management of treatment related side effects -...
TRANSCRIPT
Management of treatment related side effects
Michel Ducreux & Claus-Henning KöhneVillejuif & Oldenburg
First of all: Talk to the patient (and the family)
• Side effects have to be explained to the patients• If possible
• First time by the Medical Oncologist• A second time by a specialized nurse (oral drugs!)• General practitioner has to be informed of the choice of the
treatment
• Discussion on the toxicity profile can be useful for the choice of the treatment
• Simple explanations needed:• Insist on , potentially severe side effects: diarrhoea with
irinotecan, febrile neutropenia…, etc.
The therapeutic range of cytotoxic drugscompared to other drugs
Other drugs Antineoplastic drugs
Under dosed
overdose dosed Toxic ~10%
effectiveIndividual tolerable dose
not effective
tolerable dose
Pain killerAntibioticsHormonal TxCardiac drugsAntihypertensivsetc
In most settings doses will be adjusted and efficacy evaluated every 6-8 weeks
Chemotherapy
• General informations– Blood samples results before CT administration– Prevention of emesis is better– Documents have to be given to the patients
• Specific informations:– 5FU : mucositis, diarrhoea,– Irinotecan: diarrhoea, alopecia, nausea, vomiting– Oxaliplatin: neuropathy, nausea, vomiting– Rush: EGFR– Hypertention: VEGF
• General and specific informations• Sexuality, fertility, pregnancy• Driving, drinking alcohol• Vaccinations
Chemotherapy, general clinical parameters before…
• Performance status (ECOG 0 – 3)• Temperature, blood pressure • Weight, Size = Body surface • BMI: Look for denutrition• Central venous access• Record of all other medications• Recent CT scan• Specificity of targeted therapies
– Cetuximab – panitumumab: skin, and feet status– Bevacizumab: 28 days at least after surgery
Biological parameters
• Standard blood count at least before each cycle..
• Other blood tests depending on CT:– Irinotecan: bilirubin level– Oxaliplatin: creatinin level
• Targeted therapies– Bevacizumab: dipstick (if 2+ or 3+: 24-hour proteinuria and
creatinin clearance)– Cetuximab, panitumumab: RAS testing, magnesemia, calcemia
Contra-indications
• 5FU: known DPD homozygous deficit• Irinotecan: Gilbert’s disease (beginning at a low level of
dose is reommended)• Oxaliplatin: severe neuropathy (diabetes, alcohol),
known allergia• Cetuximab, panitumumab: interstitial pneumopathy• Bevacizumab: recent arterial thrombosis, surgery < 28
days before, unhealed wound, uncontrolled arterial hypertension
Mangement of toxicity of chemotherapy
• Neutropenia– Stop the 5FU bolus first– Then decrease of doses or (hematological growth factors)
• Thrombopenia– Decrease of doses
• Mucositis– Decrease of doses
• Diarrhoea– High-dose loperamide
• ………..
Irinotecan (CPT-11) Management of Toxicity
Cholinergic Syndrome
Diarrhea NeutropeniaNadir
d1 d8d5 d16d4
Atropin 0.25 mg s.c.
+ prior to next cycle
Watch
Loperamide 2mg / 2h+/- broad spectrum
antibiotics
Hospitalize
severe diarrhea >48h+/- fever
InformPatient
Treatment of oxaliplatin inducedneuropathy by intravenous
mangafodipir
Coriat R et al. J Clin Invest 2014;124:262-72
Infusion of cetuximab, allergicreactions
• Grade 1: transient rash and / or fever <38°CReduced rate of 50%, monitor (max length <4 h)
• Grade 2: urticaria and / or fever> 38°C:Stop and resume to 50% of the initial rate if resolution of the symptoms; Reduced rate and monitor subsequent infusions
• Grade 3-4: bronchospasm and / or edema and / or shockDefinitive exclusion of cetuximabPanitumumab has to be usedPremedication with corticosteroids Siena et al, ASCO 2007
=> Reactions 7% vs. 22% (grade 3-4: 1% vs 5%)
Management of skin toxicity of anti-EGFR
Lacouture ME et al. Support Care Cancer 2011;19:1079-95
Courtesy: O Bouché et al. GCB 2009
Skin toxicity of anti-EGFRChronology
Time (weeks)
EGFR antibody-inducedskin toxicity:
reversible during therapy
d C225 CTX Diarrhea
1 x x8 x x
15 - - 1°
22 x x29 x x36 x x43 x - 3°
50 x x
Skin Toxicity Evaluation Protocol With Panitumumab (STEPP) Pre-Emptive vs. Reactive Skin Treatment
Lacouture et al. JCO 2010
Time to first occurence of grade ≥ 2 skin toxicity
Pre-emptive skin treatment regimen (Day -1 through weeks 1 to 6)• skin moisturizer applied to face, hands, feet, neck, back, and
chest daily in the morning on rising; • sunscreen (PABA free, SPF15, UVA and UVB protec- tion)
applied to exposed skin areas before going outdoors• topical steroid (1% hydrocortisone cream) applied to face,
hands, feet, neck, back, and chest at bedtime; • doxycycline 100 mg twice per day.
