VEGF Pathway-targeted Therapy for Advanced Renal Cell Carcinoma: A Meta-analysis of Randomized Controlled Trials

Immunotherapy which has been in practice for more than 20 years proves effective for the treatment of metastatic renal cell carcinoma （mRCC）. Anti-angiogenesis-targeted therapy has recently been identified as a promising therapeutic strategy for mRCC. This study was aimed to evaluate the effectiveness of vascular endothelial growth factor （VEGF） pathway-targeted therapy for mRCC by comparing its effectiveness with that of immunotherapy. The electronic databases were searched. Randomized controlled trials （RCTs） on comparison of VEGF inhibiting drugs （sorafenib, sunitinib and bevacizumab） with interferon （IFN） or placebo for mRCC treatment were included. Data were pooled to meta-analyze. A total of 7 RCTs with 3451 patients were involved. The results showed that anti-VEGF agents improved progression-free survival （PFS） and offered substantial clinical benefits to patients with mRCC. Among them, sunitinib had a higher overall response rate （ORR） than IFN （47% versus 12%, P〈0.000001）. Bevacizumab plus IFN produced a superior PFS [risk ratio （RR）： 0.86, 95% confidence interval （CI）： 0.76-0.97; P=0.01] and ORR （RR： 2.19; 95% CI： 1.72-2.78; P〈0.00001） in patients with mRCC over IFN, but it yielded an increase by 31% in the risk of serious toxic effects （RR： 1.31; 95% CI 1.20-1.43; P〈0.00001） as compared with IFN. The overall survival （OS） was extended by sorafenib （17.8 months） and sunitinib （26.4 months） as compared with IFN （13 months）. It was concluded that compared with IFN therapy, VEGF pathway-targeted therapies improved PFS and achieved significant therapeutic benefits in mRCC. However, the risk to benefit ratio of these agents needs to be further evaluated.

Is there a role for systemic targeted therapy after surgical treatment for metastases of renal cell carcinoma?

Metastatic renal cell carcinoma(m RCC) is a challenging disease. Despite the new targeted therapies, complete remissions occur only in 1%-3% of the cases, and the most effective first-line treatment drugs have reached a ceiling in overall survival(ranging from 9 to 49 mo). Metastasectomy remains to be the only curative option in most patients with m RCC. Prognostic nomograms have been recently published, so we have tools to classify patients in risk groups, allowing us to detect the cases with the higher risk of recurrence after metastasectomy. Although sparse, there is some evidence of effectiveness of neoadjuvant targeted therapy before metastasectomy; but with an increase in surgical complications due to the effects of these new drugs in tissue healing. We have aimed to answer the question: Is there a role for systemic targeted therapy after surgical treatment for metastases of renal cell carcinoma? We have made a search in Pubmed database. As far as we know, evidence is low and it's based in case reports and small series of patients treated with adjuvant drugs after neoadjuvant therapy plus metastasectomy in cases of partial response to initial systemic treatment. Despite the limitations and high risk of bias, promising results and cases with longterm survival with this approach have been described. Two ongoing clinical trials may answer the question that concerns us.

Advances in treatment strategies for non–clear cell renal cell carcinoma

Renal cell carcinoma is the sixth most commonly diagnosed cancer in men and the tenth in women,with clear cell renal cell carcinoma accounting for nearly 75%of cases.The remaining 25%consists of non–clear cell renal cell carcinoma,a diverse and less prevalent group.Although current treatments for clear cell types are well-defined,progress in treating non–clear cell renal cell carcinoma has been limited owing to its heterogeneity and rarity,relying primarily on findings from small-scale phase Ⅱ clinical trials.This review examined recent advancements in the treatment of non–clear cell renal cell carcinoma,particularly in the areas of immunotherapy and targeted therapy.

