Renal cancer

Seminar

Renal cancer Umberto Capitanio, Francesco Montorsi

The diagnosis and management of renal cell carcinoma have changed remarkably rapidly. Although the incidence of renal cell carcinoma has been increasing, survival has improved substantially. As incidental diagnosis of small indolent cancers has become more frequent, active surveillance, robot-assisted nephron-sparing surgical techniques, and minimally invasive procedures, such as thermal ablation, have gained popularity. Despite progression in cancer control and survival, locally advanced disease and distant metastases are still diagnosed in a notable proportion of patients. An integrated management strategy that includes surgical debulking and systemic treatment with well established targeted biological drugs has improved the care of patients. Nevertheless, uncertainties, controversies, and research questions remain. Further advances are expected from translational and clinical studies.

Introduction

Pathophysiology and genetics

Abdominal imaging is used for many different medical disorders (eg, hypertension, diabetes) and, therefore, incidental detection of renal masses is becoming increasingly common. A renal mass might be merely a simple renal cyst that requires no treatment or follow-up,1 but in a notable proportion of cases masses are benign renal lesions (eg, angiomyolipomas or oncocytomas) or malignant renal cell carcinomas that might require additional procedures or interventions.2 Although most incidentally detected lesions are small low-grade tumours, up to 17% of all renal cell carcinomas have distant metastases at the time of diagnosis.3 In this heterogeneous clinical setting, developments in molecular biology, diagnostic techniques, surgery, and medical oncology are revolutionising the approach to this disease.

Renal cell carcinoma comprises a heterogeneous group of cancers with different genetic and molecular alterations underlying the many documented histological subtypes.18 Clear-cell, papillary (types 1 and 2), and chromophobe are the most common solid renal cell carcinomas within the kidney and account for 85–90% of all renal malignancies.18 Less common cancers include papillary adenoma, multilocular cystic clear-cell carcinoma, hybrid oncocytic chromophobe tumour, carcinoma of the collecting ducts of Bellini, renal medullary carcinoma, carcinoma associated with neuroblastoma, and mucinous tubular and spindle-cell carcinoma.18 The International Society of Urological Pathology Vancouver Consensus Statement added five more epithelial tumour subtypes of renal cell carcinoma: tubulocystic, acquired cystic diseaseassociated, clear-cell tubulopapillary, microphthalmia family translocation, and hereditary leiomyomatosis– renal cell carcinoma syndrome-associated.19 Although most renal masses are initially confined to one organ, early haematogenic dissemination is responsible for metastatic disease at the time of diagnosis. The most frequent sites of distant metastases are lungs, bone, and brain, but adrenal glands, contralateral kidney, and liver might be involved.20

Epidemiology In 2013, renal cell carcinoma was diagnosed in more than 350 000 people worldwide, which made it the seventh most common site for tumours, and this cancer is associated with more than 140 000 deaths per year.4 Incidence of renal cell carcinoma varies worldwide, being higher in developed countries than in developing countries (appendix). Incidence predominates in men, with the male-to-female ratio being 1·5:1·0, and peaks at age 60–70 years.5 Despite increased incidence overall, improvements in relative survival rates have been reported over the past three decades,3,5 although these might be skewed by disease stage migration.6–8 In Europe, mortality from renal cell carcinoma peaked at 4·8 per 100 000 in 1990–94 and had declined to 4·1 per 100 000 (−13%) in 2000–04.5 In the USA, 5-year relative survival rates at diagnosis increased from 50% in 1975–77 to 57% in 1987–89, and reached 73% in 2003–09.3 Established risk factors include smoking tobacco,9 hypertension,10–12 and obesity.13,14 These associations might be biased by the probability that such patients undergo routine imaging, which could increase the likelihood of incidental detection of renal masses. Several other associations have been suggested, for example, a protective effect of alcohol consumption,15 a negative effect of red meat consumption,16 and occupational exposure to carcinogens,17 but the data are unclear.

Published Online August 26, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00046-X Department of Urology, Vita-Salute San Raffaele University (U Capitanio MD) and Division of Experimental Oncology, URI, Urological Research Institute, Renal Cancer Unit (Prof F Montorsi FRCS), IRCCS San Raffaele Scientific Institute, Milan, Italy Correspondence to: Dr Umberto Capitanio, Department of Urology, San Raffaele Hospital, Via Olgettina 60, Milan 20132, Italy [email protected]

See Online for appendix

Search strategy and selection criteria We identified data for this Seminar through searches of PubMed and Web of Science. We included papers in core clinical journals that described studies in adults and were published in English from 2004 to 2014. Search terms included “renal cancer” or “kidney cancer” in combination with the terms “epidemiology”, “genetics”, “pathophysiology”, “diagnosis”, “biopsy”, “treatment”, “surgery”, “active surveillance”, “medical therapy”, or “targeted therapy”. We also searched cited references from selected articles and previous reviews to identify further relevant papers not retrieved by this search, including those outside the time period of the initial search. We also searched for updates on the main features of renal cell carcinoma, with particular attention paid to reports focusing on novel treatments, renal biopsy, new imaging technologies, and minimally invasive techniques.