Acute skin toxicity
Xerosis
Fissure recommendations
To make it simpleGrade 1 Grade 2 Grade 3
EmollientsHydrocortisone 1% cream
EmollientsHydrocortisone 1% creamOral doxycycline 100 mg
Stop treatmentDermatologist adviceOral doxycycline + local antibiotics
Robert et al. Lancet Oncol 2006
Avoid sun, hot water, "fat" emollientAdvisor makeup covering skin lesions
Paronychis
CHU REIMS
Courtesy: O Bouché
Paronychis
Schrag et al. JNCI 2005 Tejpar et al. Lancet Oncol 2007 Fakih et al. Oncology 2008
Grade 3: from 9 to 7 mg/L) Grade 4 (< 7 mg/L)
=> IV magnesium sulfate: 8 g infused in 4 hours every 2 days
Grade 1: N to 12 mg/L => New control 2 weeks later
Grade 2: from 12 to 9 mg/L => IV magnesium sulfate: 4 g infused in 2h each cycle
Follow-up of magnesemia and calcemia• Before • Every two weeks on treatment• 8 weeks after the end
Hypomagnesemia (+/- -calcemia, -kaliemia)
CHU REIMS
Hypertrichosis => waxingTrichomegaly => cut
Ocular lesions: conjunctivitis, keratitisMucosal lesions: mouth, nose, genital
Bouché et al. Ann Oncol 2005
Telangectasias => make up… laser
Bevacizumab specific toxicities
• Overestimation => Too early stop of anti-angiogenic agents
• Underestimation => serious complications, stroke, HTA
Bevacizumab specific toxicities
Hypertension
If absence of proteinuria, the 5 main classes of anti-HTA can be used
Angiotensin-converting enzyme inhibitors (IEC), Renin-angiotensin system antagonists (ARA2), beta blockers (B-bloquant), diuretics (diurétique thiazidique), calcium-channel blockers (inhibiteur calcique)
Halimi et al. Nephrol Ther 2008;4:602-15Recommended bitherapies HAS 2005
Treatment of hypertensionFrench recommandations
Proteinuria
GI perforation
• 1% of the patients• A little bit more in patients with primary in place (up to
3%)• Tumoural or non tumoural• Best surgical options have to be discussed• 20% of death rate after this kind of event…• No bevacizumab
– if symptomatic peritoneal carcinomatosis– Huge ulcerated lesion– Colic stent
Surgery in patients receivingbevacizumab
• Pooled analysis of two studies (1132 patients)
10 (13%)1 (3%)
7529
CT + bevacizumabCT + placebo
ComplicationsPts with major surgeryTreatment
Scappaticci et al. J Surg Oncol 2005
Emergency• First of all you have to inform the surgeon and discuss the risk/benefit ration• Cautious perioperative hemostasis• Cautious post-operative follow-up
Wound healing
• Bevacizumab has to be stopped 5 to 6 weeks beforesurgery– 6 weeks for huge surgery such as HIPEC
• Resume administration 4 weeks after surgery
Wound healing
Bevacizumab-associatedthomboembolism
Hemorrhage
Reversible posterior leuko-encephalopathy syndrom
• < 0.1 % of the treated patients• Signs and symptoms:
• Headache• Seizure• Lethargy• Confusion• Blindness• Hypertension
• Diagnosis is made by MRI• Treatment
• Discontinuation of bevacizumab
• Treatment of hypertension
Cassidy et al. J Cancer Res Clin Oncol 2010
Tolerance of bevacizumab and age ?Pooled analysis of phase II and III trials
Estilo et al. J Clin Oncol 2008
Unexpected side effects
Estilo et al. J Clin Oncol 2008
Unexpected side effects
• Splenic infarction• perforation of the nasal septum • eso-tracheal or bronchial fistula• mandibular osteonecrosis
Regorafenib• Oral drug
– But…..– Quite toxic at 160 mg/day
• If you begin the treatment at this level of dose– You have to see the patient after 2 weeks of treatment
• Main toxicities– Asthenia, fatigue– Hand-foot syndrome– Diarrhoea– Rash
• Treatment– Stop if severe and decrease the dose to 120 mg or even 60
mg…
Aflibercept
• Half-life: 7.13 days• Anti-angiogenic agent: no specificity:
– GI perforation– HTA– …
• But:– Aflibercept is able to increase the toxicity of chemotherapy
• Diarrhoea: up to 23% grade 3-4 in the VELOUR study
• Febrile neutropenia…
Ramucirumab
• Half-life: 14 days• Anti-angiogenic agent: no specificity:
– GI perforation– HTA– …
• But:– Very moderate increase in chemotherapy related side
effects– Maybe more active when it is more toxic…
RCP Cyramza and EMEA EPAR Cyramza CCRm Mar
Pts with any grade of neutropenia : OS = 16.1 months RAM vs 12.6 months Placebo Pts without neutropenia : OS = 10.7 months in each arm
TAS 102
• Neutropenia: main side effect…
Frequency of Adverse Events Event TAS-102
(N=533)Placebo (N=265)
Any Gr. Gr. ≥3 Any Gr. Gr. ≥3
Events associated with fluoropyrimidine treatment, n (%)
Febrile neutropenia 20 (4) 20 (4) 0 0
Stomatitis 43 (8) 2 (<1) 17 (6) 0
Hand-foot syndrome 12 (2) 0 6 (2) 0
Cardiac ischemiaa 2 (<1) 1 (<1) 1 (<1) 1 (<1)
Mayer R, et al. N Engl J Med. 2015;372:1909-1919. DOI: 10.1056/NEJMoa1414325
Per NCI CTCAE version 4.03.a Events included acute myocardial infarction, angina pectoris, and myocardial ischemia
• One treatment-related death resulting from septic shock was reported