Long-Term Survival without Progression after Treatment Discontinuation in Patient with Metastatic RCC
Agnieszka Badora-Rybicka*1, Łukasz Zarudzki2, Danuta Starzyczny-Słota1, Elżbieta Nowara1
1Clinical and Experimental Oncology Department, Maria Skłodowska-Curie Memorial Cancer Center, Gliwice Branch, ul.
Wybrzeże Armii Krajowej 101-44 ,15 Gliwice, Poland
2Radiology and Diagnostic Imaging Department, Maria Skłodowska-Curie Memorial Cancer Center, Gliwice Branch, ul.
Wybrzeże Armii Krajowej 101-44 ,15 Gliwice, Poland
Introduction: Renal cell carcinoma (RCC) development and progression is linked with angiogenesis and both systemic and locoregional immune dysfunction. Targeted agents used in the treatment of metastatic RCC exert both antiangiogenic and immunomodulatory function. We present a case of a man with advanced clear cell RCC, who received sunitynib. The treatment was ended due to significant hepatotoxicity but the disease remains stable.
Case history: A 55-year-old man after right nephrectomy was admitted to Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch in October 2004. Metastatic workup was negative. The patient received adjuvant radiotherapy. In August 2009 lungs and mediastinal lymph nodes metastases were diagnosed. On 14th October 2009 the patient started treatment with sunitynib. He achieved a partial remission of lung and lymph node metastases but significant hepatotoxicity occurred. In March 2010 the treatment was ended due to liver dysfunction. The patient remains in control, the liver parameters have normalized and the disease has remained stable (actually for four years).
Discussion: Antiangiogenic and immuostimulatory effect of sunitynib are related to each other, as VEGF affects dendric cells differentiation. We observed a long-term stabilization of the disease, despite ending the treatment with sunitynib. It may have been caused by the impact of sunitynib on the immune system. In terms of the side effects of the therapy, determining the group of patients in whom the drug can be discontinued after obtaining optimum results would be essential for improving the quality of life.
Keywords: Renal Cell Carcinoma; Sunitynib ; Immunostimulation
Renal cell carcinoma (RCC) development and progression is linked with angiogenesis and both systemic and locoregional immune dysfunction [1,2]. The majority of clear cell RCC cases harbour Von-Hippel-Landau gene defect, with high serum levels of vascular endothelial growth factor (VEGF) [3,4]. VEGF, beyond angiogenesis, also regulates dendric cell function. Inhibition of VEGF results in activation of dendric cells and cellular immunity (type 1) [5-7].
Introducing targeted treatment into clinical practice led to a significant improvement in the survival of patients suffering from metastatic clear cell renal carcinoma [8-10]. One of such agents is sunitynib, a multikinase inhibitor, which affects tyrosine kinases, like, inter alia, VEGF, PDGF, c-Kit or STAT-3 function [8,11]. Hence sunitynib exerts both antiangiogenic and immunomodulatory function. The latter function of this drug is believed to be responsible for the long term treatment effect and is under intensive investigation . Sunitynib was shown to decrease the fraction of peripheral blood myeloid derived suppressor cells (MDSC) and regulatory T cells (Treg), which are the major immunosupresive cellular components. Moreover, the fraction of dendric cells significantly increases during treatment with sunitynib . The studies are not powered enough to widely accept these changes as new prognostic markers in clinical practice, but some of them, like neutrophil- to-lymphocyte ratio (NLR), were shown to correlate with progression free survival (PFS) .
Sunitynib treatment in advanced RCC patients is continued until disease progression or unacceptable toxicity . Treatment- related toxicity of sunitynib is well defined, common adverse events are: hand-foot syndrome, fatigue, hypertension, thyroid dysfunction, leucopoenia . These toxicities are usually of mild or intermediate grade, but sometimes lead to treatment breaks or discontinuation. Moreover, even a mild but persistent adverse event can affect the quality of life among patients who have received the drug for a long time.
We present a case of a man with advanced clear cell RCC, who received sunitynib. The treatment was ended due to significant hepatotoxicity. Nevertheless, the disease remains stable (actually for 4 years).
A 55-year-old man was administered to Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch in October 2004. He did not suffer from any coexisting disease. His family history was negligible. On 22nd October 2004 he was operated on for right renal mass. The pathological examination revealed clear cell renal carcinoma with necrosis. Metastatic workup was negative. The patient received adjuvant radiotherapy (17.11.2004-23.12.2004) and remained under observation.
