Sorafenib Side effects and dose adjustment · Sorafenib-Side effects and dose adjustment - Adverse...
Transcript of Sorafenib Side effects and dose adjustment · Sorafenib-Side effects and dose adjustment - Adverse...
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SORAMIC 1
Sorafenib - Side effects and dose adjustment -
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Adverse events: prevention and management as key
• Patients should be informed to:– Take preventive measures, where
possible 1
– Be aware and report AEs as soon as possible 2,3
• Patients alerted to possible AEs before beginning treatment:– May be more accepting of these
symptoms 3
– Are more likely to stay on treatment 1-5
SORAMIC 2
1. Porta C, et al. Clin Exp Med. 2007;7:127-134. 2. Wood L. Commun Oncol. 2006;3:558-562. 3. Robert C, et al. Lancet Oncol. 2005;6:491-500. 4. Autier J, et al. Arch Dermatol. 2008;144(7):886-892. 5. Lacouture M, et al. The Oncologist. 2008;doi: 10.1634/theoncologists.2008-0131.
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Adverse events: prevention and management as key
Early intervention and symptomatic treatment may:
– Improve quality of life (QOL) 1
– Facilitate adherence to therapy, optimizing potential benefits of therapy 1-5
SORAMIC 3
For non‐life‐threatening manageable events,
The “take‐home” message is:• Symptoms can usually be alleviated with symptomatic treatment or
dose modifications, and
sorafenib treatment can continue 1‐5
1. Autier J, et al. Arch Dermatol. 2008;144(7):886-892. 2. Wood L. Commun Oncol. 2006;3:558-562. 3. Robert C, et al. Lancet Oncol 2005;6:491-500. 4. Porta C, et al. Clin Exp Med 2007;7:127-134. 5. Lacouture M., et al. The Oncologist. 2008;doi: 10.1634/theoncologists.2008-0131.
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AE usually occur early and are of short duration
SORAMIC 4
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Possible side effects
SORAMIC
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SHARP: Tolerability
Llovet JM, et al. NEJM 2008; 359(4): 378-90SORAMIC
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Sorafenib (n=149)
Placebo (n=75)
Therapy-related AE %Grade
All 3/4 All 3/4HFSR 45 11 3 0Diarrhea 26 6 5 0Alopecia 25 - 1 -Fatigue 20 3 8 1Rash 20 1 7 0Hypertension 19 2 1 0Anorexia 13 0 3 0Nausea 11 1 11 1
“Asian-Pacific-SHARP”: Tolerability
Cheng AL, et al. Lancet Oncol 2009; 10(1): 25-34SORAMIC
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System Organ Class Very Common
≥1/10
Common≥1/100, <1/10
Uncommon≥1/1,000, <1/100
Blood and Lymphatic System Disorders
Lymphopenia LeucopeniaNeutropeniaAnemiaThrombocytopenia
Immune System Disorders
Hypersensitivity reactions (incl. skin reactions and urticaria)
Endocrine Disorders Hypothyroidism
Metabolism and Nutrition Disorders
Hypophosphatemia Anorexia Hyponatriemia, dehydration
Ear and Labyrinth Disorders
Tinnitus
Cardiac Disorders Myocardial ischemia and infarction*, congestive heart failure*
Vascular Disorders Hemorraghe (incl. gastrointestinal*, respiratory tract* and cerebral hemorraghe*), hypertension
Respiratory, Thoracic and Mediastinal Disorders
Hoarseness Rhinorrhoea
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Side Effects: Protocol Overview
* may have a life-threatening or fatal outcome
SORAMIC
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System Organ Class Very Common
≥1/10
Common≥1/100, <1/10
Uncommon≥1/1,000, <1/100
Gastrointestinal Disorders
Diarrhea, nausea, vomiting Constipation, stomatitis (including dry mouth and glossodynia), dyspepsia,
dysphagia
Gastro esophageal reflux disease, pancreatitis, gastritis, gastrointestinal perforations*
Hepatobiliary Disorders Increase in bilirubin and jaundice, cholecystitis,
cholangitis
Skin and Subcutaneous Tissue Disorders
Rash, alopecia, hand foot syndrome**, erythema, pruritus
Dry skin, dermatitis exfoliative, acne, skin
desquamation
Eczema, erythema multiforme, minor keratocanthoma
(squamous cell cancer of the skin)
Musculoskeletal, Connective Tissue and
Bone Disorders
Arthalgia, myalgia
Reproductive System and Breast Disorders
Erectile dysfunction Gynaecomastia
General conditions and Administration Site
Conditions
Fatigue, pain (including mouth, abdominal, bone, tumour pain and
headache)
Asthenia, fever, influenza like illness
Investigations Increased amylase, increased lipase Weight decrease, transient increase in
transaminases
Transient increase in blood alkaline phosphatase, INR
abnormal, prothrombin level abnormal
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Side Effects: Protocol Overview
* may have a life-threatening or fatal outcome** hand foot syndrome corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA
SORAMIC
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CTCAE v4.0 (May 2009) -
general criteria -
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
CTCAE v4.0
Mild; asympto-
maticor mild symptoms;clinical or diagnosticobservations only;intervention notindicated.
