Editing Metastatic Kidney Cancer

'''INCLUDES 2019 CUA Advanced Kidney Cancer Consensus Statement, 2019 CUA Cytoreductive Nephrectomy Consensus Statement'''

== Prognostic factors in advanced RCC ==

* '''2 prognostic models have been developed: Motzer and Heng criteria'''

=== '''Motzer criteria''' ===

* '''Developed in''' 463 '''patients with advanced kidney cancer (stage IV) of any histology treated with interferon (IFN)-α as the first-line systematic therapy'''§
* '''Variables significantly associated with decreased overall survival (5):'''
*# '''Karanofsky performance status (<80)'''
*# '''Interval from diagnosis to treatment (<1 year)'''
*# '''Hemoglobin (< lower limit of normal)'''
*# '''Corrected Calcium (>10 g/dL)'''
*# '''Lactate dehydrogenase (>1.5x the upper limit of normal)'''
* '''Stratified into 3 risk groups based on the number of risk factors present:'''
** '''Favourable-risk: 0 risk factors;''' median survival 30 months
** '''Intermediate-risk: 1-2 risk factors;''' median survival 14 months
** '''Poor-risk: ≥3 risk factors;''' median survival 5 months

'''Heng (IMDC) criteria'''

* The use of targeted therapy for advanced kidney cancer has displaced immunotherapy as the first-line systemic treatment due to improved survival and better tolerability
* Heng et al. subsequently '''developed a prognostic model''' '''in''' 645 '''patients with advanced kidney cancer of any histology treated with targeted (anti-vascular endothelial growth factor) therapy as the first-line systematic therapy'''
* '''6 variables significantly associated with overall survival K-PINCH:'''
** '''4 of the Motzer criteria (without lactate dehydrogenase)'''
** '''Neutrophil count (> upper limit of normal)'''
** '''Platelets (> upper limit of normal)'''
* '''Stratified into 3 risk groups based on number of risk factors present:'''
** '''Favourable-risk: 0 risk factors'''; median survival not reached
** '''Intermediate-risk: 1-2 risk factors'''; median survival 27 months
** '''Poor-risk: ≥3 risk factors'''; median survival 9 months

