Prognostic Role of PD-L1 Expression in Renal Cell Carcinoma. A Systematic Review and Meta-Analysis.

BACKGROUND: Several clinical trials have reported that therapies targeting programmed death-1 (PD1) and its ligand (PD-L1) improve patient outcomes, while tumor response has been related to PD-L1 expression. OBJECTIVE: To investigate the prognostic role of PD-L1 expression in patients affected by renal cell carcinoma (RCC). METHODS: MEDLINE/PubMed, the Cochrane Library, and ASCO University were searched for studies investigating the prognostic role of PD-L1 expression in RCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Six studies and 1323 cases were included in the final analysis. PD-L1 was expressed in 24.2 % of clear cell tumors compared to 10.9 % of non-clear cell tumors (p = 0.002). In the overall population, a higher level of PD-L1 expression increased the risk of death by 81 % (HR; 1.81, 95 % CI 1.31-2.49; p < 0.001). When the analysis was restricted to cases evaluated by immunohistochemistry alone, the higher expression of PD-L1 more than doubled the risk of death (HR; 2.05, 95 % CI 1.38-3.05; p < 0.001). In clear cell histology, higher PD-L1 expression increased the risk of death by 53 % (HR; 1.53, 95 % CI 1.27-1.84; p < 0.001), while in metastatic patients, the evaluation of PD-L1 expression on primary tumors revealed that it retains its prognostic role (HR; 1.45, 95 % CI 1.08-1.93; p = 0.01). LIMITATIONS: Significant heterogeneity has been identified among the included studies. As a consequence, cautious interpretation of the results is recommended. CONCLUSION: This meta-analysis indicates that a higher level of PD-L1 expression is a negative prognostic factor in RCC. Its validation as an independent prognostic factor compared to other traditionally used clinical parameters in localized or advanced disease is recommended.

Targeted therapy for renal cell carcinoma: focus on 2nd and 3rd line.

INTRODUCTION: Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients. AREAS COVERED: Here we discuss the various levels of evidence supporting presently available recommendations, trying to address a number of as yet unanswered issues, and also to take a glowing glance at the future. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for relevant studies. EXPERT OPINION: Until recently, with regard to choosing the second line treatment after the failure of therapy with vascular endothelial growth factor receptors-tyrosine kinase inhibitors (VEGFR-TKIs), the continued inhibition of the VEGF/VEGR pathway, or else the switch to an mTOR inhibitor, is recommended. These two options are characterized by partly different targets, completely different toxicity profiles, but a comparable efficacy. This scenario will change soon, after the publication of two randomized, controlled, phase III trials in which cabozantinib and nivolumab proved to be superior as compared to everolimus. As regards third line treatment, where a sequence of two VEGFR-TKIs has been used beforehand, the choice is represented by the mTOR inhibitor everolimus, whilst if a VEGFR-TKI followed by everolimus has been chosen, a return to VEGF pathway inhibition is suggested.

[Current approaches to the first-line treatment of clear-cell renal cell carcinoma]. / Approccio al trattamento di prima linea del carcinoma renale a cellule chiare metastatico.

The medical treatment of renal cell carcinoma has been revolutionized in recent years, thanks to translation of our increasingly accurate knowledge on the molecular pathogenesis of this tumor, and of its clear cell histology in particular, into an accelerated drug development, and then into everyday's clinical practice. In this review, starting with the pathogenesis of clear cell renal cell carcinoma, we shall address the results of the clinical trials that led to the registration of seven targeted agents for this disease once orphan of active treatments, taking into account the different prognostic groups in which the patients suffering from it can be divided. Finally, we shall discuss the complex and controversial issue of the ideal timing to start a systemic treatment, a critical and still highly debated topic. All major international guidelines agree on the standard first line therapeutic options, which are represented by sunitinib, bevacizumab (associated with interferon-α) and pazopanib for patients with good or intermediate risk features, and temsirolimus for poor-risk patients. All these agents proved able to prolong progression-free survival within randomized phase III trials. The use of an observation period, before starting a systemic treatment, seems also reasonable, at least in the more indolent tumors and in patients with a better prognosis, even if the topic is still controversial. Finally, the individualization of therapy and the proper conduct of the same is essential for a successful outcome of the treatment.

