Adjuvant therapy for Renal Cancer

Adjuvant Therapy in Renal-Cell Carcinoma
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
HPTU
Medellín, 09.03.2018

Visión: Percepción de las
realidades físicas a través
de la vista.

Visión: Percepción de las
realidades físicas a través de
la vista.
Perspectiva: Arte o técnica de
representar los objetos de esa
manera, tal como aparecen a la
vista.

5-yr OS
300.000
cases/yr
129.000
deaths/yr
Ferlay J, Soerjomataram I, Dikshit R, et al.
Cancer incidence and mortality worldwide:
sources, methods and major patterns in
GLOBOCAN 2012. Int J
Cancer 2015;136:E359-86
Colombia:
1000-1500/yr

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009;
2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90.

1/3 localized RCC
develop metastasis

40% loco-regional RCC
develop metastasis

Patard J-J, Kim HL, Lam JS, et al. Use of the University of California Los Angeles Integrated Staging
System to predict survival in renal cell carcinoma: an international multicenter study. J Clin Oncol
2004;22:3316-3322
UISS risk
A: Stage III (N0)
A1: Low-risk A2: High-risk
B: Stage IV (N0)
Any Fuhrman grade
ECOG 0;
Fuhrman 1 grade
and ECOG of 1 or
higher
Any Fuhrman grade
2 or higher and an
ECOG score of 1 or
higher
C: N+

INF-alpha
Twice weekly
x6 mo
Observation
Nephrectomy n=247
5-yr DFS: 0.67
5-yr OS: 0.66
5-yr DFS: 0.57
5-yr OS: 0.66
Pizzocaro, et al. JCO, 2001
Single-agent cytokines

INF-alpha
Twice weekly
x6 mo
Observation
Nephrectomy n=247
5-yr DFS: 0.67
5-yr OS: 0.66
5-yr DFS: 0.57
5-yr OS: 0.66
Pizzocaro, et al. JCO, 2001; Messing EM, JCO, 2003
n=283
x12 mo
41%
37%
62%
51%

INF-alpha
Twice weekly
x6 mo
Observation
Nephrectomy n=247
5-yr DFS: 0.67
5-yr OS: 0.66
5-yr DFS: 0.57
5-yr OS: 0.66
Pizzocaro, et al. JCO, 2001; Messing EM, JCO, 2003, Clark, JCO, 2003
n=283
x12 mo
41%
37%
62%
51%
n=69
IL-2
2y DFS: 55%
2y DFS: 48%
2y OS: 86%
2y OS: 86%

INF-alpha
+
IL-2
Observation
Nephrectomy n=309
3-yr DFS: 61%
3-yr OS: 70%
3-yr DFS: 50%
3-yr OS: 63%
Atchinson
Combination-agent cytokines

INF-alpha
+
IL-2
Observation
Nephrectomy n=309
3-yr DFS: 61%
3-yr OS: 70%
3-yr DFS: 50%
3-yr OS: 63%
Atchinson; Passalacqua,
n=283
5-yr DFS: 0.73
5-yr DFS: 0.73
5-yr OS: 0.85
5-yr OS: 0.8

INF-alpha
+
IL-2
Observation
Nephrectomy n=309
3-yr DFS: 61%
3-yr OS: 70%
3-yr DFS: 50%
3-yr OS: 63%
Atchinson; Passalacqua, Atzpodien
n=283
5-yr DFS: 0.73
5-yr DFS: 0.73
5-yr OS: 0.85
5-yr OS: 0.8
n=203
5y DFS: 49%
5y DFS: 42%
5y OS: 76%
5y OS: 58%

INF-alpha
Twice weekly
x6 mo
Observation
Nephrectomy n=247
5-yr DFS: 0.67
5-yr OS: 0.66
5-yr DFS: 0.57
5-yr OS: 0.66
n=283
x12 mo
41%
37%
62%
51%
n=69
IL-2
2y DFS: 55%
2y DFS: 48%
2y OS: 86%
2y OS: 86%
Bandini M, et al. Clinical Genitourinary Cancer (2018)
INF-alpha
+
IL-2
Observation
Nephrectomy n=309
3-yr DFS: 61%
3-yr OS: 70%
3-yr DFS: 50%
3-yr OS: 63%
n=283
5-yr DFS: 0.73
5-yr DFS: 0.73
5-yr OS: 0.85
5-yr OS: 0.8
n=203
5y DFS: 49%
5y DFS: 42%
5y OS: 76%
5y OS: 58%