Cystic low-grade collecting duct renal carcinoma with liver compression—A challenging diagnosis and therapy: A case report

BACKGROUND A collecting duct carcinoma is a very rare, malignant renal epithelial tumor.Distant metastases are present in one third of cases at the time of diagnosis. It is known to have a poor prognosis.CASE SUMMARY A 42-year-old male was sent to our surgery clinic for removal of a 119.2 mm ×108.3 mm encapsulated cystic mass, which was localized in the 8th segment of the right liver lobe. The lesion was first identified on ultrasonography. A computed tomography scan confirmed the presence of a Bosniak type Ⅲ cystic lesion,which affected the liver and convexity of the right kidney. Surgical intervention involved a right nephrectomy, with removal of the cystic mass. The patient was mobilized on the first postoperative day and was discharged after 7 d. The histological and immunohistochemical examination revealed a low-grade collecting duct renal carcinoma, which is a rare variant of papillary carcinoma,with low malignant potential. The patient did not receive chemotherapy and after 21 mo of follow-up, a radiological examination and laboratory analyses showed normal aspects. No relapse or other complications were reported.CONCLUSION To manage renal tumors properly, a correct histopathological diagnosis is crucial,as is early diagnosis and correct surgical treatment.

Targeted Therapy in the Management of Elderly Patients with Pancreatic Metastases from Renal Cell Carcinoma

Background: The pancreas is an uncommon but recognizable site for metastases from renal cell carcinoma (RCC). Isolated pancreatic RCC metastases are still rarer and often present years after initial nephrectomy. Surgical resection has been the treatment of choice because of superior patient survival compared with traditional immunotherapy. In recent years, the advent of targeted therapy has transformed the outcomes of patients with metastatic RCC although little evidence is available on its effectiveness on this subset of patients. We report our experience of 6 patients with pancreatic RCC metastases. Patients and Methods: Between 2007 and 2012, 6 patients (2 men, 4 women;median age 78 years) were diagnosed to have pancreatic RCC metastases at our institute. The clinical features, treatment and outcomes were examined. Results: All 6 patients had a primary RCC of clear cell type. The median interval between initial curative nephrectomy and re-presentation with pancreatic metastases was 12.5 years. Four patients were asymptomatic at the time of diagnosis, one presented with obstructive jaundice and another with acute gastrointestinal bleed. Four patients had extra-pancreatic disease. All were deemed unsuitable or unfit for surgical metastasectomy. Five patients had a Memorial Sloan-Kettering Cancer Center (MSKCC) score of 1 (moderate risk) and the other patient had a score of 0 (good risk). Two patients were commenced on Sunitinib, one received Pazopanib and one received Temsirolimus. Two patients did not undergo further treatment. Of the 4 patients who underwent targeted therapy, the median follow up was 33 months with a median progression free survival of 16 months. One achieved complete response but recurred soon after treatment was stopped. Targetted therapy was recommenced and the disease remained stable. A second patient had long period of stable disease before disease progression. A third achieved partial response since started on targeted therapy and a fourth had disease progression despite treatment. Of the four patients who underwent systemic therapy, three are still alive at the time of this report. Conclusion: Pancreatic metastasis from RCC is a unique subgroup of disease which runs an indolent course, and a higher incidence in an elderly population. Our results demonstrate that targeted therapy can be efficacious in some patients where surgical resection is not suitable or possible.

Systemic Therapy of Advanced Renal Cell Carcinoma—Summary of Main Presentations at the ASCO, ASCO-GU and ESMO 2012 Annual Meetings

A number of very interesting studies presented this year at the ASCO (American Society of Clinical Oncology) Annual Meeting, the ASCO-GU (ASCO Genitourinary Cancers) Spring Meeting, and the ESMO (European Society for Medical Oncology) Annual Congress could strongly influence or even revolutionize the systemic treatment of advanced renal cell carcinoma (RCC). The aim of this article is to identify, summarize and discuss some outstanding studies of direct or indirect clinical relevance for systemic therapy.