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Renal cell carcinoma can be sporadic or hereditary, but both forms are generally associated with structural alterations of the short arm of chromosome 3.21 Translocation tumours are increasingly being identified in adolescents and young adults.18 Many gene variants have been associated with renal cell carcinoma. Somatic mutations or epigenetic alterations of VHL, a tumoursuppressor gene, are seen in more than 80% of clear-cell subtypes. Specifically, the VHL tumour suppressor protein is important in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitination and proteasomal degradation.22 Sequencing studies have identified other driver genes that are involved in the pathogenesis of renal cell carcinoma, including PBRM1,23 BAP1,23 SETD2,24 TCEB1,24 and KDM5C.25 Studies analysing the effects of these mutations on clinical outcomes, however, are limited by small sample sizes, short-term follow-up, and lack of assessment of multiple markers in the same cohort.24,25 Hereditary forms of renal cell carcinoma include von Hippel-Lindau syndrome (VHL 3p25–26),26 hereditary papillary renal cell carcinoma (MET 7q31–34),27 Birt-Hogg-Dubé syndrome (FLCN 17p11),28 hereditary leiomyomatosis (FH 1q42–43),29 and tuberous sclerosis (TSC1 9q34 or TSC2 16p13).30

Diagnosis With the expansion of routine imaging for many disorders, patients with renal cell carcinoma are increasingly being identified by chance. Only 30% of patients are diagnosed on the basis of symptoms. At all stages, renal cell carcinoma might produce multiple hormone-like or cytokine-like biologically active products that lead to clinically important paraneoplastic syndromes (table 1).31 The findings of routine diagnostic blood tests might be altered by renal cell carcinoma, but no change is pathognomonic. Physical examination has a limited role in diagnosis of renal cell carcinoma, but the presence of a palpable abdominal mass, new-onset varicocele, or lower extremity oedema should always prompt additional imaging assessments for retroperitoneal neoplasia.

Standard imaging Although renal cell carcinoma is frequently detected by abdominal ultrasound scanning, limitations in specificity and accuracy make it necessary to use CT or MRI to confirm suspicious findings. The main goals of imaging are to characterise the mass and possible abdominal metastases, tumour extension, and venous involvement for staging (appendix). Imaging might also be useful to

Occurrence among patients with symptomatic RCC

Proposed causes

Acute or chronic flank pain

Common

Urinary system obstruction or infiltration, invasion of adjacent organs, retroperitoneal space-occupying mass

Gross haematuria

Less frequent

Urinary system infiltration

Palpable abdominal mass

Less frequent

Retroperitoneal space-occupying mass

Varicocele

Rare

Increased venous pressure due to space-occupying mass or venous thrombus

Hypertension

Common

Increased production of renin directly by tumour; compression or encasement of the renal artery or its branches causing renal artery stenosis; or arteriovenous fistula within the tumour, polycythaemia, hypercalcaemia, ureteral obstruction, and increased intracranial pressure associated with cerebral metastases

Anaemia

Common

Bleeding, abnormal production of prostaglandins, cytokines, and inflammatory mediators

Local symptoms

Paraneoplastic disorders

Cachexia, weight loss

Common

Abnormal production of prostaglandins, cytokines, and inflammatory mediators

Pyrexia

Less frequent

Abnormal production of prostaglandins, cytokines, and inflammatory mediators

Raised hepatic enzyme concentrations in absence of liver metastases (Stauffer’s syndrome)

Less frequent

Non-specific hepatitis associated with a prominent lymphocytic infiltrate, raised concentrations of interleukin-6 in serum

Hypercalcaemia

Less frequent

Osteolytic metastatic involvement of bone, production of parathyroid-hormonelike peptides, tumour-derived 1,25-dihydroxycholecalciferol, and prostaglandins

Polycythaemia

Rare

Increased production of erythropoietin directly by the tumour or by the adjacent parenchyma in response to hypoxia induced by tumour growth

Hypoglycaemia, neuromyopathy, amyloidosis, vascular thrombosis, Cushing’s syndrome, protein enteropathy, galactorrhoea, gynaecomastia, decreased libido, hirsutism, amenorrhoea, chills, necrotising myopathy, immune thrombocytopenic purpura

Anecdotal

Abnormal production of 1,25-dihydroxycholecalciferol, renin, erythropoietin, prostaglandins, parathyroid-hormone-like peptides, lupus-type anticoagulant, human chorionic gonadotropin, insulin, various cytokines or inflammatory mediators

RCC=renal cell carcinoma.

Table 1: Most frequent local symptoms and paraneoplastic disorders associated with RCC

2

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assess additional characteristics that could be important if active management is planned (eg, bilateral renal function, renal vascular supply, retroperitoneal anatomy). If malignant renal cell carcinoma is suspected, additional imaging (eg, thoracic and brain CT scan, total-body bone scan) can be considered in symptomatic patients or in cases of bulky abdominal disease.32–35

tumours, detection of small renal lesions44 and accumulating evidence that surgically induced chronic kidney disease can increase patients’ morbidity45 have led to more conservative approaches.46 Specifically, nephronsparing surgery, active surveillance, and minimally invasive techniques46 have been introduced into daily clinical practice. These approaches limit invasiveness, iatrogenic renal function impairment, and overtreatment.