INF-alpha
Twice weekly
x6 mo
Observation
Nephrectomy n=247
5-yr DFS: 0.67
5-yr OS: 0.66
5-yr DFS: 0.57
5-yr OS: 0.66
n=283
x12 mo
41%
37%
62%
51%
n=69
IL-2
2y DFS: 55%
2y DFS: 48%
2y OS: 86%
2y OS: 86%
INF-alpha
+
IL-2
Observation
Nephrectomy n=309
3-yr DFS: 61%
3-yr OS: 70%
3-yr DFS: 50%
3-yr OS: 63%
n=283
5-yr DFS: 0.73
5-yr DFS: 0.73
5-yr OS: 0.85
5-yr OS: 0.8
n=203
5y DFS: 49%
5y DFS: 42%
5y OS: 76%
5y OS: 58%
“Taken together, alone or in combination, IL-2 and INF-
alfa cytokines have not shown OS or DFS benefits in
nmRCC patients treated with nephrectomy. In
consequence, these treatments are no longer
considered of interest in that setting”

Sunitinib
Placebo
Nephrectomy
pT1b (G3/4)
or T2-4N1
n=1943
ASSURE
Sorafenib
Haas NB, Lancet, 2017

Sunitinib
Placebo
Nephrectomy
pT1b (G3/4)
or T2-4N1
n=1943
mDFS: 5.8y
mDFS: 6.1y
mDFS: 6.6y
ASSURE
Sorafenib

Pazopanib 800 mg QD x 1y
Placebo
Nephrectomy
pT2-4N0 or
N1
n=1538
PROTECT
Motzer RJ, JCO, 2017

Placebo
Nephrectomy
pT2-4N0 or
N1
n=1538
PROTECT
600 mg OS HR: 0.79
800 mg OS HR: 0.89
600 mg DFS HR: 0.94
800 mg DFS HR: 0.69
p=0.02

Placebo
Nephrectomy
pT2-4N0 or
N1
n=1538
PROTECT
After 1 year: a new primary endpoint
was chosen due to high
discontinuation rate (DFS with 600
mg vs Placebo)
600 mg OS HR: 0.79
800 mg OS HR: 0.89
600 mg DFS HR: 0.94
800 mg DFS HR: 0.69
p=0.02

Placebo
Nephrectomy
pT2-4N0 or
N1
n=1538
PROTECT
After 1 year: a new primary endpoint
was chosen due to high
discontinuation rate (DFS with 600
mg vs Placebo)
600 mg OS HR: 0.79
800 mg OS HR: 0.89
600 mg DFS HR: 0.94
800 mg DFS HR: 0.69
p=0.02
600 mg DFS HR: 0.94
Non-significant

Eligible patients were at least 18 years of age and had
received a diagnosis of locoregional renal-cell
carcinoma (tumor stage 3 or higher, regional lymph-
node metastasis, or both) on the basis of modified
UISS criteria.
Other eligibility criteria included histologic confirmation
of clear-cell renal-cell carcinoma,
No previous systemic treatment,
A score of no more than 2 on the ECOG scale
And treatment initiation within 3 to 12 weeks after
nephrectomy.

The absence of macroscopic residual or metastatic
disease after nephrectomy, as confirmed on blinded
independent central review of computed tomographic
(CT) images, was required before enrollment.
Exclusion criteria included renal metastasis or
Histologically undifferentiated tumors,
Diagnosis of a second cancer within 5 years before
randomization,
A major cardiovascular event or disease within 6
months before enrollment, and uncontrolled
hypertension (blood pressure, >150/100 mm Hg).

Who is a candidate for adjuvant sunitnib?

Non-metastatatic
Clear-Cell Renal
Carcioma
Radical
nephrectomy
High-risk disease:
Stage III/Stage
IV/N+
Low-Risk disease:
Stage I-II
15%
1000-1500 per year in Colombia
No contraindications,
(very) highly
motivated, good
insurance
Adjuvant sunitinib x1 yr
60%

Sunitinib: Clinical
Pharmacoloy
Powered by MEDSCAPE

Adjuvant sunitinib
• Indicated for the adjuvant treatment of adult patients
at high risk of recurrent RCC following nephrectomy
• 50 mg PO qDay for 4 weeks, THEN 2 weeks drug-
free, repeat cycle for a total of nine 6-week cycles
https://reference.medscape.com/drug/sutent-sunitinib-342201#4

