INTRODUCTION –
PROBLEM STATEMENT
33% metastatic at presentation
Localised 20-40% develop metastasis
Overall 10 year survival <5%
Clear cell vs non clear cell RCC
METASTATIC WORKUP
Symptoms
Persistent cough
Bone pain
Cervical lymphadenopathy
Constitutional symptoms
Weight loss/fever/malaise
Paraneoplastic syndromes
Locally advanced disease, enlarged retroperitoneal lymph node
CXR – CT chest
Serum calcium, alkaline phosphatase, and LFT
CT thorax – pulmonary symptoms, nodules on CXR
Bone scintiscan – bone pain, raised alk phos,
PET CT – confusion on metastatic workup speci – good, poor sensitivity
MRI Brain – clinically indicated
PROGNOSTIC FACTORS
Time interval between initial diagnosis and
appearance of metastatic disease
Number of sites of metastasis
Lymph node metastasis/liver/brain metastasis -
poor prognosis
Poor performance status (Karnofsky score <80)
Serum lactate dehydrogenase level (>1.5 x)
Low hemoglobin
An elevated corrected calcium concentration
(>10 g/dL)
Lack of prior nephrectomy
RISK STRATIFICATION
CYTOREDUCTIVE NEPHRECTOMY
– BASIS FOR RECOMMENDATION
1. Spontaneous regression of metastatic
lesions after nephrectomy –
Bumpus in 1928
decreasing trend (40 years)
MOA: Tumor factors (growth and antiapoptotic),
tumor bulk (deplete load), dissemination during
resection (autovaccination phenomenon)
Against: all not related directly to
nephrectomy/4 case reports of post sunitinib
discontinuation regression/ case reports of
spontaneous regression of primary tumour
Two randomized studies - cytoreductive
nephrectomy followed by cytokine therapy
(interferon-α) compared with those receiving
cytokine therapy alone.
patients with poor performance status,
medical comorbidity, rapidly progressive
disease, and presence of brain metastases
are unlikely to benefit from this approach.
• A randomized study failed to demonstrate
an advantage in patients with intermediate
and poor prognoses.
SPONTANEOUS REGRESSION
– IMMUNE PHENOMENON
Reason to believe that rather than nephrectomy
– its activation of cell mediated immunity that is
responsible for regression of nephrectomy
Incomplete nephrectomies > infectious feverish
episodes
EORTC – 2009 – level 4 evidence to suggest that
nephrectomy leads to regression of RCC
Closing statement: Regression is real
phenomenon in RCC but there is no clinical
evidence to confirm that it may be related
METASTASECTOMY
KEY POINTS:
Resection of isolated metastatic lesions is appropriate
in selected patients.
complete resection of isolated metastatic foci - overall
survival rates of 35% to 50% in some reports.
Improved outcomes- complete resection, presence of
solitary metastatic lesions, age younger than 60 years,
smaller tumor size, presence of pulmonary metastases,
and development of metachronous metastatic disease
• There are no prospective, randomized studies
demonstrating a favorable outcome with
metastasectomy.
PALLIATIVE SURGERY IN ADVANCED
RENAL CELL CARCINOMA
In some patients with advanced RCC, cytoreductive
nephrectomy may help alleviate symptoms related to
the primary tumor (e.g., intractable pain, hematuria)
or paraneoplastic manifestations.
• However, nonsurgical options are often effective in
palliating symptoms associated with RCC;
cytoreductive nephrectomy is hence infrequently
performed with purely palliative intent.
• Resection of metastatic lesions (often in
combination with radiation or systemic therapy) is
sometimes performed for relief of symptoms or to
prevent life-threatening or disabling sequelae.
INTERFERON ALPHA
Protein – diverse properties – immunomodulator properties
Side effects: anorexia, fatigue, dry mouth, and rigors
Dose and schedule varied
Ease of administration – SC injections
Metaanalysis – coppin etal. 2005 – survival advantage slight but
INTERLEUKIN - 2
T-cell growth factor – activator of
lymphoid system.
Intravenous high doses
Severe toxicities and morbidity and
mortality
When response occurred it was
sustained and prolonged for very long
intervals of follow up
TARGETED THERAPY –
FUNDAMENTALS
VHL gene – chromosome 3 short arm
Endothelial development and Vascular pericyte function
Endothelial development and
VEGF ANTAGONISTS
Bevacizumab –
Humanised monoclonal antibody against VEGF.
Intravenous dose.
Bleeding, hypertension, fatigue, and proteinuria
AVOREN and CALGB – RCTs – beva plus inteferon better than inteferon
alone
Current role: second line therapy either alone or in combination with
interferon
Sorafenib –
Oral receptor kinase inhibitor - VEGFR-2, PDGF receptor-β (PDGFR-β), and
raf-1
hypertension, fatigue,rash, hand-foot syndrome, and diarrhea
SUNITINIB
Potent inhibitor of VEGFR-2, PDGFR-β, c-Kit, and fms-like tyrosine
kinase 3 (Flt3).
