A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities

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A phase I study on the combination of neoadjuvant
radiotherapy plus pazopanib in patients with
locally advanced soft tissue sarcoma of the
extremities CTOS 2014 Rick Haas Department of
Radiotherapy, The Netherlands Cancer Institute
Amsterdam
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Co-authors
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Disclosure
Investigator Initiated Research Grant GSK, but
GSK had no part in the design nor the conduct of
my studies
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Introduction
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Introduction
Local control in the majority of extremity soft
tissue sarcomas (ESTS) is achieved by a
combination of radical surgery and (neo-)
adjuvant RT
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Introduction
Local control in the majority of extremity soft
tissue sarcomas (ESTS) is achieved by a
combination of radical surgery and (neo-)
adjuvant RT The timing of RT in ESTS is under
debate.
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Introduction
Local control in the majority of extremity soft
tissue sarcomas (ESTS) is achieved by a
combination of radical surgery and (neo-)
adjuvant RT The timing of RT in ESTS is under
debate. Epithelial tumors (carcinomas) gt
conventional chemotherapy and/or targeted agents
RT gt an increased local control (increased
overall survival) gt at the cost of usually
temporary acute side effects.
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Introduction
Local control in the majority of extremity soft
tissue sarcomas (ESTS) is achieved by a
combination of radical surgery and (neo-)
adjuvant RT The timing of RT in ESTS is under
debate. Epithelial tumors (carcinomas) gt
conventional chemotherapy and/or targeted agents
RT gt an increased local control (increased
overall survival) gt at the cost of usually
temporary acute side effects. Myxoid
liposarcomas (crow feet vasculature) respond
rapidly to pre-op RT
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Introduction
Local control in the majority of extremity soft
tissue sarcomas (ESTS) is achieved by a
combination of radical surgery and (neo-)
adjuvant RT The timing of RT in ESTS is under
debate. Epithelial tumors (carcinomas) gt
conventional chemotherapy and/or targeted agents
RT gt an increased local control (increased
overall survival) gt at the cost of usually
temporary acute side effects. Myxoid
liposarcomas (crow feet vasculature) respond
rapidly to pre-op RT
10
Introduction
Local control in the majority of extremity soft
tissue sarcomas (ESTS) is achieved by a
combination of radical surgery and (neo-)
adjuvant RT The timing of RT in ESTS is under
debate. Epithelial tumors (carcinomas) gt
conventional chemotherapy and/or targeted agents
RT gt an increased local control (increased
overall survival) gt at the cost of usually
temporary acute side effects. Myxoid
liposarcomas (crow feet vasculature) respond
rapidly to pre-op RT This prospective phase I
clinical trial aimed to establish 1 safety 2
toxicity profile 3 recommended dose for further
studies of pazopanib concurrent with
preoperative RT in patients with extremity soft
tissue sarcomas (ESTS) amenable to treatment with
curative intent.
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Patients and Methods
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Patients and Methods
Patients with intermediate or high grade deep
seated ESTS, 5 cm in maximal dimension Once
daily pazopanib (dose escalation cohorts 400 mg,
600 mg and 800 mg) for 6 weeks Preoperative RT
(25 x 2 Gy) starting on day 8 of pazopanib.
Surgery was performed five to seven weeks
later. Toxicity was scored according to CTC
criteria 4.0.
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Toxicity definitions
DLT I toxicities during and immediately after the
induction treatment period, directly related to
chemoradiation Note systemic toxicities (like
RR, hepatotoxicity etc.) could be reasons for
drug interruption, but were not designated as
DLT
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Toxicity definitions
DLT I toxicities during and immediately after the
induction treatment period, directly related to
chemoradiation Note systemic toxicities (like
RR, hepatotoxicity etc.) could be reasons for
drug interruption, but were not designated as
DLT DLT II toxicities in the perioperative
phase
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Results
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Results patients
12 patients were enrolled 3 nonevaluable 1
never started (second thoughts refusal) 2
due to hepatotoxicity (day 17 and 24
respectively) 9 evaluable
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Results patients
Sex 2 females and 7 males Age median age 49
years (range 24-74 years) Size median size 9
cm (range 5-15 cm) Location extremities Pathol
ogy variety grade II / III conform inclusion
criteria FU Median FU 17 months (range 6-39
months).
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Toxicity profile in the induction phase DLT I
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Toxicity profile in the induction phase DLT I
No increased toxicities within the radiation
portals mild skin erythema Other toxicities
like fatigue, hair discoloration, hypertension
and diarrhea were all mild (grade I) and
transient
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Systemic toxicity profile
Grade III transaminase elevations (without
hyperbilirubinemia) in 3 cases gt leading to
stopping of pazopanib gt incompliance rate 27
(3/11) All returned to normal values lt 3 weeks
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Toxicity profile in the perioperative phase DLT
II
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Toxicity profile in the perioperative phase DLT
II
9 evaluable patients 1 refused surgery
(progressive on induction management) 8
underwent surgery
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Toxicity profile in the perioperative phase DLT
II
9 evaluable patients 1 refused surgery
(progressive on induction management) 8
underwent surgery 6 uncomplicated wound
healing uncomplicated perioperative
phase 2 delayed wound healing
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Toxicity profile in the perioperative phase DLT
II
Case I healthy male 49 years UPS III, lateral
side calf 400 mg cohort Case II male 67 years,
heavy smoker pretibial myxofibrosarcoma 600 mg
cohort
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Response volume
No significant volume reduction at date of
surgery
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Response pathology
50 necrosis 88 (7 / 8 resection
specimens) 95 necrosis (near) complete
pathological response 50 (4 / 8 resection
specimens) (near) complete responses with
replacement of the sarcoma by a
fibro-inflammatory tissue.
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Response pathology
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Response pathology
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Oncological outcome
Median follow-up 17 months, range 6-39 months,
1 local recurrence 8 months after surgery with
a pathological complete response. he was
salvaged by surgery now NED for 25 months. 1
case wide spread pulmonary metastatic disease 14
months after surgery and he died 7 months later.
Otherwise no sarcoma related events have been
seen up to now.
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Conclusions

• Pazopanib based preoperative chemoradiation
• 800 mg once daily Pazopanib and 50 Gy / 5 weeks
  RT
• Is feasible
• Does lead to a 27 incompliance rate due to
  hepatotoxicity
• Does not lead to increased toxicity within the RT
  portals
• Does not lead to increased or delayed wound
  healing
• Does not lead to significant volume reductions
• Does induce pathological (near) CR in 50

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Conclusions

• Pazopanib based preoperative chemoradiation
• 800 mg once daily Pazopanib and 50 Gy / 5 weeks
  RT
• Is feasible
• Does lead to a 27 incompliance rate due to
  hepatotoxicity
• Does not lead to increased toxicity within the RT
  portals
• Does not lead to increased or delayed wound
  healing
• Does not lead to significant volume reductions
• Does induce pathological (near) CR in 50
• And therefore, further studies to better
  understand the biology, imaging and pathological
  characteristics, efficacy and long term toxicity
  appear warranted.

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thanks for your attention and CTOS thanks for
the invitation Rick Haas Department of
Radiotherapy, The Netherlands Cancer Institute
Amsterdam