Neoadjuvant Therapy for Locally Advanced Renal Cell Carcinoma with Sorafenib in a Reference Center in Mexico

Background: neo - adjuvant therapy is usually indicated in locally advanced tumors, the aim is to decrease the tumoral burden and enhance overall survival. Renal cell carcinoma is a chemo and radio resistant neoplasm and this type of approach is not as effective as in other solid tumors. On the other hand immunotherapy is indicated in metastatic disease, demonstrating a better overall survival. Sorafenib is an antiangiogenic drug approved for locally advanced or metastatic RCC. We postulated that it can be used in a neoadjuvant way to decrease the vascularization of selected tumors. Report of the case: 57 years old male referred to our service with a right renal mass and metastatic disease to lumbar spine and suprarenal gland. He was treated with three months of sorafenib previous to the surgery. Results: The patient went into surgery three months after initiating the antiangiogenic drug, during the surgery we found less neo-formance vessels;the dissection was subjectively easier, due to peri-renal edema. The pathologic analysis of the specimen was renal cell carcinoma. Interestingly, 40% of central ischemic (coagulative) necrosis was found. Conclusion: There are no neoadjuvant drugs accepted for the treatment of renal cell carcinoma;using an antiagiogenic drug to decrease the vascular burden characteristic of this type of tumors could be a viable option in selected cases. We used a lower dose of the drug with an acceptable safety profile.

Chemotherapy,transarterial chemoembolization,and nephrectomy combined treated one giant renal cell carcinoma(T3aN1M1)associated with Xp11.2/TFE3:A case report

BACKGROUND Renal cell carcinoma(RCC)with Xp11.2 translocation/TFE3 gene fusion is a rare and distinct subtype of RCC that is classified under tumors with translocation of the microphthalmia-associated transcriptional factor.CASE SUMMARY We report an adult case of Xp11.2 translocation advanced RCC with metastasis(T3a N1M1),after targeted treatment,alcohol ablation,and transarterial chemoembolization,who eventually underwent successful surgical excision.No recurrence or transfer was seen within one year,and the survival period was more than 3 years.A review of the relevant literature was conducted to improve our understanding of the pathogenesis,epidemiology,clinical manifestations,diagnosis,differential diagnosis,treatment,and other aspects of the disease.CONCLUSION Transarterial chemoembolization and ablation did not achieve the desired tumor reduction in this patient,but had a significant effect on reducing intraoperative bleeding and inhibiting tumor activity.

Progress in targeted therapy for metastatic renal cell carcinoma

In recent years, with the deepening of research on the pathogenesis of renal cell carcinoma, anti-VEGF receptor inhibitors and mTOR inhibitors have been produced, making metastatic renal cell carcinoma into the era of targeted therapy. This article analyzes the latest research results at home and abroad. For patients with metastatic renal cell carcinoma, sunitinib and pizopanib are the first choice for targeted drugs. The drug dose starts from the standard dose, and the disease can be increased as appropriate when the disease progresses;When responding, it should be treated or reduced in time. When using an anti-VEGF inhibitor, the patient's blood pressure should be closely monitored. When the patient has high blood sugar or diabetes, anti-VEGF inhibitors should be preferred.

Current Status of Studies on Targeted Therapy for Renal Cell Carcinoma

Renal cell carcinoma(RCC)is regarded as one of the most refractory malignancies.A further study of the molecular mechanism of RCC formation has led to a series of successful examples for treatment of patients with advanced RCC.Over the past 20 years,a nonspecific immunotherapy,with cytokines,has been employed as the gold standard for therapy of metastatic RCC.However,with scientific development and clinical testing of new drugs,targeted molecular cancer therapy has become a focus of interest.At the same time,with a better understanding of RCC, the treatment method has converged on anti-vascular endothelial growth factor(VEGF)and related molecular-targeted pathways. A large amount of research and numerous clinical trials have demonstrated the clinical efficacy of the targeted molecular therapies in patients with metastatic RCC.For example sorafenib and sunitinib were approved,in 2005 and 2006 respectively,by the U.S.FDA for treating advanced RCC.In this report,issues such as the importance of VEGF in RCC and the studies of bevacizumab, sunitinib and sorafenib in treating metastatic RCC etc.,are reviewed.