Moderate; minimal,local or noninvasiveinterventionindicated; limitingage-
appropriateinstrumental ADL.
Severe or medicallysignificant but notimmediately lifethreatening;Hospitali-
zation orprolongation ofHospitali-
zationindicated; disabling;limiting self careADL.
Life-
threatening conse-
quences; urgent intervention indicated
Death related to AE
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CTCAE v4.0 Grade 2 Grade 3
Specific limit to function
limitingage-appropriateinstrumental ADL
limiting self careADL
Definition of ADL Instrumental ADL refer topreparing meals,shopping for groceries orclothes, using thetelephone, managingmoney, etc.
Self care ADL refer tobathing, dressing andundressing, feeding self,using the toilet, takingmedications, and notbedridden.
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CTCAE v4.0 (May 2009) -
general criteria /
activities of daily life ADL -
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Dosing
SORAMIC
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Dose Level 1 400mg bid (twice a day)
Dose Level -1 400mg qd (every day)
Dose Level -2 400mg qod (every other day)
Dose Level 1b (re-escalation) * (400mg –
0 –
200mg ) qd (every day)
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Dose Levels
*Dose level 1b:
not to be used in the first 20 patients of the palliative arm (+
RE/SIRT); introduction after approval by the DSMB
SORAMIC
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Primary interventional treatment(RFA /RE)
Primary interventional treatment(RFA /RE)
Dose level 1: 400mg bidDose level 1: 400mg bid
START Sorafenib:Dose level -1: 400mg qd
START Sorafenib:Dose level -1: 400mg qd
Day 0
Day 10
Day 3
Dose Escalation
SORAMIC
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Dose-Adjustment
SORAMIC
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• 1st reduction to -1: 400mg qd
• 2nd reduction to -2: 400mg qod
CAVE: Withdrawal criteria !
• After toxicity resolution: step-wise re-escalation
• Documentation according to CTCAE 4.0
Dose De-escalation: General Comments
SORAMIC
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Dose Re-escalation - Overview
SORAMIC
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Diarrhea
SORAMIC
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Common GI Symptoms: Description
•
Can occur at any time during the course of treatment and include:–
Diarrhea: usually presents as loose/more frequent stools rather than watery diarrhea (diarrhea = an increase of more than 7 stools/day)
–
Nausea–
Vomiting
–
Abdominal cramps and bloating•
GI symptoms are usually Grade 1 or 2
19NEXAVAR® (sorafenib tablets) [package insert]. Wayne, NJ: Bayer Healthcare; 2008. 2. NEXAVAR®
(sorafenib tablets) [summary of product characteristics]. Bayer Healthcare; 2008.
