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Metastatic melanoma case with positive BRAF V600E mutation
Nabil EL- hadi omaron 28 September 2014
Transcript of Metastatic melanoma case with positive BRAF V600E mutation
Metastatic melanoma case
positive BRAF V600E Mutation
it happens mainly at
Eye (uveal melanoma)
but may occur at
latitude and the intensity of solar exposure
3- Clinical features
B : border
C : Color
D : Diameter
1-Flaherty KT, et al. Cancer 2010;116:4902–4913.
Approximately 50% of metastatic melanoma patients are positive for BRAFV600 mutations¹
Role of BRAF protein on Melanoma
In healthy melanocytes, the NRAS-BRAF-MEK-ERK signalling cascade (pink) tightly regulates cellular functions such as differentiation, growth and survival. In melanoma (orange), BRAF mutations (BRAF*) bypass activation by NRAS, leading to cancer-associated signalling through the MEK-ERK pathway that favours growth and survival over differentiation
Abdominal tenderness , SOB , Cough
DG is 44 years old Pakistani male with hx of malignant melanoma of the left parotid gland presented with hx of SOB and cough and abdominal tenderness
-CT scan of the chest reveals multiple nodules bilaterally
( the disease had been metastasized )
multiple severe sunburns
Malignant melanoma of the left parotid gland
Foreman in building construction company
December 2011 he undergo superficial parotidectomy
22th March 2012
temozolamide 350 mg once daily for 5 days
31th May 2012
he receive a protocol of :
paclitaxel 160 mg QW for 4 doses
bevacizumab 900 mg Q2W for 2 doses !!
4the July 2012
he start vemurafenib 4tab BID
then at 12/8 dose adjusted to 3 tab BID
then stopped at 8/12/2012
Abdominal tenderness , SOB , Cough
Glimpride 4 mg PO once daily
Methadone 5 mg PO twice daily
Omeprazole 20 mg PO once daily
Tramadol 50 mg PO TID PRN
Vemurafenib 720 mg( 3 tab) PO BID
Mg.hydroxide 20 ml PO BID
Celecoxib 200 mg PO BID
Bisacodyl tab 10 mg PO HS PRN
Enoxaparin 40 mg SC once daily
Metastatic malignant melanoma
Prevent medication side effects
Normalize blood glucose leve
1 - Manage DRPs
2 - Follow guidelines for Metastatic melanoma treatment
3- Manage Blood glucose level
4- DVT prophylaxis (Enoxaparin 40 mg SC once daily)
Vemurafenib + Methadone
Highest Risk QTc-Prolonging Agents / Moderate Risk QTc-Prolonging Agents
Risk Rating :X= Avoid combination
Summary : Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents.
ECG at baseline, 15 days after initiation, then monthly for 3
months, then every 3 months thereafter and with dosage adjustments
Tramadol 50 mg PO Q8H
Morphine 1mg/ml 15 ml PO Q8H PRN
Celecoxib 200 mg PO once daily
Paracetamol 1000 mg PO TID
Methadone 5 mg (discontinued) PO twice daily
Bisacodyl tab 10 mg PO HS PRN
Glycerin adult supp 1 supp (added) PR BID
Metastatic Melanoma guidlines
The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE) *
Dose was adjusted from 4 tab ( 960 mg ) bid to 3 tab ( 720 mg ) bid this was due to dermatologic toxicity & photosensitivity
Lab. Result revealing dermatologic toxicity** : elevated creatine kinase Creatine kinase 309 u/L ( 25-232
*Ref : FDA vemurafenib drug information
**Ref: Association of creatine kinase and skin toxicity in phase I trials of anticancer agents
V Moreno Garcia, P Thavasu, M Blanco Codesido, L R Molife, J Vitfell Pedersen, M Puglisi, B Basu, K Shah, J Iqbal, J S de Bono, S B
Dose adjustment Vemurafenib
Clinical question: in previously treated patients with metastatic melanoma, does Bevacizumab biweekly and Weekly Paclitaxel improve Median disease-free and overall survival times??
