In 2011, the treatment armamentarium dramatically expanded with the approval of the anti-CTLA4 antibody ipilimumab and the BRAF inhibitor vemurafenib. Oncology nurses who care for patients with melanoma are beginning to administer these new agents and have numerous questions regarding their efficacy, different response patterns, unique toxicity profiles, how they may be integrated into current treatment regimens, and how to educate patients on their benefits and risks.
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Review a downloadable slide deck by Peg Esper, MSN, MSA, RN, APN-BC, AOCN®, covering the most clinically relevant new data reported from Metastatic Melanoma: An Oncology Nurse Workshop on Novel Treatments, Adverse Event Management, and Patient Education.
Target Audience
This activity has been designed to meet the educational needs of oncology nurses involved in the treatment of patients with advanced melanoma.
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This slide deck in its original and unaltered format is for educational purposes and is current as of May 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
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Metastatic Melanoma: An Oncology Nurse Workshop on Novel Treatments, Adverse Event Management, and Patient Education
1.
2. DISCLAIMER
This slide deck in its original and unaltered format is for educational purposes and is
current as of May 2012. All materials contained herein reflect the views of the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readers
should not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and references
remain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior written
permission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.
3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. IMER does not recommend the use of any
agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not necessarily
represent the views of IMER. Please refer to the official prescribing information for
each product for discussion of approved indications, contraindications, and warnings.
4. Disclosure of Conflicts of Interest
Peg Esper, MSN, MSA, RN, APRN-BC, AOCN®, reported a
financial interest/relationship or affiliation in the form of: Speakers'
Bureau, Novartis Pharmaceuticals Corporation, Pfizer, Inc.,
Prometheus.
Evan M. Hersh, MD, reported a financial interest/relationship or
affiliation in the form of: Speakers' Bureau, Bristol-Myers Squibb
Company, Pfizer and Glaxo Smith Kline and consultant to
Genentech and Pfizer.
Krista M. Rubin, MS, RN, FNP-BC, reported a financial
interest/relationship or affiliation in the form of: Consultant, Bristol-
Myers Squibb Company, Genentech, Inc., Merck & Co., Inc.
5. Learning Objectives
L
Upon completion of this activity, participants
should be better able to:
Identify the emerging role of novel therapies in the
treatment of advanced melanoma
Implement strategies for the safe administration of novel
therapies
Apply evidence-based or best practice supportive care to
manage side effects and optimize therapeutic outcomes
of patients with melanoma receiving novel therapies
Provide accurate and health-literate responses to
melanoma patients’ questions regarding their disease,
treatment guidelines, and side effects
7. Introduction to Faculty Panel
Peg Esper, MSN, MSA, RN, ANP-BC, AOCN® (Chairperson)
– Nurse Practitioner, Medical Oncology
– University of Michigan Comprehensive Cancer Center
Evan M. Hersh, MD
– Professor of Medicine, Microbiology and Immunology
– Arizona Cancer Center, University of Arizona
Krista M. Rubin, MS, RN, FNP-BC
– Nurse Practitioner, Center for Melanoma
– Massachusetts General Hospital
8. Activity Agenda
6:30 – 6:35 AM Welcome and Activity Overview
6:35 – 6:50 AM Clinical Update: What’s New in Melanoma Therapy?
6:50 – 7:10 AM The Workshop: Nursing Management Strategies for
Patients With Advanced Melanoma
7:10 – 7:55 AM Putting the Workshop Into Practice: Roundtable
Discussions on Metastatic Melanoma Case Studies
7:55 – 8:00 AM Audience Questions and Answers
10. 2012 Overview of Melanoma
Fastest rising incidence of any cancer over the
last 3 decades
– 76,250 cases in 2012
Median age at diagnosis: 60 yrs
Early metastatic potential
Early and common CNS seeding
Historic lack of effective systemic therapies until
recently
– Mortality 9,180 cases in 2012
CNS = central nervous system.
Weber, 2008; ACS, 2011.
11. Melanoma: Incidence, Mortality,
and Survival by Stage
Incidence Survival Curves by AJCC Stage
1.0
0.9
Stage I (n = 18,370)
0.8
0.7
0.6 Stage II (n = 9,269)
0.5 Stage III (n = 3,307)
0.4
0.3
0.2 Stage IV (n = 7,972)
0.1
0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
0.0 Survival, Years
20-yr survival curves for patients with melanoma
by stage. The differences between the curves
are
Age adjusted incidence rates of all ages, highly significant (p < .0001).
all races, both male and female, 1975–2008
AJCC = American Joint Committee on Cancer.
Howlader et al, 2010; Edge et al, 2010.
12. Systemic Therapy for Metastatic
Melanoma: Prior History
Surgery (metastasectomy)
Dacarbazinea (DTIC)1
High-dose bolus IL-22
Biochemotherapy with IL-2
Carboplatin/paclitaxel
Temozolomide (US)
Fotemustine (Europe)
FDA approved: 11970s, 21998.
a
OS = overall survival; IL-2 = interleukin-2.
Middleton et al, 2000; Agarwala, 2009; Serrone et al, 2000; Gonzalez-Larriba et al, 2010; Flaherty et al, 2010; Seront et al, 2010.
13. Ipilimumab Is a Member of a Novel Class
of Immunotherapeutic Antibodies
1) Co-stimulation via CD28 2) CTLA-4 ligation on 3) Blocking CTLA-4 ligation
ligation transduces T-cell activated T cells down- enhances T-cell responses
activating signals regulates T-cell responses
T-cell activation T-cell inactivation T-cell activation
T cell CTLA-4 T cell T cell
CTLA-4
TCR TCR
TCR
CTLA-4
MHC CD28 MHC CD28
CD28
B7 MHC B7
B7
Ipilimumab
APC APC APC
CTLA-4 = cytotoxic T-lymphocyte antigen-4; MHC = major histocompatibility complex;
TCR = T-cell receptor; APC = antigen presenting cell.
