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van Meekeren M, Bovee JVMG, van Coevorden F, et al. A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma. Acta Oncol. 2021;60(12):1557-1564doi: 10.1080/0284186X.2021.1971294.
van Meekeren, M., Bovee, J. V. M. G., van Coevorden, F., van Houdt, W., Schrage, Y., Koenen, A. M., Miah, A. B., Zaidi, S., Hayes, A. J., Thway, K., Krol, S., Fiocco, M., Gelderblom, H., Steeghs, N., & Haas, R. L. (2021). A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma. Acta oncologica (Stockholm, Sweden), 60(12), 1557-1564. https://doi.org/10.1080/0284186X.2021.1971294
van Meekeren, Milan, et al. "A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma." Acta oncologica (Stockholm, Sweden) vol. 60,12 (2021): 1557-1564. doi: https://doi.org/10.1080/0284186X.2021.1971294
van Meekeren M, Bovee JVMG, van Coevorden F, van Houdt W, Schrage Y, Koenen AM, Miah AB, Zaidi S, Hayes AJ, Thway K, Krol S, Fiocco M, Gelderblom H, Steeghs N, Haas RL. A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma. Acta Oncol. 2021 Dec;60(12):1557-1564. doi: 10.1080/0284186X.2021.1971294. Epub 2021 Sep 23. PMID: 34554030.
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Acta Oncol. 2021 Dec;60(12):1557-1564. doi: 10.1080/0284186X.2021.1971294. Epub 2021 Sep 23.

A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma.

Acta oncologica (Stockholm, Sweden)

Milan van Meekeren, Judith V M G Bovee, Frits van Coevorden, Winan van Houdt, Yvonne Schrage, Anne Miek Koenen, Aisha B Miah, Shane Zaidi, Andrew J Hayes, Khin Thway, Stijn Krol, Marta Fiocco, Hans Gelderblom, Neeltje Steeghs, Rick L Haas

Affiliations

  1. Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
  2. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
  3. Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  4. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  5. Department of Clinical Oncology, The Royal Marsden Hospital and The Institute of Cancer Research, London, United Kingdom.
  6. Department of Surgery, The Royal Marsden Hospital and The Institute of Cancer Research, London, United Kingdom.
  7. Department of Pathology, The Royal Marsden Hospital and The Institute of Cancer Research, London, United Kingdom.
  8. Department of Radiotherapy, Leiden University Medical Center, Leiden, the Netherlands.
  9. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
  10. Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

PMID: 34554030 DOI: 10.1080/0284186X.2021.1971294

Abstract

PURPOSE: A prior phase I study showed that the neo-adjuvant combination of pazopanib and radiotherapy was well tolerated, and induced promising pathological responses in soft-tissue sarcoma patients. Results of the subsequent prospective, multicenter phase II, PASART-2 trial are presented here, further investigating the efficacy and safety of this combination.

PATIENTS AND METHODS: Patients with high-risk, localized soft-tissue sarcoma received neo-adjuvant radiotherapy, 50 Gy in 25 fractions (PASART-2A) or with a subsequent dose de-escalation to 36 Gy in 18 fractions (PASART-2B). This was combined with 800 mg once daily pazopanib, which started one week before radiotherapy and finished simultaneously. After an interval of 4-8 weeks, surgical resection was performed. The primary endpoint was the rate of pathological complete responses (pCR), defined as ≤5% viable cells.

RESULTS: 25 patients were registered in the study, 21 in PASART-2A and 4 in PASART-2B. After central pathology review, the combination treatment led to a pCR in 5 patients (20%). 17 patients (68%) experienced grade 3+ toxicities during neo-adjuvant treatment, of which the most common were alanine aminotransferase (ALT) elevation, aspartate aminotransferase (AST) elevation, and hypertension, all asymptomatic. Grade 3+ acute post-operative toxicities occurred in 5 patients (20%), of which the most common was wound infection. All patients completed the full radiotherapy regimen and underwent surgery. Pazopanib was discontinued before completion in 9 patients (36%), due to elevated ALT and/or AST, and shortly interrupted in 2 patients (8%), due to hypertension.

CONCLUSION: Apart from asymptomatic hepatotoxicity, the study regimen was well tolerated. Although the pre-specified efficacy endpoint (30% pCR) was not met, a more than doubling of historical pCR rates after neo-adjuvant radiotherapy alone was observed, which warrants further investigation.

Keywords: Sarcoma; combined modality treatment; molecular targeted therapy; pazopanib; radiotherapy; soft tissue

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