Renal tumors (in general)

Pathologic subtypes

• Clear cell RCC (70-80%) - most common primary renal malignancy in adults; from proximal tubule; a/w VHL
  • "Clear" nature comes from glycogen/cholesterol being extracted by prep for histology
• Papillary RCC (15%) - more multifocal
• Chromophobe RCC (3-5%) - from collecting duct, a/w BHD
  • Oncocytoma (benign) - similar to chromophobe/also from collecting duct; a/w tuberous sclerosis, Birt-Hogg Dube (BHD)
• Collecting duct RCC (< 1%) - aggressive, poor prognosis
• Medullary RCC (rare) - from collecting duct, a/w sickle cell patients, poor prognosis
• Mucinous tubuar and spindle cell (rare) - favorable prognosis

*Sarcomatoid variant can be a/w any subtype - poor prognosis

Risk factors: tobacco, obesity, HTN, familial (hereditary papillary RCC, VHL, BHD, tuberous sclerosis)

Grading: Furhman grading is used for ccRCC and papillary RCC (based on nuclear size/characteristics)

• I-IV, higher grade = worse prognosis 

Staging:

*20% of T1 masses are benign (oncocytoma, AML); 60% indolent, 20% potentially aggressive

IVC thrombus (occurs in 5-10%)

• Potential surgical cure in 50-70%; not always a/w metastasis. 5 year disease-free survival ~ 65% after surgery.
• Invasion of wall (T3b) is more important prognostic factor than level. MRI can assess invasion with PPV/NPV 90%
• Mayo staging system
  • Level I - adjacent to ostium of renal vein
  • Level II - up to lower part of liver
  • Level III - intrahepatic but below diaphragm
  • Level IV - above diaphragm (requires bypass)
• MRI preferred; tumor thrombus will enhance while bland thrombus does not
• Generally put on anticoagulation
• Surgery
  • Surgical tips for IVC thrombus
  • Get imaging as close as possible to date of surgery (< 2 wks)
  • Preop embolization - no clear benefit, unless bulky RP nodes make access to artery
  • If chronic IVC collusion - avoid ligating the collaterals (lumbars through hemiazygous) that have developed. In this case don't actually need to reconstruct infrarenal IVC if taken.

• Now > 60% are found incidentally
  • Classic 'triad' - hematuria, flank pain, abdominal mass - is rare now
• 15% present with locally advanced/metastatic RCC
• Can present with spontaneous perirenal hemorrhage, which may obscure underlying mass. Follow with CT a few months later - 50% of spontaneous bleeds have an occult renal tumor (AML/RCC)

Natural history

• Metastasizes hematogenously + lymphatically to lung and bone (spine). 20% of patients present with metastatic disease.
• Paraneoplastic syndromes of note:
  • Hypertension (40%) - renin production, or encasement of renal artery
  • Anemia (36%)
  • Cachexia, weight loss, fever (15-35%)
  • Stauffer's (15%) - abnormal LFTs, but not necessarily due to liver invasion/emts
  • Hypercalcemia (5%) - PTHrP or lytic bone lesions
  • Polycythemia (↑ erythropoietin)
• In general - 5-year cancer specific survival for T1a renal masses is > 95%. For other stages:
  • T1b - 80-90%
  • T2 - 50-80%
  • T3b/c (IVC thrombus) - 20-50%
  • Metastatic - 0-10% pre-checkpoint era, now maybe ~ 25%?

• CBC, CMP, UA
• Abdominal imaging - CT/MR pre/post contrast
  • Iodinated contrast - pre-hydrate with NS if GFR < 30; consider prehydration if GFR 30-45
  • Gadolinium - OK to give for GFR < 30; lower risk of NSF than previously thought
  • In general - RCC enhances > 15-20 HU, does not have fat
• Chest imaging - CXR, or CT chest if thought to be high risk or has abnormal CXR
• Bone scan - only if bone pain or elevated alk phos
• Brain imaging - only if neurologic sx
• Renal mass biopsy - if suspect metastatic disease, inflammatory, infectious, or hematologic (e.g. lymphoma). Otherwise low utility.
• Genetic testing if: age < 46, bilateral multifocal disease, or family history of kidney cancer.
• Nephrology referral - if expect GFR < 30 postop; if DM with CKD. Can get Mag3 scan to predict expected GFR

Renal tumors (in general)

Localized disease

Surveillance 

• Reasonable for solid masses < 2 cm or predominantly cystic mass, or if limited life expectancy/don't want surgery
• Should treat if ≥ 3 cm, growing > 0.3 cm/year, symptoms, or biopsy shows high-grade cancer
• Repeat imaging in 3-6 mo

Ablation: for cT1a < 3 cm. Radio or cryoablation. Slightly worse outcomes wrt local recurrence.

