The treatment of malignant melanoma has undergone a revolution just within
this past decade. Even metastatic melanoma, once thought to be hopeless, has
vaccine and genetically modified immunomodulatory agents which may provide
hope for these patients. It must be remembered that melanoma is still a totally
curable disease if caught early enough. Thus, vigilence and self examination
are critical in identifying any suspicious moles. For more on the basic identification
and background of the disease, please visit the following link.
| SURGERY AND MARGIN ADEQUACY |
CHARACTERIZATION |
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Guidelines of care for primary cutaneous melanoma
Arthur J. Sober, MD, Chair
Tsu-Yi Chuang, MD, MPH
Madeleine Duvic, MD
Evan R. Farmer, MD
James M. Grichnik, MD
Allan C. Halpern, MD
Vincent Ho, MD
Victoria Holloway, MD, MPH
Antoinette F. Hood, MD
Timothy M. Johnson, MD
Barbara J. Lowery, MPH
Guidelines/Outcomes Committee 2001 by the American
Academy of Dermatology, Inc.
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J Am Acad Dermatol 2001;45:579-86. Abstract quote
This report reflects the best data available at the time the report
was prepared, but caution should be exercised in interpreting the data;
the results of future studies may require alteration of the conclusions
or recommendations set forth in this report.
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In situ melanoma
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0.5 cm |
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Invasive up to 1mm
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1 cm |
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Invasive >1 mm
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2-3 cm |
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Thin stage I primary cutaneous malignant melanoma.
Comparison of excision with margins of 1 or 3 cm.
Veronesi U, Cascinelli N, Adamus J, Balch C, Bandiera
D, Barchuk A, Bufalino R, Craig P, De Marsillac J, Durand JC, et al.
National Cancer Institute, Milan, Italy.
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N Engl J Med 1988 May 5;318(18):1159-62 Abstract quote
Although wide surgical excision is the accepted treatment for thin
malignant melanomas, there is reason to believe that narrower margins
may be adequate.
We conducted a randomized prospective study to assess the efficacy
of narrow excision (excision with 1-cm margins) for primary melanomas
no thicker than 2 mm.
Narrow excision was performed in 305 patients, and wide excision (margins
of 3 cm or more) was performed in 307 patients. The major prognostic
criteria were well balanced in the two groups. The mean thickness of
melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the
wide-excision group. The subsequent development of metastatic disease
involving regional nodes and distant organs was not different in the
two groups (4.6 and 2.3 percent, respectively, in the narrow-excision
group, as compared with 6.5 and 2.6 percent in the wide-excision group).
Disease-free survival rates and overall survival rates (mean follow-up
period, 55 months) were also similar in the two groups.
Only three patients had a local recurrence as a first relapse. All
had undergone narrow excision, and each had a primary melanoma with
a thickness of 1 mm or more. The absence of local recurrence in the
group of patients with a primary melanoma thinner than 1 mm and the
very low rate of local recurrences indicate that narrow excision is
a safe and effective procedure for such patients.
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Local recurrence in malignant melanoma: long-term
results of the multiinstitutional randomized surgical trial.
Karakousis CP, Balch CM, Urist MM, Ross MM, Smith
TJ, Bartolucci AA.
Department of Surgery, State University of New York,
Buffalo, USA.
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Ann Surg Oncol 1996 Sep;3(5):446-52 Abstract quote
BACKGROUND: In the past, radical margins of excision were prescribed
for cutaneous melanoma based on preconceived notions rather than on
hard clinical evidence.
METHODS: In a prospective study of 742 patients with intermediate-thickness
melanoma (1-4 mm), 470 patients with trunk or proximal extremity lesions
were randomized into a 2- or 4-cm margin. Patients with distal extremity
or head and neck lesions (n = 272) received uniformly a 2-cm margin.
RESULTS: The overall rate of local recurrence was 3.8%. This rate in
the randomized portion (n = 470) was 2.1% for the 2-cm margin and 2.6%
for the 4-cm margin (p = 0.72). A progressive increase in local recurrence
rates was observed with thickness: 2.3% for lesions 1.0-2.0 mm, 4.2%
for those 2.01-3.0 mm, and 11.7% for those 3.01-4.0 mm thick (p = 0.001).
Local recurrence occurred in 1.5% of those without ulceration and in
10.6% of those with ulceration of the primary lesion (p = 0.001). The
local recurrence rate was not significantly affected by the margin of
resection even among the thicker or ulcerated lesions. It also was not
affected significantly by the method of closure of the primary site
or management of the regional nodes, or the age or gender of the patients.
CONCLUSIONS: A 2-cm margin is as effective as a 4-cm margin in local
control and survival of intermediate-thickness melanomas. The local
recurrence rate is significantly affected by the thickness of the primary
lesion and the presence or not of ulceration.
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Long term results of a randomized study by the Swedish
Melanoma Study Group on 2-cm versus 5-cm resection margins for patients
with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm.
Cohn-Cedermark G, Rutqvist LE, Andersson R, Breivald
M, Ingvar C, Johansson H, Jonsson PE, Krysander L, Lindholm C, Ringborg
U.
Department of Oncology-Pathology, Radiumhemmet, Karolinska
Hospital, Stockholm, Sweden.
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Cancer 2000 Oct 1;89(7):1495-501 Abstract quote
BACKGROUND: Large, prospective, randomized trials with long term follow-up
are required to obtain an unbiased evaluation of the significance of
resection margins in patients with cutaneous melanoma.
METHODS: The Swedish Melanoma Study Group performed a prospective,
randomized, multicenter study of patients with primary melanoma located
on trunk or extremities and with a tumor thickness > 0.8 mm and
RESULTS: The crude rate of local recurrence, defined as a recurrence
in the scar or transplant, was < 1% (8 of 989 patients). Twenty percent
of the patients (194 of 989 patients) experienced any disease recurrence,
and 15% (146 of 989 patients) died of melanoma. There were no statistically
significant differences between the two treatment arms. In a multivariate
Cox analysis with patients allocated to wide excision as the reference
group, the estimated relative hazards for overall survival and recurrence
free survival among those allocated to a 2-cm resection margin were
0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence
interval, 0.80-1.30), respectively.
CONCLUSIONS: In this long term follow-up study, local recurrences were
found to be rare among patients with tumors > 0.8 mm thick and
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Analysis of local recurrence and optimizing excision
margins for cutaneous melanoma.
Ng AK, Jones WO, Shaw JH.
Auckland Melanoma Unit, Auckland Hospital, Auckland,
New Zealand.
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Br J Surg 2001 Jan;88(1):137-42 Abstract quote
BACKGROUND: Current guidelines for the treatment of melanoma favour
conservatism; however there is still uncertainty regarding best practice
for lesions of intermediate thickness. Local recurrence, a measure of
treatment adequacy, can be used to determine optimum excision margins
and give prognostic information for survival.
METHODS: An analysis of the Auckland Melanoma Unit database was performed.
Patients with local recurrence were identified and stratified by lesion
thickness. Optimum excision margins were derived by regression analysis
and evaluated against the database population. Survival and prognostic
factors were studied.
RESULTS: Eighty-four of 1155 patients (7 per cent) developed local
recurrence. Median follow-up was 51 months. Margins predicted to give
a local recurrence of zero were: 1 cm for lesions < or = 1 mm thick;
1.5 cm for lesions 1-2 mm thick; and 2 cm for lesions > 2 mm thick.
Applied to 1155 patients, there were significant differences in both
local recurrence and mortality rates between optimally and suboptimally
excised lesions, except for those > 4 mm thick. Thirty-three patients
(39 per cent) with local recurrence died. Thickness, local recurrence
and ulceration were of prognostic significance.
CONCLUSION: Development of local recurrence in melanomas < or = 4 mm
thick is due to inadequate treatment. It signifies progressive disease
and a poor prognosis. Care must be taken to ensure that all such lesions
are optimally excised.
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Long-term results of a prospective surgical trial
comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm
melanomas.
Balch CM, Soong SJ, Smith T, Ross MI, Urist MM, Karakousis
CP, Temple WJ, Mihm MC, Barnhill RL, Jewell WR, Wanebo HJ, Desmond R;
Investigators from the Intergroup Melanoma Surgical
Trial. Johns Hopkins Medical Center, Baltimore, Maryland, USA.
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Ann Surg Oncol 2001 Mar;8(2):101-8 Abstract quote
BACKGROUND: The Intergroup Melanoma Surgical Trial began in 1983 to
examine the optimal surgical margins of excision for primary melanomas
of intermediate thickness (i.e., 1-4 mm). There is now a median 10-year
follow-up.
METHODS: There were two cohorts entered into a prospective multi-institutional
trial: (1) 468 patients with melanomas on the trunk or proximal extremity
who randomly received a 2 cm or 4 cm radial excision margin and (2)
272 patients with melanomas on the head, neck, or distal extremities
who received a 2 cm radial excision margin.
RESULTS: A local recurrence (LR) was associated with a high mortality
rate, with a 5-year survival rate of only 9% (as a first relapse) or
11% (anytime) compared with an 86% survival for those patients who did
not have a LR (P < .0001). The 10-year survival for all patients with
a LR was 5%. The 10-year survival rates were not significantly different
when comparing 2 cm vs. 4 cm margins of excision (70% vs. 77%) or comparing
the management of the regional lymph nodes (observation vs. elective
node dissection). The incidences of LR were the same for patients having
a 2 cm vs. 4 cm excision margin regardless of whether the comparisons
were made as first relapse (0.4% vs. 0.9%) or at anytime (2.1% vs. 2.6%).
When analyzed by anatomic site, the LR rates were 1.1% for melanomas
arising on the proximal extremity, 3.1% for the trunk, 5.3% for the
distal extremities, and 9.4% for the head and neck. The most profound
influence on LR rates was the presence or absence of ulceration; it
was 6.6% vs. 1.1% in the randomized group involving the trunk and proximal
extremity and was 16.2% vs. 2.1% in the non-randomized group involving
the distal extremity and head and neck (P < .001). A multivariate (Cox)
regression analysis showed that ulceration was an adverse and independent
factor (P = .0001) as was head and neck melanoma site (P = .01), while
the remaining factors were not significant (all with P > .12).
CONCLUSION: For this group of melanoma patients, a local recurrence
is associated with a high mortality rate, a 2-cm margin of excision
is safe and ulceration of the primary melanoma is the most significant
prognostic factor heralding an increased risk for a local recurrence.
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Mohs' micrographic surgery using frozen sections alone may be unsuitable
for detecting single atypical melanocytes at the margins of melanoma
in situ.
Barlow RJ, White CR, Swanson NA.
Department of Dermatology, Oregon Health Sciences University, Portland,
OR, USA.
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Br J Dermatol 2002 Feb;146(2):290-4 Abstract quote
BACKGROUND: It remains questionable whether micrographic surgery with
frozen sections is an appropriate technique for excision of melanoma
in situ (MIS) of the lentigo maligna type. Advocates of the technique
have interpreted MIS as being histologically defined by nests and contiguous
atypical melanocytes on the basal layer. Others, however, have viewed
the periphery of MIS as consisting of scattered single atypical melanocytes,
a finding that may be difficult or impossible to establish on frozen
sections.