Sunitinib: dosage modification
• In the adjuvant RCC study, the minimum dose administered was 37.5 mg
• Strong CYP3A4 inhibitors
• Strong CYP3A4 inhibitors may increase sunitinib plasma concentrations
• Select an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended
• Reduce dose for sunitinib to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily should be
considered
• CYP3A4 inducers
• CYP3A4 inducers may decrease sunitinib plasma concentrations
• Selection of an alternate concomitant medication with no or minimal enzyme inhibition is recommended
• Increase dose for sunitinib to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily should be
considered if coadministered with a CYP3A4 inducer cannot be avoided
• If dose is increased, the patient should be monitored carefully for toxicity

Sunitinib: dosage modification
• Renal dysfunction
• No dose adjustment necessary with any degree of renal impairment in
patients not on dialysis
• ESRD on hemodialysis: No adjustment to the starting dose is required;
however, compared to patients with normal renal function, the sunitinib
exposure is 47% lower in patients with ESRD on hemodialysis; may require
gradual dose increase (up to 2-fold) based on safety and tolerability
• Hepatic impairment
• Mild to moderate impairment: Dose adjustment not necessary for initial dose;
monitor subsequent doses
• Severe impairment: Not studied

Sunitinib: Adverse Effects
• >10%
• Dyspepsia (MRCC 46%)
• Altered taste (MRCC 43%; GIST 21%)
• Fatigue (GIST 42%; MRCC 74%)
• Diarrhea (GIST 40%; MRCC 55%)
• Rash (MRCC 38%; GIST 14%)
• Vomiting (MRCC 37%; GIST 24%)
• Constipation (MRCC 34%; GIST 20%)
• Skin discoloration (MRCC 33%; GIST 30%)
• Abdominal pain (GIST 33%; MRCC 20%)
• Nausea (GIST 31%; MRCC 54%)
• Anorexia (MRCC 31%; GIST 33%)
• Mucositis/stomatitis (GIST 29%; MRCC 53%)
• Dyspnea (MRCC 28%; GIST 10%)
• HTN (MRCC 28%; GIST 15%)

• >10%
• Arthralgia (MRCC 28%; GIST 12%)
• Bleeding (MRCC 26%; GIST 18%)
• Headache (MRCC 25%; GIST 13%)
• Asthenia (GIST 22%)
• Lymphopenia (MRCC 21%)
• Fever (GIST 18%; MRCC 15%),
• Limb pain (MRCC 18%)
• Back pain (MRCC 17%; GIST 11%)
• Myalgia (MRCC 17%; GIST 14%)
• Cough (MRCC 17%; GIST 8%)
• Dry skin (17%)
• Hair color changes (17%)
• Neutropenia (MRCC 13%; GIST 11%)
• Alopecia (MRCC 12%)
• Hand-foot syndrome (MRCC 12%; GIST 14%)
• Dehydration (MRCC 11%)

• 1-10%
• Venous thrombotic events
• Hemorrhoids
• Pancreatitis
• Flu-like syndrome
• <1%
• Hepatotoxicity
• Acute renal failure
• Adrenal dysfunction

Sunitinib: Black Box
Warnings
Hepatotoxicity has been observed in clinical trials (7/2281) and post-marketing
experience (0.3%)
Hepatotoxicity may be severe and deaths have been reported
Monitor liver function tests (ALT, AST, bilirubin) before treatment initiation, during each
treatment cycle, and as clinically indicated
Interrupted for Grade 3 or 4 drug-related hepatic related adverse events and
discontinued if there is no resolution
Do not restart if subsequently experience severe changes in liver function tests or other
signs and symptoms of liver failure emerge
Safety in patients with ALT or AST >2.5 x ULN or, if due to liver metastases, >5 x ULN
has not been established
Use and handle product with caution

Sunitnib: Cautions
Hepatotoxicity, including liver failure, observed; monitor liver function tests before
initiation of treatment, during each cycle of treatment, and as clinically indicated;
interrupt therapy for Grade 3 or 4 drug-related hepatic adverse events and discontinue if
no resolution; do not restart if patient subsequently experiences severe changes in liver
function tests or have other signs and symptoms of liver failure (see Black Box Warning)
Hemorrhagic events including tumor-related hemorrhage reported; perform serial
complete blood counts and physical examinations
Adrenal hemorrhage observed in animal studies; monitor adrenal function in case of
stress such as surgery, trauma or severe infection
Monitor urine protein; interrupt treatment for 24-hr urine protein ≥3 g; discontinue for
repeat episodes of protein ≥3 g despite dose reductions or nephrotic syndrome

