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Renal Clear Cell Cancer
Introduction
Renal cell carcinoma (RCC), of which clear cell carcinoma is the most common histological subtype (80 to 90 percent), comprises 90 percent of all Kidney tumors.[1] Traditional morphological classification of these tumors divides them into 3 main subtypes – clear cell, papillary, and chromophobe subtypes.[2] Clear cell and papillary cell cancer originate from the proximal tubular cells, while chromophobe cell cancers originate from the intercalated cells.[2] The percentage of distant metastases in these subtypes varies from 15 percent in clear cell carcinoma to 3 percent in papillary and 4 percent in chromophobe cell cancers.[3] The cancer-specific 10-year survival ranges from 71 percent in clear cell cancer to 91 percent in papillary cancer, 88 percent in chromophobe cancer, and 33 percent in collecting duct cancers.[4] As is expected, diagnosis at an earlier stage offers a relatively higher chance of cure. The goals of the management of advanced RCC emphasize a focus on improvement in the quality of life parameters.[5] Clear cell tumors tend to spread hematogenous, with direct extension into the major vessels – the renal veins and the inferior vena cava.[6] Lung, bone, brain, liver, lymph nodes, liver, and adrenal glands form the main dissemination sites.[7] Lytic bony metastases, which might become sclerotic with treatment, can be present.[8] Clear cell carcinoma is considered uniformly metastatic, irrespective of the tumor size.[9]
Etiology
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Etiology
Obesity, hypertension, and cigarette smoking remain the leading potentially modifiable risk factors involved in the pathogenesis.[10] An increase in BMI of 5 kg/meter square, central adiposity, waist-hip ratio ranging between 0.86 and 2.88, and an increase in body weight between 18 and 35 years of age have been positively associated with developing RCC in various subpopulations.[11] Chronic kidney disease, renal transplantation, hemodialysis, acquired cystic kidney disease, a history of previous renal cell carcinoma, and co-existing diabetes mellitus have been recognized as potential risk factors associated with an increase in the incidence of renal cell carcinoma in population-based studies.[12]. Studies exploring the effects of moderate alcohol consumption, physical activity, and socioeconomic status on the incidence have led to conflicting outcomes, and it is generally agreed that the effect of these interventions on the etiopathogenesis of renal cell carcinoma needs to be explored further.[13][14][15]
While most of the cases of clear cell carcinoma are sporadic, 2 to 3% of the cases are related to genetic alterations in the von Hippel landau gene, chromatin remodeling genes/epigenetic regulators (Polybromo 1, BRCA protein 1, and SET D1), and genetic alterations in pathways that disrupt signal transduction involving the PI3K/Akt/mTOR pathway.[16][17] PTEN deficiency is usually associated with a more aggressive phenotype.[18] While angiomyolipoma (AML) is the most common renal neoplasm seen in patients with tuberous sclerosis, clear cell tumors may be seen rarely.[19] Clear cell tumors can also be seen in a small minority of patients with Birt Hogg Dube syndrome, who have been otherwise shown to develop hybrid-chromophobe tumors and oncocytomas.[20][21]
Epidemiology
An estimated 295,000 cases are diagnosed annually, and 134,000 are recorded worldwide.[22][23][24] The new cases in the United States in 2018 were estimated to be 65340, with 14970 annual deaths.[25] The male-to-female ratio is close to 2 to 1.[26] RCC ranked twentieth in the list of cancers, grouped in order of the number of years lost. in descending order, among both sexes in 2017 (compared to the nineteenth position in the same list in 2007).[27] The mean age at diagnosis is 64 years, and an earlier age of diagnosis should prompt a search for an underlying genetic predisposition (syndrome).[28] An increasing incidence has been attributed to an increase in rates of obesity.[29] Declining mortality rates have been shown to correlate with an improvement in treatment options.[30] Among European countries, the rates of renal cell carcinoma are highest in the Czech Republic.[31] Renal cell carcinoma accounts for 2.6 % of all cancer deaths in men and 2.1 percent of all cancer deaths in women.[32] SEER data from 2012 point towards a 5-year cancer-free survival rate of 91.7 % for localized disease, as compared to 64.2 and 12.3 percent respectively, for those with regional spread and distant metastasis.[32]
Pathophysiology
The genetic silencing of the 3p25 genetic locus, which houses the Von Hippel landau tumor suppressor gene through various mechanisms that involve a point mutation, insertion, deletion, and epigenetic silencing (via promoter methylation), is the most frequently identified driving event in clear cell carcinoma.[33][34] VHL is part of the E3 ligase complex. It is responsible for the proteasome-mediated degradation of hypoxia-inducible factors 1 alpha and 2 alpha by taking part in the ubiquitination of these molecules.[35] The accumulation of hypoxia-inducible proteins in an environment that is sufficiently oxygenated leads to an overexpression of genes involved in apoptosis, glycolysis, and angiogenesis.[36] Despite this underlying mechanism, which might lead one to attribute oncogenesis in clear cell carcinoma to a mutation in the VHL tumor suppressor gene only, it is essential to understand that this single event does not have the potential to lead to oncogenesis, as is evidenced by the long latent period, that precedes the development of tumors.[17] The primary pathway to be targeted in clear cell renal cancers includes the VEGF pathway due to VHL tumor suppressor gene loss located on the short arm of chromosome 3; however, other secondary targets may consist of mTOR c1, MET, and IL-8.[37] The presence of mutations in BAP 1 (histone deubiquitinase), PBRM1(involved in chromatin remodeling), SETD2 (histone methyltransferase), and KDM 5C and their association with prognosis has led to a proposal to classify renal cell carcinoma based on molecular pathogenesis.[38] Activating mutations in the mTOR-RHEB gene are also seen in clear cell tumors.[39] Both intratumor and intratumoral heterogeneity have been well documented.[40]
Histopathology