OBJECTIVES: To examine the reliability of micrographic surgery using
frozen sections interpreted by an experienced Mohs' surgeon, in the
excision of MIS.
METHODS: From a total of 154 specimens, frozen sections from the 50
specimens with margins that were considered difficult to interpret were
thawed, sent for routine processing and then examined 'blind' by a dermatopathologist.
RESULTS: Using the dermatopathologist's report on paraffin-embedded
sections as a reference point, the sensitivity and specificity of frozen
sections were calculated to be 59% and 81%, respectively.
CONCLUSIONS: Using these histological criteria, micrographic surgery
with frozen sections alone is unreliable in the excision of MIS.
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| SENTINEL LYMPH NODE DISSECTION |
CHARACTERIZATION |
| GENERAL |
Arch Surg 1997;132:666-73
J Clin Oncol 1999;17:976-83.
Often utilized for management of stage I-II malignant melanoma with
tumor thickness greater than 1 mm or less than 1 mm with high-risk features
(including spindle cell melanoma and DMM) involves preoperative lymphoscintigraphy
followed by selective sentinel lymph node (SLN) dissection and surgical
re-excision
The SLN histology determines whether or not formal lymphadenectomy
is warranted
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Surg Oncol Clin North Am 1992;1:247-59.
A dye with/without a radioactive tag is injected into the melanoma
site
Dye is immediately picked up by the body's lymphatic system and drains
to the regional lymph nodes-this route is the route that melanoma cells
would follow if metastasis were to occur
Melanoma tends to spread in succession from one lymph node chain to
another but usually involves the first or sentinel node of a
chain before spreading to the rest of the lymph nodes within the chain
Sentinel node is identified by the dye, the surgeonl removes it and
sends it to the pathologist for an intraoperative frozen section
If melanoma has spread to this sentinel lymph node, the surgeon will
proceed to remove all of the other lymph nodes within that chain
If the lymph node is negative and clear of melanoma, the surgeon will
stop, sparing the patient the morbidity of a complete lymph node dissection
NOTE: This technique is not reliable after wide local excision and
interruption of local lymphatics
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Lymph node micrometastases of cutaneous melanoma:
increased sensitivity of molecular diagnosis in comparison to immunohistochemistry.
Blaheta HJ, Schittek B, Breuninger H, Maczey E, Kroeber
S, Sotlar K, Ellwanger U, Thelen MH, Rassner G, Bultmann B, Garbe C.
Department of Dermatology, Eberhard-Karls-University,
Tuebingen, Germany.
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Int J Cancer 1998 Aug 21;79(4):318-23 Abstract quote
The presence of regional lymph node metastases is one of the most significant
prognostic factors for predicting survival in patients with clinical
stage I or II cutaneous melanoma. For accurate staging of the primary
tumor a sensitive technique is required to detect occult nodal micrometastases.
This prospective diagnostic study was designed to evaluate the incidence
of nodal micrometastases using nested reverse transcription-polymerase
chain reaction (RT-PCR) for tyrosinase in comparison to immunohistochemical
examination. Furthermore, the incidence of melanoma micrometastases
detected by RT-PCR was analysed in correlation to major prognostic factors.
A total of 466 regional lymph nodes from 79 patients with primary cutaneous
melanoma (tumor thickness > 0.75 mm) were investigated. In 49 lymph
nodes from 31 patients immunohistochemistry demonstrated melanoma metastases.
Using tyrosinase RT-PCR, nodal micrometastases were detected in 136
lymph nodes from 52 patients including all lymph nodes positive by immunohistochemical
examination. Out of the 417 lymph nodes negative by immunohistochemistry,
87 nodes (21%) were identified to express tyrosinase by the RT-PCR technique.
Among the 48 patients negative by immunohistochemical assessment, 21
(44%) had nodal micrometastases (n = 40) using RT-PCR. All 68 lymph
nodes from 46 non-melanoma patients serving as negative controls for
tyrosinase RT-PCR were negative.
The detection of melanocytic nodal micrometastases by tyrosinase RT-PCR
is a highly specific method with a sensitivity significantly higher
than that achieved by immunohistochemistry (p < 0.0001). Patients with
nodal micrometastases identified exclusively by RT-PCR had significantly
higher tumor thickness as compared to patients with negative results
by RT-PCR (p < 0.01).
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Multi-institutional melanoma lymphatic mapping experience:
the prognostic value of sentinel lymph node status in 612 stage I or
II melanoma patients.
Gershenwald JE, Thompson W, Mansfield PF, Lee JE,
Colome MI, Tseng CH, Lee JJ, Balch CM, Reintgen DS, Ross MI.
Department of Surgical Oncology, The University of
Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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J Clin Oncol 1999 Mar;17(3):976-83 Abstract quote
PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN)
status with that of other known prognostic factors on recurrence and
survival in patients with stage I or II cutaneous melanoma.
PATIENTS AND METHODS: We reviewed the records of 612 patients with
primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy
between January 1991 and May 1995 to determine the effects of tumor
thickness, ulceration, Clark level, location, sex, and SLN pathologic
status on disease-free and disease-specific survival.
RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy
were successful, the SLN was positive by conventional histology in 85
patients (15%) but negative in 495 patients (85%). SLN status was the
most significant prognostic factor with respect to disease-free and
disease-specific survival by univariate and multiple covariate analyses.
Although tumor thickness and ulceration influenced survival in SLN-negative
patients, they provided no additional prognostic information in SLN-positive
patients.
CONCLUSION: Lymphatic mapping and SLN biopsy is highly accurate in
staging nodal basins at risk for regional metastases in primary melanoma
patients and identifies those who may benefit from earlier lymphadenectomy.
Furthermore, pathologic status of the SLN in these patients with clinically
negative nodes is the most important prognostic factor for recurrence.
The information from SLN biopsy is particularly helpful in establishing
stratification criteria for future adjuvant trials.
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Outcome of patients with melanoma and histologically
negative sentinel lymph nodes.
Gadd MA, Cosimi AB, Yu J, Duncan LM, Yu L, Flotte
TJ, Souba WW, Ott MJ, Wong LS, Sober AJ, Mihm MC, Haluska FG, Tanabe
KK.
Department of Surgery, Massachusetts General Hospital,
Harvard Medical School, Boston 02114, USA.
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Arch Surg 1999 Apr;134(4):381-7 Abstract quote
HYPOTHESIS: Patients with melanoma and histologically negative sentinel
lymph nodes identified by lymphatic mapping have a very good prognosis.
DESIGN: Cohort study with follow-up information obtained from medical
records and telephone interviews.
SETTING AND PATIENTS: Of all patients with cutaneous melanoma who underwent
intraoperative sentinel lymph node mapping between November 15, 1993,
and April 18, 1997, at the Massachusetts General Hospital, Boston, 89
were found to have no evidence of melanoma in their sentinel nodes.
Forty-six lesions (51%) were on an extremity and 44 (49%) were of axial
location. The median tumor thickness was 1.8 mm (range, 0.36-12.0 mm)
and 11 tumors (12%) were ulcerated.
INTERVENTIONS: Patients underwent intraoperative sentinel lymph node
mapping with lymphazurin and radiolabeled sulfur colloid. Sentinel lymph
nodes were analyzed by standard hematoxylin-eosin staining. Only 2 patients
received adjuvant therapy following wide excision of the primary lesion.
MAIN OUTCOME MEASURES: Site of initial recurrence and time to initial
recurrence.
RESULTS: The median follow-up for all patients was 23 months (range,
2-54 months). Eleven patients (12%) developed melanoma recurrences,
and 78 (88%) patients remain disease free. Regional lymph nodes were
the initial site of recurrence in 7 (8%) of 89 patients, and 7 (7%)
of 106 mapped basins. Four patients had recurrence without involvement
of regional lymph nodes: 2 with distant metastases and 2 with in transit
metastases. The median time to recurrence was 12 months (range, 2-35
months). Sentinel lymph nodes were reanalyzed using serial sections
and immunoperoxidase stains in 7 patients with recurrence and metastatic
melanoma was identified in 3 (43%).
CONCLUSIONS: The risk for melanoma recurrence is relatively low in
patients with histologically negative sentinel nodes identified by lymphatic
mapping. Longer follow-up will improve our understanding of the prognostic
value of this procedure.
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Clinical relevance of molecular staging for melanoma:
comparison of RT-PCR and immunohistochemistry staining in sentinel lymph
nodes of patients with melanoma.
Li W, Stall A, Shivers SC, Lin J, Haddad F, Messina
J, Glass LF, Lyman G, Reintgen DS. Cutaneous Oncology Program, H.
Lee Moffitt Cancer Center and Research Institute at
the University of South Florida, Tampa, Florida 33612, USA.
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Ann Surg 2000 Jun;231(6):795-803 Abstract quote
OBJECTIVE: To determine the clinical significance of a molecular assay
based on the reverse transcriptase polymerase chain reaction (RT-PCR)
for the presence of micrometastatic melanoma cells in sentinel lymph
nodes (SLNs).
SUMMARY BACKGROUND DATA: Routine histologic examination of lymph nodes
often underestimates the presence of micrometastatic disease. The authors
have previously shown that an RT-PCR assay designed to detect melanocyte-specific
expression of the tyrosinase gene could be used to define a population
of patients at higher risk for both recurrence and death compared with
routine hematoxylin and eosin (H&E) histology. In this study, the authors
used the tyrosinase RT-PCR assay in a patient population examined by
a more detailed histologic analysis, including S-100 immunohistochemistry.
METHODS: Patients underwent lymphatic mapping and SLN biopsy. SLN specimens
were bivalved, and half of each specimen was serially sectioned and
examined by routine H&E histology and S-100 immunohistochemistry. The
other half of each specimen was analyzed by a nested RT-PCR assay.
RESULTS: Hematoxylin and eosin histology detected metastatic disease
in 36 (16%) of the 233 patients tested. S-100 immunohistochemistry detected
micrometastatic disease in another 16 patients, and 114 (63%) of 181
patients with histology-negative nodes had positive findings on RT-PCR.
There were significant differences between PCR-positive and PCR-negative
patient groups in Breslow thickness, Clark level, and the presence of
ulceration of the primary tumor, factors that have been shown to correlate
with recurrence and survival.
CONCLUSIONS: These results suggest that RT-PCR can increase the sensitivity
of detection of metastatic melanoma cells in SLNs over the current standard
methods, including H&E histology and S-100 immunohistochemistry. Further
long-term follow-up is needed to detect actual differences in recurrence
and overall survival.
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HMB-45 Immunohistochemical Staining of Sentinel Lymph
Nodes A Specific Method for Enhancing Detection of Micrometastases in
Patients With Melanoma
Blaire L. Baisden, M.D.; Frederic B. Askin, M.D.;
Julie R. Lange, M.D.; William H. Westra, M.D.
From the Departments of Pathology (B.L.B., F.B.A.,
W.H.W.) and Surgery (J.R.L.), The Johns Hopkins Medical Institutions,
Baltimore, Maryland
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Am J Surg Pathol 2000;24:1140-1146 Abstract quote
Despite the profound therapeutic and prognostic implications of nodal
metastases in patients with melanoma, there is no consensus strategy
for the optimal detection of metastases in sentinel lymph node biopsies.