Fong et al, 2008.
14. Ipilimumab Registration Trials
Second-line MDX010-20 trial HLA-A2 positive (N = 650)
– 3 arms 3:1:1 (ipilimumab/gp100 vaccine, ipilimumab alone,
gp100 alone)
– First study in metastatic melanoma to demonstrate OS benefit in
large randomized placebo-controlled trial
First-line CA184-024 trial, randomized placebo control
(N = 500)
– Ipilimumab/DTIC vs. placebo/DTIC
– Reported as having positive OS (ipilimumab/DTIC combination
vs. DTIC)
HLA-A2 = human leukocyte antigen-alpha 2.
Hodi et al, 2010; Wolchok et al, 2011.
15. MDX010-20: Study Design
Ipilimumab + gp100 (n = 403)
R
A
Pre-treated N
metastatic
D
melanoma
O Ipilimumab + placebo (n = 137)
(N = 676)
M
I
Z
E gp100 + placebo (n = 136)
Hodi et al, 2010.
16. Kaplan-Meier Analysis of Survival
Ipilimumab + gp100 (A)
Ipilimumab alone (B)
gp100 alone (C)
Comparison HR p Value
Arms A vs. C 0.68 .0004
Arms B vs. C 0.66 .0026
1 2 3 4
Time (yrs)
HR = hazard ratio.
Hodi et al, 2010.
17. Ipilimumab Plus DTIC Vs. DTIC Alone
(Study 024): Design
Screening Induction Maintenancea
Ipilimumab 10 mg/kg Ipilimumab 10 mg/kg
Previously q3wks x 4 q12wks
Untreated
Metastatic DTIC 850 mg/m2
R q3wks x 8
Melanoma
(N = 502)
Placebo
Placebo
q3wks x 4
q12wks
DTIC 850 mg/m2
R = blinded q3wks x 8
randomization
(1:1)
Wk 1 Wk 12 Wk 24
Baseline First Scheduled
Tumor Assessment Tumor Assessment
In absence of progression.
a
Wolchok et al, 2011.
18. Ipilimumab Plus DTIC Vs. DTIC: OS
CI = confidence interval.
Wolchok et al, 2011.
19. Study 024: Select AEs
Select AEs are shown, regardless of attribution
GI = gastrointestinal; AEs = adverse events.
Wolchok et al, 2011.
20. Study 024: Select AEs (cont.)
Select AEs are shown, regardless of attribution
1 (0.4%) hypophysitis in a patient on maintenance was reported on Day 364.
a
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
Wolchok et al, 2011.
21. Ipilimumab Patterns of Response
Baseline (Day 0) Week 12 (Day 84)
Week 16 (Day 112) Week 72 (Day 503)
Hoos et al, 2010; Images courtesy of K. Harmankaya, MD.
22. Targeted MAPK Pathway: BRAF
cKIT mutations: 3% of all
melanomas – almost exclusively
acral letiginous, mucosal, or
chronic sun damaged skin
BRAF mutations: 50%
cutaneous melanomas –
intermittent sun exposed skin
MAPK = mitogen activated protein kinase; BRAF = serine/threonine protein kinase.
Curtin et al, 2006; Presented with permission, Copyright 2011 by C Lovly, L Horn, & W Pao, 2012.
23. Phase III First-Line BRIM3
Study Design
Vemurafenib
Screening
960 mg po bid
(n = 337)
BRAFV600E mutation
Randomization
Stratification
• Stage N = 675
• ECOG PS (0 vs. 1)
• LDH level (↑ vs. nL)
Dacarbazine
• Geographic region
1,000 mg/m2 IV q3wks
(n = 338)
ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase level; IV
= intravenous; po = oral; bid = twice daily.
Chapman et al, 2011.
24. Best Tumor Response by Individual Patient
Vemurafenib: 48.4% response
Dacarbazine: 5.5% response
Chapman et al, 2011.
26. PET Scans at Baseline
and Day 15 After Vemurafenib
#69 MDACC #63 MSKCC
PET = positron emission tomography; MDACC = The University of Texas M. D. Anderson Cancer Center;
MSKCC = Memorial Sloan-Kettering Cancer Center.
Chapman, 2009.
27. Survival in BRAF V600-Mutant Advanced
Melanoma Treated With Vemurafenib
Phase II study in 132 previously-treated patients
Response Rate: 53%
– 6% CR, 47% PR
DOR: 6.7 mos
PFS: 6.8 mos (CI 5.6-8.1)
OS: 15.9 mos (CI 11.6–18.3 mos)
Comparison
– DTIC OS 6–8 mos
– Phase II chemotherapy survival: 6.3 mos
CR = complete response; PR = partial response; DOR = duration of response; PFS = progression-free survival.
Sosman et al, 2012.
28. Phase III of HD IL-2 +/- Vaccine
Study population (eligible for HD IL-2)
– Stage IV or unresectable stage III melanoma
– HLA-A0201 positive
– No brain metastases
– No previous HD IL-2
1:1 randomization
– 1) HD IL-2 q8hrs x 12 doses q3wks
– 2) IL-2 + gp100 vaccine
179 evaluable patients accrued (93 IL-2/86 Vac)
– 21 centers, 2000–2007
HD = high-dose.
Schwartzentruber et al, 2011.
29. Phase III of HD IL-2 +/- Vaccine (cont.)
Outcome IL-2, No. (%) IL-2 + Vaccine, No. (%) p Value
No. patients 93 85
CR (investigator) 2 (2) 9 (11) .02
CR + PR (investigator) 9 (10) 17 (20) .05
CR + PRa 6 (6) 14 (16) .03
(central, primary end point)
PFS (median) 1.6 m 2.2 m .008
OS (median) 11.1 m 17.8 m .06
Most of RR difference due to responses in M1b/lung met.
a
RR = response rate.
Schwartzentruber et al, 2011.
