Pazopanib in the Treatment of Bone Sarcomas: Clinical Experience

Abstract

Background:
The effect of chemotherapy in metastatic bone sarcomas is poor and the condition is invariably fatal. Therefore, new treatment modalities are intensely needed. Pazopanib is a selective multitargeted tyrosine kinase inhibitor that has proven to be effective in the treatment of metastatic soft tissue sarcomas. The objective of this study was to evaluate the off-label use of pazopanib in patients with metastatic bone sarcomas who failed standard chemotherapy.

Methods:
All patients with metastatic bone sarcomas treated with pazopanib between October 1st, 2011 and October 1st, 2017 at the Department of Oncology, Aarhus University Hospital were evaluated. Demographics, treatment, and survival outcomes were collected and analyzed.

Results:
Nineteen patients were identified. The median age was 38 years (range 18-62). Most of the patients (50%) were diagnosed with osteosarcoma. All patients had documented disease progression at the time of initiating pazopanib treatment. The median overall survival was 11 months. Median progression free survival was 5.4 months. Out of 19 patients, 13 (68%) had either partial response or stable disease. In five patients, the dose of pazopanib was reduced because of toxicity.

Conclusion:
Off-label use of pazopanib is effective in the treatment of metastatic bone sarcomas of different histologies. Pazopanib was well tolerated in the treatment of patients with refractory bone sarcomas. Studies examining the effect of pazopanib alone or in combination with chemotherapy or other targeted therapies are needed.

Full text

Pazopanib in the Treatment of
Bone Sarcomas: Clinical
Experience
*
Ninna Aggerholm-Pedersen, Phillip Rossen, Hanne
Rose and Akmal Safwat
Department of Oncology, Aarhus University Hospital,
Aarhus, Denmark
Abstract
BACKGROUND: The effect of chemotherapy in metastatic bone sarcomas is poor and the condition is invariably
fatal. Therefore, new treatment modalities are intensely needed. Pazopanib is a selective multitargeted tyrosine
kinase inhibitor that has proven to be effective in the treatment of metastatic soft tissue sarcomas. The objective
of this study was to evaluate the off-label use of pazopanib in patients with metastatic bone sarcomas who failed
standard chemotherapy. METHODS: All patients with metastatic bone sarcomas treated with pazopanib
between October 1st, 2011 and October 1st, 2017 at the Department of Oncology, Aarhus University Hospital
were evaluated. Demographics, treatment, and survival outcomes were collected and analyzed. RESULTS:
Nineteen patients were identified. The median age was 38 years (range 18e62). Most of the patients (50%) were
diagnosed with osteosarcoma. All patients had documented disease progression at the time of initiating
pazopanib treatment. The median overall survival was 11 months. Median progression free survival was 5.4
months. Out of 19 patients, 13 (68%) had either partial response or stable disease. In five patients, the dose of
pazopanib was reduced because of toxicity. CONCLUSION: Off-label use of pazopanib is effective in the
treatment of metastatic bone sarcomas of different histologies. Pazopanib was well tolerated in the treatment of
patients with refractory bone sarcomas. Studies examining the effect of pazopanib alone or in combination with
chemotherapy or other targeted therapies are needed.
Translational Oncology (2020) 13, 295–299
Introduction
Bone sarcoma is a rare and heterogeneous group of mesenchymal
cancers. Patients with advanced bone sarcoma have a poor prognosis,
and less than 25% of these patients become long-term survivors [1].
Even though different treatment modalities have been tested, no
standard regimen is recommended for second-line treatment of
metastatic osteosarcoma [2]. Therefore, new treatment modalities are
needed.
Pazopanib is a second-generation selective receptor tyrosine kinase
inhibitor (TKI) with high affinity for vascular endothelial growth factor
receptor (VEGFR), activity against platelet-derived growth factor
receptor (PDGFR), against tyrosine-protein kinase kit (KIT) and a
modest activity against fibroblast growth factor receptor (FGFR) [3].
Pazopanib is approved for second-line treatment in nonadipocytic soft
tissue sarcoma after failure of standard chemotherapy [4]. This
approval is based on the PALETTE study, a global, double blind,
randomized, Phase 3 trial comparing the efficacy of pazopanib versus
placebo for the treatment of metastatic STS. The result of the study
was a prolonged PFS for patients treated with pazopanib (median 18
weeks) compared with placebo (median 6 weeks). In addition, the
increased PFS for patients with soft tissue sarcoma treated with
pazopanib did not compromise patient quality of life [5].
Investigation of tissue samples from osteosarcoma patients have
shown that the vascular endothelial growth factor (VEGF) and the
mitogen-activated protein kinase (MAPK) pathway are critical
signaling pathway for the overall survival (OS) of these patients [6].
www.transonc.com
Volume 13 Number 2 February 2020 pp. 295–299 295
Address all correspondence to: Ninna Aggerholm-Pedersen, MD, MSc, PhD, Palle
Juul-Jensens Boulevard 998200 Aarhus N, Denmark. E-mail: ninnpe@rm.dk
*
Support: No funding.
Received 18 July 2019; Revised 26 November 2019; Accepted 1 December 2019
©2019 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
1936-5233/19
https://doi.org/10.1016/j.tranon.2019.12.001