New imaging technologies New technologies for cancer detection and characterisation are being investigated for renal cell carcinoma; for example, advanced MRI techniques, such as diffusionweighted and perfusion-weighted imaging, are being explored for the assessment of renal masses.36 Although PET might be useful for the diagnosis and follow-up of renal cell carcinoma, this technique is not yet part of the standard strategy.37 Some studies have suggested the use of combined ¹²⁴iodine PET and CT for the detection of labelled antibodies to the carbonic anhydrase IX antigen, which is widely expressed in more than 90% of clear-cell renal cell carcinomas but not in the normal kidney.38,39

Emerging role of renal biopsy The use of renal biopsy has been limited by concerns about accuracy and safety, and in the past has had little effect on treatment decisions because the standard treatment for solid renal masses was upfront removal.40 Increased active surveillance for small renal masses and individualised targeted therapy for patients with metastases, however, have pushed the scientific community to improve expertise in biopsy performance and pathological interpretation.41 Consequently, renal biopsy is now used to establish the diagnosis of radiologically indeterminate renal masses, obtain histology of incidentally detected renal masses in patients who are potential candidates for active surveillance, and to select the most suitable targeted therapy for patients with metastatic renal tumours.42 Accuracy of biopsy in detecting malignancy ranges from 38% to 100%.41 In one of the largest study cohorts reported (n=345), histological subtype and Fuhrman grade were correctly assessed at biopsy in 88% and 64% of cases, respectively.43 Renal biopsy has low associated morbidity. Contemporary series have revealed overall complication rates (mainly bleeding, infection, and arteriovenous fistula) in 0·3–5·3% of cases. Tumour seeding throughout the biopsy tract, which had been reported anecdotally in the past, is no longer a risk with modern biopsy techniques.42 Although renal biopsy has a definite and expanding role in the assessment and treatment of renal masses, it remains substantially underused.40

Management Notwithstanding advances in the understanding of renal cell carcinoma biology, surgery remains the mainstay of curative treatment. Although radical nephrectomy was historically the standard of care for management of renal

Active surveillance Management of localised renal cell carcinoma must take into account competing causes of mortality, particularly in elderly patients.47 This consideration has led to the increasing use of active surveillance46 to avoid surgically induced short-term and medium-term complications. The rationale for active surveillance is that roughly 20% of small renal masses harbour benign final pathology and the median growth rate is usually slow (2–3 mm/year).48 Moreover, the risk of metastatic progression is very low (less than 1%), with virtually no risk of cancer-specific mortality in well selected patients.49–51 Biopsy might be useful before active surveillance is started. Active surveillance has been proposed for larger tumours to determine tumour growth kinetics, especially if a patient has severe competing risks and limited life expectancy.52 Absolute cutoffs for tumour size and growth rate that should prompt intervention during active surveillance are not well defined. In various proposed protocols, imaging at 3 and 6 months initially, every 6 months during the next 2–3 years, and annually thereafter is suggested, but cumulative radiation risk and increased costs are being assessed.49,50,53 Data are needed from large cohorts with long-term follow-up to better characterise clinical indications and standardise protocols.

Minimally invasive techniques Although surgery still represents the standard of care for renal cell carcinoma, the use of minimally invasive techniques to treat incidentally detected small tumours has been increasing. Cryotherapy and radiofrequency ablation (RFA) were initially contemplated only for patients with one kidney or for those deemed unfit to undergo a major procedure. Since preliminary reports showed acceptable cancer control,37,54–57 the clinical indications for these procedures has been extending. For example, 8% of US patients are treated with cryotherapy and RFA, compared with 4% in 1998.58 Renal ablative treatment uses the cell-destroying properties of temperature (hot or cold) to cause apoptosis in cancer cells.54 RFA induces thermal damage (50–120°C) through frictional heating resulting from ionic oscillation by a high-frequency alternating current (375–500 kHz).59 Cryotherapy stimulates tumour cell death directly by damaging cell membranes and organelles and indirectly by initiating vascular compromise through thrombosis of small vessels,54 which leads to coagulative necrosis of

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the tissue. Potential complications after RFA and cryotherapy are renal bleeding or abscess formation or extrarenal effects in the bowel, pleura, spleen, pancreas, and vasculature. Most studies of outcomes after renal tumour cryoablation consist of single-institution retrospective reports with low numbers of patients and short follow-up. An analysis of the Mayo Clinic Renal Tumor Registry that included more than 1800 patients with primary cT1N0M0 renal tumours showed similar local recurrence-free survival for patients treated with nephron-sparing surgery, RFA, or cryotherapy (p=0·4). By contrast, metastases-free survival was significantly better after nephron-sparing surgery (p=0·005) and cryoablation (p=0·02) than with RFA.60 Although this comparison included a large number of cases, its retrospective nature, the differing baseline characteristics between studies, and other unmeasurable confounders make it difficult to draw conclusions about cancer control.61 A meta-analysis by Kunkle and colleagues56 suggested that recurrence-free survival might be worse for RFA and cryoablation than for partial nephrectomy, but showed no differences for metastasis-free survival. Conversely, a systematic review and meta-analysis of six clinical trials (one prospective randomised and five retrospective cohort trials) showed that recurrence-free survival and cancer-specific survival were similar for patients treated with surgery or RFA, with less postoperative decline in estimated glomerular filtration rate in the RFA group.55 The overall complication rate was significantly lower in the RFA group (7% vs 11%; relative risk 0·55, 95% CI 0·31–0·97, p=0·04). The groups had similar local recurrence rates of 3–4% (0·92, 0·4–2·14, p=0·8) and disease-free survival (hazard ratio 1·04, 95% CI 0·48–2·24, p=0·9).55