30. nab-Paclitaxel Plus Bevacizumab
in Melanoma
Patient Characteristics Toxicity #
M/F 32 / 18 26 grade 3 events related to study drug
Stage # (%) Neutropenia 10
IIIC 2 (4) Neuropathy 7
IV:M1a 4 (8) Mucositis 4
IV:M1b 11 (22) Fatigue 3
IV:M1c 34 (66) Proteinuria 1
LDH HFS 1
Normal 30 (60) No study drug-related grade 4 toxicity
Elevated 20 (40)
HFS = hand-foot syndrome; M/F= masculine/feminine.
Boasberg et al, 2011.
31. nab-Paclitaxel Plus Bevacizumab
in Melanoma (cont.)
RR (RECIST) # (%)
CR 2 (4)
PR 16 (32)
SD 22 (44)
PD 10 (20)
Clinical benefit (CR + PR + SD) 40 (80)
PFS
PFS at 4 mos 73%
Median PFS 7.63 mos
Median duration of follow-up 41.6 mos
OS
1-yr survival 62%
2-yr survival 30%
Median survival 16.8 mos
RECIST = Response Evaluation Criteria In Solid Tumors; SD = stable disease; PD = progressive disease.
Boasberg et al, 2011.
32. New Treatment Algorithm for
Stage IV Melanoma
Clinical trial
Treatment naïve
– HD IL-2 if eligible
– High priority protocol if eligible
– Vemurafenib (V600) or imatinib (c-kit) if tumor mutated
– Ipilimumab alone or with other drugs if not mutated
Previously treated
– High priority protocol if eligible
– HD IL-2, ipilimumab, vemurafenib, or imatinib if appropriate
– nab-Paclitaxel plus bevacizumab off label therapy
– Standard therapy, or phase I or II protocol
Low tumor burden: ImmunoRx; High burden: BRAF inhibitor
Chemotherapy options include
– Dacarbazine, temozolomide, dacarbazine- or temozolomide-based combination
chemotherapy/biochemotherapy, paclitaxel, paclitaxel/cisplatin, paclitaxel/carboplatin
Rx = prescription.
NCCN, 2012a.
33. Evolution of Response Criteria:
mWHO to irRC
WHO = World Health Organization; irRC = immune-related response criteria; SPD = sum of perpendicular diameters.
Wolchok et al, 2009.
34. Monitoring Disease Response in
Patients Receiving Ipilimumab
Analysis of 5 clinical trials (N = 269)
– CR 10–106 wks after treatment initiation
– PR 5–62 wks after treatment initiation
– Therapeutic responses peak between 12–24 wks, slow
responses up to and beyond 12 mos
– DOR 6–187+ wks
Clinical trial monitoring (Hodi et al, 2010)
– Baseline
– 12 wks
– 16, 20, 24 wks if no early PD and SD or better at Wk 12
– q3mos thereafter
Callahan et al, 2010; Hamid et al, 2007; Boasberg et al, 2010; Hodi et al, 2010.
35. Key Takeaways:
Treatment of Advanced Melanoma
Melanoma is increasing dramatically in incidence
2 new therapies have been approved recently
– Ipilimumab
– Vemurafenib
2 other therapies are promising
– HD IL-2 + peptide vaccine (vaccine experimental)
– nab-Paclitaxel plus bevacizumab (off label)
A new treatment paradigm for melanoma is at hand
36. The Workshop: Nursing
Management Strategies for
Patients With Advanced Melanoma
Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®
University of Michigan Comprehensive Cancer Center
37. Nursing Management:
Ipilimumab Administration
Ipilimumab (FDA approved 3/25/11)
– 3 mg/kg IV over 90 mins q3wks for a total of 4 doses
– Available as
• 50 mg / 10 mL
• 200 mg / 40 mL
– Store the diluted solution for no more than 24 hrs under
refrigeration (2–8°C, 36–46°F) or at room temperature
(20–25°C, 68–77°F)
– Compatible with 0.9% NaCl or D5W
– Discard partially used vials or empty vials of ipilimumab
NaCl = sodium chloride; D5W = 5% dextrose injection.
Yervoy™ prescribing information, 2012.
38. Nursing Management:
Vemurafenib Administration
Vemurafenib (240 mg tablets; approved 8/17/11)
– Recommended dose: 960 mg (four 240-mg tablets) bid
– The first dose should be taken in the morning and the second dose
approximately 12 hrs later
– Swallow whole with a glass of water, either with or without a meal
– Should not be crushed or chewed
– If a dose is missed, it can be taken up to 4 hrs prior to the next
dose; both doses should not be taken at the same time
Zelboraf® prescribing information, 2012.
39. Additional Regimens
HD IL-2
– 600,000 IU/kg administered as IV bolus over 15 mins q8hrs up
to 14 doses
– 1-wk break period and then repeat
Chemotherapy regimens include
– DTIC 1,000 mg/m2 IV q3wks
– Carboplatin and paclitaxel q3wks
– Temozolomide 200 mg/m2 daily x 5 days (q3wks); 75 mg/m2 x
42 days on 14 days off
Proleukin® prescribing information, 2012; Temodar® prescribing information, 2012; Sosman, 2011.
40. IL-2 Toxicities
Significant immune-mediated toxicity profile
Dose related and schedule dependent
Toxicities, while acute, reverse after completion of therapy
Common toxicities related to IL-2 therapy include
– Fever and rigors – Hypotension
– N/V/D – Mental status changes
– Oliguria, ↑ creatinine – Respiratory dysfunction
– Hematologic toxicity – Dry skin, desquamation
– Infections – Skin rashes/pruritis
– Weight gain during treatment
Most severe toxicities (grade 3/4) observed with IL-2 therapy are
associated with CLS
Rare – Cardiac related deaths
N/V/D = nausea, vomiting, diarrhea; CLS = capillary leak syndrome.
Proleukin® prescribing information, 2012; Schwartz et al, 2002.
41. IL-2 Side-Effect Monitoring and Treatment
TLC = triple lumen catheter; PRN = as needed; NSAIDs = non-steroidal anti-inflammatory drugs.