On Gross examination, clear cell carcinomas are solid and yellow cortical-based lesions interspersed with cystic changes, hemorrhage, and necrosis in varying amounts.[41] The yellow color of the tumor has been attributed to the presence of lipids – namely cholesterol, neutral lipids, and phospholipids.[2] These tumors demonstrate pushing borders in addition to an expansive pattern of growth.[2] They usually possess a fibrous capsule or a pseudo capsule, though infiltration of the surrounding tissues may also be seen.[2] The microscopic examination usually shows nests of clear cells with eosinophilic granular cytoplasm, rich in glycogen, and cytoplasm in the background of delicately branching, fine vessels.[22][42]
Nuclear morphology has been shown to form the basis of grading these tumors, with grading systems showing a gradual evolution from the 1970s to the present.[43] Fuhrmann’s system is among the most commonly used systems based upon an assessment of nuclear size, nuclear irregularity, and degree of prominence of the nucleoli.[44] This system classifies the tumor into 4 grades – with grade 4 tumors characterized by large, pleomorphic, multilobed giant cells with heavy chromatin lumps and extremely irregular outlines, being considered the most aggressive.[45] Fuhrmann’s grading system has come in for severe criticisms – foremost among them being the difficulty associated with the simultaneous examination of 3 morphological features and the absence of guidelines to characterize the tumor when at least 1 of these features may not be evident.[43][46] Poor interobserver variability and difficulty discerning the outcome based on the 3 pre-defined parameters have also been considered valid critiques.[47][44] The World Health Organization/ International Society of Urological Pathology has introduced a grading system based on the tumor's nucleolar pathology.[48] Nucleolar size assumes importance in the wake of the observation that nucleolar size correlates with ribosomal biogenesis and that nucleolar grade has often been seen to correlate with patient outcomes.[49] Multilocular cystic RCC is characterized by cystic lesions lined by a single layer of clear to pale cells, with scant papillae and fibrous components, clearly demarcated from the cortical component by a fibrous capsule and lacking a solid element.[50][51]
History and Physical
The typical triad of clinical features associated with renal cell carcinoma comprises flank pain, abdominal mass, and haematuria.[52] However, there has been a palpable shift towards tumors being diagnosed incidentally, with only around 30 percent of cases diagnosed based on clinical symptoms alone.[22] Presenting symptoms might result from hormones or cytokine-like substances produced by the tumor.[22] Patients present commonly with acute or chronic flank pain due to obstruction of the urogenital system, invasion of surrounding viscera, or the presence of retroperitoneal mass.[22] Gross haematuria (due to urogenital tract) and a palpable abdominal mass are seen less frequently.[22] An isolated varicocele due to venous obstruction or thrombosis might be seen in rare cases. Hypertension, anemia, and cancer anorexia cachexia are the common paraneoplastic conditions observed.[53] Abnormal production of inflammatory mediators and cytokines is associated with anemia, sarcopenia, and pyrexia.[53] Hepatitis, rich in a lymphocytic infiltrate with raised Interleukin 6 levels, has been postulated to underlie paraneoplastic hepatic dysfunction (Stauffer syndrome), which is diagnosed by hepatic enzyme elevation in the absence of liver metastases or intrinsic liver disease or cholestasis.[54] Stauffer syndrome is known to resolve after the resection of the kidney tumor.[54] Hypercalcemia may be due to direct bone involvement due to parathormone-related peptides, dihydrocholicalciferol derived from the tumor, and prostaglandins.[55] Erythropoietin production by the renal parenchyma or surrounding tissue in response to hypoxia may lead to polycythemia.[56] Anecdotal symptoms attributable to paraneoplastic phenomena include hypoglycemia, neuropathy, myopathy, vascular thrombosis, Cushing syndrome, protein-related enteropathy, gynecomastia, decreased libido, hirsutism, amenorrhoea, necrotizing myopathy, and immune thrombocytopenic purpura.[53][57] Although physical assessment has a limited role in diagnosing this condition, the presence of an abdominal mass, lower extremity edema, and new-onset varicocele should prompt a search for a mass lesion in the retroperitoneal region.[58][59]
Evaluation
The workup of a patient with renal/retroperitoneal mass symptoms should include laboratory evaluation, imaging, and biopsy for accurate staging.[60]
Laboratory Evaluation
Serum creatinine, hemoglobin, total and differential leucocyte counts, total platelet count, neutrophil to lymphocyte ratio, lactate dehydrogenase, C-reactive protein, and corrected calcium should be evaluated.[60][22]
Radiological Investigations- Role of Imaging
Ultrasonography can be used to make a presumptive diagnosis of a renal mass. Imaging can characterize the mass, presence of abdominal metastases, invasion of the great vessels, and local tumor spread. Renal function, vascularity, and retroperitoneal involvement must also be assessed in patients planned for surgical resection. Typical radiological features of clear cell RCC include an exophytic growth pattern, heterogeneity linked to intra-tumoral heterogeneity or hemorrhage, and the presence of enhancement with contrast intake. Additional imaging may be required for performing a complete metastatic workup, including Computed tomography scanning of the thorax, abdomen, and pelvis, MRI Brain, and bone scan. Though a CT scan of the thorax, abdomen, and pelvis is mandatory for accurate staging, a CT brain or bone scan is not recommended routinely. A non-contrast CT scan with a plain MRI abdomen is indicated in those with an allergy to intravenous contrast agents or renal insufficiency. MRI techniques such as diffusion-weighted imaging and perfusion imaging are being explored for further characterization of the lesion. Clear cell tumors have also been to have a significantly higher tumor to nontissue uptake and standardized uptake on 18FDG PET scanning. However, the utility of FDG-PET is limited due to false-negative results due to normal physiological excretion by the kidneys. It has shown a greater role in the recurrent setting and re-staging in advanced disease. Dynamic imaging has been shown to predict disease progression and survival in the recurrent setting (post-surgery).[22][60][41][60]
Renal Biopsy