Evaluation of Targeted Therapy for Locally Advanced or Metastatic Renal Cell Carcinoma in Tunisia

Introduction: Renal cell carcinoma (RCC) is known to be chemo resistant but with the introduction of targeted therapies;there has been a “revolution” in its treatment strategies. The only targeted therapy available in Tunisia for the treatment of metastatic and/or locally advanced RCC is sunitinib. Objective of the Study: To evaluate therapeutic results and tolerance of sunitinib in metastatic and/or locally advanced RCC. Subjects and Methods: This was a retrospective study covering a period of six years (from January 2008 to January 2014) conducted in 5 medical oncology departments in Tunisia. The population of the study consisted of 29 patients treated with sunitinib for metastatic and/or locally advanced RCC. Results: The mean age of patients was 51 years. Three patients had tumor recurrence and 26 patients had a metastatic RCC. The prognosis was good for 5 patients, intermediate for 19 patients and poor for 5 patients. The median duration of treatment was 5 months. Because of side effects, treatment was discontinued in 12.5% of cases and the dose was reduced in 10.3% of cases. Side effects consisted of asthenia (95.8%), stomatitis (70.8%), anemia (50%), hand-foot syndrome (55.8%) in addition to nausea and vomiting (54.2%). Objective response was observed in 37.5% of patients after 3 months of treatment and in 50% after 6 months. The median progression-free survival was 14 months (95% CI, 7.9 to 20.6). The median overall survival was 22 months (95% CI, 15.6 to 28.7). Conclusion: The prognosis of RCC in Tunisian patients has clearly improved with the introduction of sunitinib, but other therapies with a proven efficacy as a first and second line therapy should be considered.

Perfusion computed tomography in renal cell carcinoma

Various imaging modalities are available for the diagnosis, staging and response evaluation of patients with renal cell carcinoma(RCC). While contrast enhanced computed tomography(CT) is used as the standard of imaging for size, morphological evaluation and response assessment in RCC, a new functional imaging technique like perfusion CT(p CT), goes down to the molecular level and provides new perspectives in imaging of RCC. p CT depicts regional tumor perfusion and vascular permeability which are indirect parameters of tumor angiogenesis and thereby provides vital information regarding tumor microenvironment. Also response evaluation using p CT may predate the size criteria used in Response Evaluation Criteria in Solid Tumors, as changes in the perfusion occurs earlier following tissue kinase inhibitors before any actual change in size. This may potentially help in predicting prognosis, better selection of therapy and more accurate and better response evaluation in patients with RCC. This article describes the techniques and role of p CT in staging and response assessment in patients with RCCs.

Twenty-year survival after iterative surgery for metastatic renal cell carcinoma: A case report and review of literature

BACKGROUND The therapeutic approach of metastatic renal cell carcinoma(RCC)represents a real challenge for clinicians,because of the variable clinical course;the recent availability of numerous targeted therapies that have significantly improved overall oncological results,but still with a low percentage of complete responses;and the increasing role of metastasectomy(MSX)as an effective strategy to achieve a durable cure,or at least defer initiation of systemic therapies,in selected patients and in the context of multimodality treatment strategies.CA^E SUMMARY We report here the case of a 40-year-old man who was referred to our unit in November 2004 with lung and mediastinal lymph nodes metastases identified during periodic surveillance 6 years after a radical nephrectomy for RCC;he underwent MSX of multiple lung nodules and mediastinal lymphadenectomy,with subsequent systemic therapy with Fluorouracil,Interferon-alpha and Interleukin 2.The subsequent clinical course was characterized by multiple sequential abdominal and thoracic recurrences,successfully treated with multiple systemic treatments,repeated local treatments,including two pancreatic resections,conservative resection and ablation of multiple bilobar liver metastases,resection and stereotactic body radiotherapy of multiple lung metastases.He is alive without evidence of recurrence 20 years after initial nephrectomy and sequential treatment of recurrences in multiple sites,including resection of more than 38 metastases,and 5 years after his last MSX.CONCLUSION This case highlights that effective multimodality therapeutic strategies,including multiple systemic treatments and iterative aggressive surgical resection,can be safely performed with long-term survival in selected patients with multiple metachronous sequential metastases from RCC.