Traditional microscopic examination may be too crude to detect scattered,
individual tumor cells. Conversely, molecular genetic techniques are
prone to false-positive results.
The authors evaluated the ability of HMB-45 immunohistochemistry to
enhance detection of melanoma cells in histologically negative sentinel
lymph nodes.
Ninety-six sentinel lymph nodes, collected over a 25-month period from
66 consecutive patients with melanoma, were processed routinely and
sectioned serially. Slides 1, 3, and 5 were stained with hematoxylin
and eosin. HMB-45 staining was performed on an intervening slide in
histologically negative nodes. To assess the background incidence of
HMB-45-positive cells in lymph nodes draining the skin, the authors
stained 244 cervical and axillary lymph nodes from patients without
melanoma. Metastases were apparent microscopically in 12 (18%) of the
66 patients with melanoma. Of the remaining 54 patients, four patients
(7%) had lymph nodes harboring individual, scattered HMB-45-positive
cells. Benign nevocellular aggregates were present in four of the 96
sentinel lymph nodes (4% nodal incidence), but they were HMB-45-negative.
The authors did not observe a single HMB-45-positive cell in the 244
lymph nodes from patients without melanoma.
Immunohistochemistry appears to represent a specific means of enhancing
tumor detection in sentinel lymph nodes from patients with melanoma.
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Sentinel node biopsies in melanoma patients: a protocol
for accurate, efficient, and cost-effective analysis by preselection
for immunohistochemistry on the basis of Tyr-PCR.
van der Velde-Zimmermann D, Schipper ME, de Weger
RA, Hennipman A, Borel Rinkes IH.
Department of Surgery, University Hospital, Utrecht,
The Netherlands.
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Ann Surg Oncol 2000 Jan-Feb;7(1):51-4 Abstract quote
BACKGROUND: Immunohistochemistry (IHC) of serial sectioning is considered
the gold standard for detection of melanoma activity in sentinel node
(SN) biopsies. However, this is cost and labor intensive. In contrast,
tyrosinase reverse transcription-polymerase chain reaction (RT-PCR)
is simple and quick, but it is hampered by its extreme sensitivity.
This study was performed to test whether a strategy that combines the
two methods, using tyrosinase RT-PCR to preselect nodes for IHC, could
be accurate and cost effective.
METHODS: In 36 patients, SNs were identified by scintigraphy and patent
blue uptake. Of each SN, one cross section was analyzed first by hematoxylin
and eosin staining. Next, all nodes were examined by serial sectioning
and IHC of one-half and tyrosinase RT-PCR of the other. Before comparison,
all results were documented in a blinded manner. Material costs and
workload estimates were noted per SN.
RESULTS: Fifty-five SNs were retrieved from the 36 patients. Hematoxylin
and eosin staining of the first cross section revealed tumor positivity
in 3 patients (6 SN). Tyrosinase RT-PCR was positive in 11 of the remaining
33 patients (19 of 49 SN). Of these same 11 patients, only 5 were shown
to have tumor-positive SNs by using IHC on serial sections (7 SN). All
these nodes had been positive for tyrosinase on PCR. For IHC, an average
of 40 sections were prepared and examined per SN at a cost of $200(U.S.)/SN.
In contrast, routine tyrosinase RT-PCR costs $37(U.S.)/SN, and takes
5% of the time necessary for IHC. A strategy including hematoxylin and
eosin staining on the first cross section, followed by tyrosinase RT-PCR
on half of each negative (half) node, could preselect nodes to be taken
through serial sectioning. In these series, such a strategy would have
prevented serial sectioning and IHC of 30 SN from 22 patients. Apart
from a considerable gain in efficiency, this would have reduced material
costs by a minimum of $6000 (U.S.). This discrepancy would be even higher
if work intensity of analysts and pathologists were considered.
CONCLUSIONS: In routine analysis of SN biopsies in melanoma patients,
tyrosinase RT-PCR can be used effectively to preselect nodes for further
IHC of serial sections. This method seems both time and cost effective.
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Examination of regional lymph nodes by sentinel node
biopsy and molecular analysis provides new staging facilities in primary
cutaneous melanoma.
Blaheta HJ, Ellwanger U, Schittek B, Sotlar K, MacZey
E, Breuninger H, Thelen MH, Bueltmann B, Rassner G, Garbe C.
Department of Dermatology, Skin Cancer Program, Eberhard-Karls-University,
Tuebingen, Germany.
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J Invest Dermatol 2000 Apr;114(4):637-42 Abstract quote
Histopathologic parameters of the primary tumor, such as Breslow's
tumor thickness and Clark's level of invasion are the current basis
for prognostic classifications of primary cutaneous melanoma. Once patients
develop regional node metastasis, histopathologic features of the primary
melanoma no longer contribute significantly to survival prediction.
In this tumor stage, the extent of lymph node involvement is the main
prognostic factor.
This study addresses the question whether application of a highly sensitive
molecular biology assay for detection of submicroscopic melanoma cells
in sentinel lymph nodes may be suitable to improve melanoma staging.
One hundred and sixteen patients with primary cutaneous melanoma with
a total of 214 sentinel lymph nodes were enrolled. Sentinel lymph nodes
were analyzed by histopathology including immunohistochemistry and by
reverse transcription-polymerase chain reaction for tyrosinase. Patients
were examined for tumor recurrences during a follow-up period of 19
mo (median). Disease-free survival probabilities were calculated and
independent prognostic factors were determined by multivariate analysis.
Using histopathology, micrometastatic nodal involvement was detected
in 15 patients (13%). Of the 101 patients with histopathologically negative
sentinel lymph nodes, 36 were reclassified by positive tyrosinase reverse
transcription-polymerase chain reaction and 65 patients were still negative
by reverse transcription-polymerase chain reaction. Recurrences were
observed in 23 (20%) of 116 patients. These tumor recurrences were demonstrated
in 10 patients (67%) with histopathologically positive sentinel lymph
nodes, in nine patients (25%) with submicroscopic tumor cells detected
by reverse transcription-polymerase chain reaction, and in four patients
(6%) negative by both methods. The differences in recurrence rates were
statistically significant (p = 0.01). In a multivariate analysis, histopathologic
and reverse transcription-polymerase chain reaction status of the sentinel
lymph node were demonstrated to be the only significant prognostic factors
for predicting disease-free survival.
Tyrosinase reverse transcription-polymerase chain reaction for the
detection of minimal residual melanoma in sentinel lymph nodes is a
powerful tool to determine patients who are at increased risk for subsequent
metastasis. Moreover, a group of patients with high tumor thickness
was identified by negative reverse transcription-polymerase chain reaction
to be at low risk for recurrent disease. These data may have an impact
on future tumor classifications of primary cutaneous melanoma.
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Evaluation of sentinel lymph node status in spindle
cell melanomas
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J Am Acad Dermatol 2001;44:451-5
Retrospective database and medical record review from Oct 21, 1993
to Sept 29, 1999. At the University of California at San Francisco Melanoma
Center, patients with tumor thickness greater than 1 mm or less than
1 mm with high-risk features are managed with preoperative lymphoscintigraphy,
selective SLN dissection, and wide excision.
Results: Of 29 patients diagnosed with spindle cell melanoma and DMM,
28 had negative SLNs and are free of disease except for one patient
who experienced splenic, bony, and brain metastases. The mean follow-up
in this population was 16.5 and 11 months, respectively.
Conclusion: Our preliminary findings show that SLNs from patients diagnosed
with spindle cell melanoma and DMM only rarely harbor micrometastasis
despite their relative thickness. A larger number of cases from multicenter
databases may further define the true biology of SLNs in this melanoma
variant.
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Sentinel lymph node micrometastasis and other histologic
factors that predict outcome in patients with thicker melanomas
Basil S. Cherpelis, etal.
|
J Am Acad Dermatol 2001;44:762-6. Abstract quote
Background: In patients with melanoma, lymph node staging information
is obtainable by the surgical techniques of lymphatic mapping and sentinel
lymph node (SLN) biopsy. Although no survival benefit has been proven
for the procedure, the staging information is useful in identifying
patients who may benefit from further surgery or adjuvant therapy. Currently,
however, it is not being recommended for patients with thick melanomas
(>3-4 mm). The risk of hematogenous dissemination is considered too
great in these patients. Recent studies indicate, however, that a surprising
number of patients with thick melanomas become long-term survivors,
and the lymph node status may be predictive. None of the conventional
microscopic features used to gauge prognosis in patients with melanoma
have proven helpful in distinguishing the survivors with thick melanoma
from those who will die of their disease.
Objective: Our purpose was to evaluate the influence of SLN histology
and other microscopic parameters on survival of patients with thick
melanomas.
Methods: A computerized patient database at the Cutaneous Oncology
Clinic at H. Lee Moffitt Cancer Center was accessed to obtain records
on patients with melanomas thicker than 3.0 mm (AJCC T3b). A retrospective
analysis was conducted with attention paid to histologic variables,
sentinel node status, and survival. Survival curves were constructed
with the Kaplan-Meier method, and a Cox-Mantel rank testing was used
to establish statistical significance.
Results: Between 1991 and 1999, 201 patients were diagnosed with melanoma
thicker than 3.0 mm, and 180 were alive at an average follow-up of 51
months. Of these, 166 were alive without disease. The mean overall and
disease-free survival rates were 78% and 66%, respectively. There was
a statistically significant difference in disease-free survival (3-year)
between SLN-positive and SLN-negative patients (37% vs 73%, respectively;
P = .02). The overall survival (3-year) for the SLN-positive patients
was less than the node-negative patients (70% vs 82%), but it was not
statistically significant (P = .08). The disease-free survival for patients
with ulcerated lesions was less than for nonulcerated lesions (77% vs
93%, P = .05). None of the other histologic parameters studied, including
Breslow thickness, Clark level, mitotic rate, or regression, had an
influence on the overall or disease-free survival in this group of patients
with thick tumors.
Conclusions: The results indicate that the SLN node status is predictive
of disease-free survival for patients with thick melanomas. A surprising
number of patients in the study were free of disease after prolonged
follow-up. None of the histologic features of the primary tumor were
helpful in predicting outcome, except for ulceration. SLN biopsy appears
to be justified for prognostic purposes in patients with thick melanomas.
|
|
Sentinel Lymph Nodes Show Profound Downregulation
of Antigen-Presenting Cells of the Paracortex: Implications for Tumor
Biology and Treatment
Alistair J. Cochran, M.D., Donald L. Morton, M.D.,
Stacey Stern, Ph.D., Ana M.A. Lana, M.D., R. Essner, M.D. and Duan-Ren
Wen, M.D.
Departments of Pathology and Laboratory Medicine and
Surgery and Jonsson Comprehensive Cancer Center, University of California
Los Angeles, School of Medicine, Los Angeles, California (AJC, D-RW);
the John Wayne Cancer Institute, Saint John’s Hospital and Health Center,
Santa Monica, California (DLM, SS, RE); and Departamento de Anatomia
Pathológica, Faculdade de Medicina da Universidade Federal de Minas
Gerais, Belo Horizonte, Minas Gerais, Brazil (AMAL)
|
Mod Pathol 2001;14:604-608 Abstract quote
The sentinel lymph node (SN) is the first node on the direct lymphatic
drainage pathway from a tumor. Melanoma-associated SNs are the most
likely site of early metastases and their immune functions are strikingly
down-modulated.
