Case Report
Complete Pathologic Response in Soft Tissue Sarcoma Lung Metastases with Pazopanib Zeynep Eroglu, MD, Jae Kim, MD, Sharon Wilczynski, MD, PhD, and Warren A. Chow, MD
A
62-year-old man developed a right quadriceps mass in May 2011; biopsy demonstrated a high-grade undifferentiated pleomorphic sarcoma. A wide resection of a 15 × 10 × 6.8 cm tumor was performed with negative margins. He received 6000 cGy adjuvant radiation. A computed tomography (CT) scan in May 1, 2012 demonstrated two new pulmonary nodules in the left to 10 mm, and one in the right. CT-guided biopsy of the largest left lung nodule on May 17, 2012 confirmed metastasis. He received two cycles of doxorubicin and ifosfamide through June 2012. A restaging CT scan on July 5, 2012 demonstrated progression in the two left-sided pulmonary nodules, up to 18 mm. He then received pazopanib 800 mg daily. CT scan 2 months later demonstrated marked regression in the left-sided pulmonary metastases from 18 to 8 mm (Fig. 1), along with regression of the largest right-sided pulmonary lesion from 5 to 2 mm (Fig. 2). Therefore, the patient underwent metastasectomy via left-sided video-assisted thoracoscopic surgery. During surgery, five nodules were found and treated with wedge resections. Postsurgery CT showed only scattered unchanged micronodules in the right lung. Pathology demonstrated a complete pathologic response with no viable tumor in any of the resected nodules (Fig. 3A and B). Patient was continued on pazopanib for 3 more months. Repeat CT imaging February 14, 2013 showed only postsurgical changes in the left upper lobe with unchanged micronodules in the right.
DISCUSSION Soft tissue sarcomas (STSs) are malignant, mesenchymal tumors that comprise more than 50 different histological
subtypes. Surgery and radiation are the principal treatments for localized tumors. Adjuvant chemotherapy has not improved survival, and outcomes for recurrent or metastatic STS are poor because of their relative insensitivity to chemotherapy. Distant metastases will develop in about 25% of patients, with increased rates in 5 cm or higher-grade tumors; in more than 70% of patients, metastases will be to the lung.1 Pulmonary metastatectomy for sarcoma is established as standard of care; one systemic review of 1357 pulmonary metastasectomy patients revealed 25% alive after 5 years after the surgery, with better survival in patients with fewer metastases and longer interval from diagnosis.2 However, to date there has been no randomized trial comparing survival in patients who undergo pulmonary metastasectomy versus no surgery. Pazopanib is an oral angiogenesis inhibitor of multiple targets including vascular endothelial growth factor, plateletderived growth factor, and c-kit receptors. There were nine partial responses but no complete responses in a phase 2 trial of pazopanib in 138 advanced STS patients.3 A phase 3 trial compared pazopanib to placebo in advanced STS patients who had progressed after chemotherapy. Pazopanib provided a 3-month improvement in median progression-free survival from 1.6 to 4.6 months, leading to United States Food and Drug Administration approval in advanced nonliposarcoma STS after failure of anthracycline chemotherapy.4 There were 14 partial responses among the 246 patients randomized to pazopanib, although it is unclear how many were undifferentiated pleomorphic sarcoma. There were no complete responses. To the best of our knowledge, this is the first report of a pathologic complete response to pazopanib in advanced STS.
Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California. Disclosure: The authors declare no conflict of interest. Address for correspondence: Warren A. Chow, MD, FACP, Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0901-00e4
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Journal of Thoracic Oncology ® • Volume 9, Number 1, January 2014
Journal of Thoracic Oncology ® • Volume 9, Number 1, January 2014
Complete Pathologic Response in STS
FIGURE 1. Restaging CT scan after doxorubicin and ifosfamide chemotherapy on July 5, 2012 (left) demonstrated progression in the two left-sided pulmonary nodules, up to 18 mm. Patient was treated with pazopanib. Follow-up CT scan on September 27, 2012 (right) demonstrated a marked regression in the left-sided pulmonary metastases from 18 to 8 mm. CT, computed tomography.
FIGURE 2. Response in the largest right-sided pulmonary lesion from 5 to 2 mm after 2 months of pazopanib. Arrows indicate the lung metastases responding to pazopanib.
FIGURE 3. A, Pulmonary metastasis biopsy (May 17, 2012): the high power (H&E, 40×) demonstrates a high-grade spindle cell sarcoma with highly pleomorphic cells, bizarre multinucleated giant cells, and numerous mitotic figures. B, Wedge resection of pulmonary metastases (October 22, 2012) that had regressed on CT imaging after pazopanib was initiated showed only fibrosis, mild inflammatory infiltrate of histiocytes, and a few lymphoid cells. No viable tumor was identified (H&E, 4×). CT, computed tomography; H&E, hematoxylin and eosin.
Copyright © 2013 by the International Association for the Study of Lung Cancer
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Journal of Thoracic Oncology ® • Volume 9, Number 1, January 2014
Eroglu et al.
REFERENCES 1. Billingsley KG, Lewis JJ, Leung DH, Casper ES, Woodruff JM, Brennan MF. Multifactorial analysis of the survival of patients with distant metastasis arising from primary extremity sarcoma. Cancer 1999;85:389–395. 2. Treasure T, Fiorentino F, Scarci M, Møller H, Utley M. Pulmonary metastasectomy for sarcoma: a systematic review of reported outcomes in the context of Thames Cancer Registry data. BMJ Open 2012;2.
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3. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009;27:3126–3132. 4. van der Graaf WT, Blay JY, Chawla SP, et al; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebocontrolled phase 3 trial. Lancet 2012;379:1879–1886.