== Surgical management of metastatic renal cell carcinoma ==

=== '''Cytoreductive nephrectomy (CN)''' ===

* '''The role of CN before systemic therapy (IFN-''' '''α) has been extensively studied in the era of cytokine therapy'''
** '''SWOG 8949'''
*** Randomized 249 patients with metastatic RCC of any histology to IFN-α vs. CN followed by IFN- α
*** Results:
**** OS was improved, though not significantly, in the CN group (median OS 11 months CN + IFN α2b vs. 8 months IFN α2b, p=0.05)
** '''EORTC 30947'''
*** Randomized 85 patients with metastatic RCC of any histology to IFN-α vs. CN followed by IFN-α
*** Results:
**** OS was significantly improved in the CN group (median OS 17 months CN + IFN-α vs. 7 months IFN-α, p=0.03)
** Meta-analysis of the 2 trials found '''significant improved OS in CN group by 5.8 months''' (13.6 months CN IFN α2b vs. 7.8 months IFN α2b, p=0.02)
* '''The introduction of effective targeted therapy has questioned the role of CN in the modern era'''
** '''CARMENA''' (Clinical Trial to Assess the Importance of Nephrectomy)
*** '''Population: 452 patients with metastatic ccRCC'''
**** 44% had poor-risk disease, 56% had intermediate-risk
***** '''Trial does not apply to patients with favourable-risk'''
*** '''Randomized to CN followed by sunitnib vs. sunitnib alone'''
*** '''Primary outcome: OS'''
*** '''Median follow-up 50.2 months'''
*** '''Results'''
**** '''OS: sunitinib alone was non-inferior to CN followed by sunitinib''' (HR 0.89; 95% CI 0.71–1.10)
**** '''No significant difference PFS or response to treatment'''
*** Méjean, Arnaud, et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379.5 (2018): 417-427.
** '''In patients with mRCC who are being considered for CN, the optimal timing relative to the initiation of systemic therapy also remains controversial.'''
*** '''Advantages of initiating systemic therapy prior to CN:'''
***# '''May provide symptomatic control and disease stabilization or regression for patients with a large tumour burden'''
***# '''May allow the identification of patients not likely to benefit from CN; specifically, patients who progress rapidly on systemic therapy have a poor prognosis and are unlikely to derive a survival advantage by undergoing CN'''
***# '''Decreases the size of the primary tumour in a proportion of patients'''
***#* The median decrease in size is estimated to be 7-32% and the clinical impact of this is questionable
***#* Tumour may also increase in size or complexity during systemic therapy, reducing the feasibility of resection
*** '''Advantages of upfront CN (3):'''
***# '''Palliating symptoms related to the primary tumour'''
***# '''Eliminating a source of secondary metastases'''
***# '''Improving host immune dysfunction'''
*** '''SURTIME''' (Immediate Surgery or Surgery After sunitinib Malate in Treating Patients With Metastatic Kidney Cancer) '''TIMING of CN'''
**** '''99 patients with metastatic ccRCC'''
**** '''Randomized to upfront CN followed by sunitnib vs. upfront sunitinib followed by CN (deferred CN)'''
***** '''Investigated optimal timing of CN relative to initiation of systemic therapy'''
**** '''Primary endpoint: disease progression at 28 weeks'''
**** '''Results:'''
***** '''No difference in disease progression''' (42.0% vs. 42.9%, respectively at 28 weeks of follow-up; p>0.99) '''between upfront vs. deferred CN'''
***** '''OS improved in deferred CN group (median OS 32.4 vs. 15 months; p=0.034)'''
****** '''Difficult to interpret this result due to discordance with the disease progression results'''
**** Bex, Axel, et al. "Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial." JAMA oncology 5.2 (2019): 164-170.
** '''Several retrospective observational studies have identified a significant survival advantage in favour of CN for patients treated with targeted therapies'''
* '''As per the 2019 CUA Cytoreductive Nephrectomy Consensus Statement:'''
** '''Decisions regarding CN should ideally be made in a multidisciplinary setting'''
** '''In patients with metastatic RCC, offer upfront CN''' followed by metastases-directed therapy, a period of surveillance, or systemic therapy '''in patients with (5):'''
**# '''Good performance status (Eastern Cooperative Oncology Group [ECOG] ≤1 or Karnofsky performance status (KPS) ≥80%)'''
**# '''Resectable primary tumour'''
**# '''Limited burden of metastatic disease'''
**# '''Minimal symptoms related to metastases'''
**# '''No active CNS metastases'''
** '''CN should not be done in patients with (2):'''
**# '''Rapidly progressing disease'''
**# '''Limited life expectancy'''
** Also consider patient’s age, general health status, and competing health risks when making decisions regarding the role of CN, as these are surrogate markers of OS
** '''Patients with mRCC but without characteristics listed above (i.e. not optimal candidate but no contraindications) should be offered initial treatment with systemic therapy with consideration of CN given to those with a significant clinical response'''
** '''Patients with non-clear-cell mRCC should be offered CN with similar considerations to those with clear-cell mRCC.'''
*** The majority of data on CN pertain to patients with clear-cell histology, and thus whether CN provides a survival advantage for appropriately selected patients with non-clear-cell mRCC remains uncertain.
**** The 2 CN trials performed in the IFN-era mentioned above did not include information on histological subtypes
**** '''CARMENA and SURTIME excluded patients with non-clear-cell mRCC.'''
**** Limited observational data do suggest that CN may provide a survival advantage in patients with non-clear mRCC.
** '''Histologic diagnosis before treatment'''
*** '''In patients receiving initial systemic therapy, histologic diagnosis SHOULD be obtained''' (biopsy of the primary lesion or a metastatic deposit) '''prior to initiation of therapy to guide systemic treatment'''
**** Systemic therapy will depend on the histologic subtype
*** '''For patients receiving upfront CN, histologic diagnosis MAY BE PERFORMED IF the results of the biopsy will influence management'''
**** As noted above, CN appears to play a role in treating non-clear-cell mRCC, and appropriately selected patients can thus proceed directly to CN without a biopsy. However, if a non-RCC histology is questioned (e.g., imaging characteristics suggestive of urothelial carcinoma, lymphoma, etc.), a biopsy prior to CN should be performed, as the results may significantly alter the patient’s subsequent management.
** In the setting of oligometastatic disease, the link between primary and secondary masses cannot be assumed reliably. Limited data are available with regards to the role of percutaneous biopsy in this setting.
** CN can be performed through both minimally invasive and open surgical approaches at the discretion of the treating surgeon
*** Adrenal-sparing is appropriate when there is no evidence of tumour invasion or metastatic spread and when technically feasible.
** '''Lymphadenectomy'''
*** '''In patients with mRCC undergoing CN who do not have clinical evidence of nodal disease, retroperitoneal LND is not recommended.'''
*** '''Surgical resection of clinically positive lymph nodes may be considered at the time of CN after weighing the potential for increased surgical morbidity and the uncertain clinical benefit.'''
**** '''LND does not appear to provide a survival advantage in mRCC patients.''' Similar findings have been noted in patients with and without clinically positive lymph nodes