Markers of squamocolumnar junction cells in normal tonsils and oropharyngeal cancer with and without HPV infection.

HPV infection has been identified recently as the causative agent of a subset of squamous cell carcinomas arising in oropharyngeal tonsils. Factors influencing the susceptibility of tonsillar epithelium to HPV-induced oncogenesis are far from being elucidated. A 5-protein signature including cytokeratin (CK)7, anterior gradient (AGR)2, cluster differentiation (CD)63, matrix metalloproteinase (MMP)7, and guanine deaminase (GDA) has recently been found to identify a residual embryonic cell population in the squamocolumnar (SC) junction of the cervix, susceptible to HPV infection, and cancers originating from these cells. The expression of SC junction markers was investigated with immunohistochemistry in normal tonsils and in oropharyngeal carcinomas (OPC) fully characterised for HPV. All markers were constantly expressed in the reticulated epithelial cells of the tonsillar crypts, with variable diffusion and intensity; in OPC, positivity was observed in 36,5%, 29,2%, 39%, 17%, and 25% of cases with respectively AGR2, CK7, GDA, CD63, and MMP7 antibodies. No OPC was positive for all markers; 6 were completely negative. AGR2 and CK7 showed significant association with tumor- and HPV-related parameters. AGR2 expression was associated with tumor origin in the tongue base (p=0.013); CK7 was associated with non-keratinising morphology (p=0.013). p16 tumor cell expression was associated with AGR2 (p=0.021); transcriptionally active HPV infection was associated with AGR2 and CK7 (p=0.024 and 0.043). Expression of SC junction markers in tonsillar crypt cells might be related to the embryological development of tonsillar structures; their partial association with HPV oncogenic infection could help to identify HPV-susceptible cells and related OPC.

Identification of transcriptionally active HPV infection in formalin-fixed, paraffin-embedded biopsies of oropharyngeal carcinoma.

Human papillomavirus (HPV) oncogenic activity is the result of viral oncogene E6 and E7 expression in infected cells. Oncogene expression analysis is, however, not part of the routine diagnostic evaluation of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) since it requires fresh tumor tissue. We compared the diagnostic accuracy of several methods commonly employed for HPV characterization in OPSCC with the results of the newly available HPV E6/E7 mRNA in situ hybridization (ISH) on formalin-fixed, paraffin-embedded biopsy samples, in order to establish if the latter should be introduced in the diagnostic routine to increase accuracy when fresh tissue is not available. p16 immunostain, DNA ISH for high-risk HPV genotypes, SPF LiPA amplification and genotyping, and HPV16 E6 amplification were performed on 41 consecutive OPSCC samples. Twenty (48.7%) cases were positive by mRNA ISH; sensitivity and specificity were 100% and 90% for p16, 90% and 100% for DNA ISH, 70% and 76% for SPF10 LiPA, 90% and 76% for E6 amplification. A diagnostic algorithm considering p16 immunostain as first step followed by either high-risk HPV DNA ISH or HPV16 E6 amplification in p16-positive cases correctly characterized 90% of mRNA-positive and all mRNA-negative cases; combining the 3 tests correctly identified all cases. While no stand-alone test was sufficiently accurate for classifying HPV-associated OPSCC, the high sensitivity and specificity of the established combination of p16 immunostain, DNA ISH, and HPV16 DNA amplification suggests that the introduction of labour- and cost-intensive mRNA ISH, is not necessary in the diagnostic routine of oropharyngeal tumors.

Dovitinib (CHIR258, TKI258): structure, development and preclinical and clinical activity.

Dovitinib is an oral multikinase inhibitor targeting FGF receptors, PDGF receptors and VEGF receptors. Its activity against FGF receptors suggests its usefulness in treating cancers after the failure of VEGF/VEGF receptor-targeting agents. The identified dose and schedule to be used in further studies was 500 mg orally for 5 days on and 2 days off. Biological considerations and the results achieved in a Phase I/II trial suggested its activity in advanced renal cell carcinoma patients pretreated with a tyrosine kinase inhibitor and an mTOR inhibitor. Surprisingly, in a randomized controlled Phase III trial versus sorafenib in the same setting, dovitinib failed to demonstrate any superiority. At present, dovitinib is being tested in different tumor types. However, molecular-based patient selection seems to be key to fully exploit the activity of this drug.