Also, the platelet-derived growth factor receptors (PDGFRs) [7,8]
and the signal transduction pathways of phosphatidylinositol
30-kinase/mammalian target of rapamycin (PI3K/mTOR) [9] play a
role in the prognosis of osteosarcoma patients. For chondrosarcoma,
different isoforms for VEGFR are involved in the tumor development
[10]. Sorafenib is an orally active multikinase inhibitor that targets
MAPK, VEGFRs, and PDGFRs, which has been demonstrated to be
effective in patient with high-grade osteosarcoma after failure of
standard treatments [11e13]. All these studies are small and
investigate only a few patients.
A few case reports have demonstrated an effect of pazopanib in
bone sarcoma. One study has investigated the effect on refractory
Ewing sarcoma [14] and two other on metastatic osteosarcoma
[15,16] both with promising results.
Treatment of bone sarcoma with pazopanib is an example for
off-label use of an experimental drug which can be approved by the
Danish Medical Council on doctors'request. In this article, we report
our experience on treating metastatic bone sarcoma with pazopanib as
an experimental drug.
Material and Method
Study Cohort
All patients diagnosed with bone sarcoma and treated with
pazopanib for metastatic disease at Aarhus Sarcoma Centre were
included in the study. The first patient was treated on October 1st,
2011, and the study period ended October 1st. 2017 to ensure a
proper follow-up time for all patients included. Patients with
extraskeletal bone sarcoma were excluded from the analysis. This
resulted in a cohort of 21 patients. However, two patients were
excluded because of death before pazopanib treatment was initiated.
See Figure 1 for potential candidate for pazopanib treatment and
reason for exclusion.
Data Sources
Clinical data were obtained from the newly validated population--
based Aarhus Sarcoma Registry (ASR) and the National Quality
Sarcoma Database [17], which contains comprehensive clinical
information on each sarcoma patient from 1979 to 2019.
Treatment
Patients were diagnosed and treated, according to national
guidelines, by an experienced multidisciplinary sarcoma team. The
decision of using off-label pazopanib was made by the consultant in
charge of bone sarcoma treatment. The study drug was taken orally
once daily. The patients were seen on day 10, at week 4, and every 12
weeks thereafter. Treatment continued until disease progression
according to RECIST criteria, unacceptable toxic effects, or death.
Twelve-lead electrocardiograms and a multigated acquisition
(MUGA) scan were assessed before the start of treatment. Only
grade 3 or 4 toxicities are reported in this study and no differentiation
between grade 3 and 4 toxicities are made.
Data Analysis and Statistics
The primary endpoint was progression free survival (PFS) defined
as time from start of pazopanib treatment to either disease progression
or death from any cause. Patients alive at the time of analysis were
censored. Secondary endpoint was OS. The study period ended
October 1st, 2017. However, the patients were followed until
February 1st, 2019. Patients alive at this date were censored.
Descriptive data are presented and PFS is illustrated using a
KaplaneMeier plot. All statistical analyses were performed by using
Stata version 15.
Ethics
The Ethics Committee of Denmark (1-10-72-233-12) and the
Danish Agency of Data Protection (1-16-02-677-15) have approved
the study.
Results
From October 2011 to October 2017, 19 patients from Aarhus
Sarcoma Centre were treated with pazopanib for metastatic bone
sarcoma. The median age at the beginning of pazopanib treatment
was 39 years (range 18e62 year) and median duration between the
diagnosis of bone sarcoma and the beginning of pazopanib was 2.7
years (range 0.8e38 year). A median of two prior treatment
modalities of chemotherapy (range 0e6) was administrated before
start of pazopanib and all patients had radiological progression disease
at the start of pazopanib. For patient, tumor and treatment
characteristic at the time of diagnosis, see Table 1, at start of
pazopanib treatment, see Table 2.
Response to Treatment
Fifteen patients started with full dose of pazopanib (800 mg daily),
one with reduced dose of 600 mg daily and three patients with
400 mg daily based on physicians'evaluation of patients'performance
status and comorbidity. Of the 19 patients, 13 patients had clinical
benefit in the form of partial response (6 patients) or stable disease (7
patients) as best response, 4 patients had progression of the disease as
best response, and 2 patients were not evaluated as they died within 8
Figure 1. A total of 27 patients could potentially have been
treated with pazopanib in the study period. The total number of
patients with bone sarcoma were identified in the national
quality sarcoma database including all patient treated in
Denmark. These data represent patient form one of the two
sarcoma centres in Denmark. However, the reasons for not
offering the patient pazopanib were as followed. Two patients
died who before treatment were initiated. Three patients had
giant cell histology and three chordoma patients were not
considered.
296 Pazopanib in the Treatment of Bone Sarcomas Aggerholm-Pedersen et al. Translational Oncology Vol. 13, No. 2, 2020

