Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature.

BACKGROUND: Sunitinib and pazopanib are both oral small molecule multityrosine kinase inhibitors (MTKI) used in the treatment of renal cell carcinoma (RCC). Hepatotoxicity or "liver injury" is the most important adverse effect of pazopanib administration, but little is known about the underlying mechanism. Liver injury may also occur in patients treated with sunitinib, but severe toxicity is extremely rare. Herein we report two new cases of severe liver injury induced by MTKI. Both cases are unique and exceptional. We assessed both cases for drug-induced liver injury (DILI) using the updated score Roussel Uclaf causality assessment method (RUCAM). The literature on potential pathogenic mechanisms and precautionary measures is reviewed. CASE PRESENTATION: A case of a metastatic RCC (mRCC) patient treated with pazopanib who had manifestation of severe liver injury is presented. These manifestations consisted of grade 4 alanine aminotransferase (ALT) increase and grade 4 hyperbilirubinemia. Alternate causes of acute or chronic liver disease were excluded. The patient gradually recovered from the liver injury and refused any further therapy for mRCC. The patient was diagnosed with acute myeloid leukemia (AML) two years later and eventually succumbed to the disease. The second case describes a mRCC patient treated with sunitinib for 3,5 years and fatal liver failure after 2 weeks of clarithromycin co-medication for acute bronchitis. CONCLUSIONS: Liver injury has been commonly observed in TKI-treated patients with unpredictable course. Management requires regular routine liver enzyme-monitoring and the collaboration of medical oncologist and hepatologist. There is an unmet medical need for a risk stratification and definition of predictive biomarkers to identify potential genetic polymorphisms or other factors associated with TKI-induced liver injury. Any potential unrecommended concomitant therapy has to be avoided.

A Pathological Complete Response to the Combination of Ipilimumab and Nivolumab in a Patient with Metastatic Renal Cell Carcinoma.

Background and Objectives: Complete pathological response after ipilimumab and nivolumab combination therapy in a patient with intermediate prognosis renal cell carcinoma is an uncommon finding. Case presentation: A 60-year-old man presented with synchronous solitary metastatic bone lesion and renal cell carcinoma and achieved a complete pathological response after surgical resection of the bone lesion, followed by ipilimumab and nivolumab combination therapy and nephrectomy. The treatment was complicated by hypophysitis and oligoarthritis more than a year after the initiation of the therapy. Conclusions: Currently, the combination therapy based on immune checkpoint inhibitors represents the treatment of choice in patients with intermediate- and poor-risk prognosis metastatic renal cell carcinoma. In the present case, preoperative therapy with ipilimumab and nivolumab resulted in a complete pathological response in the renal tumor. Vigilance concerning potential immune-related side effects is warranted throughout the course of therapy and the subsequent follow-up.

Pembrolizumab plus axitinib combination and the paradigm change in the treatment of advanced renal cell carcinoma.

Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved outcomes obtained with combination regimens based on immune checkpoint inhibitors. Most patients treated with sequential monotherapy eventually develop drug resistance and succumb to progressive disease, leading to the search for therapies that would overcome drug resistance and result in a more durable treatment response. Improved outcomes have been demonstrated in Phase III trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab and ipilimumab plus nivolumab. A statistically significant improvement of both progression-free and overall survival has been demonstrated for the axitinib plus pembrolizumab combination.

Neopterin as a potential prognostic and predictive biomarker in metastatic renal cell carcinoma treated with immune checkpoint inhibitors.

INTRODUCTION: Immunotherapy represents a significant and essential component of renal carcinoma therapy (RCC), but the selection of an optimal regimen for an individual patient remains unclear. Despite significant improvements in therapeutic options for RCC, predictive biomarkers for immunotherapeutic agents remain elusive. Neopterin is a biomarker of cell-mediated immune response, with concentrations increased in different disorders, including cancer. High neopterin levels herald, in general, a poor prognosis. AREAS COVERED: This review briefly overviews the contemporary clinical data on biomarkers in metastatic RCC therapy, focusing on neopterin. EXPERT OPINION: Elevated neopterin levels have been observed in tumors of different primary locations. Research indicates that neopterin may serve as a potential biomarker for assessing the inflammatory status associated with certain cancers. However, it is necessary to interpret neopterin levels in the context of a comprehensive clinical evaluation, as elevated neopterin alone is not specific to cancer and can be influenced by other factors, including comorbid conditions. Neopterin has also been identified as a prognostic biomarker. An increasing neopterin level in serum and urine is associated with advanced cancer, but the role as a potential predictor of response to immunotherapy has yet to be established. A reliable biomarker for optimal therapy selection in metastatic RCC is still putative.

