Pneumothorax as adverse event in patients with lung metastases of soft tissue sarcoma treated with pazopanib: a single reference centre case series
© Verschoor and Gelderblom; licensee BioMed Central Ltd. 2014
Received: 5 September 2014
Accepted: 24 September 2014
Published: 1 October 2014
Recently, the phase III PALETTE study introduced pazopanib (Votrient®) as treatment for adult patients with locally advanced or metastatic non-liposarcoma soft tissue sarcoma after prior treatment with doxorubicin and/or ifosfamide. Pneumothorax was reported as adverse event in 8 of 246 treated patients (3.3%) in that study. This case series presents the incidence and clinic of this complication in the Leiden University Medical Centre.
Forty-three patients were treated with pazopanib of which six patients (14.0%) developed a pneumothorax. These six patients were treated for malignant peripheral nerve sheath tumour, angiosarcoma, synovial sarcoma, fibromyxomatoid sarcoma, pleomorphic sarcoma and endometrial stromal sarcoma. All six patients had subpleural pulmonary or pleural metastases at the start of pazopanib and the pneumothorax developed during or shortly after treatment with pazopanib and was difficult to treat.
The incidence reported by us is higher than the incidence in the PALETTE study. Trials with pazopanib in renal cell carcinoma, urothelial carcinoma and cervix carcinoma did not report pneumothorax as an adverse event, suggesting pneumothorax as a specific adverse event in soft tissue sarcoma patients treated with pazopanib. This may be related to the fact that there is often pleural metastatic involvement and cystic degeneration due to pazopanib treatment may add to the risk.
The risk of an, often difficult to treat, pneumothorax during pazopanib therapy should be discussed with the patient before initiation of treatment for a pulmonary metastasized sarcoma and physicians should be alert to the occurrence of such an event.
KeywordsSoft tissue sarcoma Pazopanib Pneumothorax Adverse event Pleural metastases Pulmonary metastases
Soft tissue sarcomas (STS) are rare mesenchymal tumours originating from visceral and connective tissue. This group of tumours accounts for approximately one percent of all malignancies and consists of more than 50 histological subtypes. The only curative treatment is surgical resection with large margins with or without adjuvant radiotherapy. Treatment for locally advanced and metastatic disease is usually palliative and was until recently mostly confined to anthracyclin or ifosfamide based chemotherapy, apart from specific chemotherapy regimens used for specific subgroups. Reported response rates vary between 16-27% and median survival is reported to be 12 months. Trabectedin was introduced recently for STS, mainly for patients with (myxoid) lipo- and leiomyosarcomas[3, 4].
More recently, the phase III PALETTE study introduced pazopanib (Votrient®) as treatment for adult patients with non-lipomatous advanced STS who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo)adjuvant therapy. This was based on a progression free survival of 4.6 months for pazopanib versus 1.6 months in the placebo arm. Pazopanib is an oral anti-angiogenic multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptors (VEGFR) 1, 2 and 3, platelet derived growth factor receptors and KIT. In the PALETTE study, treatment with pazopanib was complicated by the occurrence of a pneumothorax in 8 of the 246 patients. This case series reports on the incidence and clinic of this complication in all consecutive patients treated at the Leiden University Medical Centre.
The incidence of pneumothorax of 14.0% in our institution was higher than the previous reported incidence (3.3%) in the PALETTE trial. Literature does not provide the incidence of secondary spontaneous pneumothorax in STS patients, but it is probably uncommon. Other trials with pazopanib in for example urothelial cancer, renal cell cancer, pancreatic neuroendocrine tumours and cervical cancer did not report pneumothorax as an adverse event[6–11]. Trials with sunitinib, another VEGFR inhibitor, in renal cell carcinoma also do not report pneumothorax as an adverse event[12, 13]. Only, two cases are published in literature of patients with a spontaneous pneumothorax during sunitinib treatment for renal cell carcinoma[14, 15]. This suggests that this is a specific adverse event in metastatic STS treated with pazopanib, however, it could still be due to underreporting in other studies or due to the natural course of this disease that predominantly metastasizes to the lungs.
One of the proposed mechanisms is necrosis of a metastasis due to therapy, resulting in a pleural defect. Another possible explanation would be a check valve mechanism due to compression of bronchioles by a lung metastasis causing hyperinflation of a lung segment and rupture of lung parenchyma. In our patients all cases of pneumothorax were related to pleural or subpleural lung metastases, and were observed in both progressive and responding patients. Smoking is a risk factor for primary spontaneous pneumothorax, but only one of our six patients had a smoking history. We do not think smoking history is relevant for the occurrence of a pneumothorax in these patients. As with other cancer related pneumothoraxes they were difficult to treat. One of the explanations for the difficult treatment in these patients could be the use of pazopanib, which inhibits angiogenesis and thereby tissue regeneration.