Surgery Nephron-sparing surgery Although radical nephrectomy involves removal of the entire kidney, with nephron-sparing surgery only the tumour is excised and as much of the normal renal parenchyma as possible is maintained (figure 1). Although initially reserved for imperative situations, according to international guidelines, nephron-sparing surgery is now the treatment of choice whenever a healthy part of kidney can safely be spared. Nephron-sparing surgery has been used increasingly since observations suggested oncological control similar to radical nephrectomy62–64 but with the additional benefit of renal preservation.65 Moreover, a long-term protective effect has been suggested for nephron-sparing surgery relative to radical nephrectomy for risk of cardiovascular events after surgery (eg, new-onset hypertension, coronary artery disease, vasculopathy, and cerebrovascular disease).45,66,67 Because patients with organ-confined renal cell carcinoma that has been surgically treated are usually long-term cancer survivors (85–96% cancer-specific survival 10 years after surgery68), these functional outcomes are important. 4

Although many retrospective reports have suggested a benefit in overall survival for patients treated with nephron-sparing surgery relative to radical nephrectomy,67,69 no improvements with nephron-sparing techniques were found in a comparison of the two techniques.70 However, many flaws undermined the study (eg, low recruitment, selection and verification biases, and being done at the beginning of the nephron-sparing learning curve).70 Further efforts are needed to improve understanding of which patients might benefit from nephron-sparing surgery in terms of overall survival. International guidelines include standard indications for nephron-sparing surgery: absolute, indicating patients with only one anatomical or functional kidney; relative, indicating patients with a functioning opposite kidney that is affected by a disorder that might impair renal function in the future or with hereditary forms of renal cell carcinoma who are at increased risk of developing a tumour in the contralateral kidney; and elective, indicating localised unilateral renal cell carcinoma with a healthy contralateral kidney.37,58 Although nephron-sparing surgery has been proposed for use even for locally advanced disease and metastatic spread,71,72 further data are required before a conservative approach can be approved in those settings. Surgical excision of tumours is done by kidney mobilisation, resection of the tumour (with or without a rim of normal parenchyma, according to the anatomical and tumour features), and final reconstruction (renorrhaphy; figure 1). During resection of the tumour, the main renal artery can be clamped temporarily (hilar clamping) to minimise blood loss. Sustained hilar clamping might cause impairment of renal function and, therefore, limited duration of ischaemia is suggested, although the functional long-term consequences are controversial.73–75 If technically possible, techniques without clamping or selective intraparenchymal clamping (eg, clamping of only a branch of the main artery) should be considered.76 Nephron-sparing surgery should be preferred unless pre-existing disorders are likely to decrease the positive effect of a conservative approach, such as frailty or short life expectancy. Other risk factors are low surgical expertise or volume of relevant surgeries, excessive ischaemia time, use of non-conservative haemostasis techniques, or large or anatomically complex renal masses with a low percentage of nephrons that can be spared. In such situations, the potential benefit in functional outcomes might be jeopardised. Conservative surgical techniques require substantial technical expertise and might be associated with increased risk of haemorrhage (3%) and urinary leakage (4%).77 Consequently, nephron-sparing surgery is still underused for patients with renal cell carcinoma, especially in nonacademic hospitals.78–80 If the aim of the surgery is the preservation of the normal renal parenchyma, the choice of surgical approach

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A

2 1

B

C

D

Figure 1: Procedures in robot-assisted nephron-sparing surgery to remove renal cell carcinoma (A) In robot-assisted surgery, instead of directly moving the instruments, the surgeon performs the normal movements associated with the surgery, and the robotic arms make those movements and use end-effectors and manipulators to perform the actual surgery on the patient. One arm is dedicated to the laparoscope and the two others hold forceps, monopolar curved scissors, a cautery hook, and a large needle driver. The patient is positioned in a modified flank position. Port configuration can vary based on tumour location to optimise the working angles. Surgical excision of the tumour is done by (B) kidney mobilisation, (C) tumour resection (with or without a rim of normal parenchyma according to anatomical and tumour features), and (D) final reconstruction (renorrhaphy).

(open, laparoscopic, or robotic) depends largely on tumour characteristics and the surgeon’s expertise. Tumour features that dictate the feasibility of nephron-sparing surgery versus radical nephrectomy include diameter, location, depth, and proximity to hilar vessels and the urinary collecting system. The three foremost anatomical scores (PADUA,81 RENAL,82 and C-index83) may be used to assess those features before surgery, with the aim of improving selection of patients, surgical management, research reporting, and outcome prediction.81–83 Robot-assisted nephron-sparing surgery is gaining popularity because challenging cases can be approached with a minimally invasive procedure (figure 1). In hospitals that have acquired surgical robotic systems, treatment with nephron-sparing surgery has increased by 16–35% relative to hospitals without such technology.84 Conversely, laparoscopic nephron-sparing surgery might be challenging and is usually limited to simpler cases or done by experienced surgeons (appendix). Open

nephron-sparing surgery, which was the standard approach until the early 2000s, is now used only in cases where there are anatomical difficulties (eg, urinary tract invasion or hilar or larger tumours) or for which minimally invasive techniques are unavailable. A meta-analysis of non-randomised studies including 2240 patients showed that robot-assisted compared with laparoscopic nephron-sparing surgery was associated with reduced rates of conversion to open surgery (relative risk 0·4, 95% CI 0·2–0·9, p=0·02) and radical surgery (0·19, 0·1–0·5, p=0·0006).85 Additionally, robot-assisted nephron-sparing surgery resulted in significantly shorter warm ischaemia, (weighted mean difference 3 min, 95% CI 1–5, p=0·005), although the clinical relevance of this outcome was marginal, smaller change in estimated glomerular filtration rate (standardised mean difference 0·2, 0·02–0·3, p=0·03), and shorter length of stay in hospital (weighted mean difference 0·2 days, 0·1–0·4, p=0·004).85 Moreover, no differences were noted in

