Prolonged survival after treatment of metastatic renal cell cancer: a case report

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1 Gerontologija 2012; 2013; 13(1): 14(3): GERONTOLOGIJA Original article Prolonged survival after treatment of metastatic renal cell cancer: a case report A. Ulys 1, R. Grigienė 2,5, D. Šlaitas 3, A. Gradauskas 4,5,6, S. Selickaja 5, A. Žalimas 1 1 Department of Urology, Institute of Oncology, Vilnius University 2 Department of Radiology, Institute of Oncology, Vilnius University 3 Department of Urology, Vilnius University Emergency Hospital 4 Vilnius City Clinical Hospital, Clinic of Surgery 5 Vilnius University Faculty of Medicine 6 Departament of Nursing and Fundamentals of Internal Medicine, Vilnius University Abstract Objective: Introduce a successful treatment of metastatic renal cell carcinoma. Case presentation: 53-year-old woman underwent a radical left nephrectomy for renal cell carcinoma. Two years later, the disease replaced to her right pubic bone, spine and lung. Immunotherapy with interferon-alpha was assigned and discontinued after first dose due to allergic reaction. Disease progressed, a pulmonary tumor obturated the left main bronchus and she underwent fibro-bronchoscopy and a metastasectomy. Cytokine-based immunotherapy with interleukin-2 was initiated. Two month later, while she was on cytokines, the patient s condition worsened due to respiratory insufficiency and fever. It was decided to discontinue treatment with interleukin-2 and the patient was offered to participate in a clinical study with pazopanib. Pazopanib 800 mg once a day was started on September 15, More than 6 years after the initial diagnosis Address: A. Žalimas Department of Urology, Institute of Oncology, Vilnius University, Santariškių str. 1, Vilnius algis.zalimas@gmail.com of renal cell cancer, the patient s disease was stable and she had great improvement in quality of life. Conclusions: Pazopanib demonstrated durable activity in patients with metastatic renal cell carcinoma and was generally well tolerated in this population. This anti-angiogenic drug could prolong survival and improve quality of life. Key words: Pazopanib, metastatic renal cell carcinoma, immunotherapy, prolonged survival, ant-angiogenic drug Introduction Renal cell carcinoma (RCC) is a form of kidney cancer that arises from the cells of the renal tubule. RCC accounts for 90-95% of tumors arising from the kidney, and represents approximately 2% of all adult malignant tumors [1]. Over the past five years decades, the number of individuals diagnosed with RCC has dramatically increased: it is estimated that the prevalence in the US has risen by 126% in this period [1, 2]. Several factors may explain the rise including significant improvements in diagnosing due CT and MRI, but also additional factors like smoking, hypertension, obesity and diet have

2 142 A. Ulys, R. Grigienė, D. Šlaitas, A. Gradauskas, S. Selickaja, A. Žalimas contributed to the rising incidence of RCC [3]. The male to female ratio is 1.5 : 1 [4]. Advanced and metastatic carcinoma of renal cells is a fatal disease with a very poor prognosis. This disease is characterized by a lack of early warning signs, secret clinical manifestations, and resistance to radiation and chemotherapy [5, 6]. Limited clinical benefit was achieved in selected patients to whom the first line treatment of alpha-interferon (IFN-α) and interleukin-2 (IL-2) was administered [7, 8]. Treatment of metastatic renal cancer with cytokines (biological mediators of the immune response) IL-2 and (or) INF-alpha results in complete response in 10 to 15% of patients only and the treatment does not prolong overall survival [7]. There is no evidence that systemic treatment is effective in patients with advanced renal cancer, therefore there is currently an increased need for new effective treatments of advanced renal cancer. In recent years, clinical trials have established the role of targeted therapy as the first line of therapy in patients with metastatic disease. Although the optimal treatment strategy continues to evolve, 3 agents that target angiogenesis (sunitinib, bevacizumab, and pazopanib) and a mammalian target of rapamycin (mtor) targeted therapy (temsirolimus) have been approved as front-line agents. These agents have largely replaced cytokines (immunotherapy) in treatment metastatic renal cell carcinoma (mrcc). Case The patient, a 53-year-old woman, underwent left-sided nephrectomy on July 13, The confirmed histological diagnosis was a grade 2, stage 2 clear renal cell carcinoma (clear RCC) (pt2, N0 M0 2 cl. gr. G1). Concomitant diseases were primary arterial hypertension, obesity. In January 2006, the patient was hospitalized due to dyspnea and pain. A computed tomography (CT) scan showed suspect of multiple lung metastases with atelectasis of the left lung as well as a spinous process at lumbar-5 (L5), relapse in the renal bed and bone metastases in the right pubic with a pathological fracture of the upper branch. As the patient suffered pelvic pain, a palliative external radiation treatment course using the field 8 12 to the public bone was applied with 6 2 Gy, 24 Gy in total (Fig. 1). Immunotherapy with IFN-α 18 mln. International Units (IU) was initiated, however a severe toxic-allergic reaction developed after the first injection and immunotherapy was discontinued (Fig. 1). The patient s Fig. 1. Formation in right pubic bone after external radiation therapy condition worsened due to respiratory insufficiency. Fibro-bronchoscopy was performed in February 13, 2006, with the diagnosis of tumor obturation of the left main bronchus. The histological biopsy showed a metastasis of clear RCC. Endoscopic-endobronchial resection of the tumor of the left main bronchus was performed on February 28, 2006 with the aim to restore passage of the airways. Immunotherapy with IL-2 18 mln. IU was initiated and administered on days 1 5 of every week from March 9, 2006 to April 6, As the treatment was poorly tolerated, the dose was reduced to 9 mln. IU. Only short-term improvement was achieved, therefore immunotherapy with IL-2 (proleukin) 18 mln. IU on days 1 5 of the week was applied from April 24, 2006 to April 28, The patient s condition worsened with development of fever and dyspnea. Bronchoscopy on May 15, 2006 showed a complete atelectasis of the left lung with complete obturation of the left main bronchus by tumor. Endoscopic-endobronchial resection of the tumor was performed with stent implantation into the left main bronchus. Treatment with IL-2 1 dose of 18 mln. IU was continued (from July 24, 2006 to August 1, 2006), however the immunotherapy dose of IL-2 was reduced to 9 mln. IU for the last four days as the treatment was poorly tolerated (febrile fever, severe general weakness). Abdominal echoscopy was performed every month and negative dynamic of the disease was observed. The bronchoscopy was repeated on August 23, 2006 due to continuous dyspnea. Findings: progression of the disease, half of the stent in the left main bronchus was completely obturated by the tumor. Endoscopic resection of the tumor was not performed due to the risk of bleeding. It was decided to discontinue treatment with IL-2 and the patient was offered the opportunity to participate in a clinical study with administration of 800 mg of pazopanib once a day per os.

3 Prolonged survival after treatment of metastatic renal cell cancer: A case report 143 Chest, abdominal and pelvic CT imaging was performed every 8 to 12 weeks after the initiation of treatment with pazopanib (Fig. 2). The tumors were slightly reduced in size and the patient s condition became and remained stable from first pazopanib dose till 296 week (Figs. 3, 4). Adverse effects of pazopanib were observed such as hair depigmentation, increased weight, mild diarrhea, hypertension, face flush and heating. Side effects were up to 1 degree. Adverse effects were managed by conservative treatment. Fig. 2. Abdominal and pelvic CT revealed stabilized disease (a) (b) (c) Fig. 3. Response at week 6 of pazopanib (CT). (a) Formation in L4 vertebra was 27 mm in size. (b) Destructive formation in right bone was 37 mm in size. (c) Formation in left kidney s bed was 23 mm in size (a) (b) (c) Fig. 4. Response at week 296 of pazopanib (CT). (a) Formation in L4 vertebra was 12 mm in size. (b) Destructive formation in right pubic bone was 35 mm in size. (c) Formation in left kidney s bed was 11 mm in size. Compared with initial formations sizes tumors were 2 17 mm smaller Discussion Clear cell RCC accounts for 70% to 75% of all histologic subtypes of RCC [9]. It may progress insidiously over a span of years, but once metastasis becomes evident, the 5-year survival rate declines sharply from more than 60% to 6% [10]. In the all cases of renal cancer surgery remains the preferred therapy because RCC often is resistant to chemotherapy and radiation therapy. Our case presented here underwent a nephrectomy with curative intention since their disease was not metastatic at diagnosis, and was meticulously followed up with given that there was no indication for any adjuvant treatment.