=== '''Metastatectomy for distant recurrence''' ===

* No randomized trials comparing metastatectomy to systemic treatments; most studies are retrospective in nature. However, among patients who develop metachronous metastases after nephrectomy, ≈1/3 are eligible for metastatectomy and studies report long-term survival for a subset of patients after complete resection of metastases
* '''Isolated metastases to the lung, thyroid, bone, pancreas, and adrenal glands have the most favourable prognosis'''.
** '''In most series, isolated pulmonary metastases were the lesions most commonly amenable to resection with curative intent'''
* Based on available observational data, patients most likely to benefit from metastatectomy are those
** Diagnosed with metastases over 2 years following nephrectomy
** With isolated metastases
** With favourable metastatic locations (lung, thyroid, bone, pancreas, adrenals).
* '''As per the 2019 CUA Management of Advanced Kidney Cancer Consensus Statement, in select patients with limited number of sites of metastatic disease and stable clinical condition, local therapy, such as resection and/or stereotactic body radiotherapy to treat of all sites of metastatic disease may be a reasonable option'''

'''Local therapy for oligoprogression'''

* '''As per the 2019 CUA Management of Advanced Kidney Cancer Consensus Statement, local therapy may be considered in the setting of oligoprogression'''

'''Role of radiation therapy in symptom control'''

* '''Radiation therapy may be considered to palliate symptoms from the primary tumor and metastases'''

