rare tumors with
Table 1
Morc. TAH
Patients 16 52
Recurrences 10 26 Exact p=0.41
PY Follow-up 216.1 1240.6 One-sided mid-p = 0.02
IR 0.046 0.021 IR Ratio=2.21 (0.95 - 4.73)
Median RFS 11 mos 31 mos Logrank p=0.03
1-year RFS 44% (18 - 67%) 75% (60 - 84%)
2-year RFS 22% (4 - 49%) 56% (41 - 68%)
3-year RFS 22% (4 - 49%) 43% (27 - 58%)
poor prognosis when metastatic (median PFS and OS on
1st line chemotherapy of 5 and 12 months respectively).
They have moderate chemosensitivity, mainly to doxorubicine
(doxo), ifosfamide (ifo), gemcitabine (gem) and, more
recently to trabectedin (trab) and pazopanib. The most
active regimen are combinations with doxo (mostly with
ifo or DTIC), and gem + docetaxel (particularly in U-LMS)
with mean response durations of 3-6 months. Objective
Response rates (ORR) with combination as 1st-line do
not exceed 50% for U-LMS and 35% for ST-LMS. Trab
demonstrated activity on pre-treated LMS with disease
control rate (ORR+ stable disease) of 56%, and PFS rate
at 6 months (in 2d/ 3rd line) of 29%. We report the overall
results of a phase II study of trab + doxo combination as
1st line chemotherapy for metastatic LMS, with a stratification
by primary site: uterine (U-LMS) vs extra-uterine
(ST-LMS).
Methods: The primary objective was to determine the disease
control rate (DCR: ORR+SD). Secondary objectives
were: PFS at 12 wks, ORR by RECIST, response duration,
OS, and safety. 107 patients were planned; 45 with U-LMS
and 62 with ST. Treatment: at D1 doxo 60 mg/m2 followed
by trab 1.1 mg/m2 3-h and pegfilgrastim 6 mg d2 q3wks, 6
cycles. Surgery for residual disease was permitted.
Results: A total of 44 pts in the U-LMS cohort, and
61 (40 women) in the ST-LMS cohort were included,
with a median age of 60. For U-LMS 36 had metastatic
disease (mostly in lung 32/36). For ST-LMS among
42 pts with data for at least 1 cycle, 35 had metastatic
disease (mostly in lung 26/35). Thirty and 27 pts received
6 cycles in the U and ST cohorts respectively.
In the U-LMS cohort, for 44 pts with a least 1 evaluation
(2 cycles), 25 PR, 13 SD (for a DCR of 86%) were
observed, while in the ST-LMS cohort for 36 pts with
at least 1 evaluation, there were 1 CR, 13 PR, 20 SD
(for a DCR of 94%), and 2 PD. PFS rates at 12 wks
were 86% for U-LMS and 95% for ST-LMS cohorts.
Common grade 3/4 toxicities in 424 cycles were neutropenia
(46%), febrile neutropenia (6%), thrombopenia (9%),
anemia (9%), fatigue (6%), and ALAT elevation (15%). One
patient died due to a pulmonary edema associated with
prolonged febrile aplasia.
Conclusion: Doxo + trab combination is an active first102
line regimen in both U and ST-LMS despite expected but
manageable toxicity. Final data of the overall population
will be presented at CTOS meeting.
Paper 013
IMPACT OF CHEMOTHERAPY IN UTERINE
SARCOMA (UTS): REVIEW OF 12 CLINICAL TRIALS
FROM EORTC INVOLVING ADVANCED UTS
COMPARED TO OTHER SOFT TISSUE
SARCOMA (STS)
Isabelle Ray-Coquard, MD, PhD1; Agnes Natukunda2;
Jean Yves Blay1; Paolo G. Casali4; Ian Judson5;
Anders Krarup Hansen10; Lars Lindner2;
Angelo Paolo Dei Tos6; Hans Gelderblom9;
Sandrine Marreaud2; Saskia Litiere2;
Piotr Rutkowski, MD, PhD11; Peter Hohenberger8;
Alex Gronchi7; Winette van der Graaf3
1Medical Oncology, Centre Léon Bérard, Lyon, France;
2H&Q, EORTC, Brussels, Belgium; 3Medical Oncology,
Radboud UMC, Nijmegen, Netherlands; 4Medical
Oncology, Istituto Tumori, Millano, Italy; 5Medical
Oncology, Royal Marsden, London, United Kingdom;
6Anatomic Pathology, General Hospital of Treviso,
Veneto, Italy; 7Surgery, Istituto Tumori, Milano, Italy;
8Surgery, Mannheim University hospital, Mannheim,
Germany; 9Medical Oncology, Leiden University
Hospital, Leiden, Netherlands; 10Medical Oncology,
Copenhaghen University Hospital, Copenhaghen,
Denmark; 11Surgery, Maria Sodowska Curie Cancer
Center, Warsaw, Poland
Objective: UtS are a group of uncommon tumors that account
for approximately 1% of malignant neoplasms of the
female genital tract and between 3 and 8% of malignant
uterine neoplasms. The objective was to evaluate the
factors associated with the clinical behavior of patients
(pts) with advanced or metastatic first line UtS treated by
chemotherapy within clinical trials.
Methods: The database contains information on 2827 pts
who did not receive prior (adjuvant or palliative) chemotherapy.
These patients were entered between 1977 and
2001 in twelve EORTC advanced STS trials. Of these, 225
pts were diagnosed with UtS. The end points of interest
for this analysis are overall survival (OS), progression free
survival (PFS) and response rate (RR). The chemotherapy
was aggregated in 4 categories: anthracycline alone,
ifosfamide alone, the combination of doxorubicin and ifosfamide,
and CYVADIC (cyclophosphamide, vincristine,
adriamycin and DTIC).
Results: The characteristics of UtS pts are generally different
from other sarcoma except for performance status
(PS) and treatment with prior radiotherapy. As compared to
other STS in the database, UtS had a significantly higher
median age at registration (53 vs 51 years) and a higher
occurrence of histological grade 3 (40% vs 30%) compared
to other included STS. The most frequent histology was
leiomyosarcoma (LMS) (71%), followed by miscellaneous
(18.7%) and undifferentiated (3%). Among the 225 advanced
UtS pts, there were 191 deaths (median OS 10.1
months, 95% CI: 9.0-11 .9) and 213 progressions and/or
deaths (median PFS 4.1 months, 95% CI: 3.4-4.9). Multivariate
analyses reported both histological grade (p-value
0.014) and PS (p-value 0.002) to be statistically significant
prognostic factors for OS in UtS; for PFS, only histological
grade (p-value 0.027) and prior surgery (P-value 0.022).
There was no significant effect of chemotherapy regimen in
first line treatment observed neither for PFS nor OS in this
subgroup of pts. High histological grade (RR=30%) versus
low (13.5%), chemotherapy regimen containing doxorubicin
(27.3%) versus ifosfamide alone (5%) and other histologies
(33%) versus LMS (20%) are significantly (p < 0.05)
correlated with response to chemotherapy.
Conclusion: UtS are very aggressive neoplasms with
poor outcome when treated with chemotherapy consisting
of doxorubicin and/or Ifosfamide. New strategies are
urgently needed.