Combination drug regimens for metastatic clear cell renal cell carcinoma

Renal cell carcinomas(RCC)make up about 90%of kidney cancers,of which 80%are of the clear cell subtype.About 20%of patients are already metastatic at the time of diagnosis.Initial treatment is often cytoreductive nephrectomy,but systemic therapy is required for advanced RCC.Single agent targeted therapies are moderately toxic and only somewhat effective,leading to development of immunotherapies and combination therapies.This review identifies limitations of monotherapies for metastatic renal cell carcinoma,discusses recent advances in combination therapies,and highlights therapeutic options under development.The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect.However,combining targeted therapies may cause increased toxicity.The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity.To date,five combination therapies have been approved by the U.S.Food and Drug Administration,with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy.Several other combination therapies are under development,including some in the phase 3 stage.The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.

Renal cell carcinoma:An update for the practicing urologist

Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of care.The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing.(1)Though observation remains a standard of care following resection of localized disease,multiple trials are underway to assess VEGF-and mTOR-directed therapies in this setting.(2)While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents,prospective data to support this approach is still forthcoming.(3)The first-line management of mRCC may change substantially with multiple studies exploring vaccines,immune checkpoint inhibitors,and novel targeted agents currently underway.In general,prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy.Over the same span of time,the current treatment paradigm for first-line therapy may evolve.

Successful apatinib treatment for advanced clear cell renal carcinoma as a first-line palliative treatment: A case report

BACKGROUND Apatinib is an orally bioavailable small-molecule receptor tyrosine kinase inhibitor.In December 2014,the China Food and Drug Administration made it the first anti-angiogenic therapy to be approved for treating metastatic gastric cancer.It was specifically designated as a third-line or later treatment for metastatic gastric cancer.CASE SUMMARY Here,we present a case of advanced renal cell carcinoma(RCC)with multiple metastases(Stage IV)in a 48-year-old male with an extremely poor general status(Karnofsky 30%).He was initially given pazopanib as a targeted therapeutic.However,he experienced severe adverse reactions within two weeks,including grade IV oral mucositis.We,thus,tried switching his targeted treatment to an apatinib dose of 250 mg once daily since April 2018.The patient demonstrated striking benefits from this switch to the apatinib palliative treatment.Nearly one month later,his pain and other associated symptoms were alleviated.The patient was able to move freely and had an excellent general status(Karnofsky 90%).His progress has been followed up with regularly,allowing for a documented progression-free survival interval of approximately 32 mo.CONCLUSION This case suggests that,like other multi-target drugs,apatinib may be a useful first-line therapeutic drug for advanced RCC.It may be a particularly helpful curative option when patients are found to be intolerant of other targeted drugs.

Is Post Operative Radiotherapy Justified for Completely Resected Locally Advanced Renal Cell Cancers?

Background: There is an underutilization of postoperative radiation therapy (PORT) in renal cell carcinoma (RCC) following radical nephrectomy (RN). The main reason for that is the lack of strong evidence and the contradictory data in the literature regarding its benefit. We aimed to evaluate the efficacy of PORT in locally advanced patients with RCC following complete resection. Materials and Methods: The patients had RN and at least two of the poor prognostic factors like lymph nodes involvement (LN+), renal vein invasion (RVI), inferior vena cava invasion (IVCI) and renal capsule infiltration (RCI) were included in the study. Ninety-four patients were retrospectively evaluated;56 patient received PORT 50Gy/25 fractions/5 weeks and 38 patients who did not receive PORT were compared. The LN+, RVI, IVCI and RCI were documented in 63 (67%), 46 (49%), 30 (32%) and 71 (76%) patients respectively. Results: Eight patients (14%) in PORT arm developed local recurrence (LR) are compared with 10 patients (26%) for non-PORT arm. Five-year overall survival (OS) rates were 78% and 70% for PORT and non-PORT arms respectively (p = 0.3), while 5-year locoregional control (LRC) rates were 88% for PORT arm and 70% for the non-PORT arm (p = 0.05). The IVCI and LN+ affected OS significantly (p values 0.007 and 0.009) respectively. The RCI and LN+ only affected the LRC with p values 0.03, 0.04 respectively. Two out of 56 patients (3.5%) received PORT developed intestinal obstruction which was treated surgically. Conclusion: The PORT decreased the LR rate in high risk locally advanced RCC patients significantly. The high incidence of distant metastasis offsets this improvement at the level of overall survival.

