Pazopanib in Renal Cell Carcinoma Dialysis Patients: A Mini-Review and a Case Report

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1 Send Orders for Reprints to Current Drug Targets, 2016, 17, Pazopanib in Renal Cell Carcinoma Dialysis Patients: A Mini-Review and a Case Report Melissa Bersanelli 1, *, Francesco Facchinetti 1, Marcello Tiseo 1, Mariarosa Maiorana 2 and Sebastiano Buti 1 1 Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; 2 Nephrology and Dialysis Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy Abstract: Background: Sporadic data are available about pazopanib use in patients with metastatic renal cell carcinoma (mrcc) undergoing dialysis and no systematic review has been previously performed about this issue. Objective: The objective of the present mini-review is to provide an overview of clinical outcomes of pazopanib in this population, in order to support the clinical oncologist for the treatment choice and management. Results: All the literature ever published about mrcc dialysis patients receiving pazopanib, until August 2015, was evaluated: only two case series emerged from our search and one more patient from our department was also included, with a total of 11 mrcc dialysis patients overall. Moreover, we described our case of intrapatient dose titration of pazopanib during dialysis. Conclusion: The continued treatment schedule, the short half-life, the predominantly hepatic metabolism, the wide possibility of dose modulation, the favorable tolerability profile and the similar efficacy respect to sunitinib represent factors in favor of pazopanib as first line mrcc treatment in dialysis patients. The knowledge and the good management of toxicity during pazopanib treatment can lead, also in dialysis patients, to the best and longest application of the drug, taking into account the concept of a dose escalation guided by toxicity as a marker of efficacy. The review, together with our single case report, confirmed the efficacy, the good tolerability and the maneuverability of pazopanib treatment in mrcc patients undergoing dialysis. Keywords: Dialysis, dose titration, hemodialysis, pazopanib, renal cell carcinoma, TKI. 1. INTRODUCTION The coexistence of metastatic renal cell carcinoma (mrcc) and renal failure is not an uncommon clinical condition which complicates the management of both situations. Most cases of renal cancer are described in patients previously underwent renal transplantation for end stage renal disease (ERSD); on the other hand, renal function in mrcc patients is often impaired by the tumor itself or by surgical nephrectomy (sometimes bilateral) [1]. The demonstration of a certain activity and tolerability of different drugs for treatment of mrcc patients affected by ESRD undergoing dialysis have been described by the literature. Tyrosine kinase inhibitors (TKI) have contributed to step into a new era of mrcc treatment; the handling of these new drugs classes in dialysis patients is challenging and there are only case reports or case series published in the international literature on this topic, in particular describing the outcome and tolerance of treatment with sunitinib and sorafenib [2]. Very less data are reported for pazopanib use in this setting, with the lack of a clear evidence in order to *Address correspondence to this author at the University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; Tel/Fax: ; melissa.bersanelli@alice.it support the oncologist with the choice of this drug for dialysis mrcc patients. Pazopanib is a multitarget TKI that inhibits angiogenesis by suppressing signal transduction pathways involving multiple receptor tyrosine kinases, principally vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR- 3), platelet-derived growth factors (PDGFR-, PDGFR- ), and stem cell factor receptor [3]. It has been approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for mrcc patients on the basis of a phase III, placebo-controlled, randomized trial demonstrating its activity in renal cancer patients, with the prolongation of progression free survival (PFS) respect to placebo, and of the non-inferiority respect to sunitinib [4-6]. The recommended dose and schedule for pazopanib is 800 mg orally once daily until disease progression or severe toxicity. The most frequent (>10%) adverse reactions are represented by diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, asthenia, abdominal pain, headache; the most frequent hematologic and blood-chemistry alterations (>10%) are represented by leucopenia, neutropenia, thrombocytopenia and lymphocytopenia; increase in liver transaminase and bilirubin; alteration of blood glucose; decrease in sodium, magnesium and phosphorus. Potentially serious adverse reactions included hepatotoxicity, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, and hyperten /16 $ Bentham Science Publishers