== Immunologic approaches in the management of advanced clear cell RCC ==

* '''Cytokines'''
** '''Interferons'''
*** IFN-α was one of the earliest cytokines to be evaluated for activity in RCC
*** '''Response rate generally 10-15%'''
*** '''Durable complete responses are relatively rare (<2%)''' based on limited long-term survival data
*** Despite its '''relatively modest activity compared with IL-2''', IFN was often the agent of choice in the initial treatment of metastatic RCC (until the advent of VEGF pathway antagonists) due to its relative ease of administration compared to IL-2
** '''High-dose Interleukin-2 (IL-2)'''
*** '''Response rates generally 15-20%'''
*** '''Complete responses are seen in 7-9% of metastatic clear cell RCC patients''', with the majority of these remaining disease-free for long periods
*** There are no randomized phase 3 studies demonstrating survival benefit with IL-2.
*** '''Considerable associated toxicity has limited widespread use.'''
**** Vascular leak syndrome and the resulting hypotension, third-space fluid retention, respiratory compromise, and multiorgan damage are some of the potential serious sequelae and led to an unacceptably high treatment-related mortality rate (2-5%)
*** 2 RCTs demonstrated that, although well tolerated, '''lower-dose regimens are associated with lower overall response rates''', as well as with fewer durable, complete responses. Based on these data, '''only high-dose IL-2 regimens are recommended in patients being considered for cytokine therapy'''
*** '''Patients with ccRCC appear most likely to benefit from IL-2; the efficacy of IL-2 has not been adequately evaluated in patients with non–clear cell histologies'''
* Combination IL-2 and interferon
** In a randomized phase 3 study, the combination of IL-2 and interferon was associated with a higher response rate than either agent given alone, although this did not translate to an improved long-term outcome (overall survival) in the combination arm.
* Allogeneic Hematopoietic Stem Cell Transplantation
** Remains an experimental approach in the management of RCC
* '''Immune “checkpoint” inhibitors'''
** '''RCC has only modest response to traditional chemotherapeutics'''
** '''P-glycoprotein'''
*** A transmembrane protein
*** Expressed by 80% to 90% of RCCs
*** '''Acts as an energy-dependent efflux pump for a wide variety of large hydrophobic compounds, including several cytotoxic drugs.'''
** '''The response of RCC to immunomodulators''' (IL-2, IFN-α, and tumor-infiltrating lymphocytes) '''demonstrates an important role for the immune system in the tumor biology of RCC.'''
*** The host immune response to tumors is a highly complex process that is regulated at multiple levels. The interplay between multiple stimulatory and inhibitory processes determines the nature and extent of the antitumor response generated by the host immune system.
*** '''The estimated incidence of spontaneous regression of RCC is between 0.3-1%'''
** It has become increasingly evident that several inhibitory receptors on effector immune cells, such as CD8+ T lymphocytes, play a key role in tightly regulating the immune response to tumors. Furthermore, antitumor responses can be downregulated by activation of T-cell receptors such as cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) and those mediating programmed death-1 (PD-1).
** '''Pharmacologic targeting of immune checkpoints such as CTLA-4 and the PD-1 axis is being explored currently in many solid tumors, including RCC'''
*** CTLA-4 expression on the surface of activated T cells halts the immune response to the tumor. '''Blockade of CTLA-4, such as by the CTLA-4 antibody ipilimumab,''' '''leads to major tumor responses''', but also significant potential toxicity
*** PD-1 and PD-1 ligand–1 pathway lead to decreased effector T-cell activity. '''Blockade of''' '''PD-1, such as by the PD-1 antibodies nivolumab and pembrolizumab, has been associated with significant clinical response'''
*** '''CheckMate 214'''
**** '''Randomized 1096 patients with previously untreated clear-cell advanced renal-cell carcinoma to nivolumab + ipilimumab vs. sunitinib'''
***** Mostly intermediate or poor-risk patients
**** '''OS and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib''' among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma
**** Motzer, Robert J., et al."Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma." New England Journal of Medicine 378.14 (2018): 1277-1290.
*** '''CheckMate 9ER'''
**** '''Randomized 651 patients with previously untreated clear-cell advanced renal-cell carcinoma to nivolumab + cabozantinib vs. sunitinib'''
**** '''OS and progression-free survival were significantly higher with nivolumab plus cabozantinib than with sunitinib'''
**** Choueiri, Toni K., et al."Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma." ''New England Journal of Medicine'' 384.9 (2021): 829-841.
*** '''CLEAR'''
**** '''Randomized 1069 patients with advanced renal cell carcinoma and no previous systemic therapy to lenvatinib + pembrolizumab vs. lenvatinib + everolimus vs. sunitinib'''
**** '''OS and progression-free survival were significantly higher with lenvatinib + pembrolizumab'''
**** Motzer, Robert, et al."Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma." ''New England Journal of Medicine'' 384.14 (2021): 1289-1300.

== Molecular basis for targeted approached in ccRCC ==

* Mutations in VHL promote HIF accumulation even under normoxia. HIF accumulation, in turn, leads to the upregulation of a variety of proangiogenic and growth factors, including VEGF, platelet-derived growth factor (PDGF), transforming growth factor-α, glucose transporter 1, and erythropoietin, which are believed to play critical roles in the development and progression of clear cell RCC
* '''RCC has been targeted for anti-VEGF approaches''' given the dependence on angiogenesis
* '''Inhibition of mTOR, with temsirolimus or everolimus, is another target in RCC'''
* Carbonic anhydrase IX is a tumour-associated antigen that is expressed almost ubiquitously in ccRCC, and only rarely in other RCC subtypes

