Transcript Lorenzo 12

CARCINOMA DE
CÉLULAS RENAIS
Como tratar as toxicidades
da terapêutica sistémica?
Gabriela Sousa
IPO Coimbra
Espinho 2011
Guidelines…
These biologic agentes present a
toxicity profile very different from that
“convencional” chemotherapeutic
agents
Targeted Therapy and Toxicity:
Their use requires a knowledge of
possible side-effects …
Gore M, British Journal of Cancer (2011) 104(3), 399 – 406
Targeted Therapy and Toxicity:
 General Toxicity
FATIGUE
INFECCIONS
 Cardiovascular and respiratory
 Gastrointestinal, hepatic, renal
 Endocrinologic and laboratory
 Bone marrow toxicity
 Skin and mucosal
HYPERTENSION
CARDIAC EVENTS
ANOREXIA
BLEEDING
HYPOTHYROIDISM
NAUSEA
THROMBOEMBOLISM
HYPERGLYCAEMIA
VOMITING
DYSPNOEA
DIARRHOEA
HYPERCHOLESTERO
PNEUMONITIS
NEUTROPENIA
PROTEINURIA
HYPERTRIGLYCERID
LYMPHOPENIA
MUCOSITIS
HYPERCREATININ
HYPOPHOSPHATEM
ANAEMIA
toxicity
HAND-FOOT
HYPERBILIRUBIN
HYPERLIPASEMIA
SYND
THOMBOCYTOPENIA
RASH
 ALT AND  AST
HYPERAMYLASEMIA
GENERAL TOXICITY:
- FATIGUE
- INFECTIONS
FATIGUE
Defined as a distressing, persistent and subjective
sense of tiredness that affects 70-100% of patients
with cancer
Moderate fatigue (grade 2) reflects a reduction
in performance status by 1 ECOG level or 20%
in Karnofsky PS
Larkin JM et al. Oncologist. 2010; 15: 1135-46
FATIGUE
All Grades, %
Grade ¾, %
Sunitinib1
54
11
Sorafenib2
29
3
Pazopanib3
19
2
Bevacizumab
36
20
IFN-α +
bevacizumab4
33
12
1. Motzer et al. J Clin Oncol 2009; 27: 3584-3590. 2. Escudier et al. N
Engl J Med 2007; 356: 125-34. 3. Sternberg et al. J Clin Oncol 2010; 28:
1061-1068. 4. Escudier et al. Lancet 2007; 370: 2103-11
FATIGUE
SLEEP
DISTURBANCE
PAIN
STOMATITIS
EMOTIONAL COMORBIDITIES DYSGEUSIA
DIARRHOEA
DISTRESS
ANAEMIA HYPOTHYROIDISM
Practice Guidelines in Oncology: Cancer-Related Fatigue v.1. 2007
NCCNNCCN
Practice
Guidelines in Oncology: Cancer-Related Fatigue v.1. 2011
FATIGUE
Recommended Interventions
• General strategies
- Self-monitoring (e.g. diary)
- Energy conservation
• Non-pharmacological
- Support groups
- Exercise, massage therapy
• Pharmacological
- Treat co-morbidities (anaemia)
- Consider sleep medication
- Consider psychostimulants
NCCN Practice Guidelines in Oncology: Cancer-Related Fatigue v.1. 2011
FATIGUE
• Grade
Grade 0: No symptoms
Grade 1: Mild
Grade 2: Moderate or causing difficulty with activities of
daily life
Grade 3: Severe,
interfering
with activitiesorof daily life
Consider
dose reduction
treatment suspension
Grade 4: Disabling
NCI CTCAE v3
Di Lorenzo et al. Eur Urol 2011; 59: 526-540.
INFECTIONS
mTOR Inhibitors
important immunosuppression
Temsirolimus1
All grades
%
Infections
Everolimus2
Grade 3-4 All grades
%
%
27
5
37
Grade 3-4
%
10
Pneumonia
Aspergillosis
Candidiasis
Reactivation of hepatitis B virus
1.
2.
Hudes G et al. New Engl J Med 2007; 356: 2271-81
Motzer et al. Lancet 2008; 372: 449-56
INFECTIONS
Recommended Interventions
• Patient and family should receive counselling to
prevent infections (wash hands)
• Signs or symptoms possibly indicating an
infection before or during treatment should be
investigated promptly
BEFORE start
Antibody titres (Ac HBV, HCV)
mTOR inhibitors
Se HBV+ prophylatic antiviral treatment
(lamivudine, 300 mg/d) 1-2wk
Di Lorenzo et al. Eur Urol 2011; 59: 526-540.