Proleukin® prescribing information, 2012; Schwartz et al, 2002.
42. Ipilimumab: The “ITIS Syndromes”
The most frequent target organ effects of ipilimumab include
– Skin (dermatitis)
– GI tract (enterocolitis)
– Hepatic system (hepatitis)
– Neurologic system (neuritis)
– Endocrine system (hypophysitis, thyroiditis)
– Additionally: Nephritis, pneumonitis, meningitis, pericarditis, uveitis,
iritis, and vasculitis (smaller percent)
Most commonly observed adverse reactions (≥ 5%, any grade)
– Diarrhea
– Rash
– Fatigue
– Pruritis
– Colitis
Yervoy™ prescribing information, 2012.
43. Ipilimumab Boxed Warning
Severe and fatal immune-mediated adverse reactions due to T-cell
activation and proliferation can occur and may involve any organ
system
The most common adverse reactions are enterocolitis, hepatitis,
dermatitis (including toxic epidermal necrolysis), neuropathy, and
endocrinopathy
Most adverse reactions are initially manifested during treatment;
however, a minority occurred weeks to months after discontinuation
of ipilimumab
Permanently discontinue and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions
Assess patients for signs and symptoms of enterocolitis, dermatitis,
neuropathy, and endocrinopathy and evaluate clinical chemistries
including liver function tests and thyroid function tests at baseline
and before each dose
Yervoy™ prescribing information, 2012.
44. New Agent Side-Effect Profile:
Vemurafenib
Arthralgia
Rash
Nausea
Photosensitivity
Fatigue
Pruritus
HFSR / palmar-plantar dysesthesia
Development of SCC, keratoacanthoma type
HFSR = hand foot skin reaction; SCC = squamous cell carcinoma.
Puzanov et al, 2010; Lacouture et al, 2010.
45. Managing Toxicities of Treatment
GRADE OF TOXICITY
GRADE 1 Asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated
GRADE 2 Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLs
GRADE 3 Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling;
limiting self-care ADLs
GRADE 4 Life-threatening consequences; urgent intervention indicated
GRADE 5 Death
ADLs = activities of daily living.
NCI-(CTC-AE) v4.0, 2010.
47. Rash
• Use of emollient
IPILIMUMAB creams VEMURAFENIB
• Antipruritic agents
• Immune-mediated • Steroid creams if • Use of
IRAE indicated minocycline for
• Avoid hot showers
•
papular/pustular
Loose clothing
• Corticosteroid use • rashes
Avoid changing
more common detergents, softeners, • Frequent skin
etc.
• Can progress to •
evaluations to
Limit sun exposure and
Stevens-Johnson use sunscreen check for SCC
syndrome in rare • Dermatologist
cases referral PRN
• Hold or discontinue • Hold or
PRN discontinue PRN
Lemech et al, 2012; Lacouture, 2011.
48. NCI-CTCAE v4.03: Grading of Rash
Grading is based on percent of BSA covered by macules/papules
Definition: A disorder characterized by the presence of macules (flat) and
papules (elevated). Also known as morbilliform rash, it is one of the most
common cutaneous adverse events, frequently affecting the upper trunk,
spreading centripetally and associated with pruritus..
BSA = body surface area.
NCI-CTCAE v4.03, 2010.
49. HFSR (Palmar-Plantar Dysesthesia): Vemurafenib
Thickened skin with patchy
hyperkeratodermia seen
primarily over high pressure
areas
Believed to be related to affects
of agents on keratinocyte
differentiation
Discomfort can be severe and
prevent ambulation
Use of gel inserts for shoes
Podiatrist evaluation pre-Tx
Urea based creams
Foot soaks
Choi et al, 2011; Photos courtesy of Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®.
50. GI Adverse Effects (AEs)
Diarrhea – Primarily ipilimumab, but may be seen with vemurafenib
Can rapidly progress to colitis if not treated
– Grade 1 (2 or < episodes in 24 hrs)
• Antidiarrheals with close follow-up
• Consider need for stool evaluation (clostridium)
– Grade 2 (3–6 episodes in 24 hrs)
• Oral budesonide (9 mg/d) along with antidiarrheals
• Urgent sigmoidoscopy
– Grade 3 (7+ episodes in 24 hrs)
• Oral corticosteroids
– Prednisone, methylprednisolone, dexamethasone
Symptomatic treatment of diarrhea/colitis has been required up to
2 yrs in some reports
Thumar et al, 2011; Hodi, 2010.
51. Progression to Colitis: Ipilimumab
7+ stools/day over baseline, fever, ileus, peritoneal signs
Dehydration or bleeding (colitis on sigmoidoscopy)
– Inpatient admission
– IV corticosteroids
– Possible infliximab, 5 mg/kg for corticosteroid-resistant or
refractory cases
– Bowel rest
– Possible TPN for prolonged diarrhea
Severe unrelenting cases
– Tacrolimus or sirolimus may be added
– Diverting ileostomy or partial/total colectomy may be considered
Discontinuation of therapy recommended for patients with
severe enterocolitis
TPN = total parenteral nutrition.
Thumar et al, 2011; Weber, 2009; Ledezma, 2009; Greenstein, 2008, Lemech et al, 2012.
53. Autoimmune Hepatitis
Transaminitis reported in up to 20% of patients treated with
anti-CTLA-4 antibodies
Severe autoimmune hepatitis reported 2%
Liver biopsies have revealed diffuse lymphocytic infiltrates
Discontinue treatment for grade 3 or higher elevations
Oral corticosteroids for 30 days+ may be needed
Elevations of grade 4 level require hospitalization and IV
corticosteroids
LFTs/bilirubin must be checked prior to every dose
Observe for symptoms of increased fatigue, N/V, or mental
status changes
LFTs = liver function tests.
Thumar et al, 2011; Lemech et al, 2012.
