Renal cell carcinoma Flashcards
RCC response to chemo
- chemo-resistant
- doesn’t respond well to chemo (<10%), so its use is not recommended
Stauffer syndrome
cytokine-mediated paraneoplastic phenomenon in RCC manifested by hepatic dysfunction (elevated LFTs). It resolves after resection of primary tumor.
stage of presentation most commonly in RCC
usually localized but a quarter with distant metastatic disease
RCC mets most commonly to…
Lung (70-75%), lymph nodes (30-40), bone (20-25%), CNS
RF’s for RCC
smoking, obesity, toxic exposures to petroleum products, asbestos, acquired cystic disease of the kidney,
***NHL
sickle cell
Familial syndrome associated with RCC
Von Hippel-Lindau (VHL)
most common presentation of RCC
- Asymptomatic
- incidental tumor detection on imaging
paraneoplastic conditions associated with RCC
1) Hypercalcemia from PtHRP
2) polcythemia from increased epo
3) Stauffer syndrome
CT findings suggestive of malignancy
thickened irregular walls OR septa and enhancement after contrast
workup of suspected RCC
CBC, Chem-7, UA, abdominal + pelvic CT w/ contrast, CXR
Check Chem-7 for elevated ALP
IF elevated → bone scan
IF unclear cystic vs. solid tumor → abdominal US
IF CT contraindicated → MRI
IF concern for renal vein or IVC involvement → MRI abdomen
IF bone pain → Bone scan
IF cough, chest pain → chest CT
poor prognosticators in metastatic RCC
1) LDH>1.5x
2) Hgb less than 10
3) Karnofsky performance score <80
4) absence of prior nephrectomy
5) high serum calcium
6) thrombocytosis and leukocytosis
when radical nephrectomy is preferred
larger tumors (>7cm) or tumor with IVC extension
stage IV patient management with solitary resectable mass
nephrectomy and metastasectomy
Role for lymph node dissection in localized RCC
Extended lymph node dissection only done if evidence of lymph node involvement preoperatively
alternative to radical nephrectomy
“nephron-sparing” surgery (Partial nephrectomy)
Treatment options for advanced/stage IV renal clear cell carcinoma (in general)
- Immunotherapy (CPIs)
- VEGF TKI’s
- MTOR inhibitors
Treatment options for advanced/stage IV renal NONclear cell carcinoma
- Temsirolimus
- VEGF-targeted therapies
- IO
Conditions associated with increased incidence of RCC
NHL
sickle cell
workup of renal mass concerning for RCC
CBC, CMP, UA, abdominal + pelvic CT w/ contrast, CXR
IF elevated ALP → bone scan
IF unclear cystic vs. solid tumor → abdominal US
IF CT contraindicated → MRI
IF concern for renal vein or IVC involvement → MRI abdomen
IF bone pain → Bone scan
IF clinically indicated → brain MRI
IF cough, chest pain → chest CT
IF concern for renal vein or IVC involvement → MRI abdomen
Primary therapy for localized RCC – Stage I, II, II
nephrectomy
Surgical options for RCC
- Radical nephrectomy
- nephron-sparing surgery (partial nephrectomy)
indications for radical nephrectomy (generally speaking)
- larger tumor
- tumor extension into the IVC
Management of stage IV patient with solitary resectable met
debulking nephrectomy + metastasectomy
When Is lymph node dissection recommended with radical nephrectomy?
No, only if evidence of lymph node involvement
Why LDH is ordered for RCC workup + physiology
Prognosticator. Aerobic glycolysis is the most prominent characteristic of a cancer cell[10]. A large amount of lactate is produced during this process.
- high level of glucose uptake and glycolysis followed by lactic acid fermentation taking place in the cytosol, not the mitochondria, even in the presence of abundant oxygen
RCC histologies and % that are clear cell or non clear cell
80% are clear cell RCC (ccRCC) and 20% are non-clear cell RCC (nccRCC)
Trend in incidence of RCC
Annual incidence has risen over the past 10 years and now accounts for nearly 4% of new cancer diagnoses in the USA
Immunogenicity of RCC
It has significant immunogenic potential. RCC was one of the first tumor models to demonstrate objective tumor responses to CPI.
tumor vaccines colloquially referred to as
TVs
what does CN stand for
cytoreductive nephrectomy
controversy surrounding cytoreductive nephrectomy in RCC
CN is only recommended in patients with a good-to-intermediate prognosis. However, this dogma is challenged by many experts and argues that CN should be considered on an individualized basis and that overarching trials offer RCC patients a disservice by excluding patients who may benefit from CN.