HCC (n = 297)All Grades (%) Grades ¾
(%)
Diarrhea 55 10/<1Nausea 242 1/0Vomiting 152 2/0
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2020SORAMIC
Side Effects: Diarrhea
Toxicity Grade 1 2 3 4 5
Clinical presentation Increase of
<4 stools/d over baseline;mild increase in ostomy output compared to baseline
Increase of 4-6 stools/d over baseline; moderate increase in ostomy output compared to baseline;
Increase of >7 stools/day over baseline; incontinence; Hospitalisation indicated; severe increase in ostomy output compared to baseline; limiting self care ADL
Life-threatening consequences (e.g., hemodynamic collapse), ugent intervention indicated
Death
Diarrhea
CTCAE v4.0
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General GI Symptoms: Diarrhea Management
•
Advise patients to:–
Maintain hydration with plenty of fluids containing water, salts, and sugar1,2
–
Avoid fluids with meals OR when taking a bulk-forming laxative1,2
–
Avoid foods that can aggravate the diarrhea (spicy, fatty, dairy
products, caffeine)1,2
–
Eat plain, simple foods, such as bananas, potatoes, rice1
–
Avoid stool softeners 2
•
Diarrhea may be managed with:–
Increased intake of high-fiber diet–
Anti-diarrhea medications (loperamide 2mg after each loose bowel movement, racecadotril 100mg bid
or diphenoxylate), when indicated 1,2
–
Cholestyramine (cholesterol-lowering agent that decreases motility/increases reabsorption); not to be taken 1-2 hours before or after scheduled dose of sorafenib 2
•
Dose modification/interruption
(per protocol) may be initiated, if necessary1,2
211. Wood L. Comm Oncol. 2006;3:558-562. 2. Bhojani N, et al. Eur Urol. 2007; doi: 10.1016/j.euroro.2007.
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
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Dose De-escalation: Non-Haematologic (I)
Grade 1 / 2
Grade 3
Continue at same dose levelSupportive treatment
Withhold until toxicity is <
°1
In case of 2nd °3 toxicity
Withhold until toxicity is <
°1, resume at dose level -1
If no toxicity > °1, re-escalation possible
If toxicity > °1, de-escalation to -2
SORAMIC
or discontinuation
Treatment at this level for 28 days
then resume at same dose level
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
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Dose De-escalation: Non- Haematologic (II)
Grade 4 Withhold until toxicity is <
°1, resume at dose level -1
Discontinuation at discretion of investigatorDiscussion with study sponsor
SORAMIC
If toxicity > °1, de-escalation to -2 or discontinuation
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HFSR Hand-Foot-Skin-Reaction
SORAMIC
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HFSR: Typical Presentation
•
Painful, red, swollen, symmetrical, bilateral areas on palms/soles–
Also found on lateral sides of fingers and around the nail
•
Thickening of skin (hyperkeratosis)
•
Dry and/or cracked skin
•
Callus-like blisters
•
Preceded or accompanied by prickling, tingling or “creeping” sensation
25Porta et al. Clin Exp Med 2007, 7:127-134
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HFSR: Onset and Course
•
Onset usually within first 6 weeks of treatment with a Tyrosine Kinase Inhibitor (TKI)–
Symptoms can begin as early as 1 to 2 weeks–
Intensity of symptoms frequently decreases over time
•
Preventative measures before treatment may minimize incidence and severity (reduce occurence of Grade 3 events)
•
If HFSR does occur–
It must be recognized and treated promptly–
Early symptoms may quickly resolve with adequate symptomatic treatment might prevent progression to higher grade
•
Temporary treatment discontinuation often results in symptomatic improvement
–
Symptoms may be less severe when re-challenged at a dose reduction26
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HFSR: Prevention and Management
•
Patients should be informed that…–
They might have dermatological side effects–
They should take preventive measures–
They should monitor and report to their health care professionals
•
Patients who are alerted before beginning treatment…–
May be more accepting of these symptoms–
May be more likely to stay on treatment
•
Early intervention…–
Improves quality of life and treatment compliance–
Maximizes benefits of treatment
•
The “take-home”
message…–
Dermatologic symptoms can usually be alleviated with symptomatic treatment or dose modifications, and Nexavar treatment can continue
27
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Toxicity Grade 1 2 3 4 5Clinical presentation
Minimal skin changes or dermatitis (e.g.,erythema, edema, or hyperkeratosis)without pain
Skin changes (e.g.,peeling, blisters,bleeding, edema, or hyperkeratosis) with pain; limitinginstrumental ADL
Severe skinchanges(e.g. peeling,blisters, bleeding,edema, or hyper-keratosis) with pain;limiting self care ADL
- -
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Side Effects: Hand-Foot- Skin Reaction
Hand-Foot-Skin
reaction
SORAMIC
CTCAE v4.0
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HFSR Protocol-defined Grading: Grade 1
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Grade 1:“Minimal skin changes or dermatitis (e.g.,erythema, edema, or hyperkeratosis) without pain
“
Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet, and/or discomfort, which does not disrupt normal activities.