Renal biopsy is indicated to establish the diagnosis of radiologically indeterminate renal masses, histological examination of incidentally detected masses in whom active surveillance is indicated before treatment with renal ablative therapies, and help in selecting the most suitable targeted therapy in metastatic lesions. Though the histological subtype and the Fuhrmann grade can be correctly determined upon a renal biopsy, complications associated with the procedure (infection, bleeding, the formation of arteriovenous fistula) have been shown to occur in a frequency of 0.3-5.3 percent cases. Complications related to the seeding of the biopsy tract have been minimized using modern biopsy techniques; there is an emerging consensus that the biopsy remains substantially underutilized. The argument in favor of such an observation states that while complications such as bleeding and seeding of the tumor tract are rare, the diagnostic accuracy remains high.[22][60][61][62]
Liquid Biopsy
The study of circulating tumor cells and DNA has been shown to play a role in the noninvasive assessment of tumor burden with a fair degree of precision. Other cytological methods postulated to have clinical utility in the setting of RCC include exosomal protein profiling and screening of noncoding ribonucleic acid particles in the serum. Circulating tumor DNA has the potential to predict response to immune checkpoint inhibitors. These techniques have also been used to study the functional heterogeneity in tumor tissue by using a combination of genetic and transcriptomic analysis of a single circulating tumor cell or parallel single-cell epigenetic and transcriptome analysis. Clear-cell cancer has also been proposed as a model to understand the cytomorphological and genetic features of malignancy in the circulating cancer cell and the single-cell level.[63]
Treatment / Management
Localised Disease
The choice of operative procedure has shifted from a radical nephrectomy to nephron-sparing strategies with active surveillance and the use of minimally invasive techniques. This shift towards minimally invasive approaches, which limit overtreatment and iatrogenic kidney injury, has been necessitated by diagnosing smaller lesions and the potential for chronic kidney disease (which is known to develop after radical nephrectomy approaches) to impact the patient’s quality of life adversely. Targeted systemic therapies with angiogenesis inhibitors and immune checkpoint inhibitors have been used to manage metastatic, advanced, or surgically inoperable renal cell carcinoma.[63][64][65][66][67][68](A1)
Role of Active Surveillance
The slow median growth rate, as well as a substantial percentage (one-fifth) of resected tumor specimens turning out to be benign, along with the potential to prevent surgery-related complications, has led to the concept of active surveillance for renal tumors. Active surveillance may also be carried out for larger tumors in those with multiple risk factors and limited life expectancy to determine tumor growth rate. Though there has been no consensus on the absolute tumor size and the rate of growth at which a more radical approach needs to be adopted, tumor sizes of more than 3-4 cm and growth rates exceeding 0.4-0.5 cm have been defined as possible cut-offs. Initial imaging at 3 to 6 months, every 6 months for the next 2 years, and annually after that, has been recommended for tumors that meet the criteria for active surveillance.[69][70]
Minimally Invasive Techniques
Renal ablative approaches (cryotherapy and radiofrequency ablation) that use energy properties to destroy tumor cells have been used to manage small tumors that have been detected incidentally. Potential complications include bleeding, abscess formation, and adverse effects involving the bowel, bladder, spleen, and pancreas. While comparable recurrence-free and cancer-specific survival rates have been demonstrated, a lower degree of decline in the Glomerular filtration rate has been demonstrated using minimally invasive techniques (radiofrequency ablation), as per a systematic review and meta-analysis.[71][72][73]
Determination of Presurgical CKD Risk and Strategies to Preserve Renal Function Postoperatively
Cancer is not the most common cause of death in patients with solitary renal masses. It has been observed that these patients share common risk factors with patients with chronic kidney disease and that cardiovascular events are a common cause of mortality. This has been attributed to common risk factors such as increasing age, male gender, smoking, presence of diabetes mellitus, and hypertension. The presence of albuminuria usually indicates the presence of advanced disease (higher grade or later stage). It should be emphasized that the goals of management in those with T 1a tumors need to include preservation of renal function, minimizing cardiovascular mortality, and managing chronic kidney disease. Screening patients for postsurgical CKD can be done by calculating the glomerular filtration rate and measuring albuminuria. Stringent preoperative blood pressure control, good glycemic control, prevention of hypoperfusion, and avoidance of nephrotoxic strategies could mitigate renal injury. The determination of differential kidney function by nuclear scintigraphic techniques has been advised. Intrarenal damage due to hypoxia and loss of renal function due to resection might reflect changes in postoperative GFR.[74][75]
Surgery
Nephron sparing surgery involves removing all tumor tissue, with preservation of as much normal renal parenchyma as possible. It is found to be related to comparable oncological outcomes and better long-term cardiovascular outcomes than radical surgery. Indications for nephron-sparing surgery include the presence of a single anatomical and functional kidney, hereditary forms of renal cell cancer in those at risk of developing a malignancy in the contralateral kidney in the future, patients who may be prone to develop dysfunction in their functioning kidney in the future or localized tumors with a healthy contralateral kidney, those with bilateral synchronous RCC’s and Von Hippel Lindau syndrome. Partial nephrectomy is also indicated in those with T1 tumors and a normally functioning contralateral kidney, where it has been shown to have equivalent oncological outcomes when compared to radical surgery. Tumor size, depth, location, and proximity to the hilar vascular structures and pelvicalyceal system are important factors that help determine the feasibility of nephron-sparing surgery.