2 2 Current Drug Targets, 2016, Vol. 17, No. 5 Bersanelli et al. sive crisis. Pazopanib has a half-life of 31 hours; its four major metabolites constitute only 6% of the exposure in plasma and only one of them is active; the drug is principally metabolized in the liver by CYP3A4 and its isoenzymes and excreted in feces; renal excretion is < 4% [7]. Its safety, pharmacokinetics and efficacy have not yet been evaluated by clinical trials in patients with renal impairment but no dose adjustments are required based on renal function. The objective of the present mini-review with a case report is to provide an overview of clinical outcomes of pazopanib in dialysis patients, providing useful suggestions for the drug management in these special cases. 2. METHODS All the literature ever published about mrcc dialysis patients receiving pazopanib, until August 2015, was evaluated by searching in the National Library of Medicine Database MEDLINE. The search items were (Pazopanib v Votrient) and (RCC v Renal Cancer v Kidney Cancer) and (Dialysis v Hemodialysis); references of pertinent articles were handsearched for additional relevant citations. In addition, the clinical report of a single mrcc dialysis patient treated with pazopanib at our institution was also described. 3. RESULTS The literature search identified only two abstracts and titles about pazopanib use in this population, corresponding to two case series of dialysis patients treated with targeted therapies (including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, everolimus and temsirolimus). A total of 11 patients treated with pazopanib were selected for this minireview, also including our own case described above; characteristics of patients and therapy are reported in (Table 1). The first case series including dialysis patients treated with pazopanib was reported by Shetty et al. [8]; of nine patients, seven had clear cell RCC (ccrcc), whilst two had papillary histology. Four patients received pazopanib as first line treatment and five received the drug from third to fifth line of therapy. Considering all nine patients, six of them had a dose reduction because of toxicity (mostly diarrhea and fatigue); only five patients started at the full dose of 800 mg/die. Three patients received 800 mg per day without needing a dose reduction; two cases started at 800 mg per day and then decreased at 400 mg and at 600 mg per day, respectively due to toxicity; the remaining four cases started at reduced dose of 600 mg per day of pazopanib, and moreover, they all needed a dose reduction because of toxicity. The median time of treatment in this group was of 11.6 months. Outcome of treatment in terms of response rate was not reported. In a more recent case series by Czarnecka et al. [9], among nine mrcc dialysis patients only one case received pazopanib, at the full dose of 800 mg/die, not requiring reductions during the relatively short time of treatment (4 Table 1. Patients and treatment characteristics. Patients Histology MSKCC Risk Treatment Line with Pazopanib Initial Daily Dose Dose Reductions Cause for Dose Reductions Dose Titration Duration of Treatment (Months) 1 clear cell poor fifth 800 mg 400 mg diarrhea none clear cell intermediate first 600 mg 400 mg fatigue, decreased appetite none papillary intermediate third 600 mg 400 mg myalgias, decreased appetite none clear cell intermediate first 600 mg 400 mg fatigue none U 5 clear cell favorable first 800 mg none NA none U 6 clear cell poor first 600 mg 400 mg liver toxicity none papillary favorable third 800 mg 200 mg hepatic encephalopathy none clear cell favorable third 800 mg none NA none clear cell poor fourth 800 mg 600 mg diarrhea, fatigue none clear-cell U first 800 mg none NA none 4 11 clear-cell intermediate first 400 mg none NA 800 mg 14 U = unknown; NA = not applicable.

3 Pazopanib Treatment During Dialysis Current Drug Targets, 2016, Vol. 17, No. 5 3 months). In this case, treatment was discontinued due to occurrence of disease progression Case Report In March 2013, a 43-year-old male underwent surgical cytoreductive nephrectomy, together with caval ligature and left renal vein resection, for poorly differentiated clear cell renal carcinoma, G3 according to Fuhrman classification, with eosinophilic-papillary features (pt3c according to TNM staging system). In the post-surgical time the patient developed anuria, which rapidly led to hemodialysis treatment. A phenomenon of systemic widespread of arterial and venous thrombosis required chronic oral anticoagulant therapy and the occurrence of arterial hypertension required treatment with beta-blocker and calcium-antagonist combination. In July 2013, the CT scan evidenced disease progression with the involvement of left adrenal gland, the appearance of a single secondary lesion in the liver and of pathological abdominal lymph nodes. Considering the stage of disease and the intermediate risk according to the Memorial Sloan Kettering Cancer Center (MSKCC) score, at the moment of our decision for systemic treatment, no data was available for pazopanib use during dialysis, therefore, we selected this drug as a first line treatment in our patient after careful considerations as will be later discussed. We decided to start with the half dose of 400 mg per day, with the intention to titrate the dose subsequently depending on the tolerability. At baseline, in July 2013, the patient's general conditions were good (PS=0); high-efficiency on-line