neoadjuvant chemotherapy in malignant peripheral nerve sheath tumors

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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