Stage II RCC definition
tumor > 7 cm across but still only in the kidney (T2).
Stage III RCC definition
Tumor growing into a major vein (like the renal vein or the vena cava) or into tissue around the kidney, but it is not growing into the adrenal gland or beyond Gerota’s fascia (T3). There is no spread to lymph nodes (N0) or distant organs (M0).
OR
(N1) but has not spread to distant lymph nodes or other organs (M0).
Stage IV RCC anatomic definition
1) IN SHORT: Tumor growing beyond Gerota’s fascia OR metastatic spread
adrenal gland involvement
**spread to lymph nodes
or distant organs.
Preferred regimens for favorable risk metastatic clear cell RCC
Pembro + axitinib (KEYNOTE-426)
Nivolumab + cabozantinib (CHECKMATE-9ER)
Lenvatinib + pembrolizumab
sunitinib mechanism
multikinase inhibiotr (RTKs). These include all receptors for platelet-derived growth factor (PDGF-Rs) and vascular endothelial growth factor receptors (VEGFRs),
Role for tissue diagnosis in localized
Following partial or radical nephrectomy (limited role for percutaneous biopsy)
goal of treatment for localized disease
cure
Management of multiple primary renal cell carcinomas
surgery
cabozantinib mechanism
TKI of c-Met and VEGFR2
Management of renal mass questionably cystic vs. solid
Renal US
Tissue of origin of RCC
Renal cortex
Hematuria with RCC suggests what?
Tumor invasion of the collecting system
Presentation of RCC with IVC involvement
peripheral edema, ascites, hepatic dysfunction, pulmonary emboli
Anemia profile in patients with RCC
AICD
Mechanisms of hypercalcemia in RCC
1) lytic bone mets
2) overproduction of PTHrP
3) Increased prostaglandin production (promoting bone resorption)
multiple primary RCCs associated with what genetic conditions
- VHL
- tuberous sclerosis)
Role for immunotherapy in advanced RCC
Approved for first line AND subsequent therapy after targeted therapy
Gist of response to IL-2
- minority of patients respond but responses are durable and majority of complete responders remain free of relapse long term
- severe toxicity
Role for Il-2
Used to be used more often, but now that there’s better tolerated checkpoint inhibitor immunotherapy, only used for pts who’ve progressed on immunotherapy + have favorable prognostic features
Role for mTOR inhibitors
Second line (not rally anymore…)
Management of patient with advanced disease and direct involvement of ipsilateral adrenal gland without nodal involvment
Radical nephrectomy with adrenalectomy
what is cytoreductive nephrectomy? role for cytoreductive nephrectomy?
“debulking nephrectomy”
- used in select patients prior to initiating systemic therapy with immunotherapy
Role for RT
- conventionally considered a radioresistant tumor, but RT may be useful to treat a single or limited number of mets
Management of brain mets in RCC
- surgery and/or RT prior to initiation of systemic therapy (hemorrhagic tumors so they can bleed if you give systemic therapy before resecting)
Primary treatment approach for localized, resectable RCC
Surgery
Management of localized disease in older adult patients + patients with comorbid disease who aren’t surgical candidates
cryoablation
RFA
Mangement of small asymptomatic lesions
Active surveillance
vs. surgery
Combination IO/TKI regimens
Cabo + nivo
Nivolumab + iplimumab
Pembro + axitinib
Recurrence rates in general for localized
Surgery can be curative but up to 1/3 of patients eventually recur.
What are the PD-1 checkpoint inhibitors?
nivolumab
pembrolizumab
What are the PD-L1 checkpoint inhibitors?
avelumab
atezolizumab
What are the VEGF inhibitors used for RCC
Axitinib
Sunitinib
Pazopanib
Bevacizumab
Lenvatinib
How is initial therapy in advanced clear cell RCC chosen?