54. Endocrinopathies
Seen in 15% of phase III study participants
Hypothyroidism
– Elevated TSH
– Symptoms of fatigue, hair thinning, constipation, weight gain
– Replacement thyroid hormone is indicated
– Ongoing monitoring of thyroid hormone levels (baseline, prior
to each cycle and as clinically indicated)
– Some patients may ultimately be able to taper off thyroid
supplement therapy
Hyperthyroidism was also seen
TSH = thyroid stimulating hormone.
Weber, 2009; Lemech et al, 2012.
55. Hypophysitis
Inflammation of the pituitary gland
Symptoms include: Fatigue, headache, loss of libido,
pressure behind eyes, nausea, diminished visual fields
Laboratory data
– Decreased cortisol
– Decreased testosterone
– Decreased ACTH
Radiographic studies
– MRI scan of brain with attention to the sella region with diffuse
enlargement of the pituitary gland
ACTH = adrenocorticotrophic hormone; MRI = magnetic resonance imaging.
Weber, 2009; Kaehler et al, 2010; Thumar et al, 2011.
56. Hypophysitis (cont.)
Management includes
– Replacement of deficient
hormones
• Cortisol (hydrocortisone, initial
dexamethasone/prednisone)
• Thyroid replacement therapy
• Testosterone
– Consider endocrinology
consult
– Patients may ultimately be
able to taper off replacement
therapy
Thumar et al, 2011; Weber, 2009; Image adapted from Kaehler et al, 2010.
57. Additional AEs
Ocular (seen with both ipilimumab and vemurafenib)
– Uveitis (decreased visual acuity, photophobia, tearing)
– Conjunctivitis
Neurologic (ipilimumab)
– Myopathies (weakness, altered sensory function, paresthesias)
– 1 case of fatal Guillian-Barre and 1 case of grade 3 peripheral motor
neuropathy seen in investigational studies
General (ipilimumab and vemurafenib)
– Fatigue
– Anorexia
– Cough
– Anemia
– Headache
Thumar et al, 2011; Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012; Lemech et al, 2012.
58. Labs and Evaluations
IPILIMUMAB VEMURAFENIB
• Labs to be • Molecular testing to
rechecked prior to Baseline labs to confirm BRAF
each cycle of mutation
include CBC, LFTs,
treatment
Lytes • LFTs to be checked
• Monitor thyroid at least monthly and
function and as clinically indicated
chemistry panel prior
to each cycle of • EKG 15 days into Tx,
treatment then monthly x 3, then
q3mos
CBC = complete blood count; Lytes = electrolytes; EKG = electrocardiogram.
Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012.
59. Drug-Drug Interactions
Ipilimumab
– No known drug-drug interactions
Vemurafenib
– CYP substrates: Concomitant use of vemurafenib with agents
with narrow therapeutic windows that are metabolized by
CYP3A4, CYP1A2, or CYP2D6 is not recommended. If co-
administration cannot be avoided, exercise caution and consider
a dose reduction of the concomitant CYP1A2 or CYP2D6
substrate drug.
– May increase exposure to concomitantly administered warfarin.
Exercise caution and consider additional INR monitoring when
used concomitantly with warfarin.
INR = international normalized ratio; CYP = cytochrome P450.
Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012.
60. When to Discontinue Ipilimumab
Permanently discontinue ipilimumab for any of the following:
Persistentmoderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg
prednisone or equivalent per day
Failure to complete full treatment course within 16 wks from administration of first dose
Severe or life-threatening adverse reactions, including any of the following:
– Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more
over baseline)
– Stool incontinence
– Need for IV hydration for > 24 hrs
– Gl hemorrhage and Gl perforation
AST or ALT > 5 times ULN or total bilirubin > 3 times ULN
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness
dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations
Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis
Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis,
pancreatitis, non-infectious myocarditis)
Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy
ULN = upper limit of normal.
Yervoy® prescribing information, 2012.
61. Dose Modification Information:
Vemurafenib
Grade (CTC-AE)* Recommended Vemurafenib Dose Modification
Grade 1 or Grade 2 (tolerable) Maintain vemurafenib at dose of 960 mg bid
Grade 2 (intolerable) or Grade 3
1st Appearance Interrupt treatment until Grade 0–1
Resume dosing at 720 mg bid
2nd Appearance Interrupt treatment until Grade 0–1
Resume dosing at 480 mg bid
3rd Appearance Discontinue permanently
Grade 4
1st Appearance Discontinue permanently or interrupt vemurafenib treatment
until Grade 0–1
Resume dosing at 480 mg bid
2nd Appearance Discontinue permanently
*The intensity of clinical AEs graded by the CTC-AE.
Zelboraf® prescribing information, 2012.
62. Patient Education: General
Assess for both patient and family (or significant other)
– Knowledge of therapy and disease process
– Educational level
– Preferred learning methods
Develop a plan
Implement teaching, using a wide variety of materials and methods
Evaluate patient and family for continued educational needs related
to the therapy and disease process
Contact
– Who to call
– Why to call
– When to call
– Where to call (must have 24/7 clinician availability)
63. Patient Education: Challenges
Ipilimumab
– Effect of treatment is on the immune system, not directly
targeting the tumor
– Vast side-effect profile, when to notify clinician
– Variability in response to treatment
– Four treatments in the FDA approved therapy
Ledezma, 2009.
64. Patient Education: Challenges (cont.)
Vemurafenib
– What is BRAF?
– Do I have genetic mutations?
– Yes, it is 4 pills bid!
– You treat 1 skin cancer, but develop another type of skin cancer?
– Does this cure my cancer?
65. Putting the Workshop Into
Practice: Roundtable
Discussions on Metastatic
Melanoma Case Studies
Krista M. Rubin, MS, RN, FNP-BC
Massachusetts General Hospital
66. Putting the Workshop Into
Practice
Please assign a moderator for your table
You have 10 minutes to discuss the case
Moderators:
– Please record all group responses on the “Moderator
Handout”
– Leave this handout on your table; this will be
collected at the end of the presentation by IMER
staff
68. Case Study 1: History
30-yr-old man with a history of a 2.3 mm, non-ulcerated
nodular, melanoma of (R) forearm s/p wide excision and
negative sentinel node biopsy [T3aN0MX: Stage IIA]. No
adjuvant Rx recommended. Followed accordingly.