Osteonecrosis of the Jaw in Patients With Metastatic Renal Cell Cancer Treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature.

Osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates has been rarely reported in metastatic renal cell cancer (RCC) patients. Since the introduction of combined therapies consisting of nitrogen-containing bisphosphonates (NBPs) and targeted agents, an increasing number of RCC patients were reported to develop ONJ, suggesting that therapeutic angiogenesis suppression might increase the risk of ONJ in NBPs users. We performed a multicenter retrospective study and reviewed literature data to assess the occurrence and to investigate the nature of ONJ in RCC patients taking NBPs and targeted agents. Nine Italian Centers contributed to the data collection. Patients with exposed and nonexposed ONJ were eligible for the study if they had been taking NBPs and were receiving targeted agents at the time of ONJ diagnosis. Forty-four RCC patients were studied. Patients were mostly male (82%), with a median age of 63 years (range, 45-85 years). Zoledronic acid (93%) and sunitinib (80%) were the most frequently used NBP and antiangiogenic agent, respectively. Other agents included Pamidronate, ibandronate, sorafenib, bevacizumab, mammalian target of rapamycin inhibitors. Forty-nine sites of ONJ were encountered, with the mandible being the preferred site of ONJ (52%); both jaws were affected in 5 cases (12%). The most common precipitating event was dental/periodontal infection (34%), followed by tooth extraction (30%). Oral triggers of ONJ were missing in 10 cases (23%). This unexpectedly high number of ONJ cases, in comparison with literature data, suggests that frequency of ONJ in RCC patients might be largely underestimated and suggests a potential role for targeted agents in the incremental risk of ONJ.

Sunitinib, pazopanib or sorafenib for the treatment of patients with late relapsing metastatic renal cell carcinoma.

PURPOSE: Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma. MATERIALS AND METHODS: Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy. RESULTS: A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival. CONCLUSIONS: Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

Targeting PI3K/Akt/mTOR Signaling in Cancer.

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are two pathways crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions (e.g., cancer). Indeed, they are so interconnected that, in a certain sense, they could be regarded as a single, unique pathway. In this paper, after a general overview of the biological significance and the main components of these pathways, we address the present status of the development of specific PI3K, Akt, and mTOR inhibitors, from already registered medicines to novel compounds that are just leaving the laboratory bench.

A retrospective analysis of two different sequences of therapy lines for advanced kidney cancer.

BACKGROUND/AIM: the ideal sequence of targeted agents for advanced kidney cancer is still unknown. In the present study we assessed the clinical benefit of two different sequential approaches, namely sorafenib, an inhibitor of mammalian target of rapamycin (mTORi) and sunitinib, or sunitinib (an mTORi) and sorafenib. PATIENTS AND METHODS: we retrospectively reviewed the outcome of 40 advanced kidney cancer patients treated with one of the two above sequences. RESULTS: a total of 26 patients were treated with the sequence sorafenib-mTORi-sunitinib and 14 with the sequence sunitinib-mTORi-sorafenib. The actuarial overall median progression-free survival (PFS) in the sorafenib-mTORi-sunitinib group and in the sunitinib-mTORi-sorafenib group were 21.9 and 22.8 months, respectively (log-rank test: p=0.928). In the sorafenib-mTORi-sunitinib group, patients in first-, second- and third-line therapy experienced PFS of 11.7, 5.1 and 9.1 months, respectively, while in the sunitinib-mTORi-sorafenib group PFS was 14.4, 4.3, and 3.9 months, respectively. CONCLUSION: Our results suggest there is no significant difference between the two sequence modalities.

Changes in circulating pro-angiogenic cytokines, other than VEGF, before progression to sunitinib therapy in advanced renal cell carcinoma patients.

