Cutaneous Melanoma. Introduction melanocytes reside at the dermal/epidermal junction When melanoma arises in the skin, it usually arises from melanocytes.
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Slide 1
Cutaneous Melanoma
Slide 2
Introduction melanocytes reside at the dermal/epidermal
junction When melanoma arises in the skin, it usually arises from
melanocytes at the dermal /epidermal junction.
Slide 3
There are alternate presentations, 1. mucosal melanomas, 2.
ocular melanomas, 3. metastatic melanomas from unknown primary
sites 4. presumed primary visceral melanomas. Each of these has
significant differences in presentation and management.
Slide 4
The management of malignant melanoma involves prevention, early
diagnosis, surgical extirpation, and combination management of
metastatic disease.
Slide 5
Cutaneous Melanoma Biology The transition from melanocyte to
metastatic melanoma involves several histologic intermediates,
including : 1. melanocytic atypia, 2. atypical melanocytic
hyperplasia, 3. radial growth phase melanoma, 4. vertical growth
phase melanoma, 5. metastatic melanoma.
Slide 6
The RGP : melanoma in situ (MIS) or superficial invasion into
the papillary dermis, or both. rarely symptomatic ideal time to
diagnose melanoma, these lesions typically progress to the
VGP,
Slide 7
RGP very low metastatic capacity. an excellent prognosis
mortality risk at the low end of the 0% to 5% range.
Slide 8
VGP Risk of melanoma progression is most associated with the
presence of VGP, the depth of invasion, and other markers of the
malignant phenotype in the VGP component of a melanoma.
Slide 9
the extent of RGP (e.g., clinically, the diameter of the skin
lesion) and multiplicity of RGP lesions are not associated with
significant risk of metastasis or melanoma-associated
mortality
Slide 10
some melanomas are nonpigmented Others develop a VGP in the
absence of a RGP (nodular melanoma histology), some melanomas
present as metastatic melanoma in lymph nodes, skin, subcutaneous
tissue, or visceral sites without an apparent primary cutaneous
site.
Slide 11
Epidemiology sixth-most-common U.S. cancer diagnosis Overall
5-year survival rates for melanoma have increased from 82% in the
late 1970s (1975 to 1977) to 92% in the more recent era (1996 to
2002). a combined effect of ultraviolet (UV) sunlight exposure and
fair skin
Slide 12
Ocular and nonacral cutaneous melanomas are 50- to 200- fold
more likely in white populations than in nonwhite populations, but
melanomas in acral and mucosal sites are within twofold of each
other across racial groups.
Slide 13
Recent data suggest significant molecular differences between
acral melanomas and melanomas arising on the skin associated with
chronic sun damage, with B-RAF and N-RAS mutations in 81% of
melanomas on chronically sun-damaged skin, whereas those mutations
were uncommon in melanomas from acral or mucosal sites or from skin
without chronic sun damage.
Slide 14
Changes in Incidence An increase in age-adjusted melanoma A
greater proportion of patients diagnosed at earlier and noninvasive
stages of disease.
Slide 15
Gender and Age Distribution the gender ratio of melanoma at
diagnosis is approximately 1:1 but is shifting toward a greater
proportion of men
Slide 16
Melanoma in Children, Infants, and Neonates Current
recommendations for management of melanoma in children and infants
are the same as for adults, and outcomes are generally believed to
be comparable.
Slide 17
Anatomic Distribution The most common sites in males are on the
back and in the head and neck regions. In women, the most common
sites are in the lower extremities, commonly below the knee.
Lentigo maligna melanoma (LMM) most commonly arises on sun-damaged
surfaces of the head and neck in older patients.
Slide 18
Etiology and Risk Factors ultraviolet light exposure the
relative role of each type of UV irradiation in melanoma etiology
is debated. a combination of fair skin that burns easily and high
ultraviolet/sun exposure The role of sunlight intensity and
frequency is debated, but both chronic and intermittent exposure
may be relevant
Slide 19
Therapeutic Radiation as a Risk Factor for Melanoma Radiation
doses greater than 15 Gy delivered to pediatric oncology patients
has been shown to increase the risk of developing malignant
melanoma In children undergoing scalp irradiation for tinea
capitis, scalp basal cell carcinomas were reported to be 30 times
more likely to develop than melanomas in adulthood.
Slide 20
Pregnancy and Estrogen Use no evidence of any negative (or
positive) impact of prior, concurrent, or subsequent pregnancy on
clinical outcome. no clear prognostic relevance for birth control
pills or estrogen replacement therapy.
Slide 21
Pregnancy The general recommendation for treatment of women
with melanoma diagnosed during pregnancy is to manage them in the
same fashion as nonpregnant patients.
Slide 22
Pregnancy There is no evidence that a subsequent pregnancy
adversely impacts outcome. Measures of the risk of future disease
progression can be defined based on the initial prognosis and the
subsequent elapsed time without recurrence, and such information
may help to guide patients with this challenging question.
Slide 23
Prevention and Screening Sun Protection Screening for Early
Diagnosis Self-Examination Management of the Patient with Numerous
Atypical Moles
Slide 24
Sun Protection Ultraviolet exposure and sunburns, in
particular, appear to be etiologic in most melanomas. there is no
formal proof that sunscreens prevent melanoma.
Slide 25
There are some limitations inherent in sunscreen use.
Slide 26
Screening for Early Diagnosis Self-Examination family members
educating patients dermatology visits
Slide 27
Management of the Patient with Numerous Atypical Moles atypical
mole syndrom dysplastic nevus syndrome B-K mole syndrome. These
patients have a heightened risk of melanoma, and this is commonly a
familial feature.
Slide 28
Management of the Patient with Numerous Atypical Moles These
patients deserve particular attention to melanoma prevention
through sun protection and to early diagnosis through aggressive
screening. routine skin exams by a dermatologist are usually
recommended, as often as every 3 months. dermoscopy(epiluminescent
microscopy)
Slide 29
It is tempting to consider excision of all dysplastic nevi.
Melanomas may arise de novo in 30% to 70% of cases, and so it is
not clear that removal of all suspicious nevi will lead to a
meaningful improvement in survival. However, it is certainly
appropriate to biopsy any nevus that is suspicious, especially one
that is changing.
Slide 30
Diagnosis of Primary Melanoma Characteristics of Primary
Melanoma ABCD for asymmetry, border irregularity, color variation,
and diameter greater than 6 mm a wide range in the appearanc change
in a lesion over time or new development of a lesion ugly duckling
sign:amelanotic (nonpigmented) Being different: amelanotic
(nonpigmented)
Slide 31
hallmarks of a late diagnosis symptomatic, Bleeding Itching
pain ulceration these usually connote deep vertical growth
Slide 32
Biopsy a full-thickness biopsy of the entire lesion, with a
narrow (1 to 2 mm) margin of grossly normal skin. The depth of
excision should include the full thickness of dermis and thus
should be within the subcutaneous tissue, desmoplastic melanoma
often arises from lentigo maligna melanoma and is difficult to
diagnose both clinically and histologically. Shave biopsies of
these lesions can often lead to failure to appreciate the
desmoplastic melanoma in the dermis and may substantially delay
diagnosis
Slide 33
For some large lesions (e.g., greater than 2 cm diameter) in
cosmetically sensitive locations (e.g., face or genitalia), there
may be a rationale for an incisional biopsy, but that also should
be performed as a full-thickness skin biopsy. Ideally, it should
include the most suspicious area of the lesion and also should
include if possible a portion of the edge of the lesion, where it
transitions to normal skin, to enable assessment of the junctional
change. The incisional biopsy may be an elliptical incision or it
may be a full- thickness 4- to 6-mm punch biopsy..