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Figure 2: CT scan of a patient aged 55 years with a bulky right kidney tumour and caval thrombus invading the right atrium Images were taken before nephrectomy and venous thrombectomy, and are two slices from the same scan. Initial presentation was a newly diagnosed right varicocele, followed by fatigue and dyspnoea. The right varicocele was secondary to a venous thrombus occluding the vena cava and its branch, the right spermatic vein. Fatigue and dyspnoea were secondary to initial heart failure and abnormal production of prostaglandins, cytokines, and inflammatory mediators by the tumour.

operative outcomes, including complications with Clavien-Dindo classification grades 1–2 (relative risk 1·1, 95% CI 0·9–1·3, p=06) and 3–5 (0·9, 0·6–1·5, p=0·8).85

Radical nephrectomy If sparing the parenchyma is not possible and the aim of the surgery is removal of the entire kidney, open radical nephrectomy has been replaced in most cases by laparoscopic nephrectomy, which is associated with shorter stay in hospital, less perioperative blood loss, fewer analgesic requirements, and shorter convalescence time.86,87 Although randomised studies assessing oncological outcomes have never been done, similar oncological outcomes for laparoscopic and open radical nephrectomy are suggested.86,87 Robot-assisted radical nephrectomy results in increased medical expense without improving morbidity compared with laparoscopic procedures,88 but might still be worth considering for selected cases (eg, when retroperitoneal lymphadenectomy is thought to be required).

Lymph node dissection, adrenalectomy, and venous thrombectomy Adrenalectomy was historically viewed as an unavoidable part of radical procedures. Removal of the ipsilateral adrenal gland, however, is now optional if no macroscopic invasion is suggested by preoperative imaging or found during surgery.37,57,89 Irrespective of T stage, patients who have renal cell carcinoma with nodal invasion (pN1) have poor cancerspecific survival (20–30% at 3 years after surgery).90 Although lymphadenectomy provides the most accurate 6

and reliable staging of lymph node status, the value of lymphadenectomy in renal cell carcinoma remains controversial. A European Organisation for Research and Treatment of Cancer randomised trial showed no survival advantage for low-risk patients treated with nephrectomy plus lymphadenectomy versus nephrectomy only,91 although several retrospective studies have suggested a potential benefit with lymphadenectomy in intermediaterisk and high-risk patients.92 Sentinel node biopsy is not an option for renal cell carcinoma at present.93,94 Around 10% of patients with renal cell carcinoma have venous tumour thrombosis in the renal vein, inferior vena cava, or extending up to the right atrium (figure 2). Although prognosis is worse in such cases and surgery might be challenging and associated with an increased complication rate, a case–cohort study suggested that survival was better with surgical management than with non-surgical management.95 Operative management is dictated primarily by the extent of the thrombus. When confined to the renal vein, minimum modification of the standard surgical approach is required. As the thrombus extends cranially, opening of the vena cava, liver mobilisation, opening of the right atrium, and cardiopulmonary bypass might be necessary.

Metastatic disease at diagnosis Historically, patients with metastatic clear-cell renal cell carcinoma were treated with systemic therapy based on immune modulators, mainly interferon α and interleukin-2, but outcomes were only slightly improved.96 In a few cases these agents have led to T-cell-mediated tumour regression secondary to enhancement in lymphocyte mitogenesis, lymphocyte cytotoxicity, and activity of lymphokine-activated and natural killer cells.97 Immunotherapy with high-dose interleukin 2 has been associated with durable complete response in less than 10% of patients and has been associated with severe treatment-related toxic effects.97 Subsequently, combined data from 99 study groups show an overall chance of partial or complete remission in only 13% of patients, compared with 3–4% in placebo or non-immunotherapy control groups.98 Aldesleukin and interferon α (associated with bevacizumab) remain the only immune-modulating drugs approved for selected cases of metastatic renal cell carcinoma.57 Several non-randomised studies had suggested a response to systemic therapy and improved survival in patients who had undergone nephrectomy and, therefore, two randomised clinical trials were planned at the end of 1980s to test the effect of surgery on survival in patients with metastatic renal cell carcinoma. 331 patients overall were randomly assigned treatment with nephrectomy plus interferon α-2b or interferon α-2b alone.99,100 A combined analysis of the findings showed a 31% decrease in the risk of death with surgery compared with interferon α-2b alone (median survival 13·6 months, 95% CI 9·7–17·4 vs 7·8 months, 5·9–9·7).101 Several

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hypotheses were formed to explain the observed benefits of nephrectomy: reduction of disease burden; decrease of immunosuppression and improved clinical response to cytokines; decreased growth-factor secretion (mainly VEGF); and inhibited tumour microenvironment secondary to surgically induced chronic metabolic acidosis.102 Over the past decade, the main advance in the treatment of metastatic renal cell carcinoma has been the development of treatments that affect specific targets in biological pathways. Agents targeting the VEGF/PDGFR/ mTOR pathway continue to be the mainstays of treatment (table 2). Although improved target specificity has lessened the risk of toxic effects associated with these drugs, durable complete responses remain the exception. Seven targeted drugs have been approved by European Medicines Agency and the US Food and Drug

