Guidelines on renal cell cancer.

OBJECTIVES: On behalf of the European Association of Urology (EAU), Guidelines for Diagnosis, Therapy and Follow-Up of Renal Cell Carcinoma Patients were established. Criteria for recommendations were evidence based and included aspects of cost-effectiveness and clinical feasibility. METHOD: A systematic literature research using Medline Services was conducted. References were weighted by a panel of experts on renal cell carcinoma (RCC). RESULTS: RCC is characterised by a constant rise in incidence over the last 50 years, with a predominance of men over women and an incidence peak in the 6th and 7th decade. There is no risk factor established and the current TNM system (UICC, 1997) is endorsed for staging purposes. Clinical signs and symptoms of RCC are becoming less frequent, incidental discovery constitutes already a majority of cases. Diagnosis is established by ultrasound and abdominal CT, extension assessment in routine cases is done by chest X-ray. Additional examinations may be required in select cases. The therapy of choice in organ-confined RCC is surgery. Radical tumour nephrectomy is considered as a standard. Efficacy and side-effects of organ-sparing surgery, lymphadenectomy and inclusion/omission of ipsilateral adrenalectomy in selected cases is a matter of ongoing clinical research. In metastatic cases, tumour nephrectomy should only be considered in the context of modern systemic immunotherapy. A follow-up at regular intervals is recommended because certain cases of recurrences may be candidates for surgery and/or immunomodulating therapy. CONCLUSION: A rise in incidence, improved diagnostic procedures, and evolving multimodality therapeutic concepts justify the need for rational guidelines on this most challenging urologic malignancy.     

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

The promising role of radiotherapy in the treatment of advanced or metastatic renal cell carcinoma: a narrative review

Traditionally, renal cell carcinoma (RCC) has been regarded to be “radioresistant”. Conventional fractionated radiation (CFRT) has played a limited role in RCC as a palliative treatment to relieve pain and bleeding. Succeed to the rapid development of precise radiotherapy techniques, realizing safe delivery of high-dose radiotherapy, an increasing amount of convincing data suggests that the delivery of high-dose-per-fraction radiation through stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR) can help to overcome resistance to radiotherapy. Herein, we summarized and analyzed the data from randomized controlled trials, retrospective and prospective studies, and meta-analyses relating to the treatment of advanced and metastatic RCC (mRCC) with CFRT, SBRT, or SBRT combined with systemic therapy. CFRT has a limited effect on local control (LC) of advanced RCC and mRCC, but it is a major palliative treatment which could obviously relieve pain caused by cancer. SBRT and SRS have the significant advantage of being able to precisely deliver a high dose of radiation to the target tissues. SBRT could cause a higher LC for advanced and metastatic RCC and could be used as an alternative to surgery for patients with oligometastatic RCC. The combination of SBRT with systemic therapy, such as targeted therapy or immunotherapy, is safe and tolerable. Concurrent immunotherapy and SBRT is a promising treatment strategy for patients with advanced or metastatic RCC. However, research on radiotherapy combined with systemic therapy is still limited and further studies to explore this treatment for RCC are urgently needed.     

Treatment of Advanced and Metastatic Renal Cancer: A Revolution?

ContextA significant proportion of patients with renal cell carcinoma (RCC) will experience recurrence or tumour progression after surgical treatment. Nowadays, several treatment options, including immunotherapy and targeted therapies, are available for management of advanced and metastatic RCC.ObjectiveThis paper aims to give an overview of the current treatment options for patients with advanced and metastatic RCC.Evidence acquisitionThis paper is based on a presentation given at the 6th Meeting of the European Society of Oncological Urology 2009, held in Istanbul, Turkey. Data were retrieved from recent review articles, original articles, and abstracts on the treatment of advanced and metastatic RCC.Evidence synthesisThe potential role of adjuvant vaccines in treatment of patients with advanced RCC after nephrectomy has been suggested. With regard to the newly developed targeted agents for treatment of metastatic clear-cell RCC, sunitinib and bevacizumab plus interferon-α (INF-α) seem promising as first-line therapy for good- and intermediate-risk patients. Temsirolimus appears to be effective as first-line treatment in metastatic RCC (mRCC) patients with poor prognosis. Sorafenib and everolimus should be considered as second-line therapy in mRCC patients. Some targeted therapies have also demonstrated clinical activities in patients with metastatic non–clear-cell RCC. Although grade 1 and grade 2 treatment-related adverse events were common with targeted therapies, most were manageable. The effect of targeted agents in earlier stage disease is currently under investigation. Cytokine therapy was associated with a modest survival benefit in mRCC. A combined analysis, however, suggested that cytoreductive nephrectomy might improve survival in patients with mRCC treated with interferon immunotherapy.ConclusionsMore research on the use of adjuvant vaccines in treating patients with advanced RCC is warranted. Although the management of metastatic disease has undergone a revolution in recent years, a lot of questions still need to be answered.     