Slide 34
Punch biopsies are problematic if too small, if they do not
include full-thickness skin, if they are crushed during removal, if
they are oriented inaccurately in the paraffin block, or if they
are too small to include both the edge of the lesion and the most
suspicious or most raised part of the lesion
Superficial Spreading Melanoma The most common type It is
typical for the trunk and extremities, except on acral sites.
associated with pagetoid growth of atypical melanocytes in the
epidermis. associated with sun exposure
Slide 37
Nodular Melanoma Nodular melanomas (NMs) lack a radial growth
phase, may be nonpigmented, worst prognosis
Slide 38
Acral Lentiginous Melanoma acral sites (subungual, palmar,
plantar) and on mucosal surfaces (anorectal, nasopharyngeal, female
genital tract). independent of ultraviolet light exposure a
prolonged radial growth phase before vertical growth harder to
diagnose DDx subungual hematomas, which can lead to diagnostic
delay
Slide 39
Lentigo Maligna Melanoma older individuals sun-damaged skin,(
face). an extensive radial growth phase When just melanoma in situ,
this radial growth phase portion is called lentigo maligna (LM) or
Hutchinson's freckle,
Slide 40
Lentiginous Melanoma Early radial growth phase melanomas Over
time, this may represent a growing proportion of melanomas that
have traditionally been grouped as SSM, LM, ALM, or unclassified
melanomas.
Slide 41
Desmoplastic Melanoma histologically manifested by dermal
melanocytes in a dense stromal response usually nonpigmented
usually stain negative for MART-1/MelanA, gp100, and tyrosinase,
but they do stain for S-100. most commonly in the head and neck de
novo as a nonpigmented skin papule or as a dermal/vertical growth
phase component arising from a pre-existing lentigo maligna or
other pigmented junctional lesion
Slide 42
Desmoplastic Melanoma a high rate of local recurrence the risk
of lymph node metastasis is lower a higher threshold for performing
sentinel node biopsy (SNBx) in patients with pure desmoplastic
melanoma.
Slide 43
Prognostic Factors for Primary Melanomas Depth of Invasion
Ulceration age, angiolymphatic invasion mitotic rate Gender body
site
Slide 44
Depth of Invasion Clark defined depth based on the layer of
skin to which the melanoma has invaded. 1. Clark level I melanomas
are melanomas in situ, limited to the epidermis or dermal/epidermal
junction 2. Clark level II melanomas invade into the superficial
(papillary) dermis, and these are usually radial growth phase
lesions. 3. Clark level III melanomas fill the papillary dermis 4.
Clark level IV melanomas invade into the deep (reticular) dermis
and have significant metastatic risk. 5. Clark level V melanomas
are uncommon and contain invasion into the subcutaneous fat.
Slide 45
for thin melanomas, Clark level IV or V is associated with
higher risk. Breslow thickness has an effect on survival, local,
regional, and systemic recurrence rates, Thickness is considered in
defining the margins of excision for primary melanomas.
Slide 46
Ulceration as an important negative prognostic feature is
incorporated in the current staging system the overall stage
assignment groups ulcerated lesions with nonulcerated lesions one T
level higher (e.g., T2b and T3a are both stage IIA).
Slide 47
Melanoma TNM Classification
Slide 48
Tumor (T) TX:Primary tumor cannot be assessed (e.g., shave
biopsy or regressed) T0:No evidence of primary tumor Tis:Melanoma
in situ T1:1 mm in thickness (a. without ulceration or b. with
ulceration or level IV or V) T2:1.012 mm in thickness (a. without
or b. with ulceration) T3:2.014 mm in thickness (a. without or b.
with ulceration) T4:>4 mm in thickness (a. without or b. with
ulceration)
Slide 49
Nodes (N) N1: 1 lymph node (a. micrometastasisa or b.
macrometastasisb) N2: 23 lymph nodes (a. micrometastasisa or b.
macrometastasis) c. Satellite or in-transit metastasis without
nodal metastasis N3: 4 nodes; matted nodes; or in-transit
metastasis or satellites with metastasis in regional node(s)
Slide 50
M1a Skin, subcutaneous tissues, or distant nodes M1b Lung M1c
All other visceral or any distant metastasis with elevated LDH
Slide 51
Pathological Stage Grouping for Cutaneous Melanoma C STAGING P
STAGING IA T1aN0 M0 IA T1a N0 M0 IB T1b-T2aN0 M0 IB T1b-T2aN0 M0
IIA T2b, T3aN0 M0 IIA T2b, T3aN0 M0 IIB T3b, T4a IIB T3b, T4a IIC
T4b IIC T4b
Slide 52
III Any T Any N IIIA T1-T4a N1a T1-T4a N2a IIIB T1-T4b N1a
T1-T4b N2a T1-T4a N1b T1-T4a N2b T1-T4a,b N2c IIIc T1-T4b N1b
T1-T4b N2b Any T N3
Slide 53
IV Any TAny NAny M M1a M1b M1c
Slide 54
Clinically undetectable nodes are those diagnosed only with
sentinel node biopsy or elective lymphadenectomy. They are referred
to also as micrometastases, Clinically detectable nodes are also
referred to as macrometastases,
Slide 55
Patient Gender and Skin Location of Primary Melanoma for
essentially all patient subgroups, the prognosis is better for
women than men. Women are more likely to have melanomas on the
extremities, the prognostic impact of gender is difficult to
distinguish from the impact of tumor location.
Slide 56
Patient Age The impact of age on prognosis is confusing There
is a greater risk of lymph node metastasis in young patients at the
time of sentinel node biopsy, especially for patients younger than
age 35 years, but the melanoma- associated mortality risk increases
with age for all thickness ranges. Nonetheless, age does appear to
have independent prognostic significance for melanoma
patients.
Slide 57
Growth Pattern nodular melanomas have the worst prognosis,
associated with their diagnosis at a thicker stage..
Slide 58
Mitotic Rate six or more mitoses per square millimeter.
Ki67
Slide 59
Other Prognostic Factors angiolymphatic invasion has negative
prognostic significance microscopic satellites
Slide 60
Unresolved Issues in Melanoma Staging Positive Deep Margin on
Biopsy Local Recurrence after Original Incomplete Excision Skin or
Subcutaneous Lesion without Junctional Involvement and without
Known Primary Melanoma
Slide 61
Positive Deep Margin on Biopsy One approach for defining T
stage in that setting is to call it TX. The other is to use the T
stage of the original depth, even though that is incomplete
Slide 62
Thus, use of TX results in substantial loss of information for
patients and their clinicians. The best solution is to avoid shave
biopsies, but when they occur, it seems reasonable to stage based
on the thickness level that is known, when no residual tumor is
found on wide excision, while also noting that there was a positive
deep margin
Slide 63
Local Recurrence after Original Incomplete Excision Some
patients present with melanoma after excisional biopsy or
destruction (e.g., cryotherapy) of a pigmented skin lesion that was
believed to be benign (clinically or histologically) on initial
review. When such a lesion recurs and is found to contain melanoma,
re-review of the original biopsy is appropriate, if available.