Administration for management of renal cell carcinoma (table 2, figure 3). Sunitinib and sorafenib were associated significant benefits in progression-free survival and overall survival compared with placebo in two phase 3 trials,103,104 as was, temsirolimus in high-risk patients when compared with IFN monotherapy.110 In contrast, in patients with metastatic renal cell carcinoma who progressed after treatment with sunitinib, overall survival was shorter with temsirolimus than with sorafenib.111 Everolimus was associated with a significant benefit in progression-free survival relative to placebo in patients with metastatic renal cell carcinoma who progressed after sunitinib or sorafenib.112 Everolimus has been approved by the US Food and Drug Administration as the first drug to be used specifically to treat noncancerous kidney tumours (renal angiomyolipomas) in patients with tuberous sclerosis complex.30

Mechanism

Administration route

Setting

Treatment

Main findings

Sunitinib

PDGFR and VEGFR inhibitor

Capsules

Treatment naive (n=750)

Sunitinib vs interferon α

PFS, 11 months (95% CI 10–12) vs 5 months (95% CI 4–6), HR 0·42 (95% CI 0·32–0·54), p<0·001103

Sorafenib

PDGFR, VEGFR-2, and MAPK/MEK/ ERK inhibitor

Capsules

Second-line therapy (n=903)

Sorafenib vs placebo

PFS, 5·5 vs 2·8 months, HR 0·44 (95% CI 0·35–0·55), p<0·00001;104 OS, 17·8 vs 15·2 months, HR 0·74 (95% CI 0·74–1·04), p=0·146;104 OS after censoring,* 17·8 vs 14·3 months, HR 0·78 (95% CI 0·62–0·97), p=0·029104

Bevacizumab

Recombinant humanised monoclonal antibody directed against VEGF-A

Intravenous injection

Treatment naive (n=649)

Bevacizumab plus interferon PFS, 10·2 vs 5·4 months, HR 0·63 (95% CI 0·52–0·75), p<0·001;105 vs interferon plus placebo OS, 23·3 vs 21·3 months, HR 0·91 (95% CI 0·76–1·10), p=0·33106†

Treatment naive (n=732)

Bevacizumab plus interferon PFS, 8·5 vs 5·2, HR 0·72 (95% CI 0·61–0·83), p<0·001;107 OS, 18·3 vs interferon alone (95% CI 16·5–22·5) vs 17·4 (95% CI 14·4–20·0), HR 0·86 (95% CI 0·73–1·01), p=0·069108

Treatment naive (791)

Temsirolimus plus bevacizumab vs interferon plus bevacizumab

PFS, 9·1 vs 9·3 months, HR 1·1 (95% CI 0·9–1·3), p=0·8;109 OS, 25·8 vs 25·5 months, HR 1·0, p=0·6109

Treatment naive (poor-risk, n=626)

Temsirolimus vs interferon

PFS, 3·8 vs 1·9 months, p<0·0001; OS, 10·9 vs 7·3 months, HR 0·73 (95% CI 0·58–0·92), p=0·008110

Second line after sunitinib (n=512)

Temsirolimus vs sorafenib

PFS, 4·3 months (95% CI 4·0–5·4) vs 3·9 months (95% CI 2·8–4·2), HR 0·87 (95% CI 0·71–1·07), p=0·19;111 OS, 12·3 months (95% CI 10·1–14·8) vs 16·6 months (95% CI 13·6–18·7), HR 1·31 (95% CI 1·05–1·63), p=0·01111

Temsirolimus

mTOR inhibitor

Intravenous injection

Everolimus

mTOR inhibitor

Capsules

Second-line therapy (n=410)

Everolimus vs placebo

PFS, 4·0 months (95% CI 3·7–5·5) vs 1·9 months (95% CI 1·8–1·9), HR 0·30 (95% CI 0·22–0·40), p<0·0001112

Pazopanib

VEGFR/PDGFR/c-Kit inhibitor

Capsules

Treatment naive (n=233)

Pazopanib vs placebo

PFS, 11·1 vs 2·8 months, HR 0·40 (95% CI 0·27–0·60), p<0·0001;113 OS, 22·9 months (95% CI 17·6–25·4) vs 23·5 months (95% CI 12·0–34·3), HR 1·01 (95% CI 0·72–1·42)114

Treatment naive (n=1110)

Pazopanib vs sunitinib

PFS, 8·4 months (95% CI 8·3–10·9) vs 9·5 months (95% CI 8·3–11·1);115 OS, 28·3 months (95% CI 26·0–35·5) vs 29·1 months (95% CI 25·4–33·1), HR 0·92 (95% CI 0·79–1·06), p=0·24116

Cytokine refractory (n=202)

Pazopanib vs placebo

PFS, 7·4 vs 4·2 months, HR 0·54 (95% CI 0·35–0·84), p<0·0001;113 OS, 22·7 months (95% CI 19·3–28·3) vs 18·7 months (95% CI 14·2–26·3), HR 0·82 (95% CI 0·57–1·16)114

Treatment naive with mRCC (n=288)

Axitinib vs sorafenib

PFS, 10·1 month (95% CI 7·2–12·1) vs 6·5 months (95% CI 4·7–8·3), HR 0·77 (95% CI 0·56–1·05), p=0·038117

Second-line therapy for mRCC (n=723)

Axitinib vs sorafenib

PFS, 6·7 months (95% CI 6·3–8·6) vs 4·7 months (95% CI 4·6–5·6), HR 0·66 (95% CI 0·54–0·81), p<0·0001118

Axitinib

VEGFR (1–3), PDGFR, and c-Kit inhibitors

Capsules

PFS=progression-free survival. HR=hazard ratio. OS=overall survival. mRCC=metastatic renal cell carcinoma. *After crossover of placebo patients. †Unblinded after interim analysis and crossover and use of other antineoplastic therapies allowed.

