a phase i study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with...
TRANSCRIPT
A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in
patients with locally advanced soft tissue sarcoma of the extremities
CTOS 2014Rick Haas
Department of Radiotherapy, The Netherlands Cancer Institute Amsterdam
Disclosure
Investigator Initiated Research Grant GSK, but GSK had no part in the design nor the conduct of my studies
Introduction
Introduction
Local control in the majority of extremity soft tissue sarcomas (ESTS) is achieved by a combination of radical surgery and (neo-) adjuvant RT
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.
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) => conventional chemotherapy and/or targeted agents + RT
=> an increased local control (increased overall survival)=> at the cost of usually temporary acute side effects.
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) => conventional chemotherapy and/or targeted agents + RT
=> an increased local control (increased overall survival)=> at the cost of usually temporary acute side effects.
Myxoid liposarcomas (crow feet vasculature) respond rapidly to pre-op RT
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) => conventional chemotherapy and/or targeted agents + RT
=> an increased local control (increased overall survival)=> at the cost of usually temporary acute side effects.
Myxoid liposarcomas (crow feet vasculature) respond rapidly to pre-op RT
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) => conventional chemotherapy and/or targeted agents + RT
=> an increased local control (increased overall survival)=> 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 safety2 toxicity profile3 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.
Patients and Methods
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.
6 wk Pazopanib
5 wk RT 5 wk rest
surgery
3 wk observation
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
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
Results
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
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
Pathology: variety grade II / III conform inclusion criteria
FU: Median FU 17 months (range 6-39 months).
Toxicity profile in the induction phase: DLT I
6 wk Pazopanib
5 wk RT 5 wk rest
surgery
3 wk observation
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
“Systemic” toxicity profile
Grade III transaminase elevations (without hyperbilirubinemia) in 3 cases
=> leading to stopping of pazopanib
=> incompliance rate 27% (3/11)
All returned to normal values < 3 weeks
Toxicity profile in the perioperative phase: DLT II
6 wk Pazopanib
5 wk RT 5 wk rest
surgery
3 wk observation
Toxicity profile in the perioperative phase: DLT II
9 evaluable patients
1 refused surgery (progressive on induction management)
8 underwent surgery
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
Toxicity profile in the perioperative phase: DLT II
Case I healthy male 49 yearsUPS III, lateral side calf400 mg cohort
Case II male 67 years, heavy smokerpretibial myxofibrosarcoma600 mg cohort
Response: volume
No significant volume reduction at date of surgery
Size changes: at diagnosis versus at surgery
0
2
4
6
8
10
12
14
16
at diagnosis at surgery
Point in time
size
(in
cm
)
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.
Response: pathology
% necrosis
0 20 40 60 80 100
1
2
3
4
5
6
7
8 400 mg
400 mg
400 mg
800 mg
600 mg
800 mg
600 mg
600 mg
Response: pathology
% necrosis
0 20 40 60 80 100
1
2
3
4
5
6
7
8 400 mg
400 mg
400 mg
800 mg
600 mg
800 mg
600 mg
600 mg
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.
Conclusions
Pazopanib based preoperative chemoradiation
800 mg once daily Pazopanib and 50 Gy / 5 weeks RT
1 Is feasible2 Does lead to a 27% incompliance rate due to hepatotoxicity3 Does not lead to increased toxicity within the RT portals4 Does not lead to increased or delayed wound healing5 Does not lead to significant volume reductions6 Does induce pathological (near) CR in 50%
Conclusions
Pazopanib based preoperative chemoradiation
800 mg once daily Pazopanib and 50 Gy / 5 weeks RT
1 Is feasible2 Does lead to a 27% incompliance rate due to hepatotoxicity3 Does not lead to increased toxicity within the RT portals4 Does not lead to increased or delayed wound healing5 Does not lead to significant volume reductions6 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.
thanks for your attention
and CTOS: thanks for the invitation
Rick HaasDepartment of Radiotherapy, The Netherlands Cancer Institute Amsterdam