2 yrs later, develops SOB playing basketball. Presents to
ER: CXR showed large (L) pleural effusion.
– Rx: Thoracentesis (therapeutic and diagnostic) for ~ 1 L bloody
fluid
– Cytology → IHC: MART–1, HMB45, S100 all (+) c/w metastatic
melanoma
– Imaging studies: Large subcarinal LN and multiple (L) pleural
masses. Brain MRI(-). Pleurodesis with symptomatic
improvements in dyspnea.
SOB = shortnes of breath; ER = emergency room; CXR = chest X-ray; IHC = immunohistochemistry;
MART-1, HMB45, and S100 = IHC markers of melanocytic tumors; LN = lymph node; PMH = patient medical history.
69. Case Study 1: History (cont.)
Repeat imaging 1 wk later revealed an increase in size
of known tumor and new bilateral pleural masses, diffuse
LAN in the prevascular and anterior mediastinum.
PMH notable controlled asthma
Meds: Fluticasone 110 mcg INH, 2 puffs bid (albuterol
inhaler prn)
Allergies: NKA
FH: Negative for melanoma
SH: Married, 2-yr old twins, works in investment banking.
Non-smoker and social drinker.
FH = family history; SH = social history.
70. Case Study 1: Questions
What treatment options would be discussed
with this patient?
What would be recommended and why?
71. Case Study 1: Treatment Options
Clinical trials
− None available for first-line therapy at the time of diagnosis
Immunotherapy
− Ipilimumab
− HD IL-2
Targeted therapy
− BRAF inhibitor if BRAF mutation identified
Chemotherapy
− DTIC
− Temozolomide (off-label)
− Carbo/paclitaxel (off-label)
Best Supportive Care (BSC)
NCCN, 2012a.
72. Case Study 1: Treatment Options (cont.)
Given rapid progression of disease, obtaining tissue for BRAF
analysis felt to be crucial to treatment recommendations
Biopsy of plural met obtained – no mutation identified (BRAF WT)
Recommendation for ipilimumab
− Given his otherwise good health
− BRAF WT
− Concern for asthma exacerbation off inhaled corticosteroids and
pulmonary toxicity from IL-2
− Best chance of durable response
Began Rx 1 wk later after insurance approvals obtained
WT = wild-type.
NCCN, 2012a.
73. Case Study 1: Monitoring and Response
Tolerated first infusion well: No issues
F/U labs notable for increased LFTs: Grade 1
Second infusion
– Pre-Rx labs unremarkable
– Increasing dyspnea: O2 sats 92%–93%, mild intermittent pruritus
– Labs stable
– Fatigue worsening
Third infusion
– Grade 1 elevation of amylase/lipase, LFTs normal
– No abdominal complaints
– Dyspnea stable to slightly improved
– Pruritus improved with moisturizers
– Fatigue stable
F/U = follow-up.
74. Case Study 1: Monitoring and
Response (cont.)
Fourth infusion
– Labs all normal
– Dyspnea improved: Sats increased at 96%
– Erythematous papules on chest and abdomen- (+) pruritus
– Fatigue much improved
CT scans (full body) obtained 4 wks from the time of the
last dose showed minor regression of adenopathy, no
new lesions
Repeat scans 6 wks later showed further response: No
new lesions – patient continues to have slow, but clear
clinical response with improved symptoms, now 5 mos
from his last dose
CT = computed tomography.
76. Case Study 2: History
PL is a 50-yr-old man
PMH: HTN, anxiety
SH: Married, 2 adult children, respiratory therapist.
Non-smoker and social drinker.
FH: Negative for melanoma or pancreatic cancer
Medications: Venlafaxine 75 mg po qd, olmesartan
medoxomil/HCTZ 20/12.5 mg po qd
ALL: ASA → active systemic anaphylaxis
HTN = hypertension; HCTZ = hydrochlorothiazide.
77. Case Study 2 (cont.)
Presents to local dermatologist with a bleeding and
changing mole. Biopsy demonstrated a 2.0 mm,
ulcerated, SSM of the (L) lateral trunk, 8 mitoses/mm2.
He underwent wide excision and sentinel node
evaluation: Drained to both (L) groin and (L) axilla. Final
path – 0 nodes involved. No residual melanoma.
T2bN0Mx – Stage IIA disease
SSM = superficial spreading melanoma.
NCCN, 2012a.
78. Case Study 2: Questions
What treatment options would be discussed
with this patient?
What would be recommended and why?
79. Case Study 2: Treatment Options
Treatment options for stage IIA melanoma
– Observation
– Clinical trial
NCCN, 2012a.
80. Case Study 2: Treatment Course
Patient chose participation in E1697: An
intergroup trial of 1 month of IFN vs. observation
for patients with lower risk for recurrence
He was randomized to IFN arm
– Wk 2: Experienced Grade 3 nausea prompting
holding 2 doses, nausea improved, restarted with
33% DR as per protocol
– Completed the full course of induction receiving all
20 doses
– Followed q3mos with H&P and CXR
IFN = interferon; DR = dose reduction; H&P = history and physical examination.
ClinicalTrials.gov
81. Case Study 2: Monitoring
2 yrs later, patient noted a non-tender lump in (L) axilla
– Upon examination – 2 cm rubbery mobile node, no other palpable
nodes. Location was concerning, but texture not.
– Plan: Re-evaluate in 1 month
1 month later is 3 cm
– FNA obtained same day- (+) for metastatic melanoma
PET-CT and brain MRI: NED other than FDG avid, enlarged (L)
axillary node
Axillary node dissection was performed
Path → met melanoma in 1/15 nodes, with the metastasis
measured at 4.0 cm and ECE noted
Since he had already received IFN, post-operative XRT was
recommended to (L) axilla
FNA = fine needle aspiration; NED = no evidence of disease; FDG = fluorodeoxiglucose avidity;
XRT = radiotherapy; ECE = extracapsular extension.