== Targeted molecular agents in ccRCC ==

* '''Vascular endothelial growth factor (VEGF) antagonists''' '''(-nib + bevacizumab)'''
** '''Bevacizumab'''
*** Humanized '''monoclonal antibody against VEGF-A'''
*** The first VEGF pathway antagonist used in clinical trials
*** Not widely used as a single agent in the initial therapy for metastatic ccRCC but may have a role in patients who have failed standard therapy with first-line VEGFR antagonists, either alone or in combination with other agents, particularly IFN-α
** '''Sunitnib (Sutent)'''
*** An '''oral''' receptor '''kinase inhibitor''' with activity against VEGFR-2, PDGFR-β, c-Kit, and fms-like tyrosine kinase 3 (Flt3)
*** '''Widely used in the initial treatment of metastatic ccRCC'''
*** '''In an RCT comparing sunitinib vs. IFN-α in patients with metastatic clear cell RCC, sunitinib improved OS, PFS, RECIST response rates (30-40%), and quality of life'''
**** Motzer, Robert J., et al."Sunitinib versus interferon alfa in metastatic renal-cell carcinoma." New England Journal of Medicine 356.2 (2007): 115-124.  
*** The dose and schedule of sunitinib should be optimized for each patient in order to derive the most benefit. '''Recommended to start with the monograph standard of 4-week-on/2-week-off dosing schedule'''. After evaluation of type and timing of toxicities, patients may require adjustments to the schedule and/or dose
*** '''Potential adverse effects'''
***# '''Diarrhea'''
***# '''Hand-foot syndrome'''
***# '''Hypothyroidism'''
***#* '''Patients should be monitored with TSH and T4 measurements'''
***# '''Hypertension'''
***# '''Rash'''
***# '''Fatigue'''
***# '''Asthenia'''
***# '''Bone marrow suppression'''
** '''Sorafenib''' (Nexavar)
*** An oral receptor '''kinase inhibitor''' with activity against VEGFR-2, PDGF receptor-β (PDGFR-β), and raf-1.
*** '''Side effect profile comparable to that of other agents in this class and includes hypertension, fatigue, rash, hand-foot syndrome, and diarrhea.'''
*** In a randomized phase 2 study, '''sorafenib was not superior to IFN-α in previously untreated patients with metastatic clear cell RCC'''
*** Currently, '''infrequently used in the first-line setting.'''
*** Anecdotal evidence and small case series suggest that patients whose disease has progressed on other VEGFR inhibitors may respond favorably to sorafenib, and the agent is commonly used in patients whose disease has progressed on sunitinib or similar agents.
** '''Pazopanib'''
*** '''Agents such as sunitinib and sorafenib have activity against a wide array of target molecules, some of which may not be relevant in ccRCC.''' '''A variety of newer agents with''' '''selective activity against the VEGFR''' family have recently gained attention as a possible means of diminishing the side effects associated with therapy without compromising efficacy
*** '''COMPARZ'''
**** '''Randomized 1110 patients with metastatic ccRCC to pazopanib vs. sunitnib'''
**** '''OS similar between groups''', with a median OS of 28.4 months in the pazopanib group versus 29.3 months in the sunitinib group; PFS with pazopanib was noninferior to sunitinib
**** '''Different adverse event profile''':
***** '''Sunitinib associated with increased incidence of fatigue, thrombocytopenia, and hand-foot syndrome'''
***** '''Pazopanib associated with increased levels of alanine aminotransferase'''
*** Pazopanib is a reasonable first-line option for patients with advanced clear cell RCC. Although pazopanib appears to be better tolerated than sunitinib by the majority of patients, it appears to be associated with an '''increased incidence of''' '''hepatotoxicity''' and must be used with caution in patients at risk for this complication
** '''Axitinib'''
*** Highly selective oral small molecule tyrosine '''kinase inhibitor''' of VEGFR-1, VEGFR-2, and VEGFR-3
*** '''AXIS'''
**** Based on the improved PFS compared to sorafenib in the AXIS trial, axitinib was approved by the FDA for use in the second-line setting in patients with advanced RCC.
** Other agents targeting the VEGF pathway: tivozanib, nintedanib, and dovitinib
** '''Cabozantinib'''
*** Dual VEGFr/MET and AXL inhibitor
*** Not yet approved for patients with metastatic RCC or any other tumour site in Canada, and so it is not considered an option for Canadian patients

* '''Mammalian target of rapamycin (mTOR) inhibitors''' ('''-limus)'''
** mTOR inhibition correlates with a block in HIF-1α translation
** 2 analogues of sirolimus, '''temsirolimus and everolimus''', have been clinically evaluated with demonstrable activity in RCC
** '''Temsirolimus'''
*** '''ARCC'''
**** In poorer-risk patients, IV temsirolimus produces an improvement in PFS and OS compared to IFN-α alone, and the combination of temsirolimus and IFN-α does improve OS over IFN-α alone
* '''Combination and sequential therapy with agents targeting the von Hippel-Lindau pathway'''
** '''RECORD-3'''
*** A non-inferiority trial that examined oral sunitinib followed by oral everolimus at progression or the alternate order of drug administration in all risk groups of patients with metastatic RCC. Non-inferiority of first-line everolimus was rejected i.e. first-line everolimus inferior. Thus, '''data for first-line mTOR inhibitors only supports the use of temsirolimus, and only in poorer-risk patients'''
** '''First-line VEGFR–tyrosine kinase inhibitor followed by mTOR agent upon disease progression results in better outcomes than using an mTOR agent first'''
* '''Other treatment options in patients with clear cell RCC'''
** '''Conventional cytotoxic chemotherapy has been largely ineffective in the management of ccRCC'''
** Progestational and other hormonal agents have no role in the current management of RCC.