The Evolving Landscape of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma.

The role of cytoreductive nephrectomy in metastatic renal cell carcinoma (RCC) has been studied intensively over the past few decades. Interestingly, the opinion with regard to the importance of this procedure has switched from a recommendation as a standard of care to an almost complete refutation. However, no definitive agreement on cytoreductive nephrectomy, including the pros and cons of the procedure, has been reached, and the topic remains highly controversial. With the advent of immune checkpoint inhibitors, we have experienced a paradigm shift, with immunotherapy playing a crucial role in the treatment algorithm. Nevertheless, obtaining results from prospective clinical trials on the role of cytoreductive nephrectomy requires time, and once some data have been gathered, the standards of systemic therapy may be different, and we stand again at the beginning. This review summarizes current knowledge on the topic in the light of newly evolving treatment strategies. The crucial point is to recognize who could be an appropriate candidate for immediate cytoreductive surgery that may facilitate the effect of systemic therapy through tumor debulking, or who might benefit from deferred cytoreduction in the setting of an objective response of the tumor. The role of prognostic factors in management decisions as well as the technical details associated with performing the procedure from a urological perspective are discussed. Ongoing clinical trials that may bring new evidence for transforming therapeutic paradigms are listed.

Bacillus Calmette-Guérin pneumonitis after intravesical instillation: Report of two cases and a review of the literature.

OBJECTIVE: Intravesical administration of bacillus Calmette-Guérin is standard adjuvant treatment of non-muscle invasive bladder cancer. In spite of the fact that this immunotherapy is locoregional, there are still risk of some complications. METHODS: We describe two cases of systemic BCG infection after intravesical administration of BCG vaccine in patients with early stage of bladder cancer. RESULTS: Both patients suffered from systemic BCG infection manifesting as BCG pneumonitis. After standard therapy with antituberculotic agents, both of them fully recovered. CONCLUSION: BCG infection can occur as a rare but potentially serious complication of this treatment procedure. Gravity of this side effect and its specific therapy require prompt and right diagnosis.

Biomarkers of Inflammation and Progression During Immunotherapy in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: Biomarkers that would identify patients unlikely to respond to immunotherapy with immune checkpoint inhibitors (ICIs) remain an unmet medical need. PATIENTS AND METHODS: In the present study, we have retrospectively evaluated the association between biomarkers of immune activation and outcome in metastatic renal cell carcinoma (mRCC) patients treated with ICIs. The laboratory and clinical data of 79 consecutive patients with histologically confirmed mRCC treated with ICI-based immunotherapy have been analyzed. RESULTS: Patients who progressed or died at 4 months had higher prognostic score, higher serum C-reactive protein (CRP) and neopterin, and urinary neopterin, and lower serum albumin and hemoglobin concentration. CONCLUSION: Biomarkers of activation of immune response, in particular serum neopterin/creatinine ratio, are associated with outcome in mRCC patients treated with ICI immunotherapy.

Pembrolizumab plus axitinib for the treatment of advanced renal cell carcinoma.