Rationale for immunotherapy of renal cell carcinoma

Summary Metastasis to distant organs is the principal cause of death from renal cell carcinoma (RCC). No commonly accepted therapy is available for disseminated RCC at present. Immunotherapy is a mode of therapy that either interferes with the immune system or makes use of drugs that have been derived from soluble mediators of the immune system. Several lines of evidence suggest that combinations of genetically engineered cytokines (e.g. interleukin-2 and interferon alpha) may be particularly active in the treatment of advanced RCC. There are two major rationales for considering immunotherapy for RCC: (1) there is currently no other therapy available, and (2) there is hardly any innovative approach besides immunotherapy. Still, immunotherapy is far from being a standard therapy for disseminated RCC.     

肾细胞癌免疫治疗的研究进展

肾细胞癌通常有对经典放疗或化疗方法仅有轻微的反应和预后差的特点。免疫治疗是在已建立的传统的治疗模式基础上发展的替代治疗形式。事实上,以细胞因子为基础的治疗方法已被使用了许多年,在小部分患者中产生了良好的临床效应。在过去的几年中,免疫治疗以肾细胞癌的肿瘤相关抗原为试验靶点已被报道过,现综述以下几方面取得的研究进展,包括以细胞因子为基础的治疗,分子靶点、抗血管生成试剂治疗,RCC肿瘤相关性抗原和疫苗方案相关方面。     

Recent advances in molecular targeted therapy for metastatic renal cell carcinoma

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15–20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.     

进展期肾细胞癌的治疗进展

进展期肾细胞癌(RCC)的临床预后欠佳,由于其对于传统的放化疗的低敏感性,使得临床工作中缺乏较为有效的治疗手段.多个因素影响进展期肾癌的临床预后.目前免疫治疗可使部分进展期肾癌得到部分程度的缓解,新兴的靶向治疗在前期的临床实验中取得了令人满意的效果,使部分患者的肿瘤进展得以延迟,RCC靶向治疗制剂多针对RCC细胞增生、血管形成等多个靶向途径,包括Sorafenib,Sunitinib,Temsirolimus和Bevacizumab等.而联合免疫治疗,将对进展期肾癌的预后产生更为有效的改善.     

Reduced intensity stem cell transplantation for metastatic renal cell carcinoma

PURPOSE: We reviewed reduced intensity stem cell transplantation (RIST) in metastatic renal cell cancer (RCC). PATIENTS AND METHODS: Two cases of lung metastasis of immunotherapy invalidity. Six days of fludarabine 30 mg/m2 and 2 days of busulfan 4 mg/kg were given as conditioning for mini-SCT. CyA and short-term MTX were used as immunosuppressive agents. RESULTS: Size reduction of tumor was observed with dose reduction of CyA. Following steroid therapy for the treatment of GVHD, the tumor progressed. No serious complications except for GVHD. CONCLUSION: These results suggested that RIST might be considered as salvage therapy in patients metastatic RCC.     

Chemotherapy in metastatic renal cell cancer

Currently, there is no standard treatment for patients with advanced renal cell carcinoma (RCC) who do not respond to or progress after transient remission to first-line immunotherapy. At the end of the 1990s, no single chemotherapeutic drug, alone or in combination with interleukin-2 (IL-2) or interferon-alfa (IFN), had shown activity beyond the one expected by immunotherapy alone. New drugs on the market such as the pyrimidine analog gemcitabine or taxane-based chemotherapeutics may show promising tumor activity in combination with targeted therapy, but this has to be substantiated in upcoming trials. There is a great need to develop effective systemic therapy for advanced MRCC and to evaluate the efficacy of new drugs in clinical trials.     

Overview and management of toxicities associated with systemic therapies for advanced renal cell carcinoma

The advent of novel targeted agents for metastatic renal cell carcinoma (RCC) has offered clinical benefits over traditional immunotherapy (e.g., interleukin-2 and interferon-α) in both efficacy and safety profiles. The major classes of these targeted therapies for metastatic RCC include the tyrosine-kinase inhibitors, monoclonal antibody against vascular endothelial growth factor, and inhibitors of the mammalian target of rapamycin. Most recently, the success of immune checkpoint inhibitors—notably antibodies directed against programmed death-1 and its ligand—has also been demonstrated in RCC. With such progress in therapy, early detection, and subsequent management of treatment-related adverse events allow for patients to remain on active therapy for as long as possible and also enhance the probability of patients tolerating subsequent second line options. However, despite such impressive gains in efficacy with these new agents, therapeutic progress are primarily palliative in nature—hence, the critical importance of minimizing discomfort and potential harm in this patient population cannot be understated.     