4 144 A. Ulys, R. Grigienė, D. Šlaitas, A. Gradauskas, S. Selickaja, A. Žalimas After surgery other treatment option for mrcc is immunotherapy. Flanigan et al. proved that nephrectomy followed by interferon therapy results in longer survival among patients with mrcc than does interferon therapy alone [11]. Cytokines were considered the cornerstone of the treatment of mrcc, and IFN-α or IL-2 yielded durable, albeit rare, complete remissions in certain subgroups [8]. Unfortunately, in our case treatment with IFN-α and IL-2 was ineffective. Disease progression was observed. Angiogenesis is essential for tumor growth, invasion and development of metastasis [12, 13]. This process is mainly mediated by vascular endothelial growth factor (VEGF), and also by platelet derived growth factor (PDGF). These factors act by binding to the external domain of transmembrane receptors with intracellular tyrosine kinase activity [14, 15]. Pazopanib is the first- or second-line anti-angiogenic drug suppressing all known receptors of VEGF and PDGF for the treatment of advanced kidney cancer [16, 17]. Pazopanib (Votrient) was approved in 2009 by Food and Drug Administration (FDA) for the treatment of metastatic RCC. A randomized, double-blind, placebo-controlled phase III study of pazopanib was performed including 435 patients with advanced renal cell cancer who were previously untreated or who had failed to prior cytokine therapy. Pazopanib significantly prolonged progression-free (PFS) survival compared to placebo, irrespective of prior treatment with cytokines (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < ), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < ), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < 0.001) [18]. Pazopanib is well tolerated and safety. The most side effects like diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting were related to pazopanib treatment and were clinically manageable [18]. In our case just face flush and heating, hair depigmentation, increased weight, hypertension and diarrhea were observed. Pazopanib can significantly prolong the time to progression of disease with poor side effects in patients with mrcc. Despite the introduction of pazopanib, palliative care is still an acceptable treatment option for mrcc because of the disease s extremely poor prognosis. Pazopanib offer improved outcomes for patients with mrcc, but it is far short of a cure. Conclusions The angiogenesis inhibitor pazopanib administered orally once a day is able to prevent the growth of new blood vessels and directly affects the cause of renal cell cancer development. Described case shows pazopanib performance, enabling the patient to live and survive. It is unfortunate that this is an isolated case. Currently, pazopanib is been evaluated in the large clinical development program for treatment of different types of tumors. It is likely that the future of anti-angiogenic therapy will require a rational combination of inhibitors, directed by a better understanding of the biology of each individual type of cancer. There is no evidence that systemic therapy to be effective in the treatment of advance kidney cancer patients. Now is a great need for effective new treatments to treat advanced kidney cancer. References 1. McLaughlin JK, Lipworth L. Epidemiologic aspects of renal cell cancer. Semin Oncol. 