Various scoring systems such as the PADUA, RENAL, and C-index have been developed to assess the feasibility of performing a nephron-sparing procedure in selected patients. The application of these scores aids in improving the selection of patients, providing optimum surgical management, reporting of research outcomes, and predicting treatment outcomes. Robot-assisted partial nephrectomy and open approaches are utilized for complex tumors; laparoscopic approaches should be reserved for low and intermediate-risk categories and smaller tumors. Shorter warm ischemia times, lesser postoperative complications, lower blood losses, and duration of postoperative stay have been observed with RAPN (when compared to LPN approaches). Although minimal tumor-free margins have been recommended to prevent recurrences, positive tumor margins (irrespective of the technique employed) have been demonstrated in 1 – 6 % of cases. Robotic approaches have been associated with a shorter hospital stay, lower volume of perioperative blood loss, better postoperative pain control, and faster time to recovery. Most international guidelines recommend a cytoreductive approach in patients with tumors limited to the primary site without any significant metastatic spread. A cytoreductive approach may also be the preferred treatment option in patients with metastatic disease who have received multiple systemic targeted approaches earlier.[76][77][78][79][80][81]
Radical Nephrectomy
Radical nephrectomy removes the entire kidney, perirenal fat, suprarenal glands, and regional lymph nodes. Adrenal-sparing surgery can be attempted in inferior pole tumors less than 5 cm in size. Regional lymph node dissection can be performed in those with lymph node involvement demonstrated on a CT scan or the table (during the procedure). While the open approach remains the gold standard for the treatment of more complex cases, stage 1 and 2 tumors may be treated radically with a traditional laparoscopic approach. The robotic approach has also been positioned as a viable alternative in patients with venous tumor thrombosis.[82]
Adrenalectomy, Venous Thrombectomy, and Lymph Node Dissection
Adrenalectomy, which was considered a mandatory component of radical procedures, can now safely be omitted if no macroscopic disease is diagnosed at the time of preoperative workup or surgery. Lymphadenectomy has shown a survival advantage only in intermediate and high-risk patients. There is no proven role for sentinel node biopsy. Data on the utility of lymphadenectomy in this setting are not definitive. While lymphadenectomy may have a role in the staging of large tumors, there are no guidelines for its use as a salvage procedure. Surgical management has been advised for venous thrombosis involving the renal vein and inferior vena cava. Caval thrombectomy may be safely performed along with radical nephrectomy for the management of tumors with thrombus that do not extend beyond the diaphragm. The extent of resection is decided primarily by the extent of the tumor at the time of operation. A minimum modification of the operative procedure may be warranted when the thrombus is confined to the renal vein; however, dissection involving the vena cava, mobilization of the right atrium, opening up of the right atrium, and cardiopulmonary bypass may be necessary with more extensive involvement. Complete vascular control, prevention of tumor embolization, stringent hemodynamic monitoring, and ensuring ready availability of tissues for caval replacement and venous bypass, if required, are strict urological principles, that must be adhered to while performing surgical nephrectomy and thrombus removal.[83][84][85][86][87](A1)
Localized Disease Treatment According to Tumor Stage
T1 Tumors (less than 7 cm) – Partial nephrectomy is the treatment of choice. A long-term cancer-specific survival equivalent to partial nephrectomy has been demonstrated for minimally invasive approaches but at a slightly higher rate of recurrence. Active surveillance is indicated in elderly patients with short life expectancy or significant comorbidities and solid renal tumors measuring less than 40 mm. T2 Tumors (more than 7 cm): Laparoscopic radical nephrectomy is the preferred treatment option. T3 and T4 Tumors (Locally Advanced RCC) – Open radical nephrectomy is the treatment of choice, though laparoscopic approaches have gained momentum.[60][88](A1)
Adjuvant Approaches
Adjuvant Treatment
A pooled analysis of various trials using Sunitinib (S-TRAC, ASSURE), Sorafenib (ASSURE), and pazopanib (PROTECT) in the adjuvant setting has failed to show any benefit in disease-free survival or overall survival in those with intermediate/high-risk local disease or those who have undergone complete resection for localized renal cell carcinoma. It is found that high-dose adjuvant treatment in high-risk diseases may be associated with favorable disease-free survival, at the risk of incurring higher-grade adverse effects.[89](B3)
Neoadjuvant Systemic Targeted Therapy
Targeting venous tumor thrombi with an attempt to reducing their size and making them amenable for resection is an approach that is yet to find any favor. It has been a purely experimental approach and cannot be recommended outside of a clinical trial setting.[90][91](B3)
Surveillance After Definitive Treatment
Solitary Renal Masses
The American Urological Association recommends surveillance at baseline, abdominal imaging at 3 to 12 months after partial or radical nephrectomy, and annually for 3 years following partial nephrectomy. Chest imaging is also suggested annually for 3 years if indicated.[92]
Metastatic Disease
Immunomodulatory Agents
The immunogenic nature of RCC is supported by the year for 3 years after the act that spontaneous tumor regression has been reported. The role of the immune system in pathogenesis is supported by multiple infiltrates consisting of immune cells. The mechanisms proposed to be underlying the action of these drugs include T cell-mediated immune regression due to an increase in lymphocyte proliferation, cellular killing mediated by lymphocytes, and killer cells, which lymphokines have activated. Immune-modulating drugs approved in the treatment of metastatic renal cell carcinoma include aldesleukin and Interleukin 2.[93][94][95](B3)
Nephrectomy
The beneficial effects of surgical extirpation have been attributed to a reduction in the tumor burden, a direct immunomodulatory effect (attributed to the reduction in immunosuppression), and the creation of an inhospitable tumor microenvironment due to iatrogenic chronic metabolic acidosis.[96](B2)
Targeted Therapy
Sunitinib
It inhibits multiple receptor tyrosine kinases, including VEGFR 1, 2, 3, PDGRF alpha, beta, c-kit, FLT-3, and RET. It is an orally administered drug with a half-life of 40-80 hours and a bioavailability of 50 percent. A single daily dose of 37.5 mg is administered for 4 weeks, followed by a drug holiday for 2 weeks. It is metabolized by the cytochrome 3a4 enzyme system in the liver, the active drug—excreted in the urine and feces. FDA and EMA approved in 2006. Sunitinib was approved in 2007 for use in low, intermediate, and high-risk groups as a first-line treatment option for advanced metastatic disease. Sunitinib has also shown benefit as a treatment option after progression on VEGF targeting agents. It has been studied in case of progression following sorafenib, and re-challenge following progression on multiple first-line settings. ESMO magnitude of clinical benefit scale ranking of 4.[97][98]
Sorafenib
It inhibits multiple receptor tyrosine kinases, including VEGFR 1, 2, 3, PDGFR beta, c-kit, FMS-like tyrosine kinase 3, rearranged upon transfection, and rapidly accelerated fibrosarcoma kinase. While c-kit, FLT Kinase 3, and RET are located upon the cell surface, Raf is an intracellular enzyme (common to all receptor tyrosine kinase pathways). REA disruption of the signal transduction, with inhibition of transcription of various proteins, is also observed due to inhibition of the intracellular phosphorylation pathways, including the Raf/MEF/ERK and the PI3K/m TOR/AKT pathways. The anti-angiogenic effect of sorafenib is attributed to its effect on angiogenesis and lymphangiogenesis, which is mediated via the VEGFR 1,2 (angiogenesis) and 3 (lymphangiogenesis), respectively. Inhibition of the Platelet-derived growth factor receptor on the surface of the pericytes and smooth muscle cells also contributes to this effect. Sorafenib is administered orally at 400 mg twice daily, with an oral bioavailability of 92 percent. More than 9.5 percent of the drug is protein-bound to albumin and alpha 1 acid glycoprotein. It is mainly metabolized to an N oxide metabolite by the Cytochrome p 450 enzyme system. The elimination half-life of the molecule is between 20 to 39 hours. Excretion of the glucuronide metabolite occurs via the urinary and fecal routes. ESMO magnitude of clinical benefit scale ranking of 4.[98][99]
