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CLINICAL CASE SEMINAR |
Department of Medical Oncology (A.M.J., S.E., R.B., J.J.K.), Princess Margaret Hospital, University Health Network, M5G 2M9 Toronto, Ontario, Canada; and Departments of Pathology (S.L.A., A.E.) and Radiology (M.F.), University Health Network, M5G 2C4, Toronto, Ontario, Canada
Address all correspondence and requests for reprints to: Dr. Jennifer Knox, Department of Medical Oncology, Princess Margaret Hospital, University Health Network, 610 University Avenue, M5G 2M9 Toronto, Ontario, Canada. E-mail: Jennifer.knox{at}uhn.on.ca.
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Abstract |
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 Top Abstract IntroductionCase Report 1Case Report 2Case Report 3DiscussionReferences |
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Setting and Patients: Three patients with metastatic paraganglioma were treated with sunitinib at the Princess Margaret Hospital. Limited analyses of tumor tissue and germline DNA were available.
Intervention: Sunitinib at a standard dose (50 mg daily, 4 wk on, 2 wk off) was titrated to patient tolerance.
Results: One patient has achieved a near complete response, and two patients demonstrated partial responses. Two patients demonstrated germline defects suggesting a pseudo-hypoxic drive to the tumor whereas the third demonstrated immunohistochemical evidence of this phenomenon.
Conclusions: Sunitinib appears to be an active agent in this malignancy based on this limited cohort, with an understandable mechanism of action similar to that described in other hypoxia-driven tumors. A single arm phase 2 trial is underway.
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Introduction |
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TopAbstractIntroductionCase Report 1Case Report 2Case Report 3DiscussionReferences |
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Case Report 1 |
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TopAbstractIntroductionCase Report 1Case Report 2Case Report 3DiscussionReferences |
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A core biopsy containing limited tumor material was diagnosed as carcinoma with high-grade elements. Cells with clear cytoplasm were seen. There was focally positive pan-cytokeratin staining, and cytokeratin-7 staining was negative. Although not definitive, the features at biopsy were consistent with renal cell carcinoma (RCC).
After multidisciplinary review, he commenced sunitinib treatment at a standard schedule (50 mg daily for 4 wk on, 2 wk off) with a plan to reassess resectability if some response to systemic therapy was observed. He experienced mild but manageable toxicities of grade 3 neutropenia (requiring two treatment delays), grade 2 plantar-palmar erythema, and fatigue as well as grade 1 hypertension requiring treatment with an angiotensin converting enzyme inhibitor.
After two cycles of treatment, he was symptomatically improved with resolved flank pain, and the mass had diminished in size on both physical and CT examination. After six cycles of sunitinib therapy, the mass measured 9.4 cm on CT compared with baseline of 14.3 cm, meeting Response Evaluation Criteria in Solid Tumors (RECIST) criteria for a partial radiological tumor response (Fig. 1A
). His sunitinib was stopped 3 wk before surgery.
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Histological examination revealed a paraganglioma (Fig. 2A; see Table 1). Succinate dehydrogenase subunit B (SDHB) gene mutational analyses demonstrated a previously described missense germline mutation in exon 4 (I127S) in peripheral blood leukocytes; the von Hippel-Lindau (VHL) gene sequence was wild type. Postoperatively, he restarted sunitinib (after a break of 8 wk in total), but after two cycles at a dose reduction of 37.5 mg (4 wk on, 2 wk off), there was clear CT evidence of progression, with relapse in a lymph node mass posterior to the uncinate process of the pancreas (CT not shown). He remains in good health and has recently progressed after three cycles of CVD (cyclophosphamide, vincristine, and dacarbazine) chemotherapy.
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Case Report 2 |
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TopAbstractIntroductionCase Report 1Case Report 2Case Report 3DiscussionReferences |
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Surgical pathology revealed a paraganglioma invading the muscularis propria and perivesicular fat with frequent mitoses and four involved lymph nodes. Given his advanced stage, he was treated adjuvantly with combined radiation and cisplatin followed by four courses of cisplatin and etoposide.
He was subsequently lost to follow-up for 1 yr after which he presented with widespread metastatic disease in multiple organs including T3 spinal cord compression. He was managed with decompressive laminectomy and metastasectomy followed by adjuvant radiation to the area. Subsequently, he was started on sunitinib, and after two cycles a significant partial RECIST response was documented in lungs and pelvic lymph nodes. He continues on treatment and has now achieved a near complete response on CT scan after six cycles (Fig. 1B
). DNA sequencing revealed a previously undescribed germline mutation in SDHB exon 6 (C189F). He has now completed 40 wk treatment, and his disease remains stable.
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Case Report 3 |
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TopAbstractIntroductionCase Report 1Case Report 2Case Report 3DiscussionReferences |
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She remained in biochemical remission for 1 yr after which urinary catecholamines started to progressively rise. CT and octreoscanning suggested disease recurrence in the chest involving both lung fields. Treatment with a somatostatin analog for 6 months was ineffective. Similarly, 3 months of a phase 1 trial of a focal kinase adhesion inhibitor was ineffective. Subsequently, treatment with three cycles of sunitinib resulted in a marked (90%) reduction in urinary metanephrines and measurable regression of the bilateral pulmonary metastases. Adverse reactions included hypertension controlled with the 
-blocker prazosin and a self-limited facial skin rash. Posttreatment biopsy revealed down-regulation of vascular endothelial growth factor receptor (VEGFR) expression (Fig. 2B). She remains on treatment with disease that continues to regress after 40 wk (Fig. 1C).