Staging of such recurrent melanomas, when the original lesion was
not known to be melanoma, is not well addressed.
Slide 64
Skin or Subcutaneous Lesion without Junctional Involvement and
without Known Primary Melanoma Cutaneous or subcutaneous nodules
that occur in the absence of junctional melanocytic change, and in
the absence of any other known primary They may be in-transit
metastases from primary melanomas that spontaneously regressed
(stage IIIB), primary melanomas that arose from dermal nevi or that
persisted in the dermis after arising from a partially regressed
primary melanoma (stage IIB), or a distant metastasis from an
unknown primary melanoma (stage IV, M1a).
Slide 65
A review of experience with these lesions at the University of
Michigan suggests that these are best staged as stage IV by strict
application of AJCC terms, but that they behave more like primary
tumors arising in the dermis or subcutaneous tissue.
Slide 66
General Considerations in Clinical Management of a Newly
Diagnosed Cutaneous Melanoma (Stage I-II ) histologic assessment of
skin biopsy presents to a surgeon(T) definitive surgical management
therapeutic resection and pathologic staging evaluation for
regional metastases (N)
Slide 67
Clinical Evaluation and Radiologic Studies for Patients with
Clinical Stage I-II Melanoma A complete history and physical exam
Baseline chest x-ray (CBC), for serum chemistries: LFT, and (LDH)
PET
Slide 68
microcytic anemia, /GI metastasis of melanoma. Elevated LDH
should prompt a more extensive staging workup, and elevated liver
function tests should prompt a hepatobiliary ultrasound or computed
tomography (CT) scan unless there is another known
explanation.
Slide 69
PET gained an appropriate role in staging patients with
advanced melanoma,
Slide 70
The Memorial Sloan-Kettering experience recommends limiting
aggressive staging workup (CT scans, PET, magnetic resonance
imaging [MRI] of the brain, etc.) after positive SNBx to those
patients with thick melanomas and macrometastases.
Slide 71
Wide Local Excision for Clinical Stage I-II Melanoma: General
Considerations WLE for: 1. local control 2. an opportunity to
evaluate the tissue adjacent to the primary lesion for microscopic
satellites, which, if present, have clinical and prognostic
significance.
Slide 72
Appropriate margins of excision for primary melanomas,
Slide 73
Intergroup Melanoma Trial: a 2-cm margin as adequate for
melanomas 1 to 4 cm thick? ulceration of the tumor and
head-and-neck location as significant negative prognostic
features.
Slide 74
British Cooperative Group Trial excision greater than 1 cm for
thicker melanomas? The data from the Melanoma Intergroup study
support 2-cm margins for melanomas 2 to 4 mm thick. No data have
formally compared 2-cm margins to 3-cm margins for T4
melanomas.
Slide 75
Surgical Staging of Regional Nodes patients who have metastatic
disease limited to local and regional sites have substantial chance
for cure ELND technique of lymphoscintigraphy to map the actual
lymphatic drainage patterns
Slide 76
blue dye radiocolloid lymphoscintigraphy gamma probes
Slide 77
radiocolloid lymphoscintigraphy alone There is a substantial
multicenter and single-center experience with use of radiocolloid
alone, which is associated with successful identification of the
sentinel node(s) in greater than 99% of patients and with a mean of
approximately two sentinel nodes per patient.
Slide 78
blue dye alone The effectiveness of blue dye alone is limited
because some patients have drainage to lymph node basins that may
not be predicted (e.g., drainage from the right upper back to the
left axilla) or drainage to atypical nodal basins (e.g., the
triangular intermuscular space on the back, epitrochlear or
popliteal nodes, or subcutaneous in-transit nodes that are outside
a traditional nodal basin).
Slide 79
In experienced hands, lymphatic mapping should identify a
sentinel node in 98% to 100% of cases, and it should be feasible to
perform the sentinel node biopsy with minimal morbidity, on an
outpatient basis, and in many cases under local anesthesia with
sedation. The early reports of sentinel node biopsy stress a long
learning curve, but as the technology of gamma probes has improved,
the technique is less operator dependent.
Slide 80
Slide 81
Slide 82
advantages (1) It avoids the morbidity of complete node
dissection for patients without metastatic nodal disease, (2) it
provides to the pathologist a very limited amount of tissue for
examination. The rate of missed micrometastases is in the range of
10% to 20% of patients. In contrast, the standard evaluation of a
sentinel node includes evaluation of multiple sections of the node,
often combined with immunohistochemical staining for melanoma
markers (e.g., S100, HMB45, tyrosinase, and/or MART-
1/MelanA).
Slide 83
with increasing tumor thickness increases rate of positive
nodes In addition, the low morbidity of SNBx supports a threshold
for SNBx in thinner melanomas than the 1.5-mm criterion that was
used for performance of ELND.
Slide 84
The overall rate of positive SNBx : 15% to 25%. false-negative
SNBx :1.9% to 4%.
Slide 85
false-negative ELND SNBx
Slide 86
FN seeking nodes containing metastases in the remaining nodal
basin after a negative sentinel node biopsy by defining patients
who return with clinically evident nodal metastases after a prior
negative SNBx in the same node basin. it is prudent to follow
patients for nodal recurrence even after a negative SNBx.
Slide 87
FN Thus, the rate of regional control after negative SNBx is
similar to that after ELND, with lower morbidity
Slide 88
RT-PCR Another approach under investigation is to perform
molecular analysis of sentinel nodes. Reverse
transcriptase-polymerase chain reaction (RT-PCR) assay for
melanocytic differentiation proteins (e.g., gp100 and tyrosinase)
and cancer-testis antigens (e.g., MAGE-A3) permits detection of
cells containing those molecules, even when they are present below
the limit of detection for current histopathologic sampling and
immunohistochemistry.
Slide 89
In performing SNBx, melanoma metastases are sometimes
clinically evident in the operating room as small pigmented spots
just under the capsule of the node. This may be particularly
relevant for some large nodes, where the pathologist can be guided
to the portion most at risk of metastasis for detailed histologic
assessment
Slide 90
RT-PCR Early experience with RT-PCR analysis of sentinel nodes
suggested a significant negative prognostic value for RT-PCR
positive, histology-negative nodes, and suggested that patients
with RT-PCR negative, histology-negative nodes have a remarkably
high survival rate.