OBJECTIVES: This study included a cohort of advanced renal cell carcinoma patients treated with sunitinib. Since resistance to sunitinib may be mediated through angiogenic cytokines other than VEGF, we measured the circulating levels of three pro-angiogenic cytokines: basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and interleukin (IL)-6. METHODS: Cytokines were measured at baseline and on the first day of each treatment cycle until progression in 85 advanced kidney cancer patients treated with sunitinib using a quantitative sandwich enzyme immunoassay (ELISA) technique. RESULTS: Even though no statistically significant differences in the titers of the three cytokines were observed between baseline and the time of progression in the whole patient cohort, in 45.3, 46.6, and 37.3% of the patients a more than 50% increase between baseline and the time of progression was shown in circulating IL-6, bFGF, and HGF, respectively. Furthermore, this increase was more than 100% in 37.3, 44, and 30.6% of the patients, respectively. We also demonstrated that, in these patients, cytokines tended to increase and to remain high immediately before progression. CONCLUSIONS: In a large percentage of kidney cancer patients, progression is preceded by a significant increase in pro-angiogenic cytokines other than VEGF.

Could interferon still play a role in metastatic renal cell carcinoma? A randomized study of two schedules of sorafenib plus interferon-alpha 2a (RAPSODY).

BACKGROUND: Sorafenib has proven efficacy in metastatic renal cell carcinoma (mRCC). Interferon (IFN) has antiangiogenic activity that is thought to be both dose- and administration-schedule dependent. OBJECTIVE: To compare two different schedules of IFN combined with sorafenib. DESIGN, SETTING, AND PARTICIPANTS: Single-stage, prospective, noncomparative, randomized, open-label, multicenter, phase 2 study on previously untreated patients with mRCC and Eastern Cooperative Oncology Group performance status 0-2. INTERVENTION: Sorafenib 400mg twice daily plus subcutaneous IFN, 9 million units (MU) three times a week (Arm A) or 3 MU five times a week (Arm B). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end points were progression-free survival (PFS) for each arm and safety. Data were evaluated according to an intent-to-treat analysis. RESULTS AND LIMITATIONS: A total of 101 patients were evaluated. Median PFS was 7.9 mo in Arm A and 8.6 mo in Arm B (p=0.049) and the median duration of response was 8.5 and 19.2 mo, respectively (p=0.0013). Nine partial responses were observed in Arm A, and three complete and 14 partial responses were observed in Arm B (17.6% vs 34.0%; p=0.058); 24 and 21 patients (47% and 42%), respectively, achieved stable disease. The most common grade 3-4 toxicities were fatigue plus asthenia (28% vs 16%; p=0.32) and hand-foot skin reactions (20% vs 18%). CONCLUSIONS: Sorafenib plus frequent low-dose IFN showed good efficacy and tolerability. Further investigations should be warranted to identify a possible positioning of this intriguing regimen (6% complete response rate) in the treatment scenario of mRCC.

Sunitinib in advanced metastatic non-clear cell renal cell carcinoma: a single institution retrospective study.

AIM: Sunitinib is an orally active multi-targeted tyrosine kinase inhibitor that exerts its antitumor effects primarily through the selective inhibition of VEGF. Novel targeted therapies such as sunitinib have transformed the treatment of advanced metastatic renal cell carcinomas, particularly those with clear cell histology. Here, our experience in patients with non-clear cell kidney cancer treated as part of the sunitinib Expanded Access Program is reported. MATERIALS & METHODS: This was a retrospective assessment of 21 patients with non-clear cell renal cell carcinoma who were treated with oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off). Disease assessment and physical examination were recorded at baseline and tumor assessments were performed every 3 months, according to Response Evaluation Criteria In Solid Tumors. The primary outcome measure was progression-free survival. RESULTS: Patients received an average of 6.38 cycles of sunitinib; one patient was classified as a complete responder and two as partial responders. The overall response rate was 14.3% and clinical benefit was attained by 52.4%. The median progression-free survival was 4.1 months while median overall survival was 14.6 months. In general, sunitinib was well tolerated and only three patients experienced a grade 3 toxicity, which resolved with dosage reduction. CONCLUSION: As expected, sunitinib exerted lower antitumor activity in patients with non-clear cell renal cell carcinoma than was achieved in the general population with metastatic kidney cancer. However, responses (one complete and two partial) were documented and clinical benefit was observed in more than half of all patients.