CARDIOVASCULAR AND
RESPIRATORY TOXICITY
ARTERIAL HYPERTENSION
HYPERTENSION – Screening
Take a complete medical history
Performed a physical examination
Assess BP and Cardiovascular Risk
•BP ≥ 180 mmHg systolic and/or ≥ 110 mmHg diastolic
•High Systolic BP (>160 mmHg) with low diastolic BP (<70 mmHg)
•Diabetes mellitus
•Metabolic syndrome
•Three cardiovascular risk factors
•Established cardiovascular or renal disease
•Subclinical organ damages (left ventricular hypertrophy, ↓ clearance
creatinina, microalbuminuria or proteinuria)
2007 Guidelines for the management of Arterial Hypertension of ESH and ESC
HYPERTENSION – Management
BP ≥ 140/90 mmHg: start anti-hypertensive terapy
Cardiovascular Risk: high or very high, recommended a
cardiologist consultation
BP < 160/100 mmHg: start or continue anti-cancer therapy
Monitor BP at least every week
Add anti-hypertensive drug to obtain a BP<140/90 mmHg
2007 Guidelines for the management of Arterial Hypertension of ESH and ESC
HYPERTENSION – Management
Definition (NCI-CTC 3.0)
Management
Grade 1: Asymptomatic, transient
(<24 h) increase: >20 mmHg
diastolic or > 150/100 if BP normal
 No intervention indicated
Grade 2: Recurrent or persistent (>24
h) or symptomatic increase: >20
mmHg diastolic or 150/100
Consider anti-hypertensive
treatment
Dose reduction if treatment
5.4%
ineffective
Grade 3: requiring more than one
drug or more intensive treatment
than previously
Grade 4: Life-threatening
consequences (hypertensive crisis)
Dose discontinuation if
hypertension becomes severe or
uncontrolled
14.7%
Carefully evaluate to re-start
treatment after 1st event, STOP after
2nd event
HYPERTENSION - Management
ANTIHYPERTENSIVE AGENTS
Selected according to the individual patient´s comorbidities,
drug interactions, and contraindications
Thiazides (hydrochlorothiazide 12.5 -100 mg)
Anti-aldosterone diuretics (spironolactone 100-400 mg)
Beta-blockers (atenolol 50-100 mg)
ACE inhibitors (lisinopril 5-40 mg)
Angiotensin II receptor blockers (losartan 50-100 mg)
Positive effects in patients with heart failure
Dihydropyridine calcium antagonists (amlodipina 5-10 mg/d)
Benefit patients with angina pectoris
CARDIAC TOXICITY
 TKI – associated cardiotoxicity was
reported in approximately 10% of
patients
 Cardiac damage related to TKI may
occur more frequently that reported to
clinical trials …
 Datailed cardiovascular monitoring
during treatment reveal early signs of
myocardial damage
Schmidinger M, et al. J Clin Oncol 2008;26: 5204-12
CARDIAC TOXICITY
 Reduction of LVEF
 Conduction disturbances
 ST-segment or T-wave changes (early signs?)
 Elevated cardiac serum markers (TNT, CK-MB,
BNP, pro-BNP)
 Significant clinical symptoms (angina, dyspnoea,
dizziness)
 Myocardial infarction
BNP=B-natriuretic peptide
CK-MB=creatinine kinase MB mass
TNT=troponin T
Schmidinger M, et al. J Clin Oncol 2008;26: 5204-12
CARDIAC TOXICITY
Monitoring-Recommendations
• Before treatment:
–
–
–
–
history of coronary artery disease
Electrocardiogram (ECG) – QT interval
Echocardiography – LVEF
Cardiac serum markers, including CK, CK-MB, TNT,
BNP and pro-BNP
• During treatment:
– repeat ECG and serum markers monthly
– echocardiography every 2–3 months
BNP=B-natriuretic peptide
CK=creatinine kinase
CK-MB=creatinine kinase MB mass
TNT=troponin T
Schmidinger M, et al. J Clin Oncol 2008;26: 5204-12
CARDIAC TOXICITY
Monitoring-Recommendations
• Monitor LVEF:
– High-risk: baseline, every cycle x 4, then every 2-3
cycles
– Low-risk: baseline and every 3 cycles
• Monitor QT interval, electrolytes:
– Caution with pre-existing QT prolongation or receiving
anti-arrhythmics
– Avoid other agents that prolong the QT interval
– Maintain normal serum Mg2+ and K+
DI Lorenzo G, et al. Eur Urol 2011;59: 526-40
CARDIAC TOXICITY
Monitoring-Recommendations
TREATMENT SUSPENSION:
- Cardiac symptoms
- LVEF decrease to <50% or ≥ 20%
below baseline
DI Lorenzo G, et al. Eur Urol 2011;59: 526-40
BLEEDING / THROMBOEMBOLISM
Anti-VEGF Agents
alter the haemostatic balance
Bevacizumab -  risk of arterial and venous
thromboembolism,
 bleeding events
Sorafenib
 risk arterial thromboembolism
Sunitinib
 bleeding events
Incidence of 7% fatal intracerebral haemorrhage
(4 of 5 patients with brain metastasis)
BLEEDING / THROMBOEMBOLISM
Recommended Interventions
• Medical History
• Frequent clinical examinations
• Immediate investigation of any suspicious symptoms
Grade 2- 4
thrombotic or
bleeding events
Require treatment suspension and
appropriate therapy until recovery to
grade 1
Di Lorenzo et al. Eur Urol 2011; 59: 526-540.