Metastatic sarcomatoid renal cell carcinoma to the mandible treated with Sorafenib

A case of metastatic sarcomatoid renal cell carcinoma to the mandible treated with Sorafenib is reported. A 76-year-old man consulted us for hyposthesia of the right lower lip. Panorama X-ray film showed a ra-diolucent lesion in the right mandibular body. A diagnosis of metastatic tumor to the mandible from the left kidney was made after evaluation by computed tomography and positron emission tomography, which also revealed multiple bone metastases. After radiotherapy for mandibular and thoracic lesions, nephrectomy was performed. Histological diagnosis was sarcomatoid renal cell carcinoma. Interferon therapy was performed but was not effective;therefore, a molecular targeted drug, Sorafenib, was administered. Sorafenib effectively inhibited the growth of oral and other metastatic lesions for 10 months. Quality of life was relatively well maintained with tolerable adverse effects. The patient survived for as long as 2 years after appearance of the first symptom.

Sustained long-term clinical and radiological response with sunitinib for metastatic renal-cell carcinoma (RCC)

The authors herein report the case of a 67-year-old woman with metastatic renal-cell carcinoma (RCC), who has had a sustained clinical and stable radiological response to long-term therapy with an oral multi-targeted tyrosine kinase inhibitor (TKI), sunitinib with minimal lasting toxicity.

The unique genomic landscape and prognostic mutational signature of Chinese clear cell renal cell carcinoma

Background:The genomic background affects the occurrence and metastasis of cancers,including clear cell renal cell carcinoma(ccRCC).However,reports focusing on the prognostic mutational signature of Chinese ccRCC are lacking.Methods:Overall,929 patients,including a training cohort with Chinese patients(n=201),a testing cohort with Caucasian patients(n=274),and a validation cohort(n=454)were analyzed for the genomic landscape of ccRCC.Then,machine-learning algorithms were used to identify and evaluate the genomic mutational signature(GMS)in ccRCC.Analyses for prognosis,immune microenvironment,association with independent clinicopathological features,and predictive responses for immune checkpoint therapies(ICTs)were performed.Results:The DNA variation data of 929 patients with ccRCC suggested markedly differential genomic mutational frequency of the most frequent genes,such as VHL,PBRM1,BAP1,SETD2,and KDM5C between the Chinese and Caucasian populations.PBRM1 showed significant co-occurrence with VHL and SETD2.We then successfully iden-tified a seven-gene mutational signature(GMS^(Mut))that included mutations in FBN1,SHPRH,CELSR1,COL6A6,DST,ABCA13,and BAP1.The GMS^(Mut)significantly predicted progressive progression(P<0.0001,HR=2.81)and poor prognosis(P<0.0001,HR=3.89)in the Chinese training cohort.Moreover,ccRCC patients with the GMS^(Mut)had poor survival rates in the testing cohort(P=0.020)and poor outcomes were predicted for those treated with ICTs in the validation cohort(P=0.036).Interestingly,a favorable clinical response to ICTs,ele-vated expression of immune checkpoints,and increased abundance of tumor-infiltrated lymphocytes,specifically CD8^(+)T cells,Tregs,and macrophages,were observed in the GMS^(Mut)cluster.Conclusions:This study described the pro-tumorigenic GMS^(Mut)cluster that improved the prognostic accuracy in Chinese patients with ccRCC.Our discovery of the novel independent prognostic signature highlights the relationship between tumor phenotype and genomic mutational characteristics of ccRCC.