We evaluated histologic and cytologic characteristics of 21 SNs and
21 nonsentinel nodes (NSNs) from melanoma patients who had clinically
localized (AJCC Stage I–II) primary cutaneous melanoma.
SNs showed highly significant reductions in total paracortical area
and in the area of the paracortical subsector occupied by dendritic
cells. The frequency of paracortical interdigitating dendritic cells
(IDCs) was dramatically reduced in SNs, and most IDCs (99%) lacked the
complex dendrites associated with active antigen presentation.
The release of immunosuppressive factors from the primary melanoma
may induce a localized and specific paralysis in the SN, which prevents
the recognition of otherwise immunogenic melanoma antigens by IDCs.
This immune paralysis may facilitate the implantation and growth of
melanoma cells in the SN. Cytokine therapy may be able to reverse this
immune paralysis. These findings have an important practical application
in the histopathologic confirmation that a node is truly sentinel. They
also offer an hypothesis to explain the failure of the immune surveillance
mechanisms to identify and respond to a small primary melanoma that
expresses immunogenic tumor antigens.
|
|
Developing Indications for the Use of Sentinel Lymph
Node Biopsy and Adjuvant High-Dose Interferon Alfa-2b in Melanoma
Robert W. Dubois, MD, PhD; Susan M. Swetter, MD;
Michael Atkins, MD; Kelly McMasters, MD; Ron Halbert, MD, MPH; Stanley
J. Miller, MD; Ronald Shiell, MD; John Kirkwood, MD
|
Arch Dermatol. 2001;137:1217-1224 Abstract quote
Objectives
To convene a multidisciplinary panel of dermatologists, surgical oncologists,
and medical oncologists to formally review available data on the sentinel
lymph node (SLN) biopsy procedure and high-dose adjuvant interferon
alfa-2b therapy for patients with melanoma and to rate the "appropriateness,"
"inappropriateness," or "uncertainty" of the procedure and therapy to
guide clinical decision making in practice.
Participants
The panel comprised 13 specialists (4 dermatologists, 4 oncologists,
and 5 surgeons) from geographically diverse areas who practiced in community-based
settings (n = 8) and academic institutions (n = 5). Participants were
chosen based on recommendations from the relevant specialty organizations.
Evidence
A formal literature review was conducted by investigators at Protocare
Sciences Inc, Santa Monica, Calif, on the risks and benefits of performing
an SLN biopsy in patients with stage I or II melanoma and adjuvant interferon
alfa-2b therapy in patients with stage II or III disease. The MEDLINE
database was searched from 1966 through July 2000, and supplemental
information was obtained from various cancer societies and cancer research
groups. Panel participants were queried on additional sources of relevant
information. Unpublished, presented data were included in abstract form
on 1 recently closed clinical trial.
Consensus Process
The RAND/UCLA Appropriateness Method was used to review and rate multiple
clinical scenarios for the use of SLN biopsy and interferon alfa-2b
therapy. The consensus method did not force agreement.
Conclusions
The panel rated 104 clinical scenarios and concluded that the SLN biopsy
procedure was appropriate for primary melanomas deeper than 1.0 mm and
for tumors 1 mm or less when histologic ulceration was present and/or
classified as Clark level 4 or higher. The SLN biopsy was deemed inappropriate
for nonulcerated Clark level 2 or 3 melanomas 0.75 mm or less in depth
and uncertain in tumors 0.76 to 1.0 mm deep unless they were ulcerated
or Clark level 4 or higher. Interferon alfa-2b therapy was deemed appropriate
for patients with regional nodal and/or in-transit metastasis and for
node-negative patients with primary melanomas deeper than 4 mm. The
panel considered the use of interferon alfa-2b therapy uncertain in
patients with ulcerated intermediate primary tumors (2.01-4.0 mm in
depth) and inappropriate for node-negative patients with nonulcerated
tumors less than 4.0 mm deep. Specialty-specific ratings were conducted
as well.
|
|
Detection of micrometastasis in sentinel lymph nodes
of patients with primary cutaneous melanoma.
Blaheta HJ, Schittek B, Breuninger H, Garbe C.
Department of Dermatology, Eberhard-Karls-University,
Tubingen, Germany.
|
Recent Results Cancer Res 2001;158:137-46 Abstract quote
The technique of sentinel lymph node (SLN) biopsy has been demonstrated
to be highly predictive for the detection of melanoma micrometastases
in the regional lymph node basin. Therefore, the SLN was proposed to
accurately reflect the lymph node status of patients with primary cutaneous
melanoma. As the regional lymph node status is one of the most powerful
predictors of survival in patients with primary melanoma, the histopathologic
assessment is critically important for accurate staging. In approximately
20% (ranging from 9% to 42%) of patients with primary melanoma, the
SLN was found to be tumor-positive by histopathology or immunohistochemistry.
However, the true incidence of metastatic melanoma cells in (sentinel)
lymph nodes is underestimated by histopathologic examination.
Recently, the method of reverse transcription-polymerase chain reaction
(RT-PCR) for tyrosinase mRNA has been used as a molecular marker for
the presence of melanoma cells. Tyrosinase RT-PCR was demonstrated to
significantly increase the detection of melanoma cells in SLNs as compared
to histopathology. All lymph nodes positive by histopathology were shown
to express tyrosinase by RT-PCR.
Furthermore, tyrosinase transcripts were also detected in 36-52% of
stage I and II melanoma patients with SLNs negative by histopathology.
Importantly, the recurrence rate was significantly higher in patients
with histologically negative SLNs who were found to be positive by RT-PCR
than in patients with negative results by both techniques. These findings
indicate that RT-PCR status of the SLN is more sensitive for detection
of minimal melanoma disease than histopathology.
Therefore, the RT-PCR status of the SLN may be suitable to improve
melanoma staging and may serve as a prognostic factor in patients with
primary cutaneous melanoma.
|
|
Carbon dye histologically confirms the identity of
sentinel lymph nodes in cutaneous melanoma.
Haigh PI, Lucci A, Turner RR, Bostick PJ, Krasne DL,
Stern SL, Morton DL. Roy E.
Coats Research Laboratories, Division of Surgical
Oncology, John Wayne Cancer Institute at Saint John's Health Center,
2200 Santa Monica Blvd., Santa Monica, CA 90404, USA.
|
Cancer 2001 Aug 1;92(3):535-41 Abstract quote
BACKGROUND: False-negative results from lymphatic mapping and sentinel
lymphadenectomy (LM/SL) are associated with technical failures in nuclear
medicine and surgery or with erroneous histologic evaluation. Any method
that can confirm sentinel lymph node (SN) identity might decrease the
false-negative rate. Carbon dye has been used as an adjunct to assist
lymphadenectomy for some tumors, and the authors hypothesized that it
could be used for the histologic verification of SNs removed during
LM/SL. The current study assessed the clinical utility of carbon dye
as a histopathologic adjunct for the identification of SNs in patients
with melanoma and correlated the presence of carbon particles with the
histopathologic status of the SNs.
METHODS: LM/SL was performed using carbon dye (India ink) combined
with isosulfan blue dye and sulfur colloid. Blue-stained and/or radioactive
lymph nodes (two times background) were defined as SNs. Lymph nodes
were evaluated for the presence of carbon particles and melanoma cells.
If an SN lacked carbon dye in the initial histologic sections, four
additional levels were obtained with S-100 protein and HMB-45 immunohistochemistry.
Completion lymph node dissection (CLND) was performed if any SN contained
melanoma cells.
RESULTS: One hundred patients underwent successful LM/SL in 120 lymph
node regions. Carbon particles were identified in 199 SNs from 111 lymph
node regions of 96 patients. Sixteen patients had tumor-positive SNs,
all of which contained carbon particles. The anatomic location of the
carbon particles within these tumor-positive SNs was found to be correlated
with the location of tumor cells in the SNs. The presence of carbon
particles appeared to be correlated with blue-black staining (P = 0.0001)
and with tumor foci (P = 0.028). All 35 non-SNs that were removed during
LM/SL were tumor-negative, and only 2 contained carbon particles. Of
the 272 non-SNs removed during CLND, 5 contained metastases; 3 of these
5 were the only non-SNs that had carbon particles. The use of carbon
particles during LM/SL was found to be safe and nontoxic.
CONCLUSIONS: Carbon dye used in LM/SL for melanoma permits the histologic
confirmation of SNs. Carbon particles facilitate histologic evaluation
by directing the pathologist to the SNs most likely to contain tumor.
The location of carbon particles within SNs may assist the pathologist
in the detection of metastases, thereby decreasing the histopathologic
false-negative rate of LM/SL and subsequently reducing the same-basin
recurrence rate.
|
|
Elective Lymph Node Dissection in Patients With Melanoma: Systematic
Review and Meta-analysis of Randomized Controlled Trials.
Lens MB, Dawes M, Goodacre T, Newton-Bishop JA.
Centre for Evidence-Based Medicine, University of Oxford Nuffield
Department of Clinical Medicine, the Oxford Radcliffe National Health
Service Trust, Oxford OX3 9DU, England.
|
Arch Surg 2002 Apr;137(4):458-61 Abstract quote
HYPOTHESIS: Elective lymph node dissection does not improve survival
in patients with melanoma without clinically detectable lymph node metastases.
OBJECTIVE: To determine whether elective lymph node dissection in patients
with melanoma without clinically detectable regional metastases decreases
overall mortality.
DESIGN: Systematic review and meta-analysis of randomized controlled
trials comparing elective lymph node dissection with delayed lymphadenectomy
at the time of clinical recurrence.
SETTING: Randomized controlled trials available by February 2001.
SUBJECTS: The included trials comprised 1533 participants.
INTERVENTION: Elective lymph node dissection compared with delayed
lymphadenectomy or no lymphadenectomy in patients with melanoma without
clinically detectable regional metastases.
MAIN OUTCOME MEASURE: Overall mortality in treatment groups as compared
with control groups at the end of a 5-year follow-up period.
RESULTS: Three randomized controlled trials met the inclusion criteria.
The pooled odds ratio for overall mortality for the 3 trials was 0.86
(95% confidence interval, 0.68-1.09). Results are statistically nonsignificant,
but they have potential clinical significance.
CONCLUSIONS: This systematic review of randomized controlled trials
comparing elective lymph node dissection with surgery delayed until
the time of clinical recurrence shows no significant overall survival
benefit for patients undergoing elective lymph node dissection. Trials
included in this review, however, contain significant bias. The question
is not answered for all patients, and the results do not exclude the
possibility that some subgroups may benefit from elective lymph node
dissection. Further research is required.
|
|
Interval sentinel lymph nodes in melanoma.
McMasters KM, Chao C, Wong SL, Wrightson WR, Ross MI, Reintgen DS,
Noyes RD, Cerrito PB, Edwards MJ; Sunbelt Melanoma Trial Group.