Slide 91
SNBx or observation in addition to WLE
Slide 92
The rationale for performing SNBx for melanoma includes the
following: 1. A negative sentinel node biopsy is a good prognostic
indicator that may help low-risk patients feel less vulnerable,
especially in the setting of stage I melanomas, in which the
prognosis is excellent. 2. A positive sentinel node biopsy for
patients with T1-T3a clinically N0 melanomas (clinical stage I-IIA)
renders them candidates for adjuvant high-dose interferon therapy,
which offers some clinical benefit
Slide 93
The rationale for performing SNBx for melanoma includes the
following: 3.Patients with T4 melanomas or with microscopic
satellites (N2c, stage IIIB) are further up- staged by the finding
of a positive sentinel node, which helps these patients in risk
assessment and may make them candidates for selected clinical
trials 4.Many clinical trials require surgical staging of regional
nodes, and, thus, sentinel node mapping makes patients candidates
for trials that may prove to be of benefit. 5.Identification of
melanoma in a sentinel node permits selection of patients for
completion lymph node dissection to increase the chance of regional
tumor control. 6.In patients who are not good candidates for
general anesthesia, excision of the sentinel node may be curative
if there is no tumor beyond the node, even if completion node
dissection is not feasible
Slide 94
Lymphatic mapping and SNBx has been applied generally for all
cutaneous sites and may also be useful for melanomas of mucous
membranes. A challenging area for SNBx is the head and neck. FN
sentinel node biopsies are more
Slide 95
Selection of Patients for Sentinel Node Biopsy Sentinel node
biopsy is generally recommended for patients with melanomas at
least 1 mm thick Desmoplastic melanomas
Slide 96
Sentinel Node Biopsy Subsequent to a Prior Wide Local Excision
Sentinel node biopsy should be performed at the same procedure as
WLE performing SNBx after prior WLE, although performing it
concurrent with the original WLE is preferred
Slide 97
Management of Clinically Localized Melanoma
Slide 98
Management of Melanoma in situ (Clinical TisN0M0, Stage 0) wide
excision alone. regional nodes should be examined, as should the
skin and subcutaneous tissue between the primary site and these
regional node basins. No radiologic staging studies. A 5-mm margin
or 1 cm, If the margins are positive or close, re-excision to a
widely clear margin is recommended SNB is not indicated. No
adjuvant therapy is needed if the margins are widely clear.
Slide 99
Clinical Follow-Up after Surgical Treatment of Melanoma in Situ
rarely may be associated with metastasis, NCCN :follow these
patients for local recurrence, in-transit metastasis, or regional
node metastasis on an annual basis. physical exam
Slide 100
Management of Thin Primary Melanoma (Clinical T1a) studies have
shown a continuous risk association with increasing thickness,
without an absolute cutoff at 0.76 mm, 1. less than 1 mm thick 2.
Clark level of III or less 3. without ulceration.
Slide 101
Melanoma Stage Clinical Follow-Up a Radiologic and Laboratory
Follow-Up 0 Annual None needed IA Annual CXR, CBC, LDH annually; CT
scan or other radiologic workup of new findings
Slide 102
IB-IIA Every 3-6 mo, 3 y, then 4-12 mo, 2 y, then annually CXR,
LDH, and CBC every 6-12 mo; CT scan or other radiologic workup of
new findings
Slide 103
IIB-IIIA Every 3- 6 mo, 3 y then 4-12 mo,2 y, then annually
CXR, LDH, and CBC every 6- 12 mo; CT scan or other radiologic
workup of new findings; if lower-extremity primary, CT pelvis or
PET-CT to evaluate iliac nodes
Slide 104
IIIB-IIIC Every 3-6 mo, 3 y, then 4-12 mo,2 y, then annually
CXR, LDH, and CBC every 6- 12 mo; CT scan or other radiologic
workup of new findings; if inguinal nodes had been involved, get CT
pelvis (or PET-CT) every 6- 12 mo
Slide 105
IV Every 2-3 mo, 2 y, then every 3-6 mo 3 y, then annually CT
or PET-CT, plus MRI brain, LDH, and CBC every 3-6 mo, especially in
areas of prior metastases
Slide 106
A thin melanoma should be examined with a focus on the primary
site, the regional nodal basins, and in-transit locations, and a
history should elicit any findings that may lead to suspicion of
metastases (e.g., weight loss, fatigue, bone pain, headaches,
change in appetite (clinical T1a) do not need aggressive radiologic
staging studies. (CXR) and an LDH level are adequate
Slide 107
T1a :wide excision with a 1-cm margin (including skin and all
underlying subcutaneous tissue, to thedeep fascia). The margin
should be measured from the visible edge of the pigmented lesion or
from the biopsy scar, whichever is larger. Excisions of this size
can almost always be closed primarily, with exceptions being on the
face, palms, and feet, where skin grafts or rotation flaps may be
needed.
Slide 108
Surgical Methods in Wide Local Excision (Applies for All
Primary Melanoma Thicknesses) For melanomas of the trunk and
proximal extremities, wide local excisions should involve measuring
the appropriate margin (usually 1 to 2 cm) around the entire scar
from the biopsy On the upper back, it is usually best for the scar
to run transverse, to minimize tension on it.
Slide 109
T1a lesions (nonulcerated, Clark II-III), sentinel node biopsy
is not routinely recommended. when the initial biopsy is a shave
biopsy,sentinel node biopsy should be considered. However, if there
is no gross residual tumor, it is reasonable to proceed with a 1-cm
margin re- excision
Slide 110
Clinical Follow-Up for Thin Melanomas (Stage IA) annual
follow-up for many years is recommended rather than frequent
follow-up in the first few years.
Slide 111
Management of Clinical T2a, T2b Melanomas 1. an initial history
and physical exam 2. CXR and LDH. 3. wide excision with a 1- to
2-cm margin 4. sentinel node biopsy
Slide 112
T2a, T2b When it is feasible to take a 2-cm margin without a
skin graft (trunk and proximal extremities in most cases), this is
recommended to minimize the chance of local recurrence on the face
or distal extremities, a 1- to 1.5-cm margin is acceptable. If a
skin graft will be necessary even to close a 1-cm margin (rare), it
is recommended that a 2-cm margin be taken because the morbidity
and cost of the skin graft will already be needed. for lesions that
are barely above 1 mm in depth (e.g., 1.05 mm), it certainly is
reasonable to use a 1-cm margin.
Slide 113
If the sentinel node biopsy is positive: TX for stage IIIA
melanoma (T2a with positive sentinel node biopsy involving one to
three nodes) or stage IIIB melanoma (T2b with positive sentinel
node biopsy involving one to three nodes).
Slide 114
However, if the sentinel node biopsy is negative, then the
patient is considered to have been pathologically staged as T2aN0M0
(stage IB) or T2bN0M0 (stage IIA
Slide 115
Management of Clinical T3a Melanomas (Clinical Stage IIA) a
history and physical examination a CXR and serum LDH level wide
excision with a 2-cm margin sentinel node biopsy negative, then no
additional surgical or systemic therapy is indicated positive, then
management for stage IIIA melanoma should be followed.
Slide 116
Management of Clinical T3b Melanomas (Clinical Stage IIB)
high-risk localized melanomas a careful history and physical
examination at least a CXR and serum LDH level Given the higher
risk of synchronous metastases that may be detected at diagnosis,
more aggressive systemic staging to include CT scans of the chest,
abdomen, and pelvis (or PET-CT scan) plus MRI scan of the
brain.