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Grade 2: Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental ADL
HFSR Protocol-defined Grading: Grade 2
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Grade 3: “Severe skin changes (e.g. peeling, blisters, bleeding, edema, or
hyper-
keratosis) with pain; limiting self care ADL”Moist desquamation, ulceration, blistering or severe pain of the
hands
and/or feet, and/or severe discomfort that limits self care ADL.
HFSR Protocol-defined Grading: Grade 3
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HFSR Prevention and Management:
Calluses•Before sorafenib therapy:
–
Check condition of hands and feet–
Suggest a manicure/ pedicure, when indicated
–
Recommend pumice stone use for callus or ‘rough spot’
removal
32
During sorafenib therapy: Reduce-
Pressure points-
Items that rub, pinch, or create friction
Wood L. Comm Oncol. 2006;3:558-562. Robert C, et al. Lancet Oncol. 2005;6:491-500.
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Apply non
urea-based
creams liberally– Cetaphil®– Aveeno®
– Udderly Smooth®
– Gold Bond®
– Norwegian Formula®
– Eucerin®
Alpha Hydroxy Acids
(AHA)– ~5% to 8% provide gentle
chemical exfoliation– Apply liberally two
times each day
Apply urea-based creams sparingly and only to affected areas
Avoid products with >10% urea, as these may increase irritation
Avoid systemic steroids
HFSR Prevention and Management:
Wood L. Comm Oncol. 2006;3:558-562. Robert C, et al. Lancet Oncol. 2005;6:491-500.
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Protect tender areas
Use socks/gloves to cover moisturizing creams
Wear well-padded footwear
Use insole cushions or inserts (eg, silicon, gel)
Soak feet in tepid water and Epsom salts
Wood L. Comm Oncol. 2006;3:558-562. Robert C, et al. Lancet Oncol. 2005;6:491-500.
HFSR Prevention and Management:
Cushions
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
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Dose De-escalation: HFSR (I)
Grade 1
Grade 2
Supportive measures & continue at same dose level
Supportive measures and decrease to level -1 (28 days)
If toxicity <
°1
Re-escalate
If no
toxicity > °1, resume at level -1 (28 days)
Hand-Foot-Skin
reaction
Interrupt for 7 days
If no
toxicity > °1, re-escalation possible
If toxicity > °1
If toxicity <
°1
SORAMIC
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
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Dose De-escalation: HFSR (II)
Grade 2 2nd occurence
If no
toxicity > °1, resume at level -1 (28 days)
Hand-Foot-Skin
reaction
Interrupt for 7 days
If no
toxicity > °1, re-escalation possible Maximum level at which toxicity was not exceeding °1
3rd occurence
4th occurence
If no
toxicity > °1, resume at level -1 indefinitely
Interrupt for 7 days
Interrupt for 7 days
If toxicity > °1, de-escalation to -2 or discontinuation
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
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Dose De-escalation: HFSR (III)
Grade 3 1st occurence
If no
toxicity > °1, resume at level -1 (28 days)
Hand-Foot-Skin
reaction
Interrupt for 7 days / until tox. < °1
If no
toxicity > °1, re-escalation possible
2nd occurence
3rd occurence
Decrease indefinitely to level with toxicity <
°1
Interrupt for 7 days / until tox. <
°1
Interrupt for 7 days / until tox. < °1
If toxicity > °1, de-escalation to -2 or discontinuation
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38
Arterial Hypertension
SORAMIC
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SORAMIC 39
• A disorder characterised by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mmHg
• Hypertension most commonly presents early
• Monitor blood pressure weekly during the first 6 weeks
• Thereafter, blood pressure check as needed
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Hypertension
SORAMIC 40
Toxicity Grade 1 2 3 4 5
Clinical presentation
Pre-
hypertension (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg)
Stage 1 hypertension (systolic BP 140-159 mmHg or diastolic BP 90-99 mmHg); medical intervention indicated; recurrent or persistent (≥
24 hrs); symptomatic increase by > 20 mmHg (diastolic) or to > 140/90 mmm Hg if previously WNL; monotherapy indicated
Stage 2 hypertension (systolic BP ≥
160 mmHg or diastolic BP ≥
100 mm Hg) medical intervention indicated, more than one drug or more intensive therapy than previously used indicated
Life-
threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated
Death
CTCAE v4.0
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
41
Dose De-escalation: Hypertension (I)
Grade 1asymptomatic
transientConsider increased BP-monitoring
Hypertension
Grade 2asymptomatic
diastolicBP > 110mmHg: antihypertensive therapy, continue sorafenib
SORAMIC
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
42
Dose De-escalation: Hypertension (I)
Grade 2Symptomatic
Persistentor BP = 110mmHG
Grade 3
Withhold until symptoms resolve + diastolic BP < 100mmHG
When achieved, resume at dose level -1
If diastolic BP > 100mmHG: de-escalation to level -2
Hypertension
Grade 4 Discontinuation
SORAMIC
No re-esalation planned !