Division of Surgical Oncology, Department of Surgery, James Graham
Brown Cancer Center, University of Louisvill, 529 S Jackson St, Louisville,
KY 40202, USA.
|
Arch Surg 2002 May;137(5):543-7 Abstract quote
HYPOTHESIS: For patients with melanoma, interval or in-transit sentinel
lymph nodes (SLNs) have the same risk for nodal metastasis as SLN in
traditional (ie, cervical, axillary, and inguinal) nodal basins.
DESIGN: Prospective clinical trial.
SETTING: Multicenter study.
PATIENTS: Eligible patients were aged 18 to 70 years with melanomas
of at least 1.0-mm Breslow thickness and nodes with clinically negative
findings.
INTERVENTION: Sentinel lymph node biopsy was guided by preoperative
lymphoscintigraphy to identify all SLNs.
MAIN OUTCOME MEASURES: We evaluated interval nodal sites, including
epitrochlear, popliteal, and subcutaneous or intramuscular nodes outside
of traditional basins, for the presence of metastases.
RESULTS: The SLNs were identified in 2332 nodal basins from 2000 patients.
In 62 patients (3.1%), interval SLNs were identified. We found SLN metastases
in 442 (19.5%) of 2270 conventional nodal basins and 13 (21.0%) of 62
interval sites. In 11 (84.6%) of the 13 cases in which we found an interval
node that was positive for metastatic disease, it was the only site
of nodal metastasis.
CONCLUSIONS: Although interval SLNs are identified infrequently, they
contain metastatic disease at nearly the same frequency as SLNs in cervical,
axillary, and inguinal nodal basins. Positive interval SLNs are likely
to be the only site of nodal metastasis. Therefore, detailed preoperative
lymphoscintigraphy and meticulous intraoperative search for interval
nodes should be performed.
|
|
Intraoperative evaluation of sentinel lymph nodes for metastatic melanoma
by imprint cytology.
Creager AJ, Shiver SA, Shen P, Geisinger KR, Levine EA.
Department of Pathology, Duke University Medical Center, Durham,
North Carolina.
|
Cancer 2002 Jun 1;94(11):3016-22 Abstract quote
BACKGROUND
Sentinel lymph node (SLN) biopsy has revolutionized lymph node staging
in patients with malignant melanoma. Intraoperative evaluation is a
new addition to the SLN procedure that allows for a one-step regional
lymph node dissection to be performed when the SLN biopsy findings are
positive. To date, several studies have evaluated the use of intraoperative
frozen sectioning to evaluate the SLN in patients with melanoma. The
literature pertaining to the use of intraoperative imprint cytology
(IIC) to evaluate the SLN in melanoma patients is scant and to the authors'
knowledge studies published to date are relatively small. The purpose
of the current study was to evaluate the utility of IIC in patients
undergoing SLN for melanoma.
METHODS
A total of 235 SLN biopsies from 93 patients with malignant melanoma
and 3 patients with atypical Spitz nevi were examined by IIC after SLN
biopsy using a double indicator technique. The SLNs were bisected and
a pair of imprints were made from each half. One imprint from each half
was stained with hematoxylin and eosin (H & E) whereas its counterpart
was stained with Diff-Quik. Paraffin-embedded permanent sections were
examined using multiple H & E stained sections from the SLNs in
conjunction with immunohistochemical staining for S-100 and HMB-45 proteins.
RESULTS
A total of 235 SLNs were excised from 93 patients (2.5 SLNs per patient).
On a per patient basis, metastases were identified in 21 patients (23%)
on permanent section evaluation. Of these 21 patients, 8 were detected
by IIC (sensitivity of 38%). The negative predictive value was 85%.
No false-positive results were identified (specificity of 100%). The
positive predictive value was 100%. The overall accuracy of the intraoperative
evaluation was 86%. Patients found to have positive SLNs by IIC went
on to undergo lymphadenectomy under the same anesthetic.
CONCLUSIONS
The sensitivity and specificity of IIC are similar to those of intraoperative
frozen-section evaluation. Therefore, IIC appears to be a viable alternative
to frozen sectioning when intraoperative evaluation is required. IIC
evaluation of SLN makes a single surgical procedure possible for patients
with malignant melanoma who are undergoing SLN.
|
|
Processing of sentinel lymph nodes for detection of metastatic melanoma.
Prieto VG, Clark SH.
Departments of Pathology and Dermatology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX.
|
Ann Diagn Pathol 2002 Aug;6(4):257-64 Abstract quote
Within the last years, evaluation of sentinel lymph nodes (SLN) has
become the most popular method of early staging of several malignancies,
including breast carcinoma and melanoma. Because SLN are reportedly
the lymph nodes most likely to contain metastatic deposits, identification
of such nodes allows pathologists to examine the tissue in a much more
intense manner than with the usual lymphadenectomy specimens containing
multiple lymph nodes. However, there is not a universally accepted standard
protocol for pathologic processing of the SLN.
Initially, the most popular protocols called for bisection of the SLN
and examination of serial sections, with or without routinely performed
immunohistochemistry. Lately, other protocols have been proposed to
try to simplify the histologic analysis while providing at least equivalent
results.
Here we review the different protocols used for the evaluation of SLN
and describe the protocol currently in use at M. D. Anderson Cancer
Center (Houston, TX).
|
| IMMUNOTHERAPY AND CHEMOTHERAPY |
CHARACTERIZATION |
| GENERAL |
J Clin Oncol 1996;14:410
Chang etal. Cancer Invest 1992;10:357.
Rosenberg SA JNCI 1994;86:1159-1166.
Interferon (IFN)-IFN alpha-2b
High dose regimens with lymphadenectomy yielded 10% survival advantage
Significant toxicity High cost ($30,000/yr)
Currently approved for stage III disease and melanoma>4mm with negative
LNs
IL-2 combined with LAK cells
Overall response rate of 16% (3% CR 13% PR n=190)
IL-2 combined with TIL Tumor regression in 35%
|
|
A phase II study of interferon-alpha 2b with dacarbazine,
carmustine, cisplatin and tamoxifen in metastatic melanoma.
Schultz MZ, Buzaid AC, Poo WJ.
Yale Comprehensive Cancer Center, New Haven, CT, USA.
|
Melanoma Res 1997 Apr;7(2):147-51 Abstract quote
A phase II trial was conducted to determine the efficacy and toxicity
of the addition of interferon-alpha 2b (IFN-alpha) to the chemotherapy
combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin and
tamoxifen (DBCT), in patients with stage III or IV melanoma.
Treatment consisted of DTIC 220 mg/m2 and cisplatin 25 mg/m2 intravenously
on days 1-3, BCNU 100 mg/m2 IV on day 1 only, tamoxifen 20 mg orally
twice daily and IFN-alpha 5 x 10(6) units/m2 subcutaneously on days
1-5. Cycles were repeated every 4 weeks. All patients received a loading
dose of tamoxifen 100 mg orally twice daily for 5 days before the first
course of therapy. Of the 24 patients treated, three (13%) achieved
a complete response (CR) and six (25%) a partial response (PR), for
an overall response rate of 38% (95% confidence interval, 17-58%). Two
patients, one who achieved a clinical CR and one a PR, had pathologically
confirmed complete responses. Severe myelosuppression occurred in 47%
of cycles and constitutional symptoms were common.
Overall, the addition of IFN-alpha to the DBCT regimen did not appear
to enhance the response rate and may have increased toxicity.
|
|
A phase II study of carboplatin, cisplatin, interferon-alpha,
and tamoxifen for patients with metastatic melanoma.
Gause BL, Sharfman WH, Janik JE, Curti BD, Steis RG,
Urba WJ, Smith JW 2nd, Alvord WG, Longo DL.
National Cancer Institute-Frederick Cancer Research
and Development Center, Frederick, Maryland, USA.
|
Cancer Invest 1998;16(6):374-80 Abstract quote
The purpose of this trial was to determine the toxicity and antineoplastic
activity of cisplatin, carboplatin, tamoxifen, and interferon-alpha
(IFN-alpha) in patients with advanced melanoma.
Eleven patients with metastatic melanoma were enrolled. The patients
received carboplatin 400 mg/m2 i.v. on day 0; cisplatin 25 mg/m2 i.v.
on days 7, 14, and 21; tamoxifen 20 mg p.o. b.i.d. on days 0-27; and
interferon-alpha 5 million units/m2 subcutaneously 3 times per week.
Cycles were repeated every 28 days. Patients were assessed for tumor
response at the end of 2 cycles. Toxicity was severe, with 14 of 24
cycles given requiring some form of dose reduction. Carboplatin dose
reductions were related to bone-marrow toxicity, whereas IFN-alpha caused
fatigue, arthralgias, myalgias, and fever.
The overall response rate was 18% (2 partial responses [PRs]). The
combination of cisplatin, carboplatin, tamoxifen, and IFN-alpha is active
in advanced melanoma; however, the toxicity is unacceptable.
|
|
Randomized trial of treatment with cisplatin and interleukin-2
either alone or in combination with interferon-alpha-2a in patients
with metastatic melanoma: a Federation Nationale des Centres de Lutte
Contre le Cancer Multicenter, parallel study.
Dorval T, Negrier S, Chevreau C, Avril MF, Baume D,
Cupissol D, Oskam R, de Peuter R, Vinke J, Herrera A, Escudier B.
French Cancer Centers' Immunotherapy Group, Institut
Curie, Paris.
|
Cancer 1999 Mar 1;85(5):1060-6 Abstract quote
BACKGROUND: The objective of the current study was to evaluate the
response rate, survival, and toxicity of treatment with cisplatin and
high dose intravenous continuous infusion interleukin-2 (IL-2) with
or without interferon-alpha-2a (IFN) in patients with metastatic melanoma.
METHODS: One hundred and seventeen patients with metastatic melanoma
randomly were assigned to receive cisplatin, 100 mg/m2, followed after
a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days
17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus
subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration
(Arm 2). In the absence of disease progression or undue toxicity, the
cycle could be repeated on Day 29. Patients who responded after two
cycles eventually could receive a third cycle. One hundred and one patients
were evaluable for toxicity and efficacy.
RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response
(CR) and 5 patients (10%) achieved a partial response (PR) with a median
response duration of 3.8 months for the CRs and 8.7 months for the PRs.
On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9
and 33.1 months, respectively) and 11 patients (21%) a PR with a median
response duration of 8.3 months. The median durations of overall survival
were 10.4 months (range, 1.1-39.7+ months) and 10.9 months (range, 0.5-38.1+
months) for treatment Arms 1 and 2, respectively. The toxicity profile
was consistent with the known side effects of this IL-2 intravenous
regimen combined with cisplatin chemotherapy and IFN. Toxicity was more
pronounced in treatment Arm 2 compared with treatment Arm 1. There were
2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within
28 days after completion of treatment.