Laparoscopic versus open cytoreductive nephrectomy in advanced renal-cell carcinoma

BACKGROUND AND PURPOSE: There is growing evidence of the benefit of cytoreductive nephrectomy prior to immunotherapy in patients with advanced renal-cell carcinoma (RCC). We compared the outcomes of patients with metastatic RCC undergoing laparoscopic and open cytoreductive nephrectomy prior to systemic therapy. PATIENTS AND METHODS: We retrospectively analyzed 27 patients undergoing cytoreductive nephrectomy for metastatic RCC between 2000 and 2004, 16 laparoscopically and 11 by an open approach. Patients with inferior vena-caval tumor thrombus were excluded from analysis. The two groups were comparable with regard to tumor size, clinical stage, and performance status. Surgical, pathologic, and perioperative characteristics and outcomes were compared. RESULTS: The laparoscopic technique was associated with reduced blood loss (149 v 1135 mL; P = 0.03), transfusion rate and quantity (13% v 55%; P = 0.03; 0.13 v 2.0 units of packed red blood cells; P = 0.007), shorter time to oral intake (1.2 v 2.7 days; P < 0.001), and shorter hospitalization (3.6 v 6.8 days; P < 0.001) compared with open nephrectomy. No significant differences were observed with respect to pathologic stage, operative time, complications, fraction receiving subsequent systemic therapy, time to systemic therapy, or survival. CONCLUSIONS: Laparoscopic cytoreductive nephrectomy is associated with reduced morbidity and hospital stay compared with open surgery. There was no increase in complications, and the ability to proceed with subsequent systemic therapy was maintained in the majority of patients. The laparoscopic approach can be considered in patients with metastatic RCC as part of a cytoreductive and systemic-therapy regimen.     

Novel Immunotherapeutic Strategies in Development for Renal Cell Carcinoma

Context

The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase.

Objective

To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm.

Evidence acquisition

A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy.

Evidence synthesis

Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host–tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies.

Conclusions

It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy.     

Systemic therapy for chromophobe renal cell carcinoma: A systematic review

Background: Chromophobe renal cell carcinoma (chRCC) subtype accounts for almost 5% of total RCC cases. It carries the best prognosis among the rest of RCC types. However, patients with metastatic chRCC disease have worse prognosis than patients with advanced clear cell RCC. Furthermore, available data regarding systemic therapy for chRCC patients are scarce and confusing. Aim: The aim of this systematic review is to search for and critically appraise studies that investigate the results of systemic therapies in patients diagnosed with metastatic chRCC disease. Methods: Search strategy included PUBMED, CENTRAL, clinicaltrials.gov databases, and abstracts of major conferences with a focus on urologic oncology (till March 2019). Studies investigating patients that were treated with systemic therapy for advanced chRCC disease were included. Primary outcomes were progression-free survival and objective response rate. Secondary outcome was overall survival. Screening of available studies was carried out by 2 groups of reviewers, as well as the quality assessment of the included studies. Results: The systematic search yielded 369 studies, of which 15 studies (2 randomized control trials and 13 cohort studies), involving 183 patients, met the eligibility criteria. The 2 randomized control trials that directly compared sunitinib vs. everolimus, suggested an advantage for sunitinib without being statistically significant. Furthermore, sunitinib seems to be superior than sorafenib at least in terms of objective response rate. Regarding mTOR inhibitors, they may have a role in a specific subset of chRCC patients, that needs to be further explored. Finally, as far as immunotherapy is concerned, available data suggest that chRCC seems to be resistant to recent immune check point inhibitors, since just a few tumor responses were observed with the administered immunotherapy regiments. Conclusion: The optimum therapy for metastatic chRCC is still missing, as results from ongoing trials are awaited. More studies, of high quality and adequate sample size, that will be based on the specific biology of chRCC, have to be carried out in order to identify the best treatment.     

Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer

Objectives

A small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients.

Methods and materials

A systematic medline/pubmed^© literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC.

Results

Tumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers.

Conclusions

PP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.

     

Surgical excision of isolated renal-bed recurrence after radical nephrectomy for renal cell carcinoma

