Neoadjuvant Chemotherapy in Malignant Peripheral Nerve
Sheath Tumors
Elizabeth Shurell, M.D., M.Phil.UCLA General Surgery ResidentResearch Fellow, Division of Surgical Oncology
Disclosures
I have no financial disclosures or other relationships relevant to this research.
MPNST Characteristics• Neurofibromatosis type 1 (NF-1)
– Lifetime risk 10%• General Population
– Lifetime risk < 0.01%• Poor prognosis, frequent metastases and
few treatment optionsMFH Other
Fibrosarcoma Lipo Leiomyo Synovial MPNST
Increasing sarcoma-specific mortality
Figure adapted from: Kattan, Leung, and Brennan. J Clin Onc, 2002.
Background
Taylor et al. Nature Reviews Cancer 2011.
Background
Taxanes
Imatinib
TrabectedinPazopanib
Imatinib
Crizotinib
Sunitinib
Cediranib
Pazopanib
Therapy for MPNSTBackground
• Response rate of MPNSTs to standard chemotherapy is unknown
• Kroep et al, Leiden University Medical Center (2010)• n=175 unresectable/metastatic pts;
combination adriamycin/ifosfamide yielded best response: 1 year progression free survival: 25%
• Moretti et al, U of Pennsylvania (2011)• n=10 (4 pts metastatic); combination
adriamycin/ifosfamide yielded 57% DFS and 80% OS at 2 years
Neoadjuvant Therapy for MPNST
One MPNST clinical trial:
Phase II trial of neoadjuvant chemotherapy in sporadic and NF1 associated high grade unresectable MPNST (NCT00346164)
(open, not actively recruiting)
Background
Roles of Neoadjuvant Therapy
• Cytoreduction, downstaging– Decrease micro-metastatic disease– Reducing consequences of a more extensive
surgery• Tool to determine patient sensitivity to
chemotherapy
Background
Objective
What we know: Grade, Size, and Location are the most important predictors of survival in MPNST patients.
Goal: Evaluate pathologic response of neoadjuvant chemotherapy in primary MPNST patients and its impact on survival.
Background
Methods for analysis• Primary outcomes: Disease specific survival, Disease
free survival• The a priori chosen prognostic covariates were:
– Age (modeled as continuous covariate)– Sex (male, female)– Presence of Neurofibromatosis type 1 (NF1)– Tumor size (modeled as continuous covariate)– Grade (low, intermediate, high)– Location (Retroperitoneal, Extremity, Trunk, etc)– Margin status (microscopically negative, microscopically
positive)– Neoadjuvant XRT (yes, no)– Type of neoadjuvant chemotherapy (non-ifosfamide versus
ifosfamide-based)
Methods
Neoadjuvant ChemotherapyResults
88 patients with 1◦ MPNST (1974-2012)
n=48 n=40 (45.4%)
n=38
Neoadjuvant ChemotherapyResults
Respondersn=13 (34%)
Non-Respondersn=25 (66%)
n=38
90% pathologic response
Characteristic All Patients Nonresponders RespondersNumber of Patients 38 25 (66%) 13 (34%)Age
Median (range) 32.5 (16-65) 30 (16-64) 35 (19-65)Sex
Male 30 (79%) 22 (88%) 8 (61%)Female 8 (21%) 3 (12%) 5 (38%)
Size (in cm)Median (range) 13.3 (1.5-45) 15 (4-45) 7.5 (1.5-17.5)
Presence of NF-1Yes 9 (24%) 7 (28%) 2 (15%)No 29 (76%) 18 (72%) 11 (85%)
GradeLow 0 0 0Intermediate 4 (11%) 2 (8%) 2 (15%)High 34 (89%) 23 (92%) 11 (85%)
SiteExtremity 23 (61%) 16 (64%) 7 (54%)RP/Pelvis 7 (18%) 6 (24%) 1 (8%)Trunk 6 (16%) 1 (4%) 5 (38%)H&N 2 (5%) 2 (8%) 0
MarginsNegative 32 (84%) 21 (84%) 11 (85%)Positive 6 (16%) 4 (16%) 2 (15%)
Neoadjuvant Radiation TherapyYes 25 (66%) 14 (56%) 11 (85%)No 13 (34%) 11 (44%) 2 (15%)
Type of Neoadjuvant Chemotherapynon-Ifosfamide 12 (32%) 8 (32%) 4 (31%)Ifosfamide-based 26 (68%) 17 (68%) 9 (69%)
Follow-up for Survivors (in years)Median (range) 8.6 (2.3-27.3) 6.3 (2.3-17.6) 10.7 (4.2-27.3)
Results
Characteristics
p=0.032
DFS cox DSS coxp-value Hazard Ratio 95% CI p-value p-value Hazard Ratio 95% CI p-value
Sex 0.575 0.195Age 0.112 0.017 0.94 0.88-0.99 0.023NF1 0.128 0.101Grade 0.912 0.789Site 0.375 0.129Size 0.041 1.03 0.98-1.09 0.201 0.011 1.07 1.00-1.14 0.042Margins 0.135 0.357Neoadj XRT 0.495 0.502Chemo Type 0.98 0.888PathologicResponse 0.007 4.83 1.37-16.9 0.014 0.024 3.35 0.94-11.8 0.061
DSS multivariable Cox analysisDFS multivariable Cox analysis
Survival AnalysisResults
Harrell’s C = 0.72 Harrell’s C = 0.75
DSS = Disease Specific Survival; DFS = Disease Free Survival
Overall Disease Free SurvivalResults
Survival Proportions2 year 5 year 10 year60.5% 51.8% 39.6%
n=38 primary MPNST patients treated with neoadjuvant chemotherapy
Pathologic response rate correlates with disease free survival
Results
Overall Disease Specific SurvivalResults
Survival Proportions2 year 5 year 10 year68.4% 62.9% 48.0%
n=38 primary MPNST patients treated with neoadjuvant chemotherapy
Pathologic response rate correlates with disease specific survival
Results
Conclusions of clinical study
• Our pathologic response rate was 34%, and is associated with significant improvement in both DSS and DFS in primary MPNST
• Future challenge: to determine upfront which patients will be “responders” to standard systemic therapy
Conclusion
AcknowledgementsThank you!
UCLA Sarcoma ProgramDr. Fritz C. EilberDr. Frederick R. EilberDr. Sarah DryDr. Jeffrey EckardtDr. Arun SinghDr. Noah FedermanDr. Michael SelchDr. Scott NelsonDr. William Tap (MSKCC)
Pathologic response rate correlates with disease free survival: 95% necrosis
Results
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Pathologic response rate correlates with disease specific survival: 95% necrosis
Results
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