Slide 117
Clinical T3b definitive management is wide excision with a 2-cm
margin and a sentinel node biopsy. IIB (T3bN0M0): no additional
surgical therapy is needed. HDI it is available for such patients,
whose risk is comparable to that of patients with nonulcerated
thick melanomas (T4aN0). Patients with stage IIB melanoma often are
also candidates for some experimental adjuvant systemic
therapies
Slide 118
Management of Thick Melanomas (T4a, T4b, Greater Than 4 mm
Thick) a risk of metastasis and mortality in the range of 50% over
5 to 10 years. Ulceration increases this risk T4a melanomas are
clinical stage IIB T4b melanomas are clinical stage IIC.
Slide 119
T4a, T4b history and physical examination CXR, and serum LDH
more-aggressive radiologic imaging as indicated by signs and
symptoms.
Slide 120
T4a, T4b Definitive management includes wide excision with at
least a 2-cm margin plus sentinel node biopsy. strong data
supporting the adequacy of 2-cm margins in 1- to 4-mm melanomas may
be extrapolated to thicker lesions.
Slide 121
T4a, T4b most studies show that sentinel node status has
independent prognostic value for patients with thick melanomas.
Because these patients have a high risk of sentinel node positivity
(approximately 35% to 40%), there is a high chance of regional
nodal recurrence, and sentinel node biopsy, followed by completion
lymph node dissection, offers the prospect of increasing the chance
of regional control.
Slide 122
T4a, T4b In patients with negative sentinel nodes, adjuvant HDI
should be considered because it is approved by the U.S. Food and
Drug Administration (FDA) for these patients.
Slide 123
Special Considerations in Management of Primary Melanomas
Primary Melanomas of the Head and Neck Primary Melanomas of the
Mucous Membranes Primary Melanomas of the Fingers and Toes
Slide 124
Primary Melanomas of the Head and Neck anatomic constraints:the
optimal margins should be obtained and closed with an advancement
flap, skin graft, or limited rotation flap. a large-diameter
lentigo maligna on the face that is not amenable it may be treated
with superficial or Grenz x-rays with local control rates reported
above 90%. topical treatment with imiquimod ointment have also
resulted in effective local control of superficial melanomas.
Slide 125
Desmoplastic melanomas commonly occur in the head and neck
region and may have reported local recurrence rates up to 40% to
60% after resection
Slide 126
High local recurrence rates in desmoplastic melanoma : Anatomic
constraints in the head and neck amelanotic, histologic appearance
of desmoplastic melanoma, especially in fibrotic skin. Thus, in
patients with desmoplastic melanoma, every effort should be made to
obtain adequate margins. If that is not possible, postoperative
adjuvant radiation should be considered with 2- to 3-cm margins
around the resected lesion because this may reduce subsequent local
recurrences.
Slide 127
Neurotropic melanomas of the head and neck have a propensity to
recur at the skull base by tracking along cranial nerves, and
postoperative adjuvant radiation including the resection bed and
the cranial nerve pathway should be considered for this
variant
Slide 128
Primary Melanomas of the Mucous Membranes Mucosal melanomas of
the head and neck, anorectal region, and female genital tract are
usually diagnosed when they are thick. They are associated with
high risks of distant metastases and death, approaching 100%. They
are also associated with high risks of local recurrence and
regional nodal metastases. The depth of invasion is difficult to
measure because they are often biopsied in a fragmented way, but
they usually are deep lesions, with depths often of 1 cm or
more.
Slide 129
Primary Melanomas of the Mucous Membranes They should be
resected with wide margins if possible. Resection of melanomas of
the nasopharynx, oropharynx, and sinuses is limited by the bony
structures of the skull and the base of the brain. Vulvovaginal
melanomas may be widely resected in many cases but may also be
constrained by efforts to preserve urinary and sexual function.
They may also be associated with extensive radial growth in
addition to the invasive lesion, which can lead to multifocal local
recurrences. Anorectal melanoma may usually be resected widely by
an abdominoperineal resection, but this morbid operation is not
associated with higher survival rates than local excision only.
Adjuvant local radiation therapy may be of value when widely clear
margins are not feasible.
Slide 130
Primary Melanomas of the Mucous Membranes RT? SNB?
Slide 131
Mucosal melanomas their response to interferon therapy?
Slide 132
Primary Melanomas of the Fingers and Toes Subungual melanomas
Tx: amputation at the interphalangeal joint of the toe,Even for in
situ For melanoma of the toe, amputation of the toe) exception is
the great toe( occasionally :wide excision and skin grafting SNB
:at least T1b lesions
Slide 133
Clinical Follow-Up for Intermediate-Thickness Melanomas (Stage
IB-IIA) history and focused physical exam :every 3 months
-annually, CXR, LDH, and CBC at least annually, other scans 1.
Symptoms 2. high-risk primary (e.g., T4b) on the lower extremity 3.
pelvic CT scan orPET-CT :in identifying iliac nodal 4. brain
MRI
Slide 134
Stage IB-IIA Recurrences: local skin, in-transit skin, or lymph
nodes visceral metastasis : lung and liver, GI, brain, bone,
distant skin or nodes, and adrenal glands headaches, weight loss,
change in appetite, bone pain, or other symptoms that could be
associated with these metastatic sites. The diagnostic yield of
laboratory tests is low, but elevations of LDH or other liver
function tests may signal a liver metastasis or other new
metastasis. New microcytic anemia can be a first sign of
gastrointestinal blood loss due to a small bowel metastasis.
Slide 135
Regionally Metastatic Melanoma (Stage III): Lymph Node
Metastasis, Satellite Lesions, and In-Transit Metastases a high
propensity to regional metastasis a negative prognostic there is
some chance of long-term disease-free survival and cure for
patients with regional metastases, and they should be managed with
curative intent whenever feasible.
Slide 136
Regional metastases are defined as follows: Local recurrence is
best defined as recurrence of melanoma in the scar from the
original excision or at the edge of the skin graft if that was used
for closure. Satellites metastases either may occur simultaneous
with the original diagnosis or arise subsequent to original
excision. Typically, recurrences that are separate from the scar
but within 2 to 5 cm of it are considered satellite metastases
Slide 137
Regional metastases Regional recurrences beyond 5 cm of the
scar but proximal to regional nodes are considered in-transit
metastases Regional node metastases are typically in a draining
nodal basin that is near the lesion.
Slide 138
Slide 139
Slide 140
Management of Local Recurrence Local recurrence is common after
a primary lesion is inadequately excised. This type of local
recurrence thus represents a failure of initial surgical management
and may not represent the same high risk of distant metastasis and
mortality that is associated with local recurrence after what is
otherwise considered adequate surgical resection
Slide 141
Management of Local Recurrence re-resect the entire scar down
to the level of fascia, and perhaps including fascia, because there
may be more tumor in the scar than is clinically evident, and this
type of resection can generally be performed with minimal
morbidity. Excision with a 1- to 2- cm margin is reasonable if the
recurrences are limited to the scar satellite metastases, more
extensive resection may be appropriate, with a skin graft In
patients with concurrent distant disease, a less aggressive
approach to the local recurrence may be justified, and simple
excision to a clear margin may be acceptable.