hemodiafiltration (OL-HDF) went on for three times per week. During the first two weeks of treatment, we found grade 2 (G2) thrombocytopenia, neutropenia and anemia. Inadequate arterial pressure control with G3 hypertension required the addiction of alphalithic and ACE-inhibitor drugs to the previous therapies, reaching satisfactory blood pressure levels after the implementation of dialysis volumes. G2 diarrhea was easily overcome with loperamide. After two months of treatment, good clinical conditions persisted, despite suboptimal blood pressure control, G1-2 thrombocytopenia and neutropenia, bleached hair and the development of subclinical hypothyroidism, which required treatment with levothyroxine. In October 2013, after three months of 400 mg per day therapy, a CT scan revealed good disease control, showing the liver lesion stability and the necrotic evolution of adrenal and nodal localizations Fig. (1). Pazopanib was continued at the same dose; in the next three months of treatment the patient was substantially asymptomatic and the described toxicity almost completely went into remission. Fig. (1). Consecutive images of CT evaluation of target lesions during treatment with pazopanib. From July to October 2013: necrotic evolution of the adrenal lesion after three months of therapy with pazopanib 400 mg per day. From October 2013 to February 2014: increase of the solid component of the adrenal lesion after the sixth month of treatment with pazopanib 400 mg per day. From February to April 2014: necrotic evolution of the liver lesion after two months of pazopanib titration with 800 mg per day administration.

4 4 Current Drug Targets, 2016, Vol. 17, No. 5 Bersanelli et al. In spite of this, the CT scan subsequently performed in February 2014, evidenced disease progression Fig. (1), with the solid component increase both in adrenal, hepatic and nodal lesions. Considering the good treatment tolerability and the clinical benefit and reasoning about the previous concomitance between radiological response and the main toxicity occurrence, which we interpreted as a predictive marker of TKI efficacy as suggested by the literature [10], we decided to continue with pazopanib treatment beyond progression and to escalate the dose to 800 mg per day, with the aim to regain sensitivity to the drug. This dose increase led to the recurrence of some adverse effects, such as G3 diarrhea and uncontrolled hypertension (G3), which we managed without treatment discontinuation or dose reduction. Anyhow, the dose titration proved to be successful in the recovering of the disease response to treatment: a new radiological response of disease, with necrotic evolution of the liver lesion and stability of nodal and adrenal lesions, was indeed demonstrated by the CT scan performed in April 2014 Fig. (1) and confirmed by the subsequent CT evaluations until September 2014, when bone progression occurred. Pazopanib treatment was discontinued and subsequently the patient received other two treatment lines (sorafenib and then sunitinib). 4. DISCUSSION The choice of pazopanib as a first line treatment for dialysis mrcc patients is, in our opinion, definitely sustained by several factors: a) the treatment schedule, with continue administration; b) the relatively short half-life, of 31 hours; c) the drug metabolism, predominantly hepatic; d) the wide possibility of dose modulation; e) the favorable tolerability profile and the similar efficacy when compared with sunitinib in a phase 3, randomized trial, confirming pazopanib as an optimal option for the first line treatment of mrcc [11]. About the treatment schedule, an on-off therapy (such as that provided for sunitinib) would have resulted in a more complicated management in a patient undergoing oral anticoagulant therapy; conversely, the continuous schedule was more suitable also considering the regular timing of dialysis, ensuring a more constant steady-state plasma exposure. The shorter half-life with respect to other TKIs (31 hours versus hours and hours for sunitinib and its active metabolite, respectively) gives this drug a greater maneuverability; moreover, its metabolism is an element in favor of a low probability of its accumulation due to renal failure. Finally, pazopanib has more possibilities of dose escalation and modulation, with three reduction levels from 800 mg per day to 200 mg per day, accordance with other TKIs. About the best tolerability as per sunitinib, we are sustained by the results of the COMPARZ trial and the PISCES trial (the latter based on patients preference), with the assessment of a lower incidence of fatigue (55% vs. 63%), hand-foot syndrome (29% vs. 50%) and thrombocytopenia (41% vs. 78%), corresponding to a better quality of life, in patients treated with pazopanib [11, 12]. Interestingly, in the case series described by Shetty et al., considering several drugs in different lines of treatment, pazopanib was the most commonly prescribed targeted therapy even in the complete lack of previous published evidences, with a prolonged median time of treatment, despite the wide dose reductions required for toxicity during treatment. No intrapatient dose