== '''Management strategy as per the 2019 CUA Management of Advanced Kidney Cancer Consensus Statement''' ==

* Published before results of CHECKMATE 214
* Enrolling patients in clinical trials should always be considered the first option for patients with advanced or metastatic RCC

* '''Clear cell RCC'''

{| class="wikitable"
|'''Setting'''
|'''Patients'''
|'''Preferred'''
|'''Options'''
|-
|'''Untreated (first-line)'''
|'''Favourable-risk by IMDC'''
|'''Axitinib + Pembrolizumab^'''
|'''Sunitinib'''

'''Pazopanib***'''

'''Axitinib + Avelumab*'''

'''High-dose IL-2**'''

'''Active surveillance'''
|-
| 
|'''Intermediate/Poor-risk by IMDC'''
|'''Nivolumab + Ipilimumab'''

'''Axitinib + Pembrolizumab^'''
|'''Sunitinib'''

'''Pazopanib***'''

'''Axitinib + Avelumab^^*'''

'''Cabozantinib^^'''

'''Active surveillance'''
|-
|'''Second-line''' and beyond#
|'''Prior immune checkpoint inhibitor''' (ipilimumab, nivolumab)
|'''Cabozantinib^^^'''

'''Axitinib^^^'''
|'''Sunitinib'''

'''Pazopanib***'''

'''Lenvatinib + Everolimus^^^'''
|-
| 
|'''Prior VEGF''' (sunitnib, sorafenib, bevacizumab, pazopanib)
|'''Nivolumab'''

'''Cabozantinib'''
|'''Lenvatinib + Everolimus'''

'''Everolimus'''

'''Axitinib'''
|-
|
|Prior VEGF and immune checkpoint inhibitor
|Cabozantinib
|Sunitinib

Pazopanib

Axitinib^^

Lenvatinib + Everolimus

Everolimus
|}
'''^Not yet approved in Canada; until approval, sunitinib or pazopanib are preferred for favorable-risk and ipilimumab/nivolumab is preferred for intermediate-/poor-risk'''.

^^Not yet approved in Canada.

^^^Approved after one prior VEGF therapy only.

<nowiki>#</nowiki> If not used prior.

<nowiki>***</nowiki>Need to be monitored closely for first 12 weeks for liver toxicity

* '''First-line therapy'''
** '''Choice of initial systemic treatment is based in part on International Metastatic RCC Database Consortium (IMDC) risk status.'''
*** '''Preferred first-line therapy in'''
**** '''IMDC favourable-risk patients'''
***** '''Axitinib + pembrolizumab is the recommended treatment.'''
****** '''Avelumab/axitinib and targeted therapy with sunitinib or pazopanib can be considered as alternative active treatment options.'''
**** '''IMDC intermediate- or poor-risk patients:'''
****# '''Ipilimumab + nivolumab ('''
****#* '''Highest complete response rate ≈9%; similar to that for high-dose IL-2 (5-10%) much better than 1 % for sunitinib'''
****# '''Axitinib + pembrolizumab'''
***** Avelumab/axitinib and targeted therapy (sunitinib or pazopanib) remain alternative options, the latter especially for patients who have a contraindication to immunotherapy or who are felt to be unable to tolerate combination therapy.
** '''Active surveillance can also be considered in selected patients with one [IMDC] risk factor, as some patients have slow-growing, low-volume, and/or asymptomatic disease.'''
* '''Second-line and later therapy options'''
** '''Progression on or intolerance to first-line immune checkpoint inhibitor-based regimen'''
*** For patients who progress on, or who are intolerant of first-line immune checkpoint inhibitors, there is no prospective, randomized, phase 3 evidence available to select a preferred treatment option; options for patients in this situation include sunitinib, pazopanib, axitinib, cabozantinib, or lenvatinib/everolimus.
** '''Progression on or intolerance to first-line sunitinib or pazopanib'''
*** For patients who are intolerant to sunitinib or pazopanib, switching to the other VEGF inhibitor is a reasonable choice
*** For patients who progress on first-line sunitinib or pazopanib, preferred options are nivolumab, axitinib, or cabozantinib
*** Other evidence-based options are lenvatinib/everolimus (based on a small phase 2 study demonstrating a PFS advantage over everolimus monotherapy) or everolimus monotherapy (although found to be inferior to alternatives such as nivolumab and cabozantinib).
** '''Progression on or intolerance to prior VEGF inhibitor AND prior immune checkpoint inhibitor'''
*** For patients who progress on, or who are intolerant of, both prior VEGF inhibitor and prior immune checkpoint inhibitor, there is no evidence base available to select a preferred treatment option; options for patients in this situation include any of the options that have not previously been tried among: sunitinib, pazopanib, axitinib, cabozantinib, or lenvatinib/everolimus.