Preliminary Results of the Combination of Bevacizumab and Weekly Paclitaxel in Advanced Melanoma
GonzálezCao M. · Viteri S. · DíazLagares A. · González A. · Redondo P. · Nieto Y. ·Espinós J. · Chopitea A. · Ponz M. · Martín-Algarra S. Oncology 2008;74:12–16 (DOI: 10.1159/000138351)
to evaluate the activity of
the combination of weekly paclitaxel and bevacizumab in previously treated metastatic melanoma.
Patients and Methods: Patients with previously treated metastatic melanoma received paclitaxel 70 mg/m2weekly and bevacizumab 10 mg/kg biweekly for 5 consecutive weeks every 6 weeks.
Twelve patients were treated.
Two patients (16.6%) achieved a partial response and 7 patients (58.3%) stable disease. Responses were seen in soft tissue, lung and brain metastases. Median disease-free and overall survival times were 3.7 and 7.8 months, respectively. Treatment was well tolerated
: Our preliminary results suggest that the combination of bevacizumab and weekly paclitaxel is active and safe in patients with metastatic melanoma,
warranting further investigation. !!!
SCr 63 μmol/L
CrCL 95.2ml/min Cockcroft & Gault (Ideal Body Weight)
HBA1c 6.4 @ 13/8/2012 ( 4.8-6)
3- Management of Blood Glucose
Algorithmic summary of 2012 ADA-EASD policy statement recommendations for the management of hyperglycaemia in type 2 diabetes. If individualised glycaemic target not achieved, or maintained, move promptly to next therapy level using a patient-centred approach to drug selection Key: DPP4i = dipeptidylpeptidase 4 inhibitor; GLP-1a = glucagon-like peptide-1 agonist; SU = sulphonylurea; TZD = thiazolidinedione Reproduced with permission from MedEd UK.
Ref: Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site.
Treatment of unresectable or metastatic melanoma with BRAF V600E mutation (designated an orphan drug by FDA for this use)
FDA-approved in vitro diagnostic test (e.g., cobas 4800 BRAF V600 Mutation Test) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.
Not recommended for use in patients with wild-type BRAF melanoma; safety and efficacy not established.
Mechanism of action
ADVERSE REACTIONS include :
Cutaneous Squamous Cell Carcinoma
Liver Laboratory Abnormalities
New Primary Malignant Melanoma
Ref:Sosman JA, et al. N Engl J Med. 2012;366:704-14.
Zelboraf's median Overall Survival (OS) in previously treated patients with BRAFV600 mutation-positive metastatic melanoma was 15.9 months
OS results from BRIM2 study
Ref:Chapman P, et al. N Engl J Med 2011;364:2507-2516.
Survival benefits were assessed in the BRIM3 (Phase 3) trial in previously untreated patients. Zelboraf's median Overall Survival (OS) in previously untreated patients with BRAFV600 mutation-positive metastatic melanoma was 13.2 months vs 9.6 months for dacarbazine
OS results from BRIM3 study
Dermatology evaluation (for new skin lesions) at baseline and every 2 months during treatment; also consider continued monitoring for 6 months after completion of treatment
1-This medication may make you more sensitive to the sun.
2-Avoid prolonged sun exposure, and sunlamps.
3-Use a sunscreen and wear protective clothing when outdoors.
LDH at starting of vemurafenib was 230 U/L ( 135-225 u/l) and then it markedly decrease was 161 U/L at 12/9 then it start uprising at 3/12 was : 347 U/L
which reveals recurrence and progression
Ref: Prognostic Correlations and Response to Treatment in Advanced Metastatic Malignant Melanoma1
Lawrence H. Einhorn,2 M. Andrew Burgess, Carlos Vallejos, Gerald P. Bodey, Sr.,3
Jordan Gutterman, Giora Mavligit, Evan M. Hersh, James K. Luce,4 Emil Frei, III,5 Emil J Freireich, and Jeffrey A. Gottlieb