Slide 142
Management of Local Recurrence SNB This is usually successful
even if there has been a prior sentinel node biopsy or even a prior
complete lymph node dissection. This may enable regional control in
such high-risk patients, in whom the sentinel nodes may be positive
in up to 50% of cases.
Slide 143
Unresectable recurrent lesions should be considered for
palliative radiation therapy.
Slide 144
Management of Satellite and In-Transit Metastases clinical
outcomes similar to with palpable nodal metastases. When a patient
presents with a solitary in-transit metastasis or a localized
cluster of in-transit metastases it is reasonable to perform
excision of this along with sentinel node biopsy. The margin of
excision should be adequate to obtain free margins. This usually
requires a 5- to 10-mm margin. A fairly frequent clinical scenario
that is difficult to manage is the patient with multiple in-transit
metastases.
Slide 145
Satellite and In-Transit Metastases there is no reliable
systemic therapy for this process surgery remains the first best
option for regional control, when feasible
Slide 146
Satellite and In-Transit Metastases to excise them under local
anesthesia. Follow-up every 2 to 3 months new, small in-transit
metastases often can be excised For the isolated in-transit
metastases:sentinel node biopsy Radiation therapy should be
considered after surgical resection in this setting
Slide 147
Regional options for satellite and In-Transit Metastases
Intralesional therapy with 1. Interferon - 2. Interleukin -2 3.
Bacillus Calmette-Guerin (BCG) 4. Topical treatment of superficial
metastases with imiquimod
Slide 148
Management of Satellite and In-Transit Metastases Usual
recommendations : 1. limited excisions 2. If that fails isolated
limb perfusion or infusion 3. Amputation of the extremity?
Slide 149
Isolated Limb Perfusion and Infusion Melphalan TNF- complete
responses in 60% to 90% of patients, Retreatment with isolated limb
perfusion or infusion
Management of Regional Lymph Node Metastases prognosis is
related to tumor burden in the nodes and the number of nodes
involved with tumor. clinically occult metastases (sentinel node
positive, clinically negative) and clinically positive (palpable)
metastatic nodes. This was a significant prognostic
distinction.
Slide 152
Management of Patients after a Positive Sentinel Node Biopsy
(Stage IIIA If Nonulcerated Primary Lesion, One Positive Node
)
Slide 153
Several studies have identified features of the positive
sentinel node (SN) that predict a low risk of a positive CLND: 1.
the number of positive SNs 2. the tumor burden 3. the location of
tumor in the node 4. features of the primary melanoma
Slide 154
SNBx A much more rigorous histopathologic approach than non-
SNs, multiantigen RT-PCR the current limited data suggest that the
true rate of positive non-SNs after a positive SNBx may be
somewhere between 15% and 50%.
Slide 155
The standard recommendation is to perform CLND of any lymph
node basin with a positive SN for melanoma. Medical
contraindications for CLND very low tumor burden in the SN
observation after positive SNBx
Slide 156
For those patients who refuse CLND or who are not good medical
candidates for it, it is reasonable to combine imaging evaluation
with ultrasound or PET-CT to identify recurrences at an early stage
if possible.
Slide 157
Management of Palpable Metastatic Melanoma in Regional Nodes:
Therapeutic or Completion Lymphadenectomy lymphadenopaty : after a
negative sentinel node biopsy after observation of a nodal basin
from an unknown primary melanoma after a prior complete
dissection
Slide 158
stage III stage III (A, B, or C) disease is associated with a
subsequent risk of distant metastasis in the range of 40% to 80%.
there is a significant chance of cure after complete
lymphadenectomy for stage III melanoma, with overall 25- year
survival rates of 35%. in the future, there is benefit in achieving
regional control, which is obtained in about 90% of patients.
Slide 159
As discussed earlier, aggressive staging studies are of very
low yield in patients with micrometastases found on sentinel node
biopsy. However, for patients with thick melanomas or with
macrometastases or palpable clinical nodes, the yield is higher.
Preoperative staging is recommended for those patients, using MRI
of the brain and with CT or PET-CT.
Slide 160
Axillary Dissection Axillary dissection should include all
node-bearing tissue in levels I, II, and III. Tx of Lymphedema:
compression sleeve and/or massage therapy
Slide 161
Inguinal and Iliac Dissection For patients with metastatic
melanoma to inguinal nodes, complete groin dissection is indicated.
Patients with known inguinal metastases should undergo CT scan of
the pelvis or PET-CT scan
Slide 162
The risk of lymphedema with inguinal or ilioinguinal dissection
is greater than for axillary or cervical node dissections It may
require a fitted compression stocking or massage therapy
approaches
Slide 163
Cervical Dissection A modified radical neck dissection should
be performed, Melanomas of the face, ear, or anterior scalp often
drain to parotid or periparotid nodes. In such cases, superficial
parotidectomy is indicated as part of a modified radical neck
dissection.
Slide 164
Management of Regional Metastases in Patients with Visceral or
Other Distant Disease Management of regional metastases can be
important for clinical management even in the setting of distant
disease, There are three general types of regional metastasis:
satellite metastasis, in-transit metastasis, and regional lymph
node metastasis.
Slide 165
The Role of Radiation Therapy in the Management of Regional
Nodal Disease Adverse risk factors that increase the risk for nodal
basin recurrence after therapeutic nodal dissection to 30% to 50%.
lymph node extracapsular extension large lymph nodes (greater than
3 cm in diameter) four or more involved lymph nodes Recurrent
disease after previous lymph node dissection
Slide 166
postoperative adjuvant radiation delivered to nodal basins:
recurrent unresectable nodal disease with pain, ulceration,
bleeding, and lymphedema, Retrospective reports from several
centers report 5-year locoregional control rates after radiation
ranging from 80% to 93%
Slide 167
Postoperative adjuvant irradiation high-dose per fraction or
conventional fractionation ? locoregional control rates appear to
be equivalent,
In summary, review of retrospective data reveals that
postoperative adjuvant radiation for stage III patients results in
acceptable locoregional control with reasonable complication rates
and no obvious survival benefit.
Slide 170
Adjuvant Systemic Therapy (Stages IIB, IIC, and III) High-dose
interferon alpha is the only agent to have gained FDA approval for
the treatment of resected stage IIB and stage III melanoma
Slide 171
The most common severe side effects Fatigue Asthenia fever
depression elevated liver transaminases.
Slide 172
Cytotoxic Chemotherapy and Combination Chemotherapies in
Adjuvant Therapy of Melanoma Arguably, single-agent chemotherapy or
combination chemotherapies regimens have not been comprehensively
evaluated for the adjuvant treatment of melanoma. To date, however,
they have not caused significant improvement in survival.
Slide 173
Neoadjuvant Therapy for Resectable Stage III or IV Melanoma
Neoadjuvant therapy for resectable stage III or stage IV melanoma
remains an investigational approach.
