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