DYSPNOEA / PNEUMONITIS
Temsirolimus1
Everolimus2
All grades
%
Grade 3-4
%
All grades
%
Grade 3-4
%
Dyspnea
28
9
24
7
Pneumonitis
---
---
13,5
3,6
Many mechanisms have been proposed,
including:
- Cell-mediated auto-immunity and T-cell-mediated
delayed-type hypersensitivity
-The exact molecular basis remains unknown
1. Hudes G et al. New Engl J Med 2007; 356: 2271-81 2. Motzer et al. Lancet 2008; 372: 449-56
DYSPNOEA / PNEUMONITIS
Recommended Interventions
• Patients should be warned to promptly report
symptoms such as dyspnoea or cough
Spirometry
Torax Radiography
CT Scan
NON-INFECTIOUS PNEUMONITIS
• Ground
glass-opacity
• Parenchymal consolidations
• Pleural effusion
NON-INFECTIOUS PNEUMONITIS
Clinical Management
Definition (NCI-CTC 3.0)
Management
Grade 1: Asymptomatic, radiographic
findings only
 No intervention indicated
Depending 14.7%
on severity of
Grade 2: Symptomatic not interfering symptoms:
-Consider dose interruption or
with ADL
reduction
-Consider corticosteroids
5.4%
Interrupt treatment
Grade 3: Symptomatic, interfering
-Corticosteroids if infectious cause
with ADL, oxygen indicated
is excluded
- Hold treatment until recovery to
grade 1
Grade 4: Life-threatening: ventilation
support indicated
Discontinue permanently treatment
GASTROINTESTINAL
HEPATIC AND
RENAL TOXICITY
GASTROINTESTINAL TOXICITY
All grades (%)
Grade 3/4 (%)
Adverse
event
SU1
SO2
AV3
PAZ
SU
SO
AV
PAZ
Anorexia
285
16
0
22
15
<1
0
2
Diarrhoea
60
43
20
62
8
2
2
3
Nausea
52
23
28
26
4
<1
0
<1
Vomiting
31
16
14
21
11
1
0
2
GI perforation
–
–
1
–
–
1
1. Motzer, et al, ASCO 2007; 2. Escudier, et al. NEJM 2007
3. Escudier, et al. Lancet 2007; 4. Hudes, et al. NEJM 2007; 5. Bhojani, et al. Eur Urol 2007
GASTROINTESTINAL TOXICITY
SYMPTOMATIC MEDICATIONS
Nausea and/or vomiting
Metoclopramide (10-20 mg/d)
Ondansetron (8-32 mg/d)
Anorexia
Megestrol acetate (160 mg/d)
DIARRHOEA
Grade
Description
Dose management
1
Increase of less than
4 stools/day over baseline
2
Increase of 4–6 stools/day
over baseline
IV fluids indicated <24 hrs
3
7 or more stools/day over
baseline, incontinence
IV fluids ≥24 hrs,
hospitalisation
• First occurrence: Interrupt until recovery, resume
treatment at same dose with supportive measures
• Second occurrence: Interrupt until recovery,
resume treatment at reduced dose level,
supportive measures
4
Life-threatening
consequences
(haemodynamic)
• Interruption until recovery: Resume at reduced
dose level along with supportive measures
• Second occurrence: discontinue treatment
*NCI CTCAE v3
• Continue at same dose level along with
supportive measures
DIARRHOEA - Management
• Treatment should start at very first signs:
– advise patient to take loperamide 2 mg
regularly
• At occurrence:
– loperamide: 4 mg, rather than 2 mg after each
unformed stool, max. 12 mg/day
– avoid spicy food, lactose containing fluids,
fruits except grated apples (pectin)
– follow diet (bananas, rice, potatoes)
HEPATIC TOXICITY
All grades (%)
Adverse event
SU1 SO2
Grade 3/4 (%)
AV3
PAZ
SU
SO
AV
PAZ
Hyperbilir
19
0
0
36
1
0
0
3
 ALT
46
0
0
53
3
0
0
12
 AST
52
0
0
53
2
0
0
7
- About
half patients exposed to sunitinib or pazopanib
showed elevated transaminases and ¼ showed 
bilirubin levels
Antioxidant substances:
- N-acetylcysteine (600 mg/d)
- Glutathione (600-1200 mg/d)
Di Lorenzo et al. Eur Urol 2011; 59: 526-540.