Slide 174
Adjuvant Immunotherapy There is substantial evidence that the
immune system responds naturally to melanoma and that immune
modulation can be therapeutic for advanced melanoma. In the last 20
years, there have been dramatic and durable clinical tumor
regressions with high-dose interleukin-2 therapy, now approved for
use in advanced melanoma, and recent experience with antibody to
the CTLA-4 molecule
Slide 175
The WHO Trial 6 enrolled 761 patients after lymphadenectomy for
regional node metastasis and randomized them to a four-arm trial
including BCG and DTIC. Those four arms were surgery only (S),
surgery + BCG (B), surgery + DTIC + BCG (DB), and surgery + DTIC
(D).
Slide 176
Granulocyte-Macrophage Colony- Stimulating Factor (GM-CSF) as
attracted attention as a vaccine adjuvant in murine studies. in
patients with high- to extremely high risk melanoma. A single-arm
study was performed in high-risk melanoma patients in which GM-CSF
was administered subcutaneously daily at 125 mcg/m 2 for 14 days,
followed by a 14-day rest period and with repeat of that cycle for
1 year. This has been a well-tolerated regimen.
Slide 177
Clinical Follow-Up for Patients with Regionally Metastatic
Melanomas (Stage III) history and focused physical exam :every 3
months and as infrequently as annually, CXR, LDH, and CBC at least
annually CT or PET-CT is not likely to have much yield if the other
studies and clinical exam are all unremarkable. high-risk primary
(e.g., T4b) on the lower extremity, pelvic CT scan or PET-CT may be
helpful in identifying iliac nodal recurrences that are difficult
to detect on exam. brain MRI may be helpful in detecting small
brain metastases when they are asymptomatic and amenable to
treatment with gamma-knife radiation therapy.
Slide 178
Management of Distant Metastases of Melanoma (Stage IV) very
poor prognosis, with median survivals of 6 to 15 months. M1a,
(M1b),(M1c)
Slide 179
Timing of Distant Metastases In general, the interval to
detection of distant metastases is shorter for patients who
initially present with high-stage disease (e.g., stage IIB-III) and
is longest for patients who present with clinically localized thin
melanomas (e.g., stage IA). Often, metastases become evident within
2 to 3 years of diagnosis,
Slide 180
Patterns of Metastases Approximately 60% to 80% of first
metastases are at local or regional sites including regional nodes.
Common visceral sites of metastasis are lung, liver, brain,
gastrointestinal tract (especially small bowel), bone, and adrenal
gland.
Slide 181
Prognostic Factors in Distant Metastatic Melanoma (Stage IV )
Negative prognostic factors in stage IV melanoma: a large number of
metastatic sites elevated LDH level poor performance status. There
is little evidence that the available therapies significantly alter
the natural history of melanoma
Slide 182
Clinical Evaluation of Patients with Distant Metastasis (Stage
IV) The initial steps are to perform full restaging studies 1. MRI
scan of the brain 2. total-body PET-CT scan 3. CT scans of the
chest, abdomen, and pelvis. 4. Other scans or imaging studies (bone
scan, soft tissue MRI, ultrasound, or plain films) may be indicated
to evaluate known areas of metastasis (e.g., soft tissue masses in
extremities) or to evaluate symptoms (e.g., plain films or bone
scans for bony symptoms).
Slide 183
PET-CT scans 1. distinguishing tumor from scar 2. For small
bowel metastases 3. lymph node metastases that are borderline in
size 4. PET-CT scan may also be helpful in assessing patients for
resectability when there is limited disease on initial
assessment
Slide 184
Histologic or Cytologic Diagnosis tissue confirmation of
metastatic melanoma is usually recommended. Fine-needle aspiration
biopsy Biopsy Core -needle biopsy, when feasible, can improve
diagnostic accuracy further. IHC stains for S100, HMB45,
tyrosinase, and MART- 1/MelanA can all be helpful in confirming a
diagnosis of melanoma.
Slide 185
Surgery for Distant Metastases (Stage IV) Patient Selection and
Prognostic Factors
Slide 186
Cases in which the benefit of surgery is clear 1. Anemia due to
occult bleeding from intestinal metastasis 2. Bowel obstruction due
to small bowel metastasis 3. Cutaneous or subcutaneous metastasis
or metastases with ulceration, pain, or impending ulceration 4.
Lymph node metastasis with neurologic symptoms 5. Symptomatic brain
metastasis 6. Life-threatening hemorrhage from metastasis
Slide 187
Metastase to GI tract CT scan ? enterclysis study ? PET-CT is
the best Nonetheless, when a patient presents with GI blood loss or
obstruction associated with a small bowel (or other GI) metastasis
of melanoma, operation is almost always indicated. If the tumor
involves the mesenteric nodes and is matted, then it may not be
feasible or appropriate to resect the
Slide 188
operation for Metastase to GI tract if the patient can be
rendered surgically free of disease, then there may be long-term
survival greater than 5 years in as many as 25% of patients and
mean survival greater than 2 years.
Slide 189
Cutaneous, subcutaneous, and nodal metastases substantially
decreases the quality of life for patients. Even in the setting of
low-volume distant visceral disease, resection of cutaneous lesions
can benefit patients by avoiding tumor-associated skin ulceration
and drainage
Slide 190
Extensive lymph node metastasis with neurologic symptoms The
morbidity of surgery may include lymphedema complications, wound
healing issues, and brief perioperative discomfort, The major risks
of continued tumor growth include paralysis or major neurologic
dysfunction of the extremity, intractable lymphedema, disabling
pain, and unresectability.
Slide 191
Brain metastases surgery Steroid therapy
Slide 192
spontaneous hemorrhagein metastatic melanoma can be trivial can
be massive In such cases, resection of the hemorrhagic mass may
diminish future risk of bleeding, decrease pain, and delay
death.
Slide 193
cases in which the benefit of surgery is likely Solitary
asymptomatic visceral metastasis resectable with minimal morbidity
Bony metastasis with pain or joint involvement, unresponsive to
radiation Solitary brain metastasis without symptoms Large nodal
metastasis in the absence of symptoms and with concurrent
low-volume systemic disease. Extensive skin and soft tissue
metastases in the absence of visceral metastases Isolated growing
metastasis in the setting of stable or regressing metastases after
systemic therapy
Slide 194
Solitary visceral metastasis excision can be both therapeutic
and diagnostic to enroll in an experimental therapeutic trial to
take an approved systemic therapy in the hope of clinical
response
Slide 195
Bone metastases Radiation therapy is usually the first choice
for therapeutic intervention if significant pain exists. impending
fracture, orthopedic stabilization should be considered before
radiation. However, if the lesion does not respond to radiation or
is solitary, resection with bone grafting or joint replacement can
be considered.
Slide 196
Brain metastasis An asymptomatic solitary brain metastasis
Stereotactic radiosurgery surgery
Slide 197
extensive lymph node basin disease In the presence of
large-volume visceral disease, systemic therapy is the best option,
if there is low-volume asymptomatic visceral disease, it is often
likely that the nodal disease will cause disabling symptoms before
the visceral disease does.