OBJECTIVE: To present our results on managing loco-regional recurrence of renal cell carcinoma (RCC) with surgical excision, as local recurrence at the site of a previous nephrectomy is resistant to both systemic therapy and radiotherapy. PATIENTS AND METHODS: In all, 16 patients were operated on between 1994 and 2003 for local recurrence of RCC. The median (mean, range) age at the time of local recurrence was 57.9 (57.4, 28.9-71.7) years, and the median interval from primary surgery 2.22 (3.88, 0.27-14.46) years. Before surgery eight patients had been given systemic immunotherapy, with no response of their local recurrence. RESULTS: Two patients were deemed inoperable because of direct invasion of the great vessels and the liver by tumour. The remaining 14 patients had recurrence in residual adrenal tissue (two), para-aortic nodes (three), para-caval nodes (two), retrocaval nodes (one), renal bed (six), liver, spleen and stomach (one each), and diaphragm (two). Although complete macroscopic en-bloc clearance was achieved in these patients, only eight had tumour-free margins on histological examination. The histology was consistent with RCC recurrence in all cases. All of the patients were followed with computed tomography at regular intervals. At a median follow-up of 1.0 (1.65, 0.25-6.5) years, five patients remain disease-free, four have local and distant relapse, and five developed distant metastasis only. The presence of tumour at the resection margin was a significant factor in predicting local and distant disease-free survival (P < 0.05). CONCLUSIONS: En bloc excision of isolated locally recurrent RCC is possible, and complete surgical extirpation can lead to prolonged disease-free survival.     

The value of tumor nephrectomy in metastatic renal cell carcinoma

In the case of an organ-confined RCC, tumor nephrectomy is the undisputed therapy of choice even though overall 5-year survival has not surpassed the 60% threshold. Further improvement will most likely have to await the development of more effective systemic treatment strategies. For an exclusively surgical therapy of metastatic RCC, tumor nephrectomy, sometimes in combination with metastasectomy, can be applied. However, more commonly used is a multimodality approach consisting of a cytoreductive operation followed by immunotherapy. Alternatively, one may select immunotherapy first followed by adjuvant nephrectomy in the case of a response, or one may proceed directly to immunotherapy only. Long-term survival does not exceed 5-10%, and patient selection appears to have a higher prognostic impact than any treatment strategy available. Concepts and progress in the field clearly are of increasing value for modern oncologic urologists. The current standard, a multimodality treatment of metastatic RCC, in which an operation becomes necessary at a certain point in time, easily justifies a central role for the urologic surgeon.     

Cytokine therapy in renal cell cancer

Despite extensive investigations with many different treatment modalities, metastatic renal cell carcinoma (RCC) remains a disease highly resistant to systemic therapy. The outlook for patients with metastatic RCC is poor, with a 5-year survival rate of less than 10%. Late relapses after nephrectomy, prolonged stable disease in the absence of systemic therapy, and rare spontaneous regression are clinical observations that suggest host immune mechanisms could be important in regulating tumor growth. Interleukin-2 (IL-2) and interferon- (IFN-) have been extensively studied in advanced RCC with responses in the 10 to 20% range. Two randomized trials suggest that treatment with IFN- compared with vinblastine or medroxyprogesterone results in a small improvement in survival. Prolonged responses with high-dose IL-2 is significant but is accompanied by formidable toxicity. Although the combination of IFN- and IL-2 compared with monotherapy with IFN- or IL-2 increases the response proportion, no improvement in survival could be demonstrated in a recent randomized trial. In addition, three randomized trials showed no survival benefit associated with IFN- therapy given as adjuvant therapy following complete resection of locally advanced RCC. Small numbers of patients exhibit complete or partial responses to IFN- and/or IL-2, but most patients do not respond and there are few long-term survivors. Clinical investigation of new agents and treatment programs to identify improved antitumor activity against metastases remain the highest priorities in this refractory disease.     

Systemic therapy for metastatic renal cell carcinoma

Renal cell cancer (RCC) is the most common form of cancer of the kidney and accounts for approximately 44,000 cases per year in the United States. Historically, only immunotherapy showed activity in metastatic RCC. The improved survival and quality of life for patients with metastatic RCC over the last several years are direct results of advances made in understanding the development of RCC. Three targeted therapies-sunitinib, sorafenib, and temsirolimus-have been approved for use in the United States recently. Current research is aimed at developing new drugs and combining available drugs to improve upon the responses and survival seen with approved single agents.     

Chemoimmunotherapy in the systemic treatment of advanced renal carcinoma

Polychemotherapy and immunomodulating treatment using IL-2 and/or IFN-alpha produce objective responses in a proportion of advanced renal cell carcinoma patients. The goals of an improved cost effectiveness and therapeutic index of interleukin-2 and/or Interferon-alpha in combination with chemotherapeutic agents require the design of risk factor adapted individual therapeutic strategies for the outpatient setting. High dose i. v. IL-2 therapy in metastatic renal cell carcinoma has been proven effective [11]. Other modalities of applying IL-2 have been described [12-14] (Table 1). A cumulative risk-score identified three risk-groups with significant differences in median survival [16]. The SC use of IL-2 and INF-alpha has been established in the treatment of RCC [16, 23]. It appears that combination chemoimmunotherapy including p. o. retinoic acid is far more effective than single agent treatment. Further studies will have to be designed to improve therapeutic index and cost effectiveness in systemic combination therapy in metastatic RCC.