Recommended liver monitoring and
management with pazopanib1
Prior to
Pazopanib
Treatment
During Treatment
Isolated
ALT ≤8X ULN
Continue
treatment
Monitor serum liver tests
Every 4 weeks for 4
months minimum
ALT >3X ULN
AND
TBL >2X ULN
Direct / total
bilirubin >35%
YES
Weekly tests until
ALT Grade 1
or baseline
Discontinue
NO
Continue
ALT >8X ULN
Interrupt until ALT
Grade 1 or
baseline
Reintroduce, if
warranted, at
lower dose
Discontinue if ALT
>3X ULN recur
1. Votrient Summary of Product Characteristics, 2010.
RENAL TOXICITY
MUCOSAL AND
SKIN TOXICITY
MUCOSAL TOXICITY
• Characteristics
– dysgeusia, dysphagia,
sensitivity and sores
(including cheilitis)
– oral changes (‘functional
mucositis’) do not have the
appearance and severity of
chemotherapy-induced
mucositis
Creel T, et al. ISNCC 2006; Wood LS. Community Oncology 2006;3:558–562
MUCOSITIS
• Grade
– Grade 0:
No symptoms
– Grade 1:
Sore mouth, no ulcers
– Grade 2:
Sore mouth with ulcers,
but able to eat normally
– Grade 3:
Liquid diet only
– Grade 4:
Unable to eat or drink
NCI CTCAE v3
MUCOSITIS Management
• BEFORE TREATMENT
- Treatment of caries and dental disease
- Education regarding the importance of orodental hygiene
and to develop a daily routine of oral care
• DURING TREATMENT
- Clean teeth after meals and before sleep
- Avoid painful stimuli (hot food and drinks, spicy food,
alcohol and smoking)
- Regular inspection of mouth
- Provide comfort measures (lubrication of the lips, topical
anaesthesia and analgesics)
- Prompt treatment of mucositis symptoms and oral
infections
MUCOSITIS Management
• Oral care protocols (dental work to eliminate caries)
• Mouthwashes with mixed actions (benzydamine
hydrochloride)
• Topical anaesthetics (viscous lignocaine and
xylocaine)
• Antiseptics (chlorhexidine)
• Antifungal agents (nistatina)
• Mucosal barriers and coating agents (sucralfate)
HAND–FOOT SYNDROME
• Symptoms affect hands and feet
• Predominantly on pressure points
• Distinct from HFS observed with chemotherapy
(capecitabine, liposomal doxorubicin)
• Impairment of keratinocyte cell interaction
1Gore
ME, et al. J Clin Oncol 2007;25(18S):Abstract 5010;
2Robert C, et al. Lancet Oncol 2005;6(7):491–500;
3Webster-Gandy JD, et al. Eur J Oncol Nurs 2007;11(3):238–246
HAND–FOOT SYNDROME
Clinical Course
• Occurs in the first 6 weeks, often weeks 1–2
• Should be treated immediately
• Grade 1–2 may resolve with symptomatic
treatment, allowing full dose maintenance
• Completely reversible at treatment discontinuation
HAND–FOOT SYNDROME
Grade 1
Minimal skin changes or erythema
- no pain
- no loss of function
Grade 2
Skin changes (peeling, blisters, bleeding, oedema)
- possibly painful
- not interfering with function
- mild interference with patient activities possible
Grade 3
Skin changes
- very painful
- complete loss of function
HAND–FOOT SYNDROME
Grade 2
Grade 3
HAND–FOOT SYNDROME
Recommendations
• Initial nonpharmacologic measures
– patients’ recommendations:
• Manicure and pedicure before and during
treatment
• Use appropriate tools to aid in callus removal
• Use shock absorbers for pressure points, sandals,
cotton gloves and/or socks
• Wear well-padded but nonconstrictive footwear
• Avoid warm and/or hot water or objects
• Tight-fitting shoes
• Apply an alcohol-free moisturizer
HAND–FOOT SYNDROME
Recommendations
• Pharmacologic interventions
• Corticosteroids have no proven efficacy
• Fatty ointment containing lecithin, aloe vera, Dpanthenol and urea