Based on risk class
Risk stratification categories in RCC
1) favorable
2) intermediate or poor risk (lumped together)
Risk stratification model used for advanced RCC
International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model
Stage I management
Partial nephrectomy
Stage II management
Partial or radical nephrectomy
Relapsed metastatic disease management
Clinical trial
OR
metastasectomy
Surveillance modalities in general for local following definitive treatment
CT abdomen
CXR
First line therapy for metastatic clear cell (in general)
VEGF TKI monotherapy OR VEGF TKI + immunotherapy
Tissue of origin of RCC
Renal cortex
What is cytoreductive nephrectomy?
- removal of kidney and primary tumor in the face of metastatic disease
- “debulking nephrectomy”
Stage IV management (in general)
Systemic therapy as per guidelines
*Controversy as to whether debulking nephrectomy should be done upfront
Role for cytoreductive nephrectomy in stage IV
No clear benefit so not standard of care anymore
- BUT if someone has minimal metastatic burden + good performance status, then it can be considered
Role for immunotherapy in advanced RCC
Approved in the first line setting alone (ipi/nivo) or in combination with a VEGF TKI depending on risk category
Threshold in size for partial nephrectomy (also what differentiates T1 from T2 disease)
less than 7 cm
Sorafenib targets
VEGFR
PDGFR
Raf
c-KIT
FLT3
Model used for risk stratification
International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model
Common SE of VEGF TKIs
Hypertension
MS and immunotherapy
Generally avoid
Risk factor for medullary renal cancer
sickle cell trait, typically young black men
Second line therapy options
Nivolumab monotherapy
Cabozantinib
Axitinib
lenvatinib + everolimus
Sorafenib
Everolimus SE’s
pneumonitis + stomatitis
Pazopanib SE to know
Hepatotoxicity
N1 disease = stage?
Stage III
Role for adjuvant therapy in RCC
Stage III disease only
Results for TKIs and mTOR inhibitors in adjuvant settings generally
Data has been underwhelming (immunotherapy does hold promise)
Characteristic proto-oncogene of papillary RCC
c-MET
Clinical significance of developing HTN while receiving therapy with sunitinib
Positive prognosticator
Management of patients with mRCC with resectable primary tumor AND IVC thrombus
Can still do nephrectomy
Stage IV anatomic definition
*invasion beyond Gerota’s fascia
OR distant mets
Clinical features of leiomyomatosis RCC
- multiple cutaneous leiomyomas
- uterine leiomyomata
- papillary type 2 RCC
Preferred regimens for favorable risk disease
Pembro + axitinib (KEYNOTE-426)
Nivolumab + cabozantinib (CHECKMATE-9ER)
Lenvatinib + pembrolizumab
Immunotherapy approved in second line setting for pts with prior anti-angiogenic therapy
Nivo (NOT pembro)
What is the rational for active surveillance in metastatic RCC?
*a subset of patients have indolent growth of mets. Systemic therapy isn’t curative and is toxic, so risk/benefit may favor surveillance.
Most common histologic variant
Clear cell
Upfront therapy for papillary RCC and why
Cabozantinib (MET driven. They derive most benefit from cabo)
Histologic variants of non clear cell
papillary, chromophobe, collecting duct (including medullary carcinoma), translocation, and unclassified
High risk of recurrence warranting adjuvant pembro definition
1) T2 with grade 4 or sarcomatoid differentiation
2) T3 or higher
3) regional lymph node metastasis or stage M1 with no evidence of disease (NED)
Regimen that supposedly has better activity for bony disease
Cabo
Stage at which ablative techniques are appropriate
T1a
What is favorable risk in terms of IMDC?
ZERO features
Behavior of Papillary RCC
Tends to be more indolent
HIgh risk (indications for adjuvant IO) for localized
1) T2 with nuclear grade 4 or sarcomatoid differentiation
2) T3 or higher
3) node positive
4) stage M1 with no evidence of disease (NED)