* '''Non-clear cell histology'''
** Relatively rare (constituting ≈15-25% of all kidney cancer) and have been the subject of few prospective studies.
** '''No standard therapy for non-clear-cell RCC; enrollment in clinical trial is the preferred option.'''
*** '''It is generally accepted that non-clear-cell histology patients should be treated similarly to clear-cell histology patients.'''
*** '''Clinical trials support the use of immunotherapy in this setting (nivolumab + ipilimumab; axitinib + pembrolizumab) or sunitinib if immunotherapy is not felt to be an option'''

* '''Bone modifying agents'''
** '''Can be considered for patients with bone metastases to decrease skeletal related events'''
** '''Options''':
*** '''Zoledronic acid'''
**** '''Bisphosphonate'''
**** Monthly administration is a reasonable option
**** '''Careful monitoring of renal function is required'''
**** '''Should not be given in renal dysfunction'''
*** '''Denosumab'''
**** '''Inhibitor of the receptor activator of nuclear factor kappa-B (RANK) ligand'''
** '''Patients receiving bone-modifying agents are at risk of hypocalcemia, therefore calcium and vitamin D supplements are recommended; however, paraneoplastic hypercalcemia can also occur in RCC, so monitoring of serum calcium levels is important regardless'''
** '''Patients starting on any bone-targeted therapy should ensure they have had a thorough dental history and recent dental examination prior to starting therapy, given the risk for osteonecrosis of the jaw developing.'''

== Questions ==

# What are the IMDC criteria and the risk groups?
# Describe how CARMENA and SURTIME have influence the role of CN?
# As per the 2019 CUA Consensus Statement on CN, what are the criteria for offering upfront CN?
# What does nivolumab target? Ipilimumab?
# List VEGF inhibitors used in RCC.
# List mTOR inhibitors used in RCC.
# What is the first-line systemic treatment in metastatic ccRCC?

== Answers ==

# What are the IMDC criteria and the risk groups?
#* '''K-PINCH'''
## KPS < 80
## Platelets (>upper limit of normal)
## Interval from diagnosis to treatment <1 year
## Neutrophils (>upper limit of normal)
## Calcium (>10g/dL)
## Hemoglobin (<lower limit of normal)
#* Favourable-risk: 0 factors
#* Intermediate-risk: 1-2 factors
#* Poor-risk: ≥3 factors
# Describe the CARMENA and SURTIME trials?
#* CARMENA: RCT of approximately 400 patients with intermediate/poor-risk mcRCC randomized to upfront sunitnib vs. upfront CN followed by sunitnib. Primary outcome OS. Upfront sunitnib was non-inferior to upfront CN + sunitnib
#* SURTIME: RCT of approximatley 100 patients with mcRCC randomized to upfront sunitnib followed by CN vs. upfront CN followed by sunitnib. Primary outcome was progression. No difference in progression.
# As per the 2019 CUA Consensus Statement on CN, what are the criteria for offering upfront CN?
## Good performance status (Eastern Cooperative Oncology Group [ECOG] ≤1 or Karnofsky performance status (KPS) ≥80%)
## Resectable primary tumour
## Limited burden of metastatic disease
## Minimal symptoms related to metastases
## No active CNS metastases
# What does nivolumab target? Ipilimumab?
#* Nivolumab: PD-1
#* Ipilimumab: CTLA-1
# List VEGF inhibitors used in RCC.
## Sunitnib
## Sorafenib
## Bevacizumab
## Pazopanib
## Axitnib
# List mTOR inhibitors used in RCC.
## Everolimus
## Temsirolimus
# What is the preferred first-line systemic treatment in metastatic ccRCC?
#* Favourable-risk: axitnib + pembrolizumab
#* Intermediate/poor-risk: axitnib + pembrolizumab or nivolumab + ipilimumab

== References ==

* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 63