Introduction: The dominant paradigm of sequential therapy of metastatic renal cell carcinoma (mRCC) with single agents has recently been challenged by improved outcomes obtained with combined regimens with immune checkpoint inhibitors. These combined regimens include the combination of pembrolizumab plus axitinib.Areas covered: Here, we provide a brief overview of the current clinical data on the pembrolizumab plus axitinib combination including mechanism of action, pharmacokinetics, efficacy and safety profile.Expert opinion: Both agents targeting the vascular endothelial growth factor (VEGF) pathway and immune checkpoint inhibitors are active as single agents in mRCC. Improved outcomes have been demonstrated in phase 3 trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab, and ipilimumab plus nivolumab. Among these combinations, an OS benefit has, so far, demonstrated only for the combinations of axitinib with pembrolizumab and ipilimumab with nivolumab. Although there are currently no prospective data comparing the combination of ipilimumab and nivolumab with the combination of immune checkpoint inhibitors and VEGF inhibitors, currently available retrospective analyses indicate that these two approaches achieve comparable outcomes.

Administration of Nivolumab in Metastatic Renal Cell Cancer Following Treatment With mTOR Inhibitors.

BACKGROUND/AIM: Immunotherapy with checkpoint inhibitors is currently considered a cornerstone of metastatic renal clear cell cancer (mRCC) therapy. Despite the general improvement in the survival of patients with mRCC, there are some clinical situations that have not been specifically evaluated in clinical trials, such as the use of everolimus before nivolumab. PATIENTS AND METHODS: We performed a retrospective analysis evaluating the efficacy of nivolumab in the real-world setting, including a subset of patients with previous mTOR inhibitor therapy. RESULTS: From a total of 56 patients, 25 were pre-treated with everolimus before receiving nivolumab. The overall progression-free survival (PFS), overall survival (OS), and objective response rate were 10.3, 21.3 months, and 34%, respectively. There were no statistically significant differences in patients who were or were not pre-treated with everolimus. CONCLUSION: mRCC patients should be treated with checkpoint inhibitors and prior use of mTOR inhibitors should not be a definitive exclusion criterium.

Evaluation and management of toxicity of cytoreductive surgery/hyperthermic intraperitoneal chemotherapy: the initial experience of a single centre study.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment modality for peritoneal surface malignancies with efficacy reported in many trials. Discrepancies, however, in the indication criteria, the extent of the surgical procedure, HIPEC regimens and toxicity evaluation represent a problem when comparing this method with other therapeutic modalities. METHODS: We describe the initial experience with CRS/HIPEC using different chemotherapy regimens (oxaliplatin, cisplatin, mitomycin C and doxorubicin) at the Comprehensive Oncology Centre Olomouc. RESULTS: A perioperative mortality of 2% and perioperative morbidity of 11%, according to Clavien-Dindo were observed. Interestingly, all these patients underwent HIPEC with oxaliplatin 460 mg/m2. The median duration of admission to hospital was 6 days in the intensive care unit (range 2-28 days) and 7 days in the surgical ward (range 1-21 days). Hospital admission did not exceed 2 weeks in 75% of patients. These results are consistent with the published results of large centres performing this treatment modality mainly due to pre-operative preparation of patients and pre-treatment and post-treatment management of HIPEC/CRS toxicity. Evaluation of the efficacy in terms of time to progression and overall survival (OS) is limited by the short follow up period. CONCLUSION: CRS/HIPEC performed is a safe method with low perioperative mortality.

Neopterin as a biomarker of immune response in cancer patients.

With the advent of immunotherapy the topic of biomarkers of immune response is of high interest. Along with the expression of programmed death ligand 1 (PD-L1) or tumor infiltrating lymphocytes (TIL), biomarkers of macrophage activation could be of interest. Neopterin is a biomarker of immune activation increased in different disorders associated with immune activation, including cancer. Neopterin synthesis is induced by interferon-γ that also induces indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing catabolism of tryptophan to kynurenine. Increased urinary or serum concentrations of neopterin have been associated with poor prognosis across a spectrum of malignant disorders of different primary location. Neopterin concentration in peripheral blood as well as in the tumor microenvironment correlates with phenotypic and functional changes of lymphocytes, indicating immune dysfunction. Increased neopterin concentrations are also accompanied by increased rate of conversion of tryptophan to kynurenine. Increasing neopterin concentrations also accompany side effects of anticancer treatment and could predict subsequent complications. Although almost four decades have elapsed since the discovery of increased neopterin concentrations in cancer patients, the full potential of neopterin as a biomarker in this setting has not been so far realized.