Lenvatinib
Multitargeted receptor tyrosine kinase inhibitor inhibits VEGFR 2, fibroblast growth factor receptor 1, 2, 3, 4, PDGFR alpha, c kit, and RET. FGFR inhibition, unique to lenvatinib (compared to sunitinib and sorafenib), provides an additional mechanism of inhibition of angiogenesis. It is administered orally at a dose of 24 mg daily, with an oral bioavailability of 90 percent. It has hepatic and renal metabolism and is excreted in the bile. Demethylated (M2) metabolite is mainly excreted via the urinary and fecal routes. ESMO magnitude of clinical benefit scale ranking of 4.[98][100] (B3)
Axitinib
It is a multitargeted receptor tyrosine kinase inhibitor, which inhibits VEGFR 1, 2, 3, PDGFR alpha and beta, and c-kit—administered orally in a dose of 5 mg twice daily, with a bioavailability of 58 percent. Metabolized, primarily in the liver, has a half-life of 2.5 to 6 hours and is excreted in the urine (less than 1 percent). Approved for use in the second-line setting by the FDA and EMA in 2012. ESMO Magnitude of clinical benefit scale ranking of 4.[98][101][102][101]
Pazopanib
A multi-target receptor tyrosine kinase inhibitor which inhibits VEGFR, PDGFR, FGFR, and c-kit. Administered orally in a dose of 800 mg per day, with an oral bioavailability of 21.4 percent (13.5 to 38.9 percent). 99.9 percent protein-bound, mostly to albumin and, to a lesser extent, to alpha1 acid glycoprotein. Mainly excreted unchanged through the feces as the parent compound (in an unchanged form). A minor fraction (2.6 percent) is excreted via urine. ESMO magnitude of clinical benefit scale ranking of 3.[98][103] (B2)
Cabozantinib
It is a multitargeted receptor tyrosine kinase inhibitor that inhibits VEGF, AXL, and MET kinase receptors. AXL and MET receptors have been postulated to be responsible for resistance to VEGF-targeted therapy, granted FDA and EMA approval for patients with progression on first-line VEGF targeted therapy. The inactivation of the Von Hippel Lindau gene leads to the activation of various angiogenic pathways, which may be blocked specifically by cabozantinib. The substrate of cytochrome P 450 enzyme system 3A4, predominantly metabolized in the liver. It is administered in a daily oral dose of 140 mg, with a predicted half-life of 55 hours. ESMO magnitude of clinical benefit scale ranking of 3.[98][104][105]
Chemotherapy
The role of cytotoxic chemotherapy remains poorly defined. Cytotoxic chemotherapy is usually indicated in sarcomatoid and collecting ducts variants of RCC.[106]
Chemotherapy Plus Targeted Therapy
Targeted agents may also enhance the delivery of cytotoxic chemotherapy to the local site by reversing the hypoxic tumor micro-environment and normalizing the tumor vasculature. Combined with tyrosine kinase inhibitors (TKI), various agents include fluoropyrimidines, gemcitabine, capecitabine, and thalidomide. However, none have demonstrated an unequivocal clinical benefit that would warrant any change in the standard of care.[107]
Metronomic Chemotherapy
Targeted agents have been used in combination with low-dose cytotoxic chemotherapy to reduce the toxic effects of treatment. Metronomic dosing has been used to enhance the anti-angiogenic effect of targeted therapy by preventing the recruitment of endothelial progenitor cells derived from bone marrow to the tumor vasculature. Though this approach to treatment (a combination of weekly gemcitabine, daily capecitabine with sorafenib) has been associated with partial response in 50 percent of patients, however, the findings have not been replicated.[108]
Immunotherapy
PD–1 is a type 1 transmembrane glycoprotein that belongs to the CD28/CTLA-4 family of immune checkpoint inhibitors. Its expression has been shown to increase in response to immune stimulation/antigenic stimulation. Haematopoetic stem cells, T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, monocytes, and macrophages are known to express PD-1.
Anti-PD 1-directed therapy (nivolumab) and immune checkpoint inhibition (anti-cytotoxic T lymphocyte antigen 4) in the form of ipilimumab have shown beneficial outcomes in renal cell carcinoma. The checkmate 025 trial, a phase 3 trial that compared nivolumab with everolimus, demonstrated an improvement in overall survival with the use of nivolumab. The patient population in this trial consisted of locally advanced or metastatic renal cell carcinoma who had progression of disease after treatment with at least 1 VEGF/VEGFR inhibitor (targeted therapy). A higher rate of long-term durable responses and a higher overall response rate were also seen in the nivolumab arm. An improvement in overall survival, response rate, and a complete response rate of 10 percent was observed in intermediate and poor-risk patients in a phase 3 trial with the use of combination treatment with ipilimumab and nivolumab when compared with the sunitinib arm. While patients with intermediate and low-risk profiles had a better response to combination therapy with nivolumab and ipilimumab, those with poor prognoses had a more favorable response to sunitinib.[109][110][111] (B3)
Combination Therapies with Immune Checkpoint Inhibitors
Immune Checkpoint Inhibitors with Anti-Angiogenic Agents[112][113] Anti-angiogenic agents have been shown to enhance tumor-related immune suppression by leading to a decrease in immunosuppressive cells such as myeloid-derived stem cells and regulatory T cells, cytokines (TGF beta and IL -10), and decrease in the PD -1 expression on T cells. The IM Motion 150 study evaluated the role of combination treatment with atezolizumab (anti-PD-L1) and bevacizumab against a comparator arm of atezolizumab or sunitinib. It demonstrated an improvement in progression-free survival and a higher overall response rate. A PDL1 expression over 1 percent was used to define PD L1 positivity. A longer PFS and higher ORR were observed in this subset of patients in the atezolizumab monotherapy arm. The JAVELIN Renal 101 and Keynote 426 have demonstrated improved outcomes in previously untreated patients with advanced RCC with the use of avelumumab and axitinib or pembrolizumab and axitinib when compared to sunitinib alone. Recognition of potential driver mutations in deciding the choice of the therapeutic option.[114][115] VHL and PRBM1 mutant tumors, which are known to be associated with an immune and an angiogenic signature, will be expected to benefit from immune checkpoint inhibitor therapy and VEGF-targeted therapies. Whereas, tumors that possess a loss of BAP 1, which is associated with a decrease in an angiogenic profile, are expected to respond better to immune checkpoint blockade.(B2)
Resistance Strategies to Targeted Agents [116]Vaccines that have been studied in combination with targeted agents include AGS-003, which is a dendritic cell vaccine, prepared with amplified tumor RNA, which has the potential to augment the immune response against the tumor. IMA 901 is another potential vaccine candidate that underwent an evaluation in a phase 3 trial and consists of a combination of HLA class I and ii tumor-associated peptides but did not demonstrate a clinically significant increase in tumor response, which could be expected to translate into a favorable clinical outcome.[116][117]
Surgery
Surgery of resectable metastases has been advised for solitary metachronously arising lesions as long as it is possible to obtain an R0 resection. Resection of the primary tumor has also been shown to be beneficial in those with synchronous metastasis, in those with a favorable performant status (Eastern cooperative oncology group 0-1).[7][118]
Radiotherapy
Radiotherapy might be an alternative in patients who do not opt for surgery or in those in whom a complete (R0) resection might not be possible. Various approaches that have been employed include stereotactic radiosurgery (stereotactic irradiation delivered over single or multiple sessions) and high-dose external beam radiotherapy. Stereotactic irradiation can also be used in the management of bone and brain metastasis.[119][120]
Metastatic Disease
First-Line Therapy
Good risk disease—standard care: sunitinib, pazopanib, interferon, bevacizumab, and tivozanib. Other options include high-dose interleukin 2, bevacizumab, and low-dose interferon.