Table 2: Phase 3 trials of targeted therapies approved for management of mRCC

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Blood vessel

Immune modulation NK cell

Interferon α

T cell Sunitinib Sorafenib Pazopanib

PDGFR CTLA4 Aldesleukin

Angiogenesis PD-1 (Ipilimumab)) (Rilotumumab)

FGF

PDGF PD-L1

FGFR

HGF

Axitinib

(Nivolumab) Paracrine growth stimulation

VEGFR (Brivanib) (Dovitinib

MET/HGFR

AKT

Temsirolimus Everolimus

VEGF

(Erlotinib) PI3K PTEN

EGF

Bevacizumab

mTORC1–2 HIF1α

Autocrine growth stimulation

Nucleus EGFR MAPK/ERK pathway

VHL Gene expression, cell growth, proliferation, survival

TGFα

Tumour cell

Figure 3: Biological pathways related to development of renal cell carcinoma and treatment targets NK=natural killer.

Pazopanib is an oral inhibitor of the VEGFR/ PDGFR/c-Kit pathway that has shown a significant benefit in progression-free survival compared with placebo in treatment-naive patients (table 2).113 The difference in final overall survival between patients treated with pazopanib or placebo was not significant, partly because of early and frequent crossover from placebo to pazopanib.113 In a phase 3 trial, similar efficacy was found with pazopanib and sunitinib, with slightly lower incidence of toxic effects (palmar-plantar erythrodysaesthesia and fatigue) but with higher incidence of liver function test abnormalities.115,116 A randomised crossover trial revealed a significant preference for pazopanib over sunitinib by patients and physicians (70% vs 22%, p<0·001),119 mainly because of a better adverse event profile for fatigue, improved quality of life,119 and reduced cost.120 Axitinib is a potent, selective, second-generation inhibitor of VEGFR 1, 2, and 3. In patients with treatmentnaive metastatic renal cell carcinoma, progression-free survival was not significantly increased with axitinib compared with sorafenib (table 2), although adverse events of any grade were less common in the axitinib group by an average of 10%.117 Conversely, among patients treated with a cytokine-containing regimen before axitinib, progression-free survival was longer than in those who received sorafenib (table 2).118 8

Bevacizumab is a recombinant humanised monoclonal antibody directed against VEGF. In two phase 3 trials of bevacizumab plus interferon compared with interferon plus placebo105 or interferon alone,106 bevacizumab was superior in terms of progression-free survival. One of the studies was unblinded because a clinically meaningful significant benefit was found in an interim analysis.105 In the final overall survival analyses of both trials, however, no significant differences were found between treatment groups (table 2), probably because of the confounding effect of crossover after the interim analysis and the use with other targeted drugs as salvage therapies in the interferon groups. 107,108 The introduction of targeted therapies has set a new benchmark for the treatment of metastatic renal cell carcinoma, but most patients included in trials have had clear-cell metastatic disease. The results, therefore, might not be universally applicable to all histological types. A contemporary analysis of patients with metastatic renal cell carcinoma treated with VEGF-targeting agents showed median overall survival of 18·8 months (95% CI 17·6–21·4) with a remarkable peak at 43·2 months for patients in the most favourable risk group (appendix).121 The most informative clinical variables to predict the outlook of patients with metastatic renal cell carcinoma treated with targeted therapies include haemoglobin (p<0·0001),

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serum corrected calcium (p=0·0006), Karnofsky performance status (p<0·0001), time from initial diagnosis to the start of treatment (p=0·009), absolute neutrophil count (p<0·0001), and platelet count (p=0·012).122 The most common treatment-related adverse events associated with targeted therapies for metastatic renal cell carcinoma are fatigue, hypertension, nausea, diarrhoea, dysphonia, and palmar-plantar erythrodysaesthesia.123 Grade 3 or 4 adverse events are expected in around a third of patients, with profiles improving slightly for the new-generation targeted therapies (eg, pazopanib).123 Clinical and translational studies are needed to identify the phenotypic predictors of response for each of the drugs.

Controversies, uncertainties, and research questions Despite progress in the understanding of renal cell carcinoma, uncertainties, controversies, and research questions remain. Advances are expected over the next few years from translational and clinical studies. Novel tissue and genetic markers are expected to improve accuracy of renal biopsy in characterising histology and disease aggressiveness at diagnosis (indolent mass vs clinically relevant malignancy). This approach could be crucial to the selection of patients who will benefit from active surveillance and other non-surgical approaches. Data are too immature to validate universal use of minimally invasive techniques (cryotherapy and RFA) for renal cell carcinoma. Only case series, unmatched retrospective studies, and chart reviews with short followup are available. Longer follow-up data and well designed comparative trials are needed to confirm oncological results, standardise techniques, and to recommend alternatives to surgery, especially for small renal masses. In terms of the potential use of radiotherapy as part of a multimodal approach, renal cell carcinoma had been viewed as a radioresistant tumour because of poor outcomes with low-dose radiotherapy.124 This notion has been challenged by emerging evidence that stereotactic body radiotherapy with a high-fraction dose has an effect in primary tumours and oligometastatic disease.124 Randomised trials of radiotherapy regimens and radiotherapy combined with targeted drugs are awaited to confirm the potential clinical implications. Medical and integrated therapies, identification of new target pathways, and optimum sequencing and combination of existing targeted agents are areas of active study.125 Molecular markers that seem to be predictive of response to sunitinib in patients with metastatic renal cell carcinoma have been identified. Prediction is based on molecular subtypes and suggests that tailored and personalised treatment is feasible.126 Upcoming results of ongoing trials testing novel drugs will increase the choice for urologists and oncologists treating locally advanced and metastatic disease. A promising avenue of clinical research, for example, is