CONCLUSIONS: The observed overall response rates of 16% and 25% in
treatment Arms 1 and 2, respectively, is lower than that expected with
biochemotherapy; despite the fact that the objective of the trial was
not to show any difference between the 2 treatment arms, our results
indicate that the addition of IFN, at the dose and schedule used in
this trial, fails to improve the activity of a cisplatin/IL-2 regimen
significantly in patients with metastatic melanoma. Although response
rates were relatively low, the median overall survival was nearly 1
year in both groups.
|
|
Phase III multicenter randomized trial of the Dartmouth
regimen versus dacarbazine in patients with metastatic melanoma.
Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro
AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton
AN, Kirkwood JM.
Memorial Sloan-Kettering Cancer Center, New York,
NY 10021, USA.
|
J Clin Oncol 1999 Sep;17(9):2745-51 Abstract quote
PURPOSE: Several single-institution phase II trials have reported that
the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen)
can induce major tumor responses in 40% to 50% of stage IV melanoma
patients. This study was designed to compare the overall survival time,
rate of objective tumor response, and toxicity of the Dartmouth regimen
with standard dacarbazine treatment in stage IV melanoma patients.
PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients
with measurable stage IV melanoma were randomized to receive the Dartmouth
regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to
3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10
mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated
every 3 weeks. Patients were observed for tumor response, survival time,
and toxicity.
RESULTS: Median survival time from randomization was 7 months; 25%
of the patients survived > or = 1 year.There was no difference in survival
time between the two treatment arms when analyzed on an intent-to-treat
basis or when only the 231 patients who were both eligible and had received
treatment were considered. Tumor response was assessable in 226 patients.
The response rate to dacarbazine was 10.2% compared with 18.5% for the
Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting,
and fatigue were significantly more common in the Dartmouth arm.
CONCLUSION: There was no difference in survival time and only a small,
statistically nonsignificant increase in tumor response for stage IV
melanoma patients treated with the Dartmouth regimen compared with dacarbazine.
Dacarbazine remains the reference standard treatment for stage IV melanoma
|
|
Multi-institutional phase II randomized trial of integrated
therapy with cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2,
interferon alpha2a and tamoxifen in metastatic melanoma. BREMIM (Biological
Response Modifiers in Melanoma).
Sertoli MR, Queirolo P, Bajetta E, DelVecchio M, Comella
G, Barduagni L, Bernengo MG, Vecchio S, Criscuolo D, Bufalino R, Morabito
A, Cascinelli N.
Italian Cooperative Group, Istituto Nazionale Tumori,
Milan.
|
Melanoma Res 1999 Oct;9(5):503-9 Abstract quote
The aim of this study was to evaluate the toxicity and efficacy of
a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a
and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin,
DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2
in patients with metastatic melanoma.
Consecutive patients with metastatic melanoma were enrolled in this
trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every
21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting
of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine
2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus
IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon
3 MU subcutaneously three times a week and tamoxifen 20 mg orally were
given throughout. Ninety-two patients were included in this study. Patient
characteristics in the three groups were well balanced. The three regimens
were delivered on an outpatient basis without major toxicity. The toxicities
that did occur consisted primarily of flu-like symptoms in the IL-2
arms (A and C) and haematological toxicities in the CVD arms (B and
C). No grade IV toxicities were encountered and no treatment-related
deaths occurred. The total response rate was 13% in arm A, 35% in arm
B and 37% in arm C. The median duration of response was 6 months and
the median survival was 11 months.
According to this phase II randomized trial polychemoimmunotherapy
with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy
with DTIC has a response rate of 13%.
|
|
A randomized phase III study comparing dacarbazine,
BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced
melanoma.
Middleton MR, Lorigan P, Owen J, Ashcroft L, Lee SM,
Harper P, Thatcher N.
CRC Department of Medical Oncology, Christie Hospital
NHS Trust, Manchester, UK.
|
Br J Cancer 2000 Mar;82(6):1158-62 Abstract quote
The purpose of this study was to compare the response rate, overall
and 1-year survival in patients with advanced melanoma treated with
a standard therapy, dacarbazine and interferon-alpha (DTIC/IFN), or
combination chemotherapy, consisting of dacarbazine, BCNU, cisplatin
and tamoxifen (DBCT).
Treatment toxicity and time spent in hospital were secondary end points.
One hundred and five patients (of whom 100 were eligible) were randomized
to receive either DTIC/IFN or DBCT. The trial was designed to detect
a 25% absolute difference in response rate or in 1-year survival with
80% power. There was no significant difference in response rate: this
was 17.3% with DTIC/IFN and 26.4% with DBCT. Median overall survival
was similar at 199 and 202 days respectively. One-year survival rate
favoured standard treatment (30.6 vs 22.6%), but did not differ significantly
between arms. DBCT was associated with significantly greater haematological
toxicity, and a greater need for time spent in hospital (5.75 days/treatment
cycle vs 2.29 with dacarbazine and interferon).
DBCT combination therapy cannot be recommended as standard treatment
for advanced melanoma. Dacarbazine remains the standard chemotherapy
for this condition.
|
|
Cisplatin, dacarbazine, and fotemustine plus interferon
alpha in patients with advanced malignant melanoma. A multicenter phase
II study of the Italian Cooperative Oncology Group.
Daponte A, Ascierto PA, Gravina A, Melucci MT, Palmieri
G, Comella P, Cellerino R, DeLena M, Marini G, Comella G;
Italian Cooperative Oncology Group. Division of Medical
Oncology A, National Tumor Institute, Naples, Italy.
|
Cancer 2000 Dec 15;89(12):2630-6 Abstract quote
BACKGROUND: In a previous study, the authors tested the combination
of fotemustine (FM) 100 mg/m(2) intravenously (i.v.) on Day 1, dacarbazine
(DTIC) 250 mg/m(2) i.v. on Days 2-5, and interferon alpha (IFNalpha)
3 MIU intramuscularly three times per week in 43 patients with advanced
melanoma. An overall response rate of 40% and a median survival of 40
weeks were obtained. To evaluate whether the addition of cisplatin (CDDP)
to this regimen could improve these results, the authors conducted a
preliminary Phase I study and concluded that CDDP 25 mg/m(2) i.v. for
2 days can be combined safely with DTIC, FM, and IFNalpha. Herein, the
authors report the results of a Phase II trial with this regimen.
METHODS: From June 1996 to February 1999, 64 patients with metastatic
melanoma who were not amenable to surgery were enrolled in this study.
Sixty eligible patients (32 males and 28 females; median age, 53 years)
were treated with a combination of FM 100 mg/m(2) i.v. on Day 1, DTIC
300 mg/m(2) i.v. on Days 2-4, and CDDP 25 mg/m(2) i.v. on Days 3 and
4 recycled every 3 weeks. IFN alpha2b was administered at a dose of
3 MIU intramuscularly 3 times per week until disease progression.
RESULTS: A total of 189 courses were administered, with a median number
of 3 courses per patient (range, 1-8 courses per patient). Eleven complete
responses and 12 partial responses were observed, for an overall response
rate of 38.3% (95% exact confidence interval, 26.1-51.8%). The median
survival was 36 weeks. Neutropenia and thrombocytopenia affected 85%
of patients and 68% patients and was World Health Organization Grade
3-4 in 40% and 50%, respectively. The side effects attributable to IFN
alpha2b were mild and manageable. The other side effects were moderate
and well controlled by supportive therapy.
CONCLUSIONS: The schedule used in this study demonstrated significant
activity in patients with advanced, untreated melanoma. The addition
of CDDP in the management of the patients in this series seemed to increase
significantly both the proportion of patients who achieved a complete
response and the probability of long term survival compared with a previous
series of patients who were treated by the authors. However, considering
the currently available therapies, this regimen does not seem to offer
a special advantage in the treatment of patients with this disease.
New agents and new protocols are needed.
|
|
Cohort study of metastatic melanoma patients in the
Dermatology Institute of Florence 1990/1997
. Moretti S, Carli P, Biggeri A, Volpi V, Pimpinelli
N.
U.O. Dermatologia II, Ospedale Santa Maria Nuova,
Firenze, Italy.
|
J Eur Acad Dermatol Venereol 2001 Jan;15(1):30-3 Abstract quote
BACKGROUND: Chemotherapy and immunotherapy are treatments currently
employed in advanced melanoma, but responses obtained are poor, and
metastatic melanoma patients with visceral localization rarely survive
for more than 6 months. Thus, different therapeutic regimens are used
in metastatic melanoma and no standardized therapy exists so far.
METHODS: We report a retrospective survival study involving 80 patients
with metastatic melanoma who were treated either with chemotherapy [dacarbazine
(DTIC) alone or DTIC in monotherapeutic or polychemotherapeutic regimen]
or immunochemotherapy [interferon (IFN)-alpha at low doses added to
chemotherapy]. Survival of patients was statistically evaluated in an
actuarial curve taking into account as predictive variables sex, age,
marital status, site of primary tumour, histological type, Clark level,
sites of metastases, and the different therapeutic regimens (i.e. DTIC
alone, DTIC plus IFN-alpha, or others, with or without IFN-alpha).
RESULTS: Site of primary melanoma, histological type, Clark level and
therapy regimen appeared to exhibit a prognostic significance in survival;
when a multivariate analysis was performed to obtain a mutual adjustment
of survival values for each variable, only the therapeutic regimen was
found to be significant as an independent prognostic variable. Patients
treated with immunochemotherapy, i.e. DTIC plus IFN-alpha, showed a
probability of dying of 0.41 (95% confidence interval 0.2-0.8) compared
with patients treated with DTIC alone.
CONCLUSIONS: In our study immunochemotherapy, comprised of DTIC plus
IFN-alpha at low doses, was associated with a significantly longer survival
of patients, in comparison with chemotherapy comprised of only DTIC.
|
|
Phase II randomized study of dacarbazine, carmustine,
cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma
patients.
Chiarion Sileni V, Nortilli R, Aversa SM, Paccagnella
A, Medici M, Corti L, Favaretto AG, Cetto GL, Monfardini S.
Department of Medical Oncology, Padova Hospital, Azienda
Ospedaliera, Italy.
|
Melanoma Res 2001 Apr;11(2):189-96 Abstract quote
This randomized phase II trial was performed to define the activity
and toxicity of the combination of dacarbazine (DTIC), carmustine (BCNU),
cisplatin (DDP) and tamoxifen (DBDT regimen) versus DTIC alone in patients
with metastatic melanoma. Sixty patients with metastatic melanoma were
randomly assigned to receive BCNU 150 mg/m2 intravenously (i.v.) on
day 1, cisplatin 25 mg/m2 i.v. daily on days 1 to 3, DTIC 220 mg/m2
i.v. daily on days 1 to 3 and tamoxifen 160 mg orally daily for 7 days
prior to chemotherapy (DBDT arm; arm A). Treatment cycles were repeated
every 28 days, while BCNU was given every two cycles. The DTIC arm (arm
B) patients received DTIC alone 1200 mg/m2 i.v. on day 1, repeated every
21 days. Patients were evaluated every two cycles; responding patients
continued the treatment for a maximum of 12 cycles. The overall response
rate was 26% in the DBDT arm and 5% in the DTIC arm. Complete responses
were 2.5% for DBDT and 0% for DTIC. The median progression-free survival
and the median survival were 4 and 9 months, respectively for DBDT,
and 2 and 7 months for DTIC. DBDT was associated with significant haematological
toxicity: 33% of the patients experienced a grade III or IV neutropenia
and 28% a grade III or IV thrombocytopenia. In conclusion, the overall
response rate obtained with DBDT was greater than that obtained with
DTIC alone; however, this combination increases toxicity with limited
impact on overall survival.
|
|
Dacarbazine and interferon alpha with or without interleukin
2 in metastatic melanoma: a randomized phase III multicentre trial of
the Dermatologic Cooperative Oncology Group (DeCOG).