Intermediate risk disease – standard care – nivolumab and ipilimumab. Optional treatments include sunitinib, pazopanib, cabozantinib, tivozanib, a combination of bevacizumab, and interferon.
Poor risk disease – standard care – nivolumab and ipilimumab; optional treatments include cabozantinib, sunitinib, pazopanib, and temsirolimus.[60] (A1)
Second-Line Treatment
Treatment options depend upon the initial treatment used in the frontline setting, either a tyrosine kinase inhibitor or immunotherapy with a combination of nivolumab and ipilimumab. If a tyrosine kinase inhibitor was used in the first-line setting, the standard options include nivolumab, cabozantinib. Other optional treatments include axitinib, everolimus, or a combination of lapatinib and everolimus. If the combination immunotherapy regimen of nivolumab and ipilimumab was used in the frontline setting, the following treatment recommendations need to be considered – Any Tyrosine kinase inhibitor or a combination of lenvatinib and everolimus.[60] (A1)
Third Line Treatment
Treatment options depend upon the drugs used in the first line and the second line setting. Those who have received treatment with first-line TKI and second-line nivolumab should be considered for standard therapy with cabozantinib. Those who have received treatment with first-line TKI and second-line cabozantinib should be considered for standard treatment with nivolumab. Those who have received first-line TKI and second-line TKI should be considered for standard treatment with either nivolumab or cabozantinib. Those who have received first-line nivolumab, ipilimumab, and second-line TKI should be considered for standard treatment with another TKI or everolimus.[60] (A1)
Recent Update
In an update published in February this year, the European Society of Medical Oncology has endorsed the use of combination therapy with pembrolizumab and axitinib as the frontline therapy for treatment of naïve advanced disease, based upon the results of the Keynote 426 trials, where this combinatorial therapy was compared with sunitinib, irrespective of the IMDC subgroup and the PD-L1 biomarker status. While the same update also makes a recommendation in favor of the use of ipilimumab and nivolumab in the intermediate and low-risk settings after analysis of the long-term survival results (32 months), VEGF targeted tyrosine kinase inhibitor treatment is recommended after progression on PA/IN combinatorial regimens. Targeted therapy is also indicated when the above-mentioned combinatorial therapy cannot be used or is contraindicated.[121]
Response Assessment
Response assessment CT scans are recommended 3 – 6 monthly in those with high risk for the first 2 years, a yearly CT scan is recommended in high-risk patients. A 2-4 monthly CT scan is recommended for response assessment in those receiving targeted therapy. The beneficial effect of a long term follow up is yet to be demonstrated. Although the RECIST criteria (response evaluation criteria in solid tumors) have been used to calibrate the response to treatment, its clinical utility in predicting changes that require dose modification or discontinuation and valid clinical endpoints is still debatable.[60] (A1)
Palliative Medicine
Management of adverse effects of chemotherapy, symptom-directed treatment, counseling regarding goals of care, prognostication, management of cancer-associated syndromes (such as complex cancer pain syndromes, malignant bowel obstruction, metastatic spinal cord compression, pathological fractures, hypercalcemia, hyponatremia), medical symptoms in advanced cancer and provision of good end of life care are considered within the ambit of palliative medicine. Specialized palliative medicine might include a dissection of various ethical dimensions of decisions concerning continuation and cessation of treatment, nutrition, and hydration in advanced cancer, provision of palliative sedation in the management of refractory symptoms, and end-of-life care. Discussions about organ donation and withdrawal of treatment (provision of passive euthanasia) should also be considered the domain of specialized palliative medicine. In the setting of the SARS Cov -2 pandemic, telemedicine and counseling of families of patients who are expected to have a limited life expectancy and may not be put on artificial ventilation also become the valid agenda of a palliative medicine consultation-liaison.[60] (A1)
Management of metastasis to the central nervous system:
Brain Metastasis
Recursive partitioning analysis and graded prognostic assessment are used to prognosticate patients with brain metastasis. Available treatment options include the use of stereotactic brain radiotherapy, whole-brain radiotherapy, and supportive management in the form of decompressive medical therapy using mannitol, glycerol, or carbonic anhydrase inhibitors such as acetazolamide. Corticosteroids, tapered according to the symptoms, also form an important component of medical decompressive therapy.[122]
Metastatic Spinal Cord Compression
Various prognostication systems include the ASIA, and the Frankel scoring systems, are used to assess the severity of involvement. Treatment modalities include long course, short course external beam radiotherapy, bone-targeted agents, and corticosteroids. Surgical treatment might also be considered for patients with single-level metastasis or the presence of a bony fragment impinging upon the cord.[123][124] (A1)
Metastatic Bone Disease
External beam radiotherapy and the use of bone-targeted agents have been recommended for palliation of symptoms and prevention of skeletal-related events (with an increase in time to the first skeletal-related event). The Mirels scoring system is used to calculate the risk of development of a pathological fracture. Among the bone-targeted agents used bisphosphonates and a monoclonal antibody against the RANKL (receptor activator of nuclear factor kappa beta ligand), denosumab has been used. While zoledronic acid is the most commonly used bisphosphonate, used in a frequency ranging from monthly (in those with prior history of skeletal-related events) to 3 monthly, denosumab can be used in dosing of 120 mg monthly subcutaneously.[125]
Emerging and Future Immunotherapy Targets