the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances on immune responses. By blocking inhibitory molecules or activating stimulatory molecules, it is hoped that pre-existing anticancer immune responses will be restored. Nivolumab, for instance, is a fully human IgG4 monoclonal antibody that binds to the PD-1 receptor and restores T-cell immune activity. This drug has shown promising results in the treatment of metastatic renal cell carcinoma.127 Many other new drugs are being investigated, and tivozanib128,129 dovitinib,130 cabozantinib,131 erlotinib,132 and sirolimus133 are being tested as potential treatments (figure 3). Additionally, two phase 3 studies are assessing the role of cytoreductive nephrectomy in the context of novel systemic therapies and the best treatment sequencing for surgery and targeted drugs (NCT01099423).134 The role of adjuvant therapy after surgery is also being investigated. Past attempts to prove clinical benefit with adjuvant immunotherapy (interferon α and interleukin-2) systematically failed.135–137 Five phase 3 trials including more than 6000 patients with non-metastatic renal cell carcinoma are being done to assess the role of targeted therapies in the adjuvant setting,138 no benefit has yet been found with adjuvant VEGF inhibitors (sorafenib or sunitinib) in patients at high risk of recurrence (NCT00326898). Surgical metastasectomy has been gaining popularity as part of a multimodal approach to treating patients with oligometastatic renal cell carcinoma and has shown acceptable morbidity in selected patients.139–141 Partial or complete removal of the metastatic lesions was associated with improved overall survival, especially in patients with adequate performance and functional statuses.139–142 Patients are being recruited into randomised clinical trials to assess the efficacy of a multimodal approach based on targeted therapy after surgical metastasectomy (NCT00918775 and NCT01444807).

Conclusions Renal cell carcinoma provides one of the best examples in oncology of how innovative basic research, novel clinical findings, and improved surgical techniques can converge to improve the care of patients. Alternative management strategies, such as active surveillance or cryotherapy, can be considered for an increasing number of patients. For patients who are candidates for surgical excision, the development of minimally invasive techniques, such as robot-assisted laparoscopic nephronsparing surgery, has decreased the risk of surgically induced functional impairment. Additionally, extended understanding of biological pathways and novel targeted therapies has led to improved survival outcomes in patients with metastatic disease. Further developments in translational research and findings from trials are expected to integrate surgical and systemic treatments to enhance cancer control.

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Contributors Both authors did the literature search, wrote the drafts, and reviewed the contents of the paper. Declaration of interests UC has received consultancy and lecturer honoraria and FM has received research support, consultancy fees, and lecturer honoraria from Recordati. Acknowledgments We thank Jeni Crockett-Holme for editorial support and Nicola Spreafico for graphics support. References 1 Ellimoottil C, Greco KA, Hart S, et al. New modalities for evaluation and surveillance of complex renal cysts. J Urol 2014; 192: 1604–11. 2 Shah S, Watnick T, Atta MG. Not all renal cysts are created equal. Lancet 2010; 376: 1024. 3 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9–29. 4 Ferlay JSI, Ervik M, Dikshit R, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. 2013. http://globocan.iarc.fr (accessed Jan 1, 2015). 5 Levi F, Ferlay J, Galeone C, et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int 2008; 101: 949–58. 6 Chow WH, Linehan WM, Devesa SS. Re: rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2007; 99: 569–70. 7 Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2006; 98: 1331–34. 8 Welch HG, Schwartz LM, Woloshin S. Are increasing 5-year survival rates evidence of success against cancer? JAMA 2000; 283: 2975–78. 9 Theis RP, Dolwick Grieb SM, Burr D, Siddiqui T, Asal NR. Smoking, environmental tobacco smoke, and risk of renal cell cancer: a population-based case-control study. BMC Cancer 2008; 8: 387. 10 Deckers IA, van den Brandt PA, van Engeland M, et al. Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid. Int J Cancer 2015; 136: 1104–16. 11 Zucchetto A, Dal Maso L, Tavani A, et al. History of treated hypertension and diabetes mellitus and risk of renal cell cancer. Ann Oncol 2007; 18: 596–600. 12 Corrao G, Scotti L, Bagnardi V, Sega R. Hypertension, antihypertensive therapy and renal-cell cancer: a meta-analysis. Curr Drug Saf 2007; 2: 125–33. 13 Gati A, Kouidhi S, Marrakchi R, et al. Obesity and renal cancer: Role of adipokines in the tumor-immune system conflict. Oncoimmunology 2014; 3: e27810. 14 Bergström A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A. Obesity and renal cell cancer—a quantitative review. Br J Cancer 2001; 85: 984–90. 15 Karami S, Daugherty SE, Purdue MP. A prospective study of alcohol consumption and renal cell carcinoma risk. Int J Cancer 2015; 137: 238–42. 16 Rohrmann S, Linseisen J, Overvad K, et al. Meat and fish consumption and the risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition. Int J Cancer 2015; 136: E423–31. 17 Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60: 615–21. 18 Shuch B, Amin A, Armstrong AJ, et al. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity. Eur Urol 2015; 67: 85–97. 19 Srigley JR, Delahunt B, Eble JN, et al, and the ISUP Renal Tumor Panel. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol 2013; 37: 1469–89. 20 Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol 2012; 23: 973–80.

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