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Discussion |
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TopAbstractIntroductionCase Report 1Case Report 2Case Report 3DiscussionReferences |
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Established treatment modalities for malignant paraganglioma include surgery and radionucleotide treatment. Systemic treatment approaches advocated to date for these patients have included combination chemotherapy with CVD (cyclophosphamide, vincrsitine, dacarbazine) (6, 7), MAID (mesna, doxorubicin, dacarbazine, ifosfamide) (8), gemcitabine (9), paclitaxel (10), and etoposide-cisplatin (11); however, treatment experience with all these regimens is limited and toxicities severe. There are no reports of targeted therapies for this malignancy. More experience with targeted agents is available for the treatment of neuroendocrine tumors in general (12) where targeted regimens based on angiogenesis have modest effectiveness (13, 14, 15, 16).
Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity, which targets platelet-derived growth factor receptor (PDGFR), VEGFR, KIT, and FLT3. In malignancies such as RCC where a therapeutic role of sunitinib has been established, the absence of the VHL gene causes accumulation of hypoxia-inducible factor- (HIF) and the production of several growth factors, including VEGF and platelet-derived growth factor (PDGF) against which sunitinib has efficacy (17).
Recent insights into the genetics of hereditary paraganglioma syndromes suggest a plausible mechanism of action of sunitinib in this malignancy. Tumors from patients with germline mutations of VHL, SDHB, SDHC, or SDHD as well as selected sporadic tumors demonstrate evidence of HIF dysregulation and activation of hypoxia-inducible target genes (18, 19). A major function of the VHL tumor suppressor protein is the targeting of the -subunits of the HIF-1 and HIF-2 transcription factors for ubiquitination and degradation (20). The ability of VHL to bind to the HIF subunits depends on the hydroxylation of two proline residues (21). Hydroxylation of these residues by proyl hydroxylases is dependent on the availability of oxygen. Furthermore, inactivation of succinate dehydrogenases increases intracellular succinate, which impairs HIF proyl hydroxylases, leading to HIF dysregulation (22). This pseudohypoxic drive is functionally analogous to defects in the VHL protein and may account for the activity of sunitinib seen in our patients with paragangliomas (Fig. 3). Our second patient demonstrates a previously undescribed mutation in a critical iron-sulfur binding site that in silico analysis (23) suggests is likely to be damaging. Several mutations have been reported near this locus that have similarly resulted in malignant phenotypes (24). Although our third patient had normal germline analysis of SDHB, SDHD, and VHL, we demonstrated immunohistochemical findings suggestive of down-regulation of VEGFR on rebiopsy (Fig. 2B), the mechanism of which remains unclear but which is consistent with the clinical response of the tumor.
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). Of particular concern with the use of this agent in this condition, is the potential for an exacerbation of hypertension, a side effect well characterized with tyrosine kinase inhibitors of VEGF (25, 26). Thus, control of baseline hypertension is of critical importance. The treating clinician must also be attentive to other side effects such as hypothyroidism, neutropenia, thrombocytopenia, diarrhea, and left ventricular dysfunction in the ongoing management of these patients (27). Given these results reported, further investigation of sunitinib in paraganglioma is warranted, and a single arm phase 2 trial is underway. This trial will aim to evaluate the clinical benefit rate [complete response (CB) + partial response (PR) + stable disease (SD)] of sunitinib in metastatic paraganglioma/ pheochromocytoma. Secondary endpoints include the effect of sunitinib on biochemical markers of disease, overall survival, time to progression, overall response rate (PR + CR), and toxicity. There will initially be up to 28 patients enrolled in a two-stage Fleming design. This information will provide crucial information about the tolerability, duration of treatment, risks, and benefits of sunitinib in this condition. The mechanism of action suggested with sunitinib suggests that other drugs of benefit in HIF-driven RCC such as sorafenib, bevacizumab, and temsirolimus may also have activity in this setting.
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Footnotes |
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First Published Online November 11, 2008
Abbreviations: CT, Computed tomography; HIF, hypoxia-inducible factor-; RCC, renal cell carcinoma; SDHB, succinate dehydrogenase subunit B; VEGFR, vascular endothelial growth factor receptor; VHL, von Hippel-Lindau.
Received August 20, 2008.
Accepted October 23, 2008.
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References |
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TopAbstractIntroductionCase Report 1Case Report 2Case Report 3DiscussionReferences |
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in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239 to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472 prolyl hydroxylase. Cancer Cell 7:77–85[CrossRef][Medline]This article has been cited by other articles:
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  S. Gonias, R. Goldsby, K. K. Matthay, R. Hawkins, D. Price, J. Huberty, L. Damon, C. Linker, A. Sznewajs, S. Shiboski, et al. Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma J. Clin. Oncol., September 1, 2009; 27(25): 4162 - 4168. [Abstract] [Full Text] [PDF]
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 J.-P. Grunfeld Lessons from Rare Renal and Adrenal Diseases Clin. J. Am. Soc. Nephrol., May 1, 2009; 4(5): 870 - 872. [Full Text] [PDF]
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