Several combinatorial strategies have been proposed to have shown promise in developing future therapeutic strategies against tumors that show resistance to currently available strategies. The Ang/Tie 2 pathway is thought to be responsible for basal angiogenesis and vascular stability following vascular endothelial growth factor blockade.[126] Inhibitors such as trebananib, which block this novel pathway, may have a role in combination with VEGF blockade.[127] ALK 1 inhibitors, such as dalantercept, may have a role in interfering with the formation of the vascular bed.[128] Dual mTOR c1/c2 inhibitors may be a potential therapeutic option since the existing therapies only target them on the TOR c1 pathway.[129] Inhibitors targeting hypoxia-inducible factor 2 and aberrant glycolysis, aberrant glutamine, and tryptophan metabolisms, such as CB 839 (glutamine metabolism) indoleamine 2.3 dioxygenase inhibitors, are being developed with an intent to lead to potential additional benefit.[130][131] It has been suggested that the relationship between the tumor and it’s immune micro-environment needs to be studied further, with the intent to developing beneficial combinatorial therapy options. Other studied approaches include personalized vaccination, targeted radiotherapy to enhance immune responses, cytoreductive surgery following systemic therapy, and immunotherapy or targeted therapy in the neoadjuvant setting.[132][133] Several molecules that are being investigated as potential targets include chemokine receptors, lymphocyte activation gene – 3, OX -40 (CD 134), B and T lymphocyte attenuator (BTLA), and V-domain containing immunoglobulin containing suppressor of T – lymphocytes activation, soluble.[134](A1)
Differential Diagnosis
Abscess, metastasis from a distant primary lesion, metastatic melanoma, renal cyst, renal infarction, sarcoma, renal AML, renal oncocytoma, and lymphoma form close differentials of a renal mass.[41] Chromophobe renal cell carcinoma, oncocytoma, clear cell tubulopapillary carcinoma, multilocular cystic renal cell carcinoma, adenoma, and MIT family transitional renal cell carcinomas are close histopathological differentials.[135][136][135]
Renal Angiomyolipoma
The most common benign renal tumor, mostly sporadic, may be associated with tuberous sclerosis and lymphangioleiomyomatosis. Those with tuberous sclerosis have a larger size and are bilateral, multicentric, and symptomatic. These are mostly seen in females in middle age. Usually asymptomatic, though, larger tumors may be associated with an increased propensity to cause hemorrhage. The presence of macroscopic fat is pathognomonic, though 15 -30 percent of tumors associated with tuberous sclerosis may be lipid deficient. On MRI, low T2 intensity is shared by lipid-poor AML and clear cell renal carcinoma. Compared to hypovascular clear cell tumors, AMLs are usually hypervascular. Larger tumor size, calcification, and intratumoral necrosis favor a diagnosis of renal cell carcinoma. Another clear cell mimic seen in these patients with tuberous sclerosis is AML with epithelioid features.[137][19]
Renal Oncocytomas
It is the second most common renal benign tumor after AML. There remains a strong body of opinion that oncocytoma cannot be reliably distinguished from renal cell carcinoma based on radiological features alone, although parameters such as corticomedullary phase TCR, nephrogenic phase TCR higher than a corticomedullary phase TCR, CT de-enhancement characteristics have been proposed as features capable of characterizing this tumor.[138]
Renal Lymphomas
The presence of a cystic component, vascular extension into the renal vein or inferior vena cava, and calcification are features considered to be atypical for lymphoma and point toward a diagnosis of renal cell carcinoma.[139]
Staging
The American Joint Committee on Cancer staging/UICC classification system is used for staging.[140] While the stage, size, and necrosis score is used in localized RCC, the Memorial Sloane Kettering score or the Motzer score is the standard prognostication system used in advanced/metastatic cancer.[141] The new targeted therapies have led to the up-gradation of these criteria and the development of the international metastatic RCC database consortium criteria or the Heng score, which consists of the Karnofsky performance score (lower than 80 percent), hemoglobin (lower than normal lower limit), time from diagnosis to treatment (less than 1 year), corrected calcium (higher than 10 mg per dl), platelets and neutrophils (both higher than the normal upper limit).[142][143]
Prognosis
Inflammatory Markers
Increasing evidence supports inflammation's role in determining prognosis in renal cell carcinoma. Local immune responses and systemic inflammation have been shown to play a central role in the initiation, maintenance, and progression of the cancer process. The pathogenic role of neutrophils, lymphocytes, and monocytes in promoting intravasation of tumor cells, thereby promoting angiogenesis and allowing the propagation of distant metastasis, associated with a poorer outcome, has also been recognized. The degree of systemic inflammation can be assessed by measuring the C – reactive protein levels (which has the drawback of not having a specific cut-off value) and ratios involving various blood components, including the neutrophil/lymphocyte ratio (NLR), platelet/ lymphocyte ratio (PLR) and measures such as the prognostic nutritional index (PNI), systemic immune inflammation index (SIII) and systemic inflammation response index (SIRI). An NLR more than equal to 4 has been associated with poor outcomes.[144][145][146]
Laboratory Parameters
Variables that have been used to determine response to targeted therapy include hematological (serum hemoglobin, absolute neutrophil count, platelet count), biochemical (serum corrected calcium), functional parameters (Karnofsky performance status), and time from time of diagnosis to beginning of treatment. Morphological features that are known to predict survival include the size of the tumor, stage at presentation, degree of vascular invasion, the extent of tumoral necrosis, and grade. Biomarkers proposed to guide individualized treatment include clinical parameters such as blood pressure, endogenous substances such as proteins in the plasma, and pathobiological features such as specific mutations. Failure to obtain a clinically beneficial response with radiotherapy, metastasis at multiple sites, sarcomatoid differentiation, neutrophilia, thrombocytosis, and elevated alkaline phosphatase have also been identified as potential prognostic factors from various studies. High serum interleukin 6 levels above 35 pg/ml and adverse prognosis on the modified Glasgow prognostic score also correlate with poor survival.[147][22]
Nomograms
Among the various nomograms that have been used to decide upon the modality of treatment, the following deserve mention – the university of California Los Angeles (UCLA) integrated staging system and stage, size, grade, necrosis (SSGN) score which integrate the clinical TNM stage and Fuhrmann grade, among other variables. The Memorial Sloane – Kettering cancer center score, which comprises of the following parameters – Karnofsky performance status, history of prior nephrectomy, lactate dehydrogenase levels, hemoglobin level, and serum calcium levels has been used to predict survival in those with advanced disease who have undergone treatment with immunotherapy or chemotherapy.[148][149]