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Management of arterial hypertension
•
Control elevated blood pressure before starting Nexavar therapy
•
Standard oral antihypertensive agents may be used
•
Permanent discontinuation of Nexavar should be considered in cases of severe or persistent hypertension (despite adequate antihypertensive therapy)
•
Advise patients
–
that their blood pressure needs to be monitored regularly
–
Seek medical advice if symptoms of hypertension appear, such as headache or blurred vision
SORAMIC 43Wood L. Comm Oncol. 2006;3:558-562. Bhojani N, et al. Eur Urol. 2007; doi: 10.1016/j.euroro.2007.
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Management of arterial hypertension
•
Standard antihypertensives may be used
–
However, as sorafenib is cleared hepatically, appropriate antihypertensives without hepatic clearance may be a reasonable first choice
–
Country-specific hypertension management guidelines should be consulted
–
If possible, avoid diuretics as patients may use fluids with increased stool frequency as well
–
Unselective beta-blockers may additionally help control complications of portal hypertension
SORAMiC 44
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45
Hematologic side effects
SORAMIC
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Hematologic side effects
SORAMIC 46
Toxicity Grade 1 2 3 4 5Leukocytes <LLN -
3000/mm3
<LLN –
3.0 x 109/L
<3000-
2000/mm3
<3.0 –
2.0 x 109/L
<2000-
1000/mm3
<2.0 –
1.0 x 109/L
<1000/mm3
<1.0 x 109/LDeath
Neutrophils <LLN -
1500/mm3
<LLN –
1.5 x 109/L
<1500-
1000/mm3
<1.5 –
1.0 x 109/L
<1000-
500/mm3
<1.0 –
0.5 x 109/L
<500/mm3
<0.5 x 109/L
Patelets <LLN –
75,000/mm3
<LLN –
75.0 x 109/L
<75,000-
50,000/mm3
<75.0 –
50.0 x 109/L
<50,000 –
25,000/mm3
<50.0 -
25.0 x 109/L
<25,000/mm3
<25.0 x 109/L
Hb Hgb < LLN –
6.2 mmol/l
Hgb < 6.2 –
4.9 mmol/l
Hgb < 4.9 –
4.0, transfusion indicated
Life-
threatening
consequences; urgent
intervention indicated
death
CTCAE v4.0
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
47
Dose De-escalation: Haematologic (I)
Grade 1 / 2
Grade 3
Continue at same dose level
In case of 2nd °3 toxicity
Withhold until toxicity is <
°2, resume at dose level -1
If no
toxicity > °1, re-escalation possible
47
Haematopoetic reactions
SORAMIC
If toxicity > °1, de-escalation to -2 or discontinuation
Treatment at this level for 28 days
Withhold until toxicity is <
°1 then resume at same dose level
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
48
Dose De-escalation: Haematologic (II)
Grade 4 Withhold until toxicity is <
°2, resume at dose level -1
Discontinuation at the investigator‘s discretion Discussion with study sponsor
48
Haematopoetic reactions
SORAMIC
If toxicity > °1, de-escalation to -2 or discontinuation
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49
Fatigue
SORAMIC
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Fatigue: grading of severity
SORAMIC 50
Toxicity Grade 1 2 3 4 5Clinical presentation:
Fatigue relieved by rest
Fatigue not relieved by rest; limiting instrumental ADL
Fatigue not relieved by rest, limiting self care ADL
- -
Characterized by a state of general weakness with a pronounced inability to summon sufficient energy to accomplish daily activities
CTCAE v4.0
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Fatigue: Management
•
Fatigue related to other diseases should be excluded:
–
Hypothyroidism
–
Anemia
–
Depression (organic cause)
•
Symptoms of fatigue may be relieved by:1
–
Setting priorities so they can complete their most important tasks
–
Saving demanding activities for when they have the most energy
–
Avoiding long naps that will keep them awake at night
–
Distracting themselves with games, music, books, etc.