Oral dose – 50 mg OD for 4 weeks – 2 weeks off
Better quality of life along with other benefits
Diarrhea, dermatologic (rash and hand-foot syndrome), fatigue and
asthenia, hypertension, bone marrow suppression and
hypothyroidism
First line agent in management of metastatic clear cell RCC patients
PAZOPANIB
Wide array of target molecules - high toxicities – low dose/ discontinuation
Activity only against VEGFR and PDGFR (800 mg OD)
Less toxic than sunitinib – better quality of life and preferred by patients (PISCES).
Beware: hepatotoxicity. Diarrhoea, hypertension, hair color, fatigue
Now considered as first line agent of choice in mRCC
COMPAR
AXITINIB
Highly selective VEGFR antagonist
Active even when sunitinib fails
Improved PFS than sorafenib in second
line (same OS) - AXIS trail
Dose escalation is possible and increases
response rate (5 mg to 10 mg) - Rini et al,
2013.
CARBOZANTINIB
Small molecule inhibitor of TK – VEGFR, MET and AXLs –
non specific
CABOSUN (II) – better than sunitinib in intermediate and
poor risk patients as first line therapy – PFS and ORR.
Toxicity profile is equivalent
METEOR trail (III) – second line therapy – better than
everolimus – PFS, ORR, OS and Quality of life assessement
NCCN metaanalysis – second line therapy over 3 years –
PFS was best with cabozantinib in comparision with
everolimus, nivolumab, axitinib, sorafenib and best
supportive care.
M-TOR INHIBITORS
Regulating translation and stability of HIF-1 α
Temsirolimus:
25 mg weekly IV
Poor risk – improved OS and PFS (ARCC trail)
First line for poor risk patients
mucositis, fatigue, rash, hyperglycemia,
hypophosphatemia, hypercholesterolemia, and
pulmonary complications
EVEROLIMUS
Oral
Modest improvement in PFS in patients
progressing on first-line VEGFR antagonists
(RECORD 1 trail)
Stomatitis, rash, fatigue
RECORD 3 trial – sunitinib followed by
everolimus better than first line everolimus
followed by ARCC
sunitinib
and RECORD 1 trails
CN IN ERA OF TARGETED
THERAPY
Era of VEGF and mTOR inhibitors
Retrospective studies – CN plus systemic
therapy favourable outcome – CN continued
to be standard of care (univariate analysis)
Two RCTs evaluated this and were under
process – CARMENA and SURTIME
CARMENA TRAIL
Sunitinib alone vs CN plus sunitinib
Median OS 18.4 vs 13.9 months
Both equal
Critics – many patients were poor risk
patients, high metastatic load to start
systemic therapy, not including patients
candidates for observation
SURTIME TRIAL
Unpowered trail
Sequence of CN and sunitinib
Accrued poorly and only extrapolations
can be made
No difference in PFS
Median OS in patients with sunitinib
followed by CN was better. (35 vs 15
months).
EUA - GUIDELINES
Only cure possible is with surgery and complete
resection of all metastasis along with systemic
therapy
CN has been recommended in mRCC patients with
a good PS, large primary tumours and low
metastatic volume
In patients with poor PS or Metastatic Renal
Cancer Database Consortium (IMDC) risk, small
primaries and high metastatic volume and/or a
sarcomatoid tumour, CN is not recommended
EUA
CURRENT RECOMMENDATIONS
FOR CN - NCCN
Oligometastatic sites – resectable
disease of lung, brain and bone
Multiple metastatic site
poor risk group and intermediate risk group
with poor performance status should not be
offered upfront CN.
Good risk and intermediate risk with good
performance status and poor risk with
intractable symptoms (hematuria/pain –
palliative nephrectomy) will be offered CN
Individualised treatment
SYSTEMIC THERAPY AND
OBSERVATION IN MRCC
Systemic therapy is non curative and
toxic
Favourable risk patients with clear RCC
histology and asymptomatic metastasis
can be offered active surveillance with
radiological follow ups till they
experience disease progression
Rest other will be offered systemic
therapy
IMMUNOTHERAPY
RESURGENCE
Nivolumab and Iplimumab
Nivolumab – antibody blocks PD -1 receptor
(t cell) and its ligand interaction
Iplimumab – antibody blocks binding of
CTLA-4 (t cell) and its ligand CD80/86
1 mg/kg and 3 mg/kg IV every 3 weekly for
4 doses then every 2 weekly
CHECKMATE TRIAL 214
(PHASE III)
In favourable risk group sunitinib had better OS, PFS and ORR than nivolumab
plus ipilimumab. But CR rates were better in later group
Separate trial checkmate 016 (phase I) demonstrated combination better
than sunitinib in all risk groups
SYSTEMIC THERAPY –
NCCN
ESMO
NON CLEAR CELL
VARIANTS - NCCN
ESMO NON CCRCC
CONCLUSIONS
CN continues to play role in favourable
and intermediate risk mRCC
Intermediate mRCC may be offered
deffered CN post sunitinib
Targeted therapy remains first line agent
in favourable risk group
With resurgence of immunotherapy
again as first line agents in mRCC, CN
may have a greater role to play in near
future in moderate and high risk groups