In May 2009 a suspicion of lung metastases was made. A spread of the disease was confirmed in August 2009, due to progression in size of the lesions in lungs. The patient started treatment with sunitynib on 14th October 2009. At the beginning of the treatment the blood and biochemical parameters were within normal, neutrophil-to-lymphocyte ratio (NLR) was 3,67. In February 2010, in CT scan of the chest a partial regression of metastases was described, with no further spread
to other organs. The patient continued treatment with good tolerance. Hand-foot syndrome grade 1 was observed, but the symptoms subsided after standard treatment. The patient also experienced twice neutropenia grade 2, which normalized after
one week of treatment break.
Since January 2010 we observed increase in activity of AST and ALT, without other symptoms of liver dysfunction. The patient received hepatoprotective treatment, but the liver function did not normalize. In March 2010 treatment with sunitynib was stopped, but AST and ALT reminded elevated (3 fold above the upper limit of normal range and 7 fold above the upper limit of normal range, respectively). Moreover, in CT scan of abdomen, signs of significant liver damage were described. On 17th March 2010 we decided to end sunitynib treatment due to significant hepatotoxicity. In April 2010 the liver function normalized. A CT scan of the chest was also performed. One lesion in the left lung slightly grew, other lesions were stable. To date, 4 years after treatment discontinuation, the patient has remained under control, with no further spread of RCC. Lung and lymph node metastases are still stable. The function of the liver is also correct. Chest CT scans are presented in Figures 1 – 3. Changes in AST and ALT activity are presented in Figure 4 and 5 respectively.
Figure 1. Chest CT scan of the described patient - 17.08.2009 (before sunitynib).
Figure 2. Chest CT scan of the described patient - 25.05.2010 (first CT after sunitynib cessation).
Figure 3.Chest CT scan of the described patient – 12 Sept 2014 (control).
Figure 4. Changes of AST activity during treatment and subsequent patient observation.
Figure 5. Changes of ALT activity during treatment and subsequent patient observation.
Tumor induced immune deviation is believed to be a major cause of RCC progression [1,2]. Spontaneous regressions of metastases after palliative nephrectomy were described, which was attributed to the removal of the majority of cancer cells producing immunosupresive agents [15,16]. Antiangiogenic and immuostimulatory effect of sunitynib are related to each other, as VEGF affects dendric cells differentiation . Ongoing studies indicate that activation of dendric cells and their interaction with T cells creates a powerful antitumor milieu, which results in long-term disease stabilization.
Some immunological parameters, like NLR, are proposed as new prognostic and predictive factors in patients with advanced RCC treated with sunitynib . NLR reflects balance between host immunity (lymphocytes) and cancer-related inflammation (neutrophils) . In advanced cancer patients neutrophils have been implicated as a major cause of T-cell suppression and poor prognosis [17,18]. Moreover, myeloid cells could be involved in tumor angiogenesis. RCC patients often have abnormally high frequencies of myeloid cells due to interleukin 6 (IL-6) paraneoplastic syndrome . Early phase studies suggest that lower baseline NLR is associated with longer PFS . Moreover, patients whose low pre-treatment NLR is sustained during initial therapy survive significantly longer [19,20]. A simple cut-off of NLR has not been determined yet . In most of the available analyses NLR cut-off is defined between 3,5 and 4 [14,19,20].
The second point of our case report is treatment related toxicity. Sunitynib-induced adverse events are usually of mild or intermediate grade and are curable with additional drugs and treatment break . Moreover, in many studies the occurrence of toxicity, especially hypertension or skin toxicity was associated with better response [22-25]. Hepatotoxicity of sunitynib is rare, with overall occurrence 0,4% . Our patient experienced significant hepatotoxicity, which led to treatment discontinuation. However, the disease has remained stable for four years. The liver function normalized. According to this case we can raise a question: is there a group of patients who can end sunitynib treatment after reaching the optimal effect and achieve long-term survival without disease progression? A selection of such a subgroup of patients would be attractive in the context of the quality of life. Actually, it seems that the occurrence of treatment-related toxicity alone is not enough to predict long-term PFS. An immunomodulating effect of sunitynib may contribute to long-term disease stabilization even after treatment discontinuation. Creating an anti-tumor immunological milieu with the dominance of cellular immunity (type 1) can lead to tumor regression or at least stabilization. It would be interesting to distinguish markers, which are easy to designate and indicate if we can expect a long-term anti-tumor immune response after targeted treatment in a given patient.
Cite this article: Badora-Rybicka A, Zarudzki Ł, Starzyczny-Słota D, Nowara E. Long-Term Survival without Progression after Treatment Discontinuation in Patient with Metastatic RCC. J J Clini Case Rep. 2015, 1(4): 016.