A larger series is needed in a case control setting to gain more understanding of this phenomenon.
The risk of a difficult to treat pneumothorax during pazopanib therapy should be discussed with the patient before initiation of treatment for a pulmonary metastasized sarcoma and physicians should be alert to the occurrence of such an event.
Written informed consent was obtained from every patient in the PALETTE study or the pazopanib compassionate use program for use of their medical data for scientific purposes. A copy of the written informed consent is available for review by the Editor-in-Chief of this journal.
Soft tissue sarcoma
Vascular endothelial growth factor receptor.
- ESMO/European Sarcoma Network Working Group: Soft tissue and visceral sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012, 23 (Suppl 7): vii92-vii99.Google Scholar
- Sleijfer S, Seynaeve C, Verweij J: Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care. Oncologist. 2005, 10 (10): 833-841. 10.1634/theoncologist.10-10-833View ArticlePubMedGoogle Scholar
- Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, Rodenhuis S, Ray-Coquard I, Bonvalot S, Collin F, Jimeno J, Di Paola E, Van Glabbeke M, Nielsen OS: Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005, 23 (3): 576-584.View ArticlePubMedGoogle Scholar
- Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A: Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009, 27 (25): 4188-4196. 10.1200/JCO.2008.21.0088View ArticlePubMedGoogle Scholar
- van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schoffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P, : Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012, 379 (9829): 1879-1886. 10.1016/S0140-6736(12)60651-5View ArticlePubMedGoogle Scholar
- Friedlander M, Hancock KC, Rischin D, Messing MJ, Stringer CA, Matthys GM, Ma B, Hodge JP, Lager JJ: A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 2010, 119 (1): 32-37. 10.1016/j.ygyno.2010.05.033View ArticlePubMedGoogle Scholar
- Necchi A, Mariani L, Zaffaroni N, Schwartz LH, Giannatempo P, Crippa F, Morosi C, Lanocita R, Sava T, Ortega C, Messina C, Sacco C, Pennati M, Daidone MG, Nicolai N, De Braud F, Gianni AM, Salvioni R: Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol. 2012, 13 (8): 810-816. 10.1016/S1470-2045(12)70294-2View ArticlePubMedGoogle Scholar
- Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID: A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013, 49 (6): 1287-1296. 10.1016/j.ejca.2012.12.010View ArticlePubMedGoogle Scholar
- Rautiola J, Utriainen T, Peltola K, Joensuu H, Bono P: Pazopanib after sunitinib failure in patients with metastatic renal cell carcinoma. Acta Oncol. 2014, 53 (1): 113-118. 10.3109/0284186X.2013.794957View ArticlePubMedGoogle Scholar
- Pili R, Qin R, Flynn PJ, Picus J, Millward M, Ho WM, Pitot H, Tan W, Miles KM, Erlichman C, Vaishampayan U: A phase II safety and efficacy study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer. Clin Genitourin Cancer. 2013, 11 (4): 477-483. 10.1016/j.clgc.2013.05.005PubMed CentralView ArticlePubMedGoogle Scholar
- Ahn HK, Choi JY, Kim KM, Kim H, Choi SH, Park SH, Park JO, Lim HY, Kang WK, Lee J, Park YS: Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours. Br J Cancer. 2013, 109 (6): 1414-1419. 10.1038/bjc.2013.470PubMed CentralView ArticlePubMedGoogle Scholar
- Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA: Sunitinib versus interferon Alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007, 356 (2): 115-124. 10.1056/NEJMoa065044View ArticlePubMedGoogle Scholar
- Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee S-H, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R: Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009, 10 (8): 757-763. 10.1016/S1470-2045(09)70162-7View ArticlePubMedGoogle Scholar
- Katta A, Fesler MJ, Tan A, Vuong G, Richart JM: Spontaneous bilateral pneumothorax in metastatic renal cell carcinoma on sunitinib therapy. Cancer Chemother Pharmacol. 2010, 66 (2): 409-412. 10.1007/s00280-010-1291-3View ArticlePubMedGoogle Scholar
- Kleontas A, Asteriou C, Lalountas M, Konstantinou E, Barbetakis N: Spontaneous pneumothorax complicating sunitinib therapy. Hippokratia. 2011, 15 (3): 281-282.PubMed CentralPubMedGoogle Scholar
- Lee M-J, Kim E-K, Kim MJ, Kwak JY, Hong S, Park CS: Spontaneous pneumothorax in metastatic thyroid papillary carcinoma. J Clin Oncol. 2007, 25 (18): 2616-2618. 10.1200/JCO.2007.11.0130View ArticlePubMedGoogle Scholar
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