NCCN, 2012a.
83. Case Study 3: History
30-yr-old man with a history of a 2.3 mm, non-ulcerated nodular,
melanoma of (R) forearm [T3aN0MX: Stage IIA]
2 yrs later: Presents to ER and CXR showed large (L) pleural
effusion
Due to rapid progression of disease, tissue was obtained for BRAF
analysis: No mutation identified (BRAF WT)
Ipilimumab recommended
– Given his otherwise good health
– BRAF WT
– Concern for asthma exacerbation off inhaled corticosteroids and
pulmonary toxicity from IL-2
– Best chance of durable response
Therapy started 1 wk later after insurance approvals were obtained
84. Case Study 3: Monitoring and
Response
Tolerated first infusion well (no issues)
F/U labs notable for increased LFTs (Grade 1)
Second infusion: Increasing dyspnea, labs stable, fatigue
worsening
Third infusion: Dyspnea stable to slightly improved,
pruritus improved with moisturizers, fatigue stable
Fourth infusion: Dyspnea improved, erythematous
papules on chest and abdomen- (+) pruritus, fatigue
much improved
CT scans (full body) obtained 4 wks from the time of the
last dose showed minor regression of adenopathy, no
new lesions
85. Case Study 3 (cont.)
Tolerated 4 doses (induction) ipilimumab no issues
Repeat scans 6 wks later showed further response
– No new lesions: Patient continues to have slow, but clear clinical
response with improved symptoms, now 5 mos from his last
dose
Repeat imaging 8 wks later demonstrated small, but
clear progression of pleura based nodules, and brain
MRI demonstrated a 4 mm cerebellar metastasis
There was no edema, patient remained asymptomatic
from a neurologic standpoint. Slight increase in cough,
but overall, respiratory status was stable from last
evaluation.
86. Case Study 3: Clinical Question
What treatment options are recommended?
– Recall
• Patient is BRAF WT
• Now has a new brain metastasis
• He is young
• No other comorbidities
87. Case Study 3: Treatment Course
CNS: Decision made to proceed with stereotactic
radiosurgery (SRS)
Systemic disease
– Given his initial response to ipilimumab before progression, data
supports re-induction with another
4 cycles
SRS was administered in a single session: Given the
small size of the met, there was little risk of seizure or
edema, thus neither anti-seizure medications nor
steroids were recommended. A 6-wk F/U brain MRI was
scheduled.
NCCN, 2012b.
88. Case Study 3: Treatment Course
(cont.)
1 wk after SRS, he received his first dose of re-induction which he
tolerated without adverse event, but his fatigue was moderate to
severe (Grade 2–3)
Second dose of ipilimumab was held for Grade 3 amylase/lipase,
but without pancreatitis. Labs were repeated bwkly and did resolve
to Grade 1 prior to the third infusion.
6-wk F/U MRI showed response to SRS and no new lesions
He received his fourth dose of induction without further toxicity.
Fatigue stable, cough worse.
Given worsening cough, CTs obtained 1 wk later, demonstrated
stable disease, no new lesions
NCCN, 2012b.
89. Case Study 3: Clinical Question
What are the treatment recommendations for
this patient at your facility?
– Chemotherapy
• CVD + IL-2/IFN (biochemotherapy)
• Carbo/paclitaxel (combination)
• DTIC or temozolomide (single-agent)
– Observation (repeat scans again in some designated
time period: 6, 8, 10, or 12 wks)
– Hospice
NCCN, 2012a.
91. Case Study 4: History
PL is a 50-yr-old man
PMH: HTN, anxiety
SH: Married, supportive wife, 2 children, respiratory therapist.
Non-smoker and social drinker.
FH: Negative for melanoma or pancreatic cancer
Medications: Venlafaxine 75 mg po qd, olmesartan
medoxomil/HCTZ 20/12.5 mg po qd
ALL: ASA → active systemic anaphylaxis
T2bN0Mx – Stage IIA melanoma, patient chose a clinical trial:
E1697: Randomized to IFN for 1 month
92. Case Study 4: Follow-Up
2 yrs later, patient noted a nontender lump in (L) axilla.
Exam: 2-cm rubbery mobile node, no other palpable nodes.
Location was concerning, but texture not. Plan: Re-evaluate in
1 month.
1 month later, the node is 3 cm. FNA obtained same day- (+)
for metastatic melanoma.
PET-CT and brain MRI: NED other than FDG avid, enlarged
(L) axillary node
Axillary node dissection was performed
Path → met melanoma in 1/15 nodes, with the metastasis
measured at 4.0 cm and ECE noted
Since he received IFN, post-operative XRT was
recommended to (L) axilla
NCCN, 2012a.
93. Case Study 4: Follow-Up (cont.)
1 month after XRT completed, patient called to report low back pain “pulled
a muscle”; endorsed severe pain making it difficult to walk
– MRI L-spine: Diffuse bony metastatic disease with destruction of the L4 vertebral
body with pathological fracture and extensive surrounding edema and
enhancement.
– CT: Splenic lesion, 2 small liver lesions – possibly perfusion anomalies vs. mets.
New multiple bilateral pulmonary nodules, the largest in the RLL, ~ 1.3 cm.
– Brain MRI: NED
Palliative XRT to (L) spine planned, and at the same time, BRAF status was
to be obtained
BRAF mutation status returned V600E mutant: Difficulty obtaining drug d/t
insurance issues
Patient did again require admission for intractable pain and nausea
Started vemurafenib while in-house
Ultimately required kyphoplasty X2 to stabilize fractures and subsequently
had placement of intrathecal infusion pump
Remained on vemurafenib for ~ 3 mos. An interval scan showed stable
disease, but repeat imaging demonstrated progression with new brain mets.