• Delay and adjust treatment if grade 3 -4
toxicity occurs
RASH
Macular or papular eruption or erythema without
Grade 1
symptoms
Macular or papular eruption or erythema with
Grade 2
pruritus or other symptoms covering <50% BSA
Severe generalised erythroderma or macular,
Grade 3
papular or vesicular eruption covering ≥50% BSA
Generalised exfoliative ulcerative or bullous
Grade 4
dermatitis
BSA=body surface area
1Gore
ME, et al. J Clin Oncol 2007;25(18S):Abstract 5010
RASH - Grade 2
• Prominent on trunk
• Small erythema
• Tendency for
confluence
RASH - Management
Grade 1-2: -Moisturising creams and topical
hydrocortisone creams
Grade 3-4: Systemic antihistamines and low
dose oral prednisone (10-25 mg/d) and require
treatment suspension until recovery to grade 1
ENDOCRINOLOGIC AND
METABOLIC TOXICITY
HYPOTHYROIDISM
All grades (%)
Grade 3/4 (%)
Adverse event
SU1
SO2
AV3
PAZ
SU
SO
AV
PAZ
Hypothyroidism
14
-
-
<10
2
-
-
<1
Subclinical hypothyroidism
 Serum TSH
N Free thyroxine index
Clinical hypothyroidism
 Serum TSH
↓ Free thyroxine index
1. Motzer, et al, ASCO 2007; 2. Escudier, et al. NEJM 2007
3. Escudier, et al. Lancet 2007; 4. Hudes, et al. NEJM 2007; 5. Bhojani, et al. Eur Urol 2007
HYPOTHYROIDISM
Grade Description
1
Asymptomatic, intervention not indicated
2
Symptomatic, not interfering with ADL, thyroid
replacement indicated
3
Symptoms interfering with ADL, hospitalisation
indicated
4
Life-threatening myxoedema coma
ADL=activities of daily living
1Gore
ME, et al. J Clin Oncol 2007;25(18S):Abstract 5010
HYPOTHYROIDISM - Management
• Thyroid function should be controlled prior to
treatment and at regular intervals (monthly)
during treatment
• Hypothyroidism may be an underlying cause of
fatigue
• According to endocrinologist’s recommendation:
Thyroid replacement therapy at first increase of
TSH1
SUTENT (sunitinib malate) EU SPC. Pfizer Ltd 2007
1Rini BI, et al. J Natl Cancer Inst 2007;99:81–83
HYPOTHYROIDISM - Management
Assess TSH and T4
levels before starting
treatment
Pre-existing thyroid condition
If hypothyroidism
↓FTI,TSH or
TSH>10 and
Symptomas
Start thyroid
hormones
Start treatment if thyroid function
is normal or medically controled
Check TSH levels
D1, D28 for the first
four cycles
If TSH levels abnormal
without overt hypothyroid
or symptoms, continue
check on D1, D28 after
four cycles
If TSH levels N,
them measure
on D28 every 2
cycles
METABOLIC TOXICITY
Temsirolimus1
Hyperglycaemia
Hypercholester
Hypertriglycerid
Everolimus2
All grades
%
Grade 3-4
%
All grades
%
Grade 3-4
%
26
24
27
11
1
3
57
77
73
15
4
<1
1. Hudes G et al. New Engl J Med 2007; 356: 2271-81 2. Motzer et al. Lancet 2008; 372: 449-56
METABOLIC TOXICITY
Management
Diabetes
HyperCT
HyperTG
INITIAL
APPROACHES
Metformina or
Acarbose
Lifestyle
modifications
Statins
(atorvastatina)
Treat HyperCT
as long as TG is
below 500 mg/dl
SUBSEQUENT
APPROACHES
Add a bile acid
Start fibrates
Add
Sulphonylureas sequestrant
(cholestyramine)
Add glitazones
Di Lorenzo et al. Eur Urol 2011; 59: 526-540.
Conclusions
• Targeted agents becomes the “state-of-art” in the
treatment mRCC
• Safety issues might be the most important
factors for decision, as we have no strong
difference in terms of efficacy
• The management of their toxic effects is of
utmost complexity
Conclusions
• The main goal of management side
effects is not to reduce long-term
mortality,
but … avoid:
 acute and life-threatening side-effects
 dose reductions
 interruption of anticancer medication