Radical nephrectomy (RN): removal of Gerota's fascia (containing kidney and perirenal fat)

• Remove adrenal if: upper pole tumor > 7 cm, tumor thrombus involving, imaging/intraoperative suspicion of adrenal involvement. Adrenal insufficiency rare if contralateral adrenal is OK
• Regional lymph node dissection: only if there is clinically concerning lymphadenopathy. Does not improve cure/survival for T1-T3N0M0; maybe for N1.
  • L - para-aortic + interaortocaval; R - paracaval + interaortocaval. Template: from diaphragm crus to common iliac.
• Adjuvant therapy for high risk of recurrence: Many negative studies pre-IO, but FDA approved for
  • Stage II (T2N0) Gr 4 clear cell +/- sarcomatoid - pembrolizumab
  • Stage III (T3 or N1) clear cell - pembro (or sunitinib - less evidence)
  • KEYNOTE-564 (pembro, 2021) positive study (disease-free survival 77% vs 68% at 24 mo), but atezo and nivo were negative studies 
  • ASSURE nomogram for cancer-free survival

Nephron sparing (NSS): Partial nx, enucleation, or ablation; less hit to GFR. Use if renal mass ≤ 7 cm (eg T1, similar cure rate as RN), or need to preserve more kidney function (solitary, poor renal function, b/l tumors).

• Local recurrence after PNx for small renal masses in < 2%
• Consider ablation (thermal, radio, cryo) for solid masses < 3 cm.
  • Should do biopsy prior to (preferred) or during ablation for pathologic confirmation.
  • Should get pre/post contrast imaging within 6 mo after ablation (5-10% failure rate for ablation)

If GFR < 45 or expected to be < 30 after intervention, consider referral to nephrology

• EORTC 30904 - PNx reduces incidence of moderate renal dysfunction (GFR < 60), but PNx/RNx equivalent incidence of severe dysfunction (GFR < 30, GFR < 15)
• PNx on solitary kidney - 5-15% required temporary dialysis, 5% required permanent dialysis

Follow-up after nephrectomy:

• If microscopic margins positive, increase risk by one level
• Follow-up intervals (in months) below based on risk
  • H&P
  • Abdominal imaging (CT or MR, pre+post contrast). Can switch to US after 5 years or after 2 years in LR/IR groups
  • Chest imaging (CXR (LR/IR) or CT chest (HR/VHR)). Can switch to CXR after 5 years for HR/VHR groups.
• 30% of recurrences are diagnosed after 5 years. After 5 years, informed/shared decision-making should dictate further abdominal imaging. (Previous guidelines stopped surveillance after 3-5 years).
• *? Partial nephrectomy only - yearly imaging (US/CT/MRI) for 3 years

Advanced disease

Systemic therapy

• Mainstay is immunotherapy + checkpoint inhibitors - chemo generally ineffective
• Risk stratification for advanced disease: IMDC (International Metastatic RCC Database Consortium)
  • Risk factors: Karnofsky performance status < 80%, time from diagnosis to treatment < 1 year, Hgb < LLN (12), calcium > ULN, ANC > ULN, platelets > ULN, LDH > 1.5x ULN (MSKCC)
  • 0 risk factors - favorable risk (44mo survival)
    • Limited disease burden
      • Can consider close active surveillance
      • Single-agent anti-angiogenic (sunitinib or pazopanib)
      • Single-agent immunotherapy (pembro or nivo)
    • Substantial disease burden - immuno + anti-angiogenic, or combo immuno
      • Nivolumab + ipilimumab
      • Pembro + axitinib
      • Nivolumab + cabozantinib
  • 1-2 risk factors - intermediate risk (27mo survival), ≥ 3 risk factors - poor risk  (9mo survival)
    • Symptomatic or life threatening disease - lenvatinib + pembro, or nivolumab + cabozantinib
    • Otherwise - above options plus nivolumab + ipilimumab, pembro + axitinib
  • 1st line poor performance: temsirolimus