Hauschild A, Garbe C, Stolz W, Ellwanger U, Seiter
S, Dummer R, Ugurel S, Sebastian G, Nashan D, Linse R, Achtelik W, Mohr
P, Kaufmann R, Fey M, Ulrich J, Tilgen W.
Department of Dermatology, Christian-Albrechts-University,
Kiel.
|
Br J Cancer 2001 Apr 20;84(8):1036-42 Abstract quote
In several phase II-trials encouraging tumour responses rates in advanced
metastatic melanoma (stage IV; AJCC-classification) have been reported
for the application of biochemotherapy containing interleukin 2.
This study was designed to compare the efficacy of therapy with dacarbazine
(DTIC) and interferon alpha (IFN-alpha) only to that of therapy with
DTIC and IFN-alpha with the addition of interleukin 2 (IL-2) in terms
of the overall survival time and rate of objective remissions and to
provide an elaborated toxicity profile for both types of therapy.
290 patients were randomized to receive either DTIC (850 mg/m(2)every
28 days) plus IFN-alpha2a/b (3 MIU/m(2), twice on day 1, once daily
from days 2 to 5; 5 MIU/m(2)3 times a week from week 2 to 4) with or
without IL-2 (4.5 MIU/m(2)for 3 hours i.v. on day 3; 9.0 MIU/m(2) i.v.
day 3/4; 4.5 MIU/m(2) s.c. days 4 to 7). The treatment plan required
at least 2 treatment cycles (8 weeks of therapy) for every patient.
Of 290 randomized patients 281 were eligible for an intention-to-treat
analysis. There was no difference in terms of survival time from treatment
onset between the two arms (median 11.0 months each). In 273 patients
treated according to protocol tumour response was assessable. The response
rates did not differ between both arms (P = 0.87) with 18.0% objective
responses (9.7% PR; 8.3% CR) for DTIC plus IFN-alpha as compared to
16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-alpha and IL-2. Treatment cessation
due to adverse reactions was significantly more common in patients receiving
IL-2 (13.9%) than in patients receiving DTIC/IFN-alpha only (5.6%).
In conclusion, there was neither a difference in survival time nor
in tumour response rates when IL-2, applied according to the combined
intravenous and subcutaneous schedule used for this study, was added
to DTIC and IFN-alpha. However, toxicity was increased in melanoma patients
treated with IL-2. Further phase III trials with continuous infusion
and higher dosages must be performed before any final conclusions can
be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced
melanoma.
|
|
The EORTC melanoma group translational research program
on prognostic factors and ultrastaging in association with the adjuvant
therapy trials in stage II and stage III melanoma.
European Organization for Research and Treatment
of Cancer. Eggermont AM, Keilholz U, Testori A, Cook M, Lienard D, Ruiter
DJ.
EORTC-Melanoma Group, Brussels, Belgium.
|
Ann Surg Oncol 2001 Oct;8(9 Suppl):38S-40S Abstract quote
Last year the Melanoma Group of the European Organization for Research
and Treatment of Cancer (EORTC-MG) completed accrual (1418 patients)
for trial EORTC 18952, a three-arm phase III trial evaluating adjuvant
therapy with two different intermediate doses of interferon (IFN) alfa-2b
versus observation for stage IIB-III melanoma.
About 25% of the patients entered the trial with tumor-positive sentinel
nodes (SNs). Prognosis was significantly better in SN-positive patients
than in patients with palpable regional node involvement (P < .00001).
Subsequently the EORTC-MG embarked on two large phase III trials of
adjuvant therapy based on the tumor status of the SN. In trial EORTC
18961 for stage II melanoma, GM2-KLH/QS-21 vaccination is compared with
observation (1300 patients); in trial EORTC 18991 for stage III melanoma,
5-year treatment with pegylated interferon alfa-2b (PEG-Intron) is compared
with observation (900 patients). Translational research projects will
compare SN assessment by hematoxylin and eosin (H&E) staining, immunohistochemistry
(IHC), and reverse transcriptase-polymerase chain reaction (RT-PCR)
to determine the relative accuracy of each method and its correlation
to relapse and survival of patients with stage II melanoma.
In stage III patients, a similar workup of the most proximal nonsentinel
node in the full lymph-node dissection specimen will indicate the accuracy
of each methodology to detect nodal metastasis beyond the SN and thJ
Clin Oncol 2002 Mar 1;20(5):1311-8 Related Articles, Books, LinkOut
Quality-of-Life--Adjusted Survival Analysis of High-Dose Adjuvant Interferon
Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial
Data.
Kilbridge KL, Cole BF, Kirkwood JM, Haluska FG, Atkins MA, Ruckdeschel
JC, Sock DE, Nease RF Jr, Weeks JC.
University of Virginia, Charlottesville, VA.
PURPOSE: High-dose adjuvant interferon alfa-2b (IFNalpha2b) for high-risk
melanoma is a 1-year regimen that improves relapse-free and overall
survival but has significant toxicity. A quality-of-life--adjusted survival
(QAS) analysis analysis of two cooperative group phase III trials, E1684
and E1690/S9111/C9190, was performed, incorporating patient values (utilities)
for the toxicity of IFNalpha2b treatment and melanoma recurrence. PATIENTS
AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology
was used with melanoma patient utilities and trial data to estimate
the effect of IFNalpha2b on QAS. The increase or decrease in QAS that
patients could expect from treatment was estimated based on their utilities.
Eleven utility predictor questions were tested to identify patients
with utilities that result in decreased QAS. RESULTS: Using E1684 data,
IFNalpha2b would result in an increase in QAS for all sets of patient
utilities. This benefit was significant (P <.05) for 16% of patients.
Using E1690/S9111/C9190 data, 77% of patients would experience a benefit
in QAS from IFNalpha2b and 23% would experience a decrease in QAS; neither
of these effects was statistically significant. Using utility predictors
and the E1690/S9111/C9190 analysis, a decision rule was formulated that
helps identify patients in whom IFNalpha2b may detract from QAS. CONCLUSION:
Most patients experienced improvement in QAS in both trials, but this
benefit was statistically significant in only 16% of patients in E1684.
Change in QAS depends more on the utility for IFNalpha2b toxicity than
on the utility for melanoma recurrence. Cancer patients probably have
higher utilities for IFNalpha2b toxicity than members of the general
population and will tend to favor IFNalpha2b treatment as a result.
e prognostic significance thereof. These findings will be correlated
to the results of sequential blood testing by RT-PCR and by tumor marker
assays for S100, TA90, and angiostatin. In addition, tumor-positive
and tumor-negative SNs will be assessed for activated cytotoxic T lymphocytes
and downregulation of dendritic cell functions.
|
|
Quality-of-Life--Adjusted Survival Analysis of High-Dose Adjuvant Interferon
Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial
Data.
Kilbridge KL, Cole BF, Kirkwood JM, Haluska FG, Atkins
MA, Ruckdeschel JC, Sock DE, Nease RF Jr, Weeks JC.
University of Virginia, Charlottesville, VA.
|
J Clin Oncol 2002 Mar 1;20(5):1311-8 Abstract quote
PURPOSE: High-dose adjuvant interferon alfa-2b (IFNalpha2b) for high-risk
melanoma is a 1-year regimen that improves relapse-free and overall
survival but has significant toxicity. A quality-of-life--adjusted survival
(QAS) analysis analysis of two cooperative group phase III trials, E1684
and E1690/S9111/C9190, was performed, incorporating patient values (utilities)
for the toxicity of IFNalpha2b treatment and melanoma recurrence.
PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity
methodology was used with melanoma patient utilities and trial data
to estimate the effect of IFNalpha2b on QAS. The increase or decrease
in QAS that patients could expect from treatment was estimated based
on their utilities. Eleven utility predictor questions were tested to
identify patients with utilities that result in decreased QAS.
RESULTS: Using E1684 data, IFNalpha2b would result in an increase in
QAS for all sets of patient utilities. This benefit was significant
(P <.05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of
patients would experience a benefit in QAS from IFNalpha2b and 23% would
experience a decrease in QAS; neither of these effects was statistically
significant. Using utility predictors and the E1690/S9111/C9190 analysis,
a decision rule was formulated that helps identify patients in whom
IFNalpha2b may detract from QAS.
CONCLUSION: Most patients experienced improvement in QAS in both trials,
but this benefit was statistically significant in only 16% of patients
in E1684. Change in QAS depends more on the utility for IFNalpha2b toxicity
than on the utility for melanoma recurrence. Cancer patients probably
have higher utilities for IFNalpha2b toxicity than members of the general
population and will tend to favor IFNalpha2b treatment as a result.
|
|
Interferon alfa therapy for malignant melanoma: a systematic review
of randomized controlled trials.
Lens MB, Dawes M.
Center for Evidence-Based Medicine, University of Oxford, Oxford,
United Kingdom.
|
J Clin Oncol 2002 Apr 1;20(7):1818-25 Abstract quote
PURPOSE: No standard systemic adjuvant therapy has been proven to increase
overall survival in melanoma patients. The effect of interferon alfa
(IFNalpha) as a single agent or in combination has been widely explored
in clinical trials. The purpose of this study was to assess the benefit
of IFNalpha therapy in malignant melanoma.
METHODS: We performed a systematic review of randomized controlled
trials comparing regimens with or without IFNalpha adjuvant therapy
in melanoma patients. We assessed the effect of IFNalpha therapy on
overall survival (OS), disease-free survival (DFS), melanoma recurrences,
and toxicity. The quality of each trial was systematically evaluated.
RESULTS: Nine randomized controlled trials (RCTs) of IFNalpha therapy
in melanoma patients were identified. Eight were published and one was
unpublished. Eight trials comprising 3,178 patients fulfilled our inclusion
criteria and were analyzed. Quality assessment scores ranged from 22
to 71, with a mean score of 55.4 (95% confidence interval, 53.8 to 57.0).
For OS, only one trial reported a statistically significant benefit
for IFNalpha, but our analysis did not confirm it. Two trials reported
statistically significant benefit in DFS for the patients treated with
IFNalpha, but our analysis confirmed it in only one trial. There was
a wide clinical heterogeneity between included trials, making meta-analysis
inappropriate.
CONCLUSION: In our review, results from included RCTs demonstrated
no clear benefit of IFNalpha therapy on OS in melanoma patients. A large
RCT is required to answer whether a full regimen of IFNalpha therapy
is effective and to identify the subgroups of patients who might benefit
from IFNalpha treatment.
|
|
Results from a randomized phase III study comparing combined treatment
with histamine dihydrochloride plus interleukin-2 versus interleukin-2
alone in patients with metastatic melanoma.