titration has been reported among the 10 published cases; all doses modifications were in sense of reduction related to toxicity. A metabolic accumulation of the small percentage of drug requiring a renal elimination could be responsible of a higher exposure to pazopanib and consequently of a worse tolerability in these patients. Conversely, in our own case, after primary partial response and significant toxicity with the reduced dose of pazopanib, at the moment of disease progression, given the remission of toxicity, we decided to titrate the exposure to the drug, beyond radiological disease progression, with the purpose of recovering sensitivity to treatment. The attempt to regain objective response of disease in mrcc by intrapatient dose escalation of TKI treatment has been previously reported as somewhat successful in the literature, demonstrating the feasibility of toxicity-driven dose titration to improve drug exposure in patients with stable disease or previous response to the same treatment [13, 14], but it has never been attempted with pazopanib nor in dialysis patients. The apparent correlation between clinical and radiological outcome and the intensity of adverse events noticed in our patient Fig. (2) confirmed the strong correlation between toxicity and response of disease to TKI treatment already reported in mrcc, in which the entity of adverse events could represent an important predictive marker of drug efficacy [10]. Furthermore, a recent publication has strongly emphasized the link between drug blood concentrations, adverse effects and efficacy of TKI in mrcc [15]. In the absence of available molecular predictive markers, the identification of pure clinic predictive factors is strongly required in mrcc patients, especially in dialysis patients having more limited therapeutic chances, for whom the best drug selection is mandatory. An interesting field of research from this point of view could be represented by a better knowledge of specific polymorphisms of genes encoding enzymes and efflux transporters, candidate to influence each drug metabolism and pharmacokinetic, conditioning and predicting its effectiveness, regardless of the molecular pathway implicated in the specific mechanism of action of the drug [16-19]. In our case, the decline of toxicity in the last period of treatment with pazopanib at 400 mg per day could have been due to an increase of the drug metabolism, possibly ascribable to cytochrome P450 (CYP) hyperactivity induced by pazopanib itself and by other substances ERSD-related through months, and also to a certain adaptation to the achieved systemic drug levels. A considerable amount of work has been made to assess TKI in vivo metabolism with the influence of systemic alteration caused by ERSD: it is actually known that non-renal drug metabolism is influenced by renal disease and dialysis [20-22]. For other TKIs, such as sunitinib and sorafenib, although only a small amount of drug and its metabolites are presents in the dialysate, the blood concentrations have been shown to be widely dependent on the day in which dialysis occurs, in a way not simply explained by the variation of the blood volume [23-25]. The

5 Pazopanib Treatment During Dialysis Current Drug Targets, 2016, Vol. 17, No. 5 5 transcription and expression levels and the biological activity of CYP-3A4, a key-enzyme for pazopanib metabolism, are strongly influenced by several endogenous and exogenous substances [26-28]. Applying these considerations to the patients herein described, we admit that the lack of knowledge of pazopanib blood and dialysate levels, in concomitance with the assumption of several concomitant drugs potentially affecting CYP activity, constitute the limiting factors of our speculation. In fact, an accurate knowledge of the pharmacokinetics of the drug will be required to sustain our hypothesis: nevertheless, we unsuccessfully requested the Glaxo Smith & Kline for the pure standard of pazopanib in order to perform a pharmacokinetic (PK) study at least in our patient. Fig. (2). Graphical representation of toxicity trend during pazopanib treatment and its correlation with dose change and radiologic findings. CONCLUSION With the limits described above, we can state that pazopanib demonstrated to be safe and potentially effective also in dialysis mrcc patients. The knowledge and the good management of toxicity during pazopanib treatment can lead, also in these frail patients, to the best and longest application of the drug, taking into account the concept of a dose escalation guided by toxicity as a marker of efficacy. CONFLICT OF INTEREST None to declare for Dr. Melissa Bersanelli, Dr. Francesco Facchinetti, Dr. Marcello Tiseo, Dr. Mariarosa Maiorana and for Dr. Sebastiano Buti. ACKNOWLEDGEMENTS Dr. Melissa Bersanelli and Dr. Sebastiano Buti managed the design, performance, descriptive analysis and reporting of the work. Dr. Frascesco Facchinetti contributed substantially to the data collection, performance and reporting of the work. Dr. Marcello Tiseo contributed substantially to the design, descriptive analysis and reporting of the work. 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