–
Staying as active as they can during the day
–
Exercising regularly: advise them to talk to their doctor before starting an exercise program
–
Avoiding caffeine after midday
•
No standard treatment exists for cancer-
or cancer treatment related fatigue
SORAMIC 51
National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/PDF/fatig ue.pdf.Accessed 11 December 2008.
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52
Renal Failure
SORAMIC
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SORAMIC 53
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Renal Failure under therapy with sorafenib
• 252 cases of significant renal events were identified in the Serious Adverse Event (SAE) database (~ 40000 treated patients)
• 1. Pre-renal in 105 cases (41%)
- Most cases originated due to pre-renal renal dysfunction
- This suggests that Nexavar may have the potential to contribute to the development of renal failure through inducing diarrhea, vomiting and dehydration with subsequent volume depletion
• 2. renal in 11 cases (4%)
- Most of these cases were considered to have additional confounding factors in addition to Nexavar dosing
- HOWEVER it cannot be excluded that in rare instances Nexavar may have contributed to renal adverse events of primary renal origin
• 3. Post-renal in 7 cases (3%)
• 4. Unknown in 129 cases (51%)
SORAMIC 54
• It is estimated that by the end of 2007, approximately 40,000 patients had received Nexavar, including patients in clinical trials and marketed use
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Renal failure
SORAMIC 55
Toxicity Grade 1 2 3 4 5Clinical presentation
eGFR or CrCl < LLN-60 ml/min/1.73 m2 or proteinuria 2+ present; urine protein/creati
nine > 0.5
eGFR or CrCl 59-30 ml/min/1.73 m2
eGFR or CrCl 29-15 ml/min/1.73m
2
eGFR or CrCl < 15 ml/min/1.73 m2; dialysis or renal transplant indicated
death
CTCAE v4.0
Characterized by gradual and usually permanent loss of kidney function resulting in renal failure
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Renal failure – prevention and management
•
Monitoring of fluid balance and electrolytes in patients at risk
of
renal dysfunction is advised
•
In a clinical pharmacology study, the pharmacokinetics of Nexavar
were evaluated following administration of a single 400 mg dose to
subjects with normal renal function, and in subjects with mild
(creatinine clearance [CrCl] 50-80 ml/min), moderate (CrCl 30 to <
50 ml/min), or severe (CrCl< 30ml/min) renal impairment, not
requiring dialysis
•
There was no relationship observed between Nexavar exposure and
renal function
•
No dosage adjustment is necessary based on mild, moderate or
severe renal impairment not requiring dialysis.
•
Sorafenib has not been studied in patients undergoing dialysis.SORAMIC 56
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57
Liver function impairment
SORAMIC
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Liver function impairment
SORAMIC 58
Toxicity Grade 1 2 3 4 5Clinical presentation
Asterixis, mild encepha-
lopathy, limiting self care ADL
Moderate to severe encephalopath y, coma, life threatening consequences
death
CTCAE v4.0
Toxicity Grade 1 2 3 4 5Clinical presentation
ALAT/ASAT > ULN –
3.0 ULNAsymptomatic with ALT/AST > 3.0-5.0xULN; > 3 x ULN with the appearance of worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia
ALAT/ASAT > 5.0-20.0 x ULN; > 5 x ULN for > 2 weeks
ALAT/ASAT> 20 x ULN
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Sorafenib in patients with impaired liver function
•
Patients in SHARP and AP Trial primarily had HCC with CPA liver disease (due to inclusion criteria)1,2
•
The US FDA3and EMEA4 approved Nexavar for HCC* without specifying the underlying cirrhosis status:–
US FDA3: Indication: unresectable HCC; Special Populations:
Hepatic impairment: No dose adjustment is
necessary in HCC patients with CPA and CPB hepatic impairment. Nexavar has not been studied in patients with Child-Pugh C (CPC) hepatic impairment.
–
EU SPC4:
Indication: treatment of HCC; Posology Adjustments: No dose adjustment is required in patients with CPA and CPB (mild to moderate) hepatic impairment. No data is available on patients with CPC.