Brain MRI: Multiple new small brain mets – largest being 6 mm
RLL = right lower lobe.
NCCN, 2012a.
94. Case Study 4: Clinical Question
What would be the next step at your institution?
What other services may be offered?
95. Case Study 4: Treatment Options
CNS options: WB-XRT vs. SRS
Systemic options: Chemotherapy, immunoRx, BSC
After much discussion, a treatment plan was established
to pursue ipilimumab for the following reasons
– CNS disease was small, patient was asymptomatic
– Given multiple sites, WB-XRT would be recommended vs.
multiple SRS
– Data supporting CNS effect with ipilimumab
WB-XRT = whole brain radiotherapy.
NCCN, 2012b; Margolin et al, 2012.
96. Case Study 4 (cont.)
Patient received his first dose of ipilimumab
at the time of this writing
Remains on 4 mg po dexamethasone for
nausea
– Discussion points:
• Dexamethasone and ipilimumab
• Plans for CNS progression
• Plans for systemic progression
Editor's Notes
Figure adapted from Fong et al, 2008
A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma - Study MDX010-20
Graph adapted from Hodi et al, 2010.
Maint was offered but protocol doesn ’t test necessity Phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) vs DTIC alone as first line treatment in patients with unresectable stage III or IV melanoma - Jedd Wolchok 1 , Luc Thomas 2 , Igor Bondarenko 3 , Steven O ’Day 4 , Jeffrey Weber 5 , Claus Garbe 6 , Stephen Francis 7 , Ramy Ibrahim 8 , Axel Hoos 8 , Caroline Robert 9
Graph adapted from Wolchok et al, 2011.
Presented with permission, Copyright 2011 by C. Lovly, L. Horn, and W. Pao. Lovly, C., L. Horn, and W. Pao. 2012. BRAF. My Cancer Genome http://www.mycancergenome.org/mutation.php?dz=gist&gene=BRAF&code=BRAF-WT (Accessed April 5). Image taken form website: http://www.mycancergenome.org/mutation.php?dz=gist&gene=BRAF&code=BRAF-WT
Graphs need permission from Chapman et al, 2011
Graph adapted from Chapman et al, 2011
Clinical Trial is always a first therapeutic consideration in treatment options for patients , this slide presents a step wise presentation of choices and potential and sound order for selection of potential treatments for patients who are treatment naïve, who are previously treated, pts who have rapidly progressive disease, and potential multi line therapies. Patients who have a lower volume of tumor burden are better candidates for immunotherapy, for they have the time for the immune system to create an immune response. Conversely, those patients with rapidly progressive disease, should be considered for clinical trial, use of targeted agents such as a braf inhibitor (if V600 mutated) or possibly a chemotherapeutic approach in an attempt to control the progression of disease.
Monitoring for disease response in patients on CTLA-4 antibodies is a challenge in that responses may be delayed. Trials demonstrate a therapeutic peak response between 12-24 weeks, and yet some patients have experienced disease progression before regression and others, a delayed response. While no set guideline for monitoring exists, practice should be based on objective response data indicated in the slide and subjective response of the patient. Monitoring should continue beyond disease monitoring criteria. In the NEJM study by Hodi et al. (2010), disease was monitored as follows: at baseline, and all patients who did not have documented early disease progression and who had stable disease or better at week 12 had confirmatory scans at weeks 16 and 24 and every 3 months thereafter.
Eggermont AMM. (2010). Advances in systemic treatment of melanoma. Annals of Oncology, 21(7), 339-344. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23.
Zelboraf, PI, 2012.
Mier, 2011
Boyle, GM. (2011). Therapy for metastatic melanoma: an overview and update. Expert Rev. Anticancer Ther. 11(5), 725-737. Esper, P. Immune Modulation in Melanoma and Advanced Cancer Therapy: Anti-Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA4) Monoclonal Antibodies. Clin J Onc Nsg, 13(5), 547-554, 2009. Mansfield AS, Markovic SN. (2009). Novel therapeutics for the treatment of metastatic melanoma. Future Oncology 5(4):543-557.
Puzanov, I. et al., Biological challenges of BRAF inhibitor therapy, Molecular Oncology (2010), doi:10.1016/j.molonc.2011.01.005 Lacouture, M.E., McArthur, G.A., Chapman, P.B., Ribas, K., Flaherty, K.T., Lee, R.J., et al., 2010. PLX4032 (RG7204), a selective mutant RAF inhibitor: clinical and histologic characteristics of therapy-associated cutaneous neoplasms in a Phase I trial. J. Clin. Oncol. 28 (15 Suppl.) (Abstract No. 8592).
NCI-Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Lin et al, 2008 Lemech, C., & Arkenau, H. T. (2012). Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clinical Medicine Insights.Oncology, 6, 53-66. doi:10.4137/CMO.S5855
NCI, 2011.
Thumar JR, Kluger HM. (2011). Ipilimumab: A promising immunotherapy for melanoma. Oncololgy, 24(14), January. http://www.cancernetwork.comdisplay/article/10165/1771398
Weber, J. (2009). Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. May;58(5):823-30. Ledezma B. (2009). Ipilimumab for advanced melanoma: a nursing perspective. Onc Nurs Forum, 36(1), 97-104. Thumar JR, Kluger HM. (2011). Ipilimumab: A promising immunotherapy for melanoma. Oncololgy, 24(14), January. http://www.cancernetwork.comdisplay/article/10165/1771398 Lemech, C., & Arkenau, H. T. (2012). Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clinical Medicine Insights.Oncology, 6, 53-66. doi:10.4137/CMO.S5855
Kaehler, K. C., Sondak, V. K., Schadendorf, D., & Hauschild, A. (2009). Pegylated interferons: Prospects for the use in the adjuvant and palliative therapy of metastatic melanoma. European Journal of Cancer (Oxford, England : 1990), 46 (1), 41-46. doi:10.1016/j.ejca.2009.10.004
Figure 8. Hypophysitis with thickened pituitary gland and stalk.