Sunitnib: Cautions
Hypothyroidism reported; measure baseline thyroid function in
patients with hypothyroidism or hyperthyroidism and treat per
standard medical practice prior to initiating therapy
Impaired wound healing reported; temporary interruption of therapy
recommended if undergoing major surgical procedures
Severe cutaneous reactions have been reported, including cases of
erythema multiforme, Stevens-Johnson syndrome, and toxic
epidermal necrolysis, some of which were fatal; necrotizing fasciitis,
including fatal cases, also reported

Sunitnib: Cautions
Stevens-Johnson syndrome, and toxic epidermal necrolysis, some
of which were fatal; necrotizing fasciitis, including fatal cases, also
reported
Advise women of childbearing potential of potential hazard to fetus
and to avoid becoming pregnant (see Pregnancy)
Prolonged QT intervals and Torsade de Pointes may occur in a
dose-dependent manner; use caution in patients at higher risk for
developing QT interval prolongation; consider monitoring with on-
treatment ECG and electrolytes; hypertension may occur; monitor
blood pressure and treat as needed

Sunitnib: Cautions
Cases of tumor lysis syndrome (TLS) reported in atients with
RCC and GIST with high tumor burden; monitor closely and
treat as necessary
Thrombotic microangiopathy, including thrombotic
thrombocytopenic purpura and hemolytic uremic syndrome,
sometimes leading to renal failure or fatal outcome reported in
clinical trials and post-marketing experience
Hypoglycemia may occur; monitor blood glucose levels
regularly during and after discontinuation treatment; assess if
antidiabetic drugs dosage modifications are necessary

Sunitnib: Cautions
Osteonecrosis of the jaw reported; consider preventive
dentistry prior to treatment; avoid, if possible, invasive
dental procedures, particularly in patients receiving
intravenous bisphosphonate therapy
Monitor patients for hypertension and treat as needed
with standard antihypertensive therapy; in cases of
severe hypertension, temporary suspend treatment
until hypertension is controlled

Sunitnib: See Dosage
Modifications
• Coadministration with strong CYP3A4 inhibitors (eg,
ketoconazole, itraconazole, clarithromycin, atazanavir,
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, voriconazole) may increase sunitinib
concentrations
• Coadministration with CYP3A4 inducers (eg,
dexamethasone, phenytoin, carbamazepine, rifampin,
rifabutin, rifapentine, phenobarbital, St. John’s Wort) may
decrease sunitinib concentrations

Sunitnib: Cardiovascular
events
• Cardiovascular events (eg, heart failure,
cardiomyopathy, myocardial ischemia, and myocardial
infarction), some of which were fatal, have been
reported

events
Increased risk for heart failure and high grade heart failure;
discontinue treatment if patient presents with signs or
symptoms of congestive heart failure (CHF);
Interrupt and/or reduce dose in patients without clinical
evidence of CHF who either have an ejection fraction
(EF) of >20% but <50% below baseline or below the
lower limit of normal if baseline EF is not obtained

Sunitnib: Pharmacology
Mechanism of Action
Multikinase inhibitor (including VEGF and PDGF receptor tyrosine kinases) some
of which are implicated in tumor growth, angiogenesis, and metastasis
Pharmacokinetics
Bioavailability: Not affected by food
Peak plasma time: 6-12 hr
Half-life elimination: 40-60 hr
Vd: 2230 L
Protein bound: Sunitinib 95%; primary active metabolite: 90%
Metabolism: by CYP3A4 to a primary active metabolite which is further
metabolized by CYP3A4
Excretion: Feces (61%); urine (16%)

Sunitnib: Administration
Oral administration
Take with or without food
Do not drink grapefruit juice or eat grapefruit during your
treatment
Missed dose
• Missed dose <12 hr: Take the missed dose right away
• Missed dose >12 hr: Take next dose at regular time
• Do not make up missed dose
Storage
Tablets: Store at room temperature at 68-77°F (20-25°C)

events
• Cardiac dysfunction occurs 28 to 180 days after
sunitinib initiation and most commonly after the third
cycle
• Heart failure risk is associated with preexisting
hypertension and coronary artery disease
• Monitor patients for signs and symptoms of
congestive heart failure

Adjuvant therapy for Renal Cancer

Adjuvant therapy for Renal Cancer

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Adjuvant therapy for Renal Cancer

Similar to Adjuvant therapy for Renal Cancer (20)

More from Mauricio Lema

More from Mauricio Lema (20)

Recently uploaded

Recently uploaded (20)

Adjuvant therapy for Renal Cancer