SORAMIC 59
HCP = healthcare professional1. Llovet JM, et al. N Engl J Med 2008;359:378–90. 2. Cheng A-L, et al. Lancet Oncol 2009;10:25–34; 3. US prescribing information. 4. EU summary of product characteristics. 5. Abou-Alfa GK, et al. J Clin Oncol 2008;26(May 20 Suppl.):217s (Abstract 4518). 6. Abou-Alfa GK, et al. J Clin Oncol 2006;24:4293– 300. 7. Yau T, et al. Cancer 2009;114:428–36. 8. Furuse J, et al. Cancer Sci 2008;99:159–65. 9. Pinter M, et al. Oncologist 2009 [Epub]. 10. Zhu AX, Clark JW. Oncologist 2009 [Epub]
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Recommendations
• Liver cirrhosis is the underlying chronic disease in most patients with HCC
• Liver function impairment and complications of portal hypertension can occur independently of the additional malignant disease and its treatment
• Prevention of complications of liver cirrhosis and its sequels should be aimed at
• Liver function needs to be monitored regularly in patients treated with sorafenib
• Progression to Child C or Child B (> 7 points) cirrhosis should lead to study exclusion
SORAMIC 60
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61
Pulmonary side effects
SORAMIC
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Dyspnea
SORAMIC 62
Toxicity Grade 1 2 3 4 5Clinical presentation
Shortness of breath with moderate exertion
Shortnes of breath with minimal exertion, limiting instrumental ADL
Shortness of breath at rest; limiting self care ADL
Life-threatening consequences; urgent intervention indicated
death
CTCAE v4.0
Characterized by an uncomfortable sensation of diffculty breathing
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Interstitial lung disease
• ILD and TKI
- Gefitinib was associated with an increase in the frequency of ILD in Japanese patients
- the potential association of Nexavar with ILD was assessed in the overall pharmacovigilance program
- Case report: “Interstitial pneumonia probably associated with sorafenib treatment: An alert of an adverse event”
- interstitial pneumonia occurred in 4 among approximately 2000 Japanese patients treated with sorafenib
SORAMIC 63
Nakagawa et al.:Interstitial lung disease in gefitinib-treated Japanese patients with non-small cell lung cancer - a retrospective analysis.BMC Res Notes. 2009 Aug 5;2:157.Ide et al.: Interstitial pneumonia probably associated with sorafenib treatment: An alert of an adverse event. Lung Cancer. 2010 Feb;67(2):248-50
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• 1. ILD
a group of lung diseases affecting the interstitium (alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues)
• 2. symptoms
- breathlessness during exercise
- dry cough
- signs of heart failure
• 3. causes
- inhaled substances (e.g. Asbestosis)
- drug induced (chemotherapeutics)
- Connective tissue disease (polymyositis)
- infectionSORAMIC 64
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Interstitial lung disease
• Very rare differential diagnsosis in case of dyspnoeic patients treated with sorafenib
• Perform chest x-ray, pulmonary function tests, CT Thorax if necessary
• Rule out infectious causes, pleural effusions and other causes of dyspnoea
• Supplement oxgen if necessary
• Induce specific therapy, consider steroids
SORAMIC 65
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
66
Dose De-escalation: Non-Haematologic
(I)
Grade 1 / 2
Grade 3
Continue
at same
dose levelSupportive
treatment
Withhold
until
toxicity
is
<
°1
In case
of 2nd °3 toxicity
Withhold
until
toxicity
is
<
°1, resume
at dose level
-1
If
no toxicity
> °1, re-escalation
possible
If
toxicity
> °1, de-escalation
to -2
SORAMIC
or
discontinuation
Treatment at this
level
for
28 days
then
resume
at same
dose level
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400mg qod
400mg qd
400mg bid
(400–0–200mg ) qd
67
Dose De-escalation: Non- Haematologic
(II)
Grade 4 Withhold
until
toxicity
is
<
°1, resume
at dose level
-1
Discontinuation
at discretion
of investigatorDiscussion
with
study
sponsor
SORAMIC
If
toxicity
> °1, de-escalation
to -2 or
discontinuation
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Key messages
• Patients need to be informed about possible side-effects
• Prevention is better than treatment• Grading the severity of AE is crucial• Dose-adjustment!
– Hematologic – arterial hypertension – HFSR – others
• Please keep in- and exclusion criteria in mind
SORAMIC 68