Classes of therapies

• PD-1 checkpoint inhibitors (pembrolizumab, nivolumab (2015))
• PD-L1 checkpoint inhibitors (avelumab, atezolizumab)
• Anti CTLA-4 antibody (ipilimumab)
• mTOR inhibitor (tumor cell growth/survival inhibitors) (everolimus (2008), temsirolimus (2007) for non-ccRCC)
  • Decreases VEGF (angiogenesis), HIF (cell proliferation)
• VEGF tyrosine kinase inhibitors (TKI) (axitinib, sunitinib, pazopanib, cabozantinib, lenvatinib, bevacizumab)
  • Toxicity: HTN, impaired wound healing, GI perforation, hand/foot/mouth mucositis
  • Soarafenib, sunitinib (2005-2006)
  • Pazopanib - same response as sunitinib; less side effects
  • Cabozantinib - superior survival to sunitinib (46% response vs 18%)
  • Bevacizumab - stop bevacizumab 28 days before/after surgery for wound healing.
• Nivolumab + ipilimumab
  • FDA approved (2020) for first line for intermediate/poor risk, used off label for favorable risk
  • Checkmate 214 trial: nivo/ipi vs sunitinib. Intermediate/poor risk - complete response 9% vs 1% (~40% of these had durable response). 5-year OS 43% vs 31%, 5-year PFS 31% vs 11%. (for favorable risk - similar OS, lower PFS, higher CR).
• Pembro + axitinib
  • FDA approved (2019) for first line treatment regardless of risk
  • KEYNOTE-426 trial: pembro/axi vs sunitinib. Entire cohort: complete response 9% vs 3%. 2-year OS 74% vs 65%, 2-year PFS 38% vs 27%. 
• Nivolumab + cabozantinib
  • FDA approved (2021) for first line treatment regardless of risk
  • CheckMate 9ER trial: nivo/cabo vs sunitinib. Entire cohort: complete response 12% vs 5%. 2-year OS 70% vs 60%, 2-year PFS 40% vs 21%. 
• Lenvatinib + pembrolizumab
  • FDA approved (2021) for first line treatment regardless of risk
  • CLEAR trial: nivo/cabo vs sunitinib. Entire cohort: complete response 16% vs 4%. Improved OS, PFS 24mo vs 9mo
• Avelumab + axitinib vs sunitinib - improved PFS but not OS
• Second line therapy - depends on how long first agent worked and what they had before
  • If failed TKI - can try another TKI or IO. Cabozantinib superior to everolimus (METEOR trial)
  • If failed IO - use a TKI
• General principles
  • Tumor may look larger initially due to infiltration of T cells - wait 3 mo for first scan; may take 6 mo to start shrinking
  • Can have flares of autoimmune conditions (eg mostly anything besides autoimmune thyroiditis)
• Older agents
  • High dose IL-2 (durable remission for ccRCC in only 3-5%) - stimulates cell-mediated immunity. Very toxic (vascular leak, syndrome, renal failure, arrhythmias)/high mortality (1990s). Need to have high performance status; not used much anymore
  • Interferon alpha - no longer manufactured

Metastatectomy

• Solitary metastasis or oligometastasis: resect if can render disease free with resection.
  • Lung metastasis has better prognosis than other locations.
  • 44% 5-year survival for complete metastectomy vs 10-15% if not
• Bone met > 3cm in weight-bearing bone - ortho surgery before systemic therapy

Cytoreductive nephrectomy

• Intermediate/poor-risk patients: should do upfront systemic therapy.
  • If complete reponse, -> cytoreductive nephrectomy
  • If stable or partial response, can consider cytoreductive nephrectomy
  • Progression -> no nephrectomy
  • Poor risk or worsened performance status -> no nephrectomy
• Data
  • Interferon era - data supported cytoreductive nephrectomy prior to IFN/IL-2, but these are no longer used
  • TKI/Anti-angiogenic era
    • CARMENA trial showed upfront nephrectomy + sunitinib not superior to sunitinib alone (however trial included many poor risk patients)
  • IO/Checkpoint inhibitor era - no prospective data yet, but SWOG 1931/PROBE trial underway to study IO followed by cytoreductive nephrectomy (if stable or partial reponse to IO) vs IO alone
  • Delayed nephrectomy benefits - SURTIME trial - deferred nx improved OS by 17.4 mo compared to immediate nx.
    • Antigen load may help IO work better, and can identify those who wouldn't benefit from nephrectomy (disease progression on IO)
  • Upfront cytoreductive nephrectomy more likely to benefit: good performance status, lung-only metastases