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

Haas, Rick L.; Gelderblom, Hans; Sleijfer, Stefan; Boven, Hester H. van; Scholten, Astrid N.; Dewit, L.; Borst, Gerben R.; Hage, Jos A. van der; Kerst, J. Martijn; Nout, Remi A.; Hartgrink, Henk H.; Pree, Ilse de; Verhoef, Cornelis; Steeghs, Neeltje; Coevorden, Frits van

doi:10.3109/0284186x.2015.1037404

Cited by 56 publications

(34 citation statements)

References 27 publications

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“…Only 1 case report observed a complete response of gastric metastases from renal cancer treated with pazopanib and RT (30 Gy in 10 fractions) [42]. Other studies investigated the RT-pazopanib combination in soft tissue sarcoma [43], breast cancer [40], and in 1 case of radiation recall dermatitis [44]. …”

Section: Resultsmentioning

confidence: 99%

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

et al. 2018

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Treatment of metastatic renal cell carcinoma (mRCC) has seen substantial progress over the last decade. A number of targeted therapies have been shown to improve clinical outcome. Vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs) are an effective option in treating mRCC. RCC is traditionally perceived to be a radioresistant malignancy with a limited role of radiotherapy (RT) in the management of localized disease. While RCC appears to be radioresistant using conventionally fractionated RT, preclinical data suggest increased radiosensitivity when an ablative, hypofractionated schedule is used. RT is a common treatment for metastases; therefore, it is important to understand how best to use the combination of RT with targeted therapies. Preclinical studies have suggested that the combination of anti-angiogenic drugs with RT enhances the therapeutic effect compared with ionizing radiation alone. However, clinical data gave rise to warnings due to an increased incidence of severe gastrointestinal side effects. This article reviews the literature behind the preclinical and clinical data of the combination of RT with VEGFR-TKIs currently approved for RCC (sunitinib, sorafenib, pazopanib, and axitinib), with a focus on dose schedules as well as efficacy and toxicity.

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Section: Resultsmentioning

confidence: 99%

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

et al. 2018

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“…A recent phase I trial assessed the neoadjuvant combination of pazopanib and radiotherapy in locally advanced soft tissue sarcoma [106]. While none of the ten patients showed a volume reduction after radiotherapy, a high pathologic complete response rate (>95%) was observed in four patients.…”

Section: Targeted Therapymentioning

confidence: 99%

Advances in sarcoma diagnostics and treatment

2016

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The heterogeneity of sarcomas with regard to molecular genesis, histology, clinical characteristics, and response to treatment makes management of these rare yet diverse neoplasms particularly challenging. This review encompasses recent developments in sarcoma diagnostics and treatment, including cytotoxic, targeted, epigenetic, and immune therapy agents. In the past year, groups internationally explored the impact of adding mandatory molecular testing to histological diagnosis, reporting some changes in diagnosis and/or management; however, the impact on outcomes could not be adequately assessed. Transcriptome sequencing techniques have brought forward new diagnostic tools for identifying fusions and/or characterizing unclassified entities. Next-generation sequencing and advanced molecular techniques were also applied to identify potential targets for directed and epigenetic therapy, where preclinical studies reported results for agents active within the receptor tyrosine kinase, mTOR, Notch, Wnt, Hedgehog, Hsp90, and MDM2 signaling networks. At the level of clinical practice, modest developments were seen for some sarcoma subtypes in conventional chemotherapy and in therapies targeting the pathways activated by various receptor tyrosine kinases. In the burgeoning field of immune therapy, sarcoma work is in its infancy; however, elaborate protocols for immune stimulation are being explored, and checkpoint blockade agents advance from preclinical models to clinical studies.

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“…Recently, Jakob et al published the results of two phase I trials that explored the feasibility of concurrent sunitinib and radiotherapy for treatment of locally advanced soft tissue sarcoma (STS) prior to surgery [95, 96]. They observed acceptable toxicity which was comparable to other studies that evaluated the combination of radiotherapy with angiostatic drugs in STS, including pazopanib [97] and bevacizumab [98]. Based on favorable responses, all these studies recommended further investigation of the combination treatment in future trials [95–98].…”

Section: The Present Progress In Combined Angiostatic/radiation Therapymentioning

confidence: 99%

“…For other inhibitors, some information is available. As mentioned above, pazopanib was combined with radiotherapy in soft tissue sarcoma patients [97]. Based on a dose–escalation study, Haas et al [97] concluded that neoadjuvant pazopanib (daily dose of 800 mg daily for 6 weeks) in combination with 50 Gy (25 × 2 Gy) appeared safe, albeit that toxicity should be carefully monitored in future studies.…”

Section: The Present Progress In Combined Angiostatic/radiation Therapymentioning

confidence: 99%

“…As mentioned above, pazopanib was combined with radiotherapy in soft tissue sarcoma patients [97]. Based on a dose–escalation study, Haas et al [97] concluded that neoadjuvant pazopanib (daily dose of 800 mg daily for 6 weeks) in combination with 50 Gy (25 × 2 Gy) appeared safe, albeit that toxicity should be carefully monitored in future studies. Of note, a case study reported complete remission of gastric and esophageal metastases in a renal cancer patient after treatment with radiotherapy (10 × 3 Gy) and neoadjuvant as well as adjuvant pazopanib [101].…”

Section: The Present Progress In Combined Angiostatic/radiation Therapymentioning

confidence: 99%

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The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future

et al. 2017

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Although monotherapy with angiostatic drugs is still far from effective, there is abundant evidence that angiostatic therapy can improve the efficacy of conventional treatments like radiotherapy. This has instigated numerous efforts to optimize and clinically implement the combination of angiostatic drugs with radiation treatment. The results from past and present clinical trials that explored this combination therapy indeed show encouraging results. However, current findings also show that the combination has variable efficacy and is associated with increased toxicity. This indicates that combining radiotherapy with angiostatic drugs not only holds opportunities but also provides several challenges. In the current review, we provide an update of the most recent insights from clinical trials that evaluated the combination of angiostatic drugs with radiation treatment. In addition, we discuss the outstanding questions for future studies in order to improve the clinical benefit of combining angiostatic therapy with radiation therapy.

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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

Cited by 56 publications

References 27 publications

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

Advances in sarcoma diagnostics and treatment

The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future

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