Slide 198
extensive regional skin and subcutaneous metastases Thus
selection of these patients for surgery depends on multiple
considerations
Slide 199
Multiple metastases Tx systemic Resecting the one or several
tumor deposits that are progressing
Slide 200
Cases in which some patients may benefit from surgery but risk
and benefit are closely balanced More than one visceral metastasis,
without symptoms Multiple lung nodules Bilateral adrenal metastases
Extensive skin and soft tissue metastases in the setting of
visceral disease
Slide 201
A Situations that may push the patient and the clinician toward
such an aggressive surgical approach include (1) prior failure of
systemic therapy (2) a young patient for whom perioperative
morbidity is not a major concern, (3) disease sites that are
particularly amenable to surgery through limited surgery
Slide 202
Adjuvant Therapy for Resected Stage IV Melanoma There is no
standard or approved adjuvant therapy after resection of metastatic
melanoma (stage IV). Interferon ? Therefore, observation remains
the standard management of patients in this setting.
Slide 203
Treatment of Unresectable Metastatic (Stage IV) Melanoma
Single-Agent Chemotherapy
Slide 204
Alkylating agents Dacarbazine,Temozolomide, Nitrosoureas
Lomustine, Fotemustine, P latinum analogs Cisplatin, Carboplatin
Microtubule-stabilizing/destabilizing Paclitaxel, Docetaxel,
Vincristine, Vinblastine, Vindesine
Slide 205
Immunotherapy for Systemic Treatment of Stage IV Melanoma
Interleukin-2 The intravenous administration of high-dose
interleukin-2 (IL-2; aldesleukin) represents the most effective
treatment for patients with metastatic melanoma and the treatment
most likely to provide long-term complete responses in these
patients. IL-2 has no direct effect on cancer cells, and all of its
antitumor activity is a function of its ability to modulate
immunologic responses in the host.
Slide 206
IL-2 an intravenous bolus infusion of 600,000 to 720,000 IU/kg
every 8 hours to tolerance using two cycles separated by
approximately 10 days (maximum of 15 doses per cycle). Results of
this treatment are evaluated at 2 months after the first dose, and
if tumor is regressing or stable, a second course is then
administered. FDA Approved
Slide 207
The durability of complete responses is the hallmark of IL-2
therapy, and greater than 80% of complete responders are likely
cured, with ongoing complete regression in many series now beyond
15 years.
Slide 208
Slide 209
Regimens of IL-2 high-dose bolus IL-2 alone is superior
subcutaneous administration continuous infusion Although the
Surgery Branch of the NCI uses a dose of 720,000 IU/kg, most
centers use a dose of 600,000 IU/kg, and both are approved by the
FDA. There is no clear evidence favoring one dose regimen over the
other.
Slide 210
High -dose bolus IL-2 Only in selected patients 1. younger than
the age of 70 years 2. with an ECOG performance status of 2 or less
3. do not have active systemic infections or other major medical
illness of the cardiovascular respiratory or immune system. 4.
normal serum creatinine and serum bilirubin.
Slide 211
The toxicities of IL-2 administration are transient, and
virtually all returning to baseline after IL-2 administration is
stopped.
Slide 212
Toxicities of IL-2 Administration Supportive measures are often
required for patients during treatment IL-2 can be administered to
patients with metastatic melanoma with a treatment
related-mortality expected to be less than 0.5%
Slide 213
Most Common and Most Severe Adverse Events with High-Dose
Interleukin- 2 Therapy Cardiovascular Hypotension Tachycardia
Supraventricular Ventricular Myocardial infarction Myocardial
ischemia Gastrointestinal Nausea Vomiting Diarrhea Stomatitis
Neurologic Confusion Somnolence Coma
Combination Chemotherapy The most intensively investigated
combination chemotherapy regimens are cisplatin, vinblastine, and
dacarbazine (CVD) andthe Dartmouth regimen (cisplatin, BCNU,
dacarbazine, and tamoxifen). In the absence of an improvement in
overall survival, combination chemotherapy regimens cannot be
considered as standard therapy for metastatic disease. The toxicity
of these combination regimens is considerably greater than that of
single-agent chemotherapy
Slide 216
Inpatient treatment is standard for these regimens, and the
severity of myelosuppression often requires growth factor support
not needed for single-agent chemotherapies. Given that the duration
of life is not affected for these patients who have such a short
life expectancy, the quality-of- life detriment associated with
combination therapy cannot be justified tamoxifen ?
Slide 217
Biologic Agents Combined with Chemotherapy it is not safe
Interferon alpha and interleukin-2 are standard therapies for the
treatment of stage III and stage IV melanoma. lower-dose
interleukin-2 regimens can be safely coadministered even with
combination chemotherapy.
Slide 218
Radiation Therapy for Metastatic Melanoma (Stage IV) Radiation
Dose Fractionation Schedules There is no consensus regarding the
optimal dose fractionation schedule for melanoma.
Slide 219
Radiation Dose Fractionation Schedules Risk of late radiation
toxicity? High-dose-fractionation schedules are more convenient
Particularly for patients with widespread disease and short life
expectancies
Slide 220
The Role of Radiation Therapy in the Management of Distant
Metastatic Disease Similar to other solid tumors, In general,
patients with one to two sites of metastatic melanoma, good
performance status, and long interval from diagnosis of the primary
lesion should be considered for surgical resection. Patients with
widespread metastatic disease may be managed with systemic
chemotherapy or immunotherapy with palliative radiation to
symptomatic areas of progressive disease. Patients with widespread
systemic disease and short life expectancies should be treated with
short courses of high-dose per fraction radiation
Slide 221
Radiation Therapy for Brain Metastases WBRT has limited
activity in the treatment of malignant melanoma metastatic to the
brain and should be reserved for patients with widespread systemic
metastases or diffuse brain metastases not amenable to surgical
resection or stereotactic radiosurgery. Stereotactic radiosurgery
)less than 3 cm and do not involve the brainstem.(
Slide 222
The authors concluded that delaying WBRT may be appropriate for
some subgroups of patients with radioresistant tumors, but routine
avoidance of WBRT should be approached judiciously, given the high
intracranial failure rates.
Slide 223
Recommendations for patients with brain metastases from
melanoma All patients with symptomatic cerebral edema should be
initiated on corticosteroids Patients with good performance status
and no or minimal systemic disease and a solitary resectable brain
lesion should undergo resection similar patients but with an
unresectable brain lesion or up to 5 small metastatic lesions
should be treated with stereotactic radiosurgery both groups should
be considered for WBRT or close observation with serial imaging
Patients with poor performance status, diffuse systemic disease,
and greater than five brain lesions have a poor overall prognosis
and should be considered for palliative WBRT only.
Slide 224
Radiation Therapy for Vertebral Metastases operative
candidates, : subsequent postoperative radiotherapy Patients who
are not operative candidates should be considered for radiation
therapy alone.
Slide 225
Stereotactic body radiation therapy (SBRT) for lesions in
multiple organ sites (lung, liver, and spine). With SBRT, patients
are treated with one to five fractions of high-dose and highly
conformal radiation isodose distributions. Patients who have
limited systemic disease burden who are not considered surgical
resection candidates, including patients with spinal cord
compression from disease progression after palliative conventional
radiation therapy techniques, should be considered for SBRT.