Motzer Score
Prognostic assessment in metastatic RCC includes the Motzer score, which requires estimating laboratory parameters such as hemoglobin, total leucocytes, platelet counts, lactate dehydrogenase, and corrected calcium levels. While the survival for those with a favorable risk profile has been estimated to be 43.2 months, those with intermediate and unfavorable risk profiles have a survival corresponding to 22.5 and 7.8 months, respectively.[150]
Clinical Features
Hypertension is associated with improved progression-free survival and overall survival in those receiving targeted therapy with multi-target tyrosine kinase inhibitors.[151][152][151]
Histopathological Features
The histopathological prognostic features that have been validated by the International Society of Urological Pathology and WHO classification of RCC include histological subtype of the tumor, the ISUP nucleolar grade (in preference to the Fuhrmann grade), sarcomatoid or rhabdoid differentiation that defines a stage 4 tumor (nonclear cell RCC), presence of necrosis, presence of microscopic vascular invasion, pathological tumor, node, metastasis staging, and description of the nonneoplastic renal tissue. Among morphological features, large size, intralesional necrosis, renal vein thrombosis, retroperitoneal collateral vessels, and interruption of the tumor capsule have been associated with high tumor grade. The presence of sarcomatoid change and extensive necrosis is usually associated with a poor prognosis. While most clear cell carcinomas are not associated with an intense inflammatory response, those that show a dense lymphocytic or neutrophil-rich infiltrate are usually associated with a poor prognosis. Cystic change in clear cell RCC has been associated with a favorable prognosis. Multilocular clear cell RCC has been associated with an indolent course and uniformly excellent survival. Nodal invasion usually points towards poor cancer-specific survival, nearing 20 to 30 percent after 3 years of surgery.[153][50]
Radiological Features
CT perfusion might also be useful in prognosticating the tumor, as a higher microvascular density has been associated with a better outcome.[154]
Genetic Markers
There has been a move towards studying genetic markers, potentially impacting treatment in the metastatic setting. RECORD 3 trial, a randomized phase 2 trial in the metastatic setting, which compared sunitinib with everolimus, showed that BAP 1 mutations have the potential to impact progression-free survival. Molecular profiling based upon BAP1 and PBRM1 or KDM5C has been advised, with the potential to impact clinical outcomes. Activation mutations of m TOR and biallelic inactivation of TSC1 and TSC2 have been identified as potential biomarkers for assessing long-term response in case-based mTOR inhibitor outlier studies.[155]
Immune Markers
PD-L1 expression, associated with increased aggressiveness and lymphocyte density in the tumor microenvironment, has also been identified with potential prognostic factors that might be used to determine responses to immune checkpoint inhibitor therapy. The potential disadvantage of using PD-L1 lies in the heterogeneous expression of this biomarker between the primary tumor and the metastatic sites.[156]
Complications
Complications of Surgery
Radical Nephrectomy
Common complications reported with radical nephrectomy include hemorrhage, wound infection, seroma, wound disruption, seroma, pneumothorax, sepsis, ileus, cardiac failure, renal events, peritonitis, and perihepatic collection.[157]
Complications According to the Site of Metastasis
Metastatic bone disease may present with skeletal-related events such as pathological fractures, hypercalcemia, and metastatic extradural spinal cord compression [158]. Intracranial metastases may present with altered sensorium and signs of raised intracranial tension, such as headache, blurred vision, early morning nausea, and vomiting. Physical examination may demonstrate papilledema (on Ophthalmoscopy) [159].
Specific Side Effects of VEGF Targeted Therapy
The median time to onset of hypertension in a study of 1120 patients treated with multitargeted receptor tyrosine kinase inhibitors was 29 days after the initiation of therapy. Pre-existing hypertension, a body mass index above 25, and an age of more than 60 years were identified as potential risk factors for developing hypertension.[160]
Renal Disease with Multitargeted RTK Therapy
Proteinuria was shown to occur at 18.7 percent. In contrast, high-grade proteinuria was shown to have an incidence of 2.4 percent in an analysis of 33 trials of patients with solid tumors treated with TKIs. An analysis of biopsy specimens revealed podocytopathies such as minimal change disease and focal segmental glomerulosclerosis. Tyrosine phosphorylation of nephrin has been postulated as the mechanism underlying the development of glomerular disease.[161]
Consultations
Consultations that are typically requested for patients with clear renal cell carcinoma include the following:
- Urologist
- Nephrologist
- Radiologist
- Pathologist
- Surgical oncologist
- Oncologist
Deterrence and Patient Education
Patients must consult a urologist whenever they detect any hematuria, abdominal mass, or flank pain. The interprofessional team should ensure that the patients are well-informed about renal cancer. Patients should be informed about educational websites to help them better understand this malignant neoplasm, its outcome, and its treatment. Patient education helps in the deterrence of the processes that can cause renal cancer. Specialty-trained nurses often do this. For instance, advise the patient to stop smoking since renal cancer is linked to tobacco.
Enhancing Healthcare Team Outcomes
Discussing the chosen modality of surgery should involve a core multidisciplinary team consisting of specialists from medical oncology, surgical oncology, radiation oncology, radiology, interventional radiology, and nursing. Specialists from nuclear medicine, geriatric oncology, oncology pharmacy, psycho-oncology, and palliative medicine usually form a part of the extended MDT. The presence of a nephrologist in the MDT may be necessary, given the risk of development of chronic kidney disease post-surgery and given the common adverse effects of targeted therapy, like hypertension (and its potential to impact residual renal function).[162]
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