Copyright © 2013 by the International Association for the Study of Lung Cancer
Complete Pathologic Response in Soft Tissue Sarcoma Lung Metastases with Pazopanib Zeynep Eroglu, MD, Jae Kim, MD, Sharon Wilczynski, MD, PhD, and Warren A. Chow, MD
A
62-year-old man developed a right quadriceps mass in May 2011; biopsy demonstrated a high-grade undifferentiated pleomorphic sarcoma. A wide resection of a 15 × 10 × 6.8 cm tumor was performed with negative margins. He received 6000 cGy adjuvant radiation. A computed tomography (CT) scan in May 1, 2012 demonstrated two new pulmonary nodules in the left to 10 mm, and one in the right. CT-guided biopsy of the largest left lung nodule on May 17, 2012 confirmed metastasis. He received two cycles of doxorubicin and ifosfamide through June 2012. A restaging CT scan on July 5, 2012 demonstrated progression in the two left-sided pulmonary nodules, up to 18 mm. He then received pazopanib 800 mg daily. CT scan 2 months later demonstrated marked regression in the left-sided pulmonary metastases from 18 to 8 mm (Fig. 1), along with regression of the largest right-sided pulmonary lesion from 5 to 2 mm (Fig. 2). Therefore, the patient underwent metastasectomy via left-sided video-assisted thoracoscopic surgery. During surgery, five nodules were found and treated with wedge resections. Postsurgery CT showed only scattered unchanged micronodules in the right lung. Pathology demonstrated a complete pathologic response with no viable tumor in any of the resected nodules (Fig. 3A and B). Patient was continued on pazopanib for 3 more months. Repeat CT imaging February 14, 2013 showed only postsurgical changes in the left upper lobe with unchanged micronodules in the right.
DISCUSSION Soft tissue sarcomas (STSs) are malignant, mesenchymal tumors that comprise more than 50 different histological
subtypes. Surgery and radiation are the principal treatments for localized tumors. Adjuvant chemotherapy has not improved survival, and outcomes for recurrent or metastatic STS are poor because of their relative insensitivity to chemotherapy. Distant metastases will develop in about 25% of patients, with increased rates in 5 cm or higher-grade tumors; in more than 70% of patients, metastases will be to the lung.1 Pulmonary metastatectomy for sarcoma is established as standard of care; one systemic review of 1357 pulmonary metastasectomy patients revealed 25% alive after 5 years after the surgery, with better survival in patients with fewer metastases and longer interval from diagnosis.2 However, to date there has been no randomized trial comparing survival in patients who undergo pulmonary metastasectomy versus no surgery. Pazopanib is an oral angiogenesis inhibitor of multiple targets including vascular endothelial growth factor, plateletderived growth factor, and c-kit receptors. There were nine partial responses but no complete responses in a phase 2 trial of pazopanib in 138 advanced STS patients.3 A phase 3 trial compared pazopanib to placebo in advanced STS patients who had progressed after chemotherapy. Pazopanib provided a 3-month improvement in median progression-free survival from 1.6 to 4.6 months, leading to United States Food and Drug Administration approval in advanced nonliposarcoma STS after failure of anthracycline chemotherapy.4 There were 14 partial responses among the 246 patients randomized to pazopanib, although it is unclear how many were undifferentiated pleomorphic sarcoma. There were no complete responses. To the best of our knowledge, this is the first report of a pathologic complete response to pazopanib in advanced STS.
Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California. Disclosure: The authors declare no conflict of interest. Address for correspondence: Warren A. Chow, MD, FACP, Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0901-00e4
e4
Journal of Thoracic Oncology ® • Volume 9, Number 1, January 2014
Journal of Thoracic Oncology ® • Volume 9, Number 1, January 2014
Complete Pathologic Response in STS
FIGURE 1. Restaging CT scan after doxorubicin and ifosfamide chemotherapy on July 5, 2012 (left) demonstrated progression in the two left-sided pulmonary nodules, up to 18 mm. Patient was treated with pazopanib. Follow-up CT scan on September 27, 2012 (right) demonstrated a marked regression in the left-sided pulmonary metastases from 18 to 8 mm. CT, computed tomography.
FIGURE 2. Response in the largest right-sided pulmonary lesion from 5 to 2 mm after 2 months of pazopanib. Arrows indicate the lung metastases responding to pazopanib.
FIGURE 3. A, Pulmonary metastasis biopsy (May 17, 2012): the high power (H&E, 40×) demonstrates a high-grade spindle cell sarcoma with highly pleomorphic cells, bizarre multinucleated giant cells, and numerous mitotic figures. B, Wedge resection of pulmonary metastases (October 22, 2012) that had regressed on CT imaging after pazopanib was initiated showed only fibrosis, mild inflammatory infiltrate of histiocytes, and a few lymphoid cells. No viable tumor was identified (H&E, 4×). CT, computed tomography; H&E, hematoxylin and eosin.
Copyright © 2013 by the International Association for the Study of Lung Cancer
e5
Journal of Thoracic Oncology ® • Volume 9, Number 1, January 2014
Eroglu et al.
REFERENCES 1. Billingsley KG, Lewis JJ, Leung DH, Casper ES, Woodruff JM, Brennan MF. Multifactorial analysis of the survival of patients with distant metastasis arising from primary extremity sarcoma. Cancer 1999;85:389–395. 2. Treasure T, Fiorentino F, Scarci M, Møller H, Utley M. Pulmonary metastasectomy for sarcoma: a systematic review of reported outcomes in the context of Thames Cancer Registry data. BMJ Open 2012;2.
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3. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009;27:3126–3132. 4. van der Graaf WT, Blay JY, Chawla SP, et al; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebocontrolled phase 3 trial. Lancet 2012;379:1879–1886.
Copyright © 2013 by the International Association for the Study of Lung Cancer