weeks after treatment with pazopanib was initiated. All patients stop
treatment because of progression at the time of evaluation.
Four patients with chondrosarcoma were included in this study,
two patients had low grad tumors, one patient had intermediate grade
tumor, and one patient had high-grade tumor. The two patients with
low-grade tumors had stable disease as best response, whereas the
patients with high- or intermediate-grade tumors both progressed and
did not have any effect of Pazopanib. The rest of the patients treated
with pazopanib had a high-grade malignancy.
Patients with partial response had all high-grade tumors, three
patients with osteosarcoma, one patient with radiation-induced
osteosarcoma, one patient with Ewing sarcoma, and one patient with
spindle cell sarcoma. For these patients, the median time from the
start of pazopanib treatment until progression was 8.4 months (range
minemax: 2.7e19.3).
Toxicity to Treatment
Five patients did not experience any grade 3/4 toxicity during
pazopanib treatment. Ten patients experienced one or two grade 3/4
toxicities and four patients had more than two grade 3/4 toxicities
during pazopanib treatment. Pazopanib-related grade 3 or 4 toxicities
are summarized in Table 3. No toxic deaths were reported. Five
patients were reduced in pazopanib dose because of toxicity and two
patients terminated treatment because of toxicity.
Follow-Up and Progression Free Survival
The median follow-up time after start of pazopanib treatment was
10 months (range 1.5e41 months). The median OS rate from the
start of pazopanib treatment was 11 months (85% CI: 5.4e19.3).
The median PFS from start of pazopanib treatment was 5.5 months
(95% CI: 2.7e7.7). Figure 2 shows the PFS from start of pazopanib
treatment to progression. Three patient has a PFS >15 months. None
of these patients had the same histological subtype.
Eight patients were treated after progression of pazopanib and for
eleven patients pazopanib was the last treatment received. Four
Table 1. Patient Characteristic at Time of Diagnosis
Primary Tumor n(%)
Age
Mean (range) 35 (10e54)
Gender
Male 14(74)
Female 5 (26)
Stage
Localized advanced 13(68)
Metastatic 6(32)
Comorbidity
No 16(84)
Yes 3(16)
Primary Location
Extremities 10(53)
Thorax/pelvis 9(47)
Histology
Osteosarcoma 8(42)
Chondrosarcoma 4(21)
Ewing sarcoma 3(16)
Spindle cell/other 4(21)
Treatment
Surgery 4(21)
Surgery þCht/RT 10(52)
Surgery þRT þCht 3(16)
Cht þ/RT 2(11)
Primary Cured
Yes 16(84)
No 3(16)
RT: radiation therapy, Cht: Chemotherapy.
Table 2. Patient Characteristic at Start of Pazopanib Treatment
Start of Pazopanib n(%)
Age
Median (range) 39(18e62)
Site of Metastasis
Lung 1(5)
Extra pulmonary 2(11)
Lung and extra pulmonary 11(58)
Local 5(26)
Time from Diagnosis
Median in year (range) 2.67(0.8e38)
Treatment Before Pazopanib
*
Median number of lines 2(0e6)
Median number of cycles
y
10.5(4e20)
Pazopanib Start Dose
800 mg 15(79)
600 mg 1(5)
400 mg 3(16)
Best Response to Pazopanib
Partial response 6(32)
Stable disease 7(37)
Progression 4(21)
Not evaluable 2(11)
*
Treatment given for metastatic disease.
y
For patient who were treated with chemotherapy before pazopanib.
Table 3. Pazopanib Related Toxicity (Grade 3/4)
Number (%)
Hematological 2(11)
Neutropenia 1(5)
Elevated lever parameters 2(11)
Elevated creatinine 1(5)
Elevated blood pressure 3(16)
Fatigue 5(26)
Mucositis 2(11)
Others 6(32)
Diarrhea 3(16)
0.25 .5 .75 1
0 5 10 15 20 25
Months (timed from start of pazopanib treatment)
19 11 3 3 1 0
Number at risk
95% CI Survivor function
Progression free survival
Figure 2. Progression free survival for patient with metastatic
bone sarcoma treated with pazopanib. The number of
patients is 19. All patients have at the time of follow-up
progressed.
Translational Oncology Vol. 13, No. 2, 2020 Pazopanib in the Treatment of Bone Sarcomas Aggerholm-Pedersen et al. 297