2000; 27: Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol. 2001; 166: Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States. JAMA. 1999; 281: Wingo PA, Tong T, Bolden S. Cancer statistics, CA Cancer J Clin. 1995; 45: Nelson EC, Evans CP, Lara PN. Renal cell carcinoma: Current status and emerging therapies. Cancer Treat Rev. 2007; 33: Spronsen DJ, Weijer KJ, Mulders PF, et al. Novel treatment strategies in clear-cell metastatic renal cell carcinoma. Anticancer Drugs. 2005; 16: Negrier S, Maral J, Drevon M, et al. Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J Sci Am. 2000; 1: Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005; 1: CD Cheng L, Zhang S, MacLennan GT, et al. Molecular and cytogenetic insights into the pathogenesis, classification, differential diagnosis, and prognosis of renal epithelial neoplasms. Hum Pathol. 2009; 40: Sene AP, Hunt L, McMahon RF, et al. Renal carcinoma in patients undergoing nephrectomy: Analysis of survival and prognostic factors. Br J Urol. 1992; 70:

5 Prolonged survival after treatment of metastatic renal cell cancer: A case report 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. 2001; 345: Kamba T, McDonald DM. Mechanisms of adverse effects of anti-vegf therapy for cancer. Br J Cancer. 2007; 96: Folkman J. Anti-angiogenesis: New concept for therapy of solid tumors. Ann Surg. 1972; 175: Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996; 86: Berse B, Brown LF, van de Water L, et al. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, mac- rophages, and tumors. Mol Biol Cell. 1992; 3: Schutz BF, Choueiri TK, Sternberg CN. Pazopanib: Clinical development of a potent anti-angiogenic drug. Crit Rev Oncol Hematol. 2011; 77: Pick AM, Nystrom K. Pazopanib for the treatment of metastatic renal cell carcinoma. Clin Ther. 2012; 34: Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. JCO. 2010; 28: Received: February 20, 2013 Accepted: September 24, 2013 ILGESNIS IŠGYVENAMUMAS PO IŠPLITUSIO INKSTŲ VĖŽIO GYDYMO: KLINIKINIS ATVEJIS A. Ulys 1, R. Grigienė 2,5, D. Šlaitas 3, A. Gradauskas 4,5,6, S. Selickaja 5, A. Žalimas 1 1 Vilniaus Universiteto Onkologijos Institutas, Urologijos skyrius 2 Vilniaus Universiteto Onkologijos Institutas, Radiologijos skyrius 3 Respublikinė Vilniaus universitetinė ligoninė, Urologijos skyrius 4 Vilniaus miesto klinikinė ligoninė, Chirurgijos klinika 5 Vilniaus universiteto Medicinos fakultetas 6 Vilniaus universiteto Medicinos fakulteto Slaugos ir vidaus ligų pagrindų katedra Santrauka Tikslas: Pristatyti sėkmingą išplitusio inksto vėžio gydymą. Atvejo pristatymas: Pacientė 53 metų moteris, kuriai dėl inksto ląstelių karcinomos buvo pašalintas kairysis inkstas. Po operacijos praėjus 2 metams vėžys recidyvavo ir progresavo į plaučius, stuburą ir gaktikaulį. Taikyta imunoterapija interferonu-alfa, tačiau dėl alerginės reakcijos gydymas buvo nutrauktas jau po pirmos vaisto dozės. Paskirtas gydymas interleukinu-2 buvo neefektyvus, kadangi praėjus 2 mėnesiams pacientės būklė vis blogėjo, karščiavimas ir kvėpavimo nepakankamumas didėjo. Gydymą interleukinu-2 nuspręsta nutraukti ir pasiūlyta dalyvauti pazopanibo klinikiniame tyrime. Geriamasis vaistas pazopanibas 800 mg 1 kartą per dieną pradėtas skirti 2006 metais rugsėjo 15 dieną. Praėjus daugiau nei 6 metams pacientė jautėsi gerai ir liga išliko stabili. Išvados: Pazopanibas yra veiksmingas ir gerai toleruojamas vaistas, gydant pacientus, sergančius išplitusiu inkstų ląstelių vėžiu. Šis angiogenezės inhibitorius gali prailginti išplitusiu inksto vėžiu sergančių ligonių išgyvenamumą ir pagerinti gyvenimo kokybę. Raktažodžiai: pazopanibas, metastazavusi inksto ląstelių karcinoma, imunoterapija, ilgas išgyvenamumas, antiangiogeniniai vaistai