Primary resistance to tyrosine kinase inhibitors in patients with advanced renal cell carcinoma: state-of-the-science.

Although over 70% of patients with metastatic renal cell carcinoma (RCC) respond to initial therapy with tyrosine kinase inhibitors (disease control rate 70-80%), approximately 20-30% of patients do not respond to first-line therapy and progress within ≤3 months. Understanding the mechanisms of resistance to targeted therapies is vital in the development of prospectively defined sequences and because the choice of first-line therapy determines that of second and subsequent line therapy, identification of the optimal first-line therapy is a priority for clinicians treating patients with metastatic RCC. By preselecting those patients most likely to respond to antivascular endothelial growth factor therapy, clinicians can begin to optimize therapeutic strategies. This review focuses on primary antivascular endothelial growth factor-refractory patients and the move towards individualizing treatment for RCC. The authors include a review of the growing number of studies, as yet retrospective, which provide important information on the group of primary refractory patients with advanced RCC for whom the prognosis is not good. First, the percentage of primary refractory patients (26%) is in agreement with disease control rate - the sum of objective responses and disease stabilization, observed in registration studies for a range of tyrosine kinase inhibitors. Second, the prognosis for these patients is poor as they do not respond to first-line nor to second-line therapy, and changing the mechanism of action (with inhibition of mTOR pathway) does not appear to produce additional benefits. Third and most importantly, the results of these studies demonstrate the need to better characterize the mechanism of primary resistance to current therapeutic agents with the ultimate aim of developing a therapeutic strategy for this important subgroup of patients.

Lingual metastasis from renal cell carcinoma: a case report and literature review.

Renal cell carcinoma (RCC) accounts for the 3% of all solid tumors. Despite continuous improvement in the therapy regimen, less has been achieved in terms of enabling an earlier diagnosis: the neoplasia usually reveals its presence at an advanced stage, obviously affecting prognosis. The most frequent sites of secondary disease are shown to be lungs (50-60%), bone (30-40%), liver (30-40%) and brain (5%); while the head and neck district seems to account for less than 1% of patients with primary kidney lesion. We report here the case of a 70-year old man who presented with acute renal failure due to abdominal recurrence of RCC 18 years post nephrectomy. After a few months of follow up without any systemic therapy due to the renal impairment, the patient presented a vascularized tongue lesion that was demonstrated to be a secondary localization of the RCC. This lesion has, therefore, been treated with microsphere embolization to stop the frequent bleeding and to lessen the unbearable concomitant symptoms it caused, such as dysphagia and pain. A tongue lesion that appears in a RCC patient should always be considered suspect and a multidisciplinary study should be conducted both to assess whether it is a metastasis or a primary new lesion and to understand which method should be selected, if necessary, to treat it (surgery, radiation or embolization). Lingual metastasis should be examined accurately not only because they seem to implicate a poor prognosis, but also because they carry a burden of symptoms that not only threatens patients' lives but also has a strong impact on their quality of life.

The effect of sorafenib treatment on the diabetic status of patients with renal cell or hepatocellular carcinoma.

AIM: To evaluate the effect of sorafenib on the glucose tolerance and diabetic status of patients with metastatic renal cell carcinoma (RCC) or advanced hepatocellular carcinoma (HCC). MATERIALS & METHODS: Eighty patients with metastatic RCC or advanced HCC received 400 mg sorafenib twice daily for an average of approximately 8 and 5 months, respectively; 22 had diabetes mellitus and three had prediabetes. RESULTS: One of 55 nondiabetic patients, and one of three patients with impaired fasting glucose or impaired glucose tolerance developed diabetes mellitus, one of 12 patients on oral antihyperglycemic agents switched to insulin and no patient treated with insulin needed to increase their dose. CONCLUSION: Sorafenib has the potential to be a feasible and safe treatment option for patients with advanced HCC or metastatic RCC and comorbid diabetes mellitus or prediabetes.