patient received chemotherapy, two patient other tyrosine kinases
inhibitors, and two patients received more than one treatment
modalities. Figure 3 shows a swimmer plot from the start of
pazopanib treatment until progression or death.
Discussion
Despite different salvage strategies, refractory or metastatic bone
sarcoma is usually fatal. Given the limited success of chemotherapy,
efforts focusing on identifying targetable molecules are needed. Our
results showed that pazopanib is well tolerated and seem to have a
benefit in terms of PFS.
When metastatic or recurrence has occurred, the prognosis is much
poorer as chemotherapy resistance develops, along with the lack of a
recommended second-line treatment for refractory metastatic
osteosarcoma, new modalities must be explored.
Pazopanib is a second-generation selective multitargeted receptor
TKI and objective responses to treatment with a vascular endothelial
growth factor receptor inhibitor have been observed in patients with
Ewing sarcoma, synovial sarcoma, and osteosarcoma [16,18]. A resent
paper on pazopanib treatment of relapsed osteosarcoma patients find
a PFS of 6 months which is in accordance with our findings [16]. A
study published by Seto et al. including 18 bone sarcoma patients of
different histology showed a disease control rate (DCR) for bone
sarcoma of 39% [19]. Our results show a DCR of 68% which much
higher. Furthermore, the response rates, progression free survival, and
overall survival shown in our study are comparable with the efficacy
shown using sorafenib either alone or in combination with
Everolimus [11e13].
In terms of toxicity, pazopanib appeared to be an acceptable
treatment. The toxicity profile in our cohort is in line with the
PALETTE study [4].
“In 2018 Duffaud et al. published a randomized double-blinded
placebo-controlled phase 2 study investigating the efficacy and safety
of regorafenib in adult patients with metastatic osteosarcoma. They
showed that regorafenib was well tolerated and that the PFS was 16.4
weeks with a DCR of 64% and 8% of the patients were partial
responders. These results are comparable with our result on
Pazopanib [20].”“However, a limitation of this study is the
retrospective nature or our study, the low number of patients treated
with pazopanib along with the fact that these patients represent many
different histological subtypes with different prognosis. Osteosarco-
mas represent highly aggressive tumors and Chordomas represent
slow-growing tumors. These differences should be taken into account
with interpreting the results of this paper”.
Multimodal treatment including chemotherapy and/or radiation
therapy might be necessary and the role for pazopanib in this setting
needs further investigations in bone sarcomas. The addition of
chemotherapy to Pazopanib treatment has been tested in malignant
melanoma with manageable toxicity. The foremost grade 3 toxicity
was increase in alanine aminotransferase [21]. The combination of
radiation therapy with pazopanib had been tested in the adjuvant
treatment of breast cancer patient who developed less dermatological
toxicity than matched control groups treated with radiation therapy
alone [22]. Furthermore, ongoing trials are currently assigning the
addition of pazopanib to radiotherapy in the neoadjuvant treatment
of STS [23].
Our article suggests that antiangiogenic molecules alone could be
useful in the treatment of bone sarcomas and further research
investigating the role of pazopanib in bone sarcoma could be
investigated in a phase II trial. Future studies on Pazopanib alone or
in combination with chemotherapy could with advantage be
compared with regorafenib either alone or also in combination with
chemotherapy in randomized trial.
In conclusion, our data suggest that pazopanib have some activity
against bone sarcoma. Pazopanib is approved for STS treatment and
therefore available for treating bone sarcoma. Yet, despite the
evidence indicating that pazopanib can stabilize the disease, the
PFS and OS are still poor for patients with metastatic bone sarcoma.
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