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Originally published as JCO Early Release 10.1200/JCO.2009.23.4021 on August 10 2009 © 2009 American Society of Clinical Oncology.
Long-Term Response in Primary Renal Cancer to Sequential Antiangiogenic TherapyNevada Cancer Institute, Las Vegas, NV To the Editor: The role of cytoreductive nephrectomy (CRN) in the face of metastatic renal cancer was established by two key studies—one conducted by the Southwest Oncology Group (SWOG) and the other by the European Organization for Research and Treatment of Cancer (EORTC).1,2 Both trials randomly assigned patients to interferon alone or CRN followed by interferon, and both trials showed a statistically significant survival advantage for the CRN arm. However, only patients with an operable primary were entered into the studies, and patients with performance status (PS) 2 had no benefit with CRN. PS 1 patients did not benefit as much as PS 0 patients. Many investigators have speculated that the highly active systemic agents such as sunitunib, sorafenib, temsirolimus, and bevacizumab would make the use of CRN less necessary.3 A number of phase II trials have shown that in some patients, systemic therapy can cause regression of the primary lesion but no pathologic complete responses have been reported.4–8 We report a patient with a dramatic and ongoing response in the primary lesion to a sequence of highly active systemic agents. In October 2006, a 49-year-old woman experienced progressive dyspnea, cough, diffuse back pain, and a 35-lb weight loss. A work-up revealed multiple metastatic lesions to the lungs and an 8.7- x 6.8-cm right renal mass (Fig 1) with retroperitoneal lymphadenopathy, and a L3 vertebral body metastasis. The patient underwent a biopsy of the L3 vertebral body lesion and was found to have metastatic renal carcinoma. The magnetic resonance imaging of the abdomen demonstrated the mass in the kidney to be approximately 10 cm, with extension into the renal vein and pushing into the inferior portion of the inferior vena cava. A cardiac echogram excluded tumor thrombus in the atrium, but identified pulmonary hypertension. The patient was felt not to be a candidate for nephrectomy due to her extensive metastatic disease and dyspnea.
She was given sunitunib 50 mg daily for 4 weeks. By 1 month, shortness of breath persisted. A computed tomography (CT) scan showed reduction in the size of the renal mass, but not of lung metastases. Sunitunib was therefore changed to continual dosing at 37.5 mg daily. Over repeated monthly cycles, symptomatic improvement occurred. Imaging showed further diminution of the renal mass and decrease in the pulmonary nodules. Back pain improved. One year (November 2007) after beginning sunitunib, signs of small bowel obstruction developed, and a new metastatic lesion in her small bowel with intussusception was identified. This lesion was resected without complications. The pathologic specimen showed a classical clear cell carcinoma. CT of the right kidney showed that the mass in the right lower pole had diminished to 4.3 cm. Due to apparent progression on continuous-dose sunitunib, she was enrolled on a clinical trial of the AKT inhibitor perifosine.9 After 12 weeks, a new lesion was identified in the left adrenal gland. The pulmonary nodules remained stable, as did the renal mass. The patient was subsequently enrolled onto a clinical trial of sorafenib 400 mg bid plus AMG 386 (a peptibody directed against the TIE2 vascular receptor). She has been receiving this treatment for 9 months, without clinical or radiographic evidence of disease progression. She no longer requires oxygen and has minimal back pain. A CT performed March 12, 2009, (Fig 2) shows that the right renal mass is now calcified and exophytic. In addition, dramatic clearing of the lung metastases has occurred. The left adrenal cystic mass remains visible, and the inferior vena cava mass has regressed. The L3 metastatic lesion has begun to recalcify.
This patient has had longer than 28 months control of the advanced renal carcinoma with an unresected renal primary following systemic antiangoigenic therapy. The ongoing improvement in renal, bone, lung, and adrenal lesions has encouraged us to continue treatment without cytoreductive nephrectomy. While we have had dramatic success in this initially unresectable patient, relatively little data are available to indicate which patients might benefit from this approach and what the duration of neoadjuvant therapy should be before CRN (if it is to be employed). In contrast to low potency agents like sorafenib, high potency agents such as sunitunib, pazopanib, or axitinib may prove advantageous for this approach.10 It has been suggested that the greater the fraction of total tumor burden removed by CRN, the greater the benefit of CRN to the patient.11 A randomized study of CRN followed by sunitunib (4 weeks on/2 weeks off schedule) versus sunitunib and delayed CRN (after 3 cycles/18 weeks in nonprogressors) is being developed by SWOG and EORTC with the hypothesis that clinical responders to neoadjuvant sunitunib will predict patients who will gain the greatest benefit from CRN. In addition, there is a French study underway for patients with an intact primary and metastatic disease who will be randomly assigned to CRN followed by sunitunib or sunitunib alone. The 570-patient trial is powered for equivalence. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: Wolfram Samlowski, Amgen Honoraria: Wolfram Samlowski, Genentech, Novartis, Pfizer, Enzon Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal cell cancer. N Engl J Med 345:1655–1659, 2001. 2. Mickisch GH, Garin A, van Poppel H, et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal cell carcinoma: A randomised trial. Lancet 358:966–970, 2001.[CrossRef][Medline] 3. Samlowski WE, Wong B, Vogelzang NJ: Management of renal cancer in the tyrosine kinase inhibitor era: A view from 3 years on. BJU Int 102:162–165, 2008.[CrossRef][Medline] 4. van der Veldt AA, Meijerink MR, van den Eertwegh AJ, et al: Sunitinib for treatment of advanced renal cell cancer: Primary tumor response. Clin Cancer Res 14:2431–2436, 2008. 5. Shuch B, Riggs SB, Larochelle JC, et al: Neoadjuvant targeted therapy and advanced kidney cancer: Observations and implications for a new treatment paradigm. BJU Int 102:692–696, 2008.[CrossRef][Medline] 6. Amin C, Wallen E, Pruthi RS, et al: Preoperative tyrosine kinase inhibition as an adjunct to debulking nephrectomy. Urology 72:864–868, 2008.[CrossRef][Medline] 7. Jonasch E, Tannir NM: Adjuvant and neoadjuvant therapy in renal cell carcinoma. Cancer J 14:315–319, 2008.[Medline] 8. Rathmell KW, Cowey C, Amin C, et al. A pilot study of neoadjuvant sorafenib for the treatment of stage T2 or higher renal cell carcinoma American Society of Clinical Oncology 2009 Genitourinary Cancers Symposium, Orlando, FL, February 26-28, 2009, abstr 315. 9. Vogelzang NJ, Hutson TE, Samlowski W, et al. Phase II study of perifosine in metastatic RCC (clear and non-clear) progressing after one prior therapy (Rx) with a VEGF receptor inhibitor American Society of Clinical Oncology 2009 Genitourinary Cancers Symposium, Orlando, FL, February 26-28, 2009, abstr 302. 10. Shuch B, Said J, La Rochelle JC, et al. Cytoreductive nephrectomy for patients with advanced kidney cancer and sarcomatoid histology: Is up-front resection indicated, avoidable, and is there an alternative? American Society of Clinical Oncology 2009 Genitourinary Cancers Symposium, Orlando, FL, February 26-28, 2009, abstr 282. 11. Barbastefano J, Garcia JA, Elson P, et al. Association of percentage of tumor burden removed with debulking nephrectomy and progression free survival (PFS) in metastatic renal cell carcinoma (mRCC) patients (Pts) treated with VEGF-targeted therapy American Society of Clinical Oncology 2009 Genitourinary Cancers Symposium, Orlando, FL, February 26-28, 2009, abstr 280.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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