Agarwala SS, Glaspy J, O'Day SJ, Mitchell M, Gutheil J, Whitman
E, Gonzalez R, Hersh E, Feun L, Belt R, Meyskens F, Hellstrand K, Wood
D, Kirkwood JM, Gehlsen KR, Naredi P.
Melanoma Center, University of Pittsburgh Cancer Institute, 200
Lothrop Street, Pittsburgh, PA 15213-2582, USA.
|
J Clin Oncol 2002 Jan 1;20(1):125-33 Abstract quote
PURPOSE: Reactive oxidative species (ROS) produced by phagocytic cells
have been ascribed a role in the localized suppression of lymphocyte
function within malignant tumors. Histamine has been shown to inhibit
ROS formation and possibly synergize with cytokines to permit activation
of natural killer cells and T cells. This study was designed to determine
whether the addition of histamine to a subcutaneous (SC) regimen of
interleukin-2 (IL-2) would improve the survival of metastatic melanoma
patients.
PATIENTS AND METHODS: A phase III, multicenter, randomized, parallel
group study comparing IL-2 plus histamine with IL-2 alone was conducted
in 305 patients with advanced metastatic melanoma. Patients were randomized
to IL-2 (9 MIU/m(2) bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m(2)
bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0
mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival,
was prospectively applied to all randomized patients (intent-to-treat-overall
population, ITT-OA) and all patients having liver metastases at randomization
(ITT-LM population). Secondary end points included safety of the combined
treatment, time to disease progression, and response rate.
RESULTS: Combined treatment with histamine plus IL-2 significantly
improved overall survival in the ITT-LM population (P =.004) and showed
a trend for improved survival in the ITT population (P =.125). Grade
3 and 4 adverse events were comparable in the two arms.
CONCLUSION: Use of histamine as an adjunct to IL-2 is safe, well tolerated,
and associated with a statistically significant prolongation of survival
compared with IL-2 alone in metastatic melanoma patients with liver
involvement. Further trials to confirm and understand the role of histamine
in this combination treatment are underway.
|
| VACCINE THERAPY |
CHARACTERIZATION |
| GENERAL |
Whole cell vaccine
Tumor lysate vaccine
Melanoma associated antigens (MAA):
MAGE 1 and 3
BAGE
GAGE 1 and 2
Tyrosinase TRP-1
MART-1
gp100
Potential Peptide Vaccines Antigens encoded by genes that are expressed
in various tumors but silent in normal adults
Differentiating antigens encoded by genes in melanoma and normal melanocytes
These MAA are HLA restricted so typing must be performed before enrollment
in vaccine protocols
|
|
Vaccination with irradiated autologous melanoma cells
engineered to secrete human granulocyte-macrophage colony-stimulating
factor generates potent antitumor immunity in patients with metastatic
melanoma.
Soiffer R, Lynch T, Mihm M, Jung K, Rhuda C, Schmollinger
JC, Hodi FS, Liebster L, Lam P, Mentzer S, Singer S, Tanabe KK, Cosimi
AB, Duda R, Sober A, Bhan A, Daley J, Neuberg D, Parry G, Rokovich J,
Richards L, Drayer J, Berns A, Clift S, Dranoff G, et al.
Department of Adult Oncology, Dana-Farber Cancer
Institute and Harvard Medical School, Boston, MA 02115, USA.
|
Proc Natl Acad Sci U S A 1998 Oct 27;95(22):13141-6 Abstract quote
We conducted a Phase I clinical trial investigating the biologic activity
of vaccination with irradiated autologous melanoma cells engineered
to secrete human granulocyte-macrophage colony-stimulating factor in
patients with metastatic melanoma.
Immunization sites were intensely infiltrated with T lymphocytes,
dendritic cells, macrophages, and eosinophils in all 21 evaluable patients.
Although metastatic lesions resected before vaccination were minimally
infiltrated with cells of the immune system in all patients, metastatic
lesions resected after vaccination were densely infiltrated with T lymphocytes
and plasma cells and showed extensive tumor destruction (at least 80%),
fibrosis, and edema in 11 of 16 patients examined. Antimelanoma cytotoxic
T cell and antibody responses were associated with tumor destruction.
These results demonstrate that vaccination with irradiated autologous
melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating
factor stimulates potent antitumor immunity in humans with metastatic
melanoma.
|
|
Immunizing patients with metastatic melanoma using recombinant adenoviruses
encoding MART-1 or gp100 melanoma antigens.
Rosenberg SA, Zhai Y, Yang JC, Schwartzentruber DJ,
Hwu P, Marincola FM, Topalian SL, Restifo NP, Seipp CA, Einhorn JH,
Roberts B, White DE.
Surgery Branch, National Cancer Institute, Bethesda,
MD, USA.
|
J Natl Cancer Inst 1998 Dec 16;90(24):1894-900 Abstract
quote
BACKGROUND: The characterization of the genes encoding melanoma-associated
antigens MART-1 or gp100, recognized by T cells, has opened new possibilities
for the development of immunization strategies for patients with metastatic
melanoma. With the use of recombinant adenoviruses expressing either
MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated
the safety, immunologic, and potential therapeutic aspects of these
immunizations.
METHODS: In phase I studies, 54 patients received escalating doses
(between 10(7) and 10(11) plaque-forming units) of recombinant adenovirus
encoding either MART-1 or gp100 melanoma antigen administered either
alone or followed by the administration of interleukin 2 (IL-2). The
immunologic impact of these immunizations on the development of cellular
and antibody reactivity was assayed.
RESULTS: Recombinant adenoviruses expressing MART-1 or gp100 were safely
administered. One of 16 patients with metastatic melanoma receiving
the recombinant adenovirus MART-1 alone experienced a complete response.
Other patients achieved objective responses, but they had received IL-2
along with an adenovirus, and their responses could be attributed to
the cytokine. Immunologic assays showed no consistent immunization to
the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses.
High levels of neutralizing antibody were found in the pretreatment
sera of the patients.
CONCLUSIONS: High doses of recombinant adenoviruses could be safely
administered to cancer patients. High levels of neutralizing antibody
present in patients' sera prior to treatment may have impaired the ability
of these viruses to immunize patients against melanoma antigens.
|
|
Development of a polynucleotide vaccine from melanoma
antigen recognized by T cells-1 and recombinant protein from melanoma
antigen recognized by T cells-1 for melanoma vaccine clinical trials.
Lee SW, Li H, Strong TV, Moore SE, Conry RM.
Department of Medicine, University of Alabama at Birmingham
35294-3300, USA
|
J Immunother 2000 May-Jun;23(3):379-86 Abstract quote
MART-1, a melanoma antigen recognized by T cells-1, is a melanocyte
lineage-differentiation antigen expressed only in melanocytes and melanoma
cells. This protein is recognized by many T-lymphocyte lines that are
human leukocyte antigen (HLA)-A2 restricted and melanoma reactive. These
observations have culminated in an array of clinical trials of MART-1
immunization using recombinant viruses or MART-1 immunodominant peptides.
Polynucleotide immunization is a promising alternative to recombinant
viral vaccines that allows delivery of the full-length cDNA encoding
all potential peptide epitopes in a vector that is uncompromised by
anti-viral immunity.
In preparation for a phase I clinical trial of MART-1 polynucleotide
immunization in patients with resected melanoma who were at significant
risk for recurrence, the authors constructed a plasmid DNA encoding
the MART-1 cDNA under transcriptional regulatory control of the cytomegalovirus
immediate early promoter-enhancer and partially deleted intron A. This
plasmid directs high-level MART-1 expression in transduced myoblasts
and maturing myocytes diffusely throughout the cytoplasm. Immunization
of mice with this construct by intramuscular injection elicited MART-1-specific
immune responses in all animals. Previous trials of MART-1 immunization
have been unable to examine the humoral immune response to MART-1 because
of a lack of sufficient, highly purified protein.
We have produced and purified Escherichia coli recombinant MART-1 protein
using a glutathione-S-transferase fusion protein expression system.
Protein staining of a sodium dodecyl sulfate-polyacrylamide gel electrophoresis
revealed a band of MART-1 protein at approximately 20 kD; and Western
immunoblotting with an anti-MART-1 monoclonal antibody confirmed a doublet
at approximately 20 kD. These findings are consistent with previous
reports using different expression systems for recombinant MART-1. This
protein preparation functioned well in enzyme-linked immunosorbent assays
(ELISAs) to detect anti-MART-1 antibody responses in a mouse model;
and a panel of healthy donor human sera showed minimal binding to ELISA
plates coated with the protein, supporting its utility in monitoring
human anti-MART-1 antibody responses. The glutathione-S-transferase
fusion method yielded approximately 200 micrograms MART-1 per 2-L bacterial
culture, enough to coat 100 ELISA plates.
|
|
Phase 1 clinical trial of irradiated autologous melanoma
cells adenovirally transduced with human GM-CSF gene.
Kusumoto M, Umeda S, Ikubo A, Aoki Y, Tawfik O, Oben
R, Williamson S, Jewell W, Suzuki T.
Department of Microbiology, Molecular Genetics and
Immunology, University of Kansas Medical Center, Kansas City 66160,
USA.
|
Cancer Immunol Immunother 2001 Sep;50(7):373-81 Abstract quote
The objective of this study was to determine the safety and antitumor
activity of an autologous GM-CSF-secreting melanoma cell vaccine that
was engineered ex vivo with recombinant replication-incompetent adenovirus
harboring a human GM-CSF gene (Adv/hGM-CSF).
Melanoma samples were surgically obtained from 30 patients (15 female
and 15 male, ages ranging from 23 to 87) and were processed for vaccine
preparation. Due to stringent eligibility criteria, 9 out of 30 patients
were enrolled in the phase 1 clinical trial (FDA IND7677). Melanoma
cell lines established from surgical specimens of 9 patients were transduced
with Adv/hGM-CSF (MOI of 100) and subsequently irradiated at 35 Gy.
These cell lines secreted human GM-CSF in vitro at an average rate of
80-424 ng/10(6) cells/24 h. All patients were intradermally and subcutaneously
injected at several sites with irradiated autologous melanoma cells
(2x10(6)-1x10(7) in 300 microl saline), 2-10 times, at intervals of
4-8 weeks. None of the patients vaccinated showed any serious adverse
systemic response. Three patients (nos.1, 6 and 7) demonstrated local
reaction (erythema) to the vaccination. Tumor-specific CTL assays performed
in the absence of K562 cells showed that the levels of CTLs in peripheral
blood of 5 patients increased following vaccination, whereas those in
one patient declined. Levels of CTLs assayed in the presence of K562
cells were considerably lower than those assayed in the absence of K562
cells, but were also found to increase following vaccination in the
peripheral blood of 6 patients. A patient who had been vaccinated 10
times (patient 1) responded to the vaccination by apparent reduction
in size of metastatic tumor in the lung. Immunohistochemical examination
of the vaccination sites of patient 1, biopsied after the 3rd and 4th
vaccination. showed that the vaccination sites responded with infiltration
of inflammatory cells, such as T cells (CD3+, CD8+), macrophages and
dendritic cells (CD83+), for a period up to about 8 days.
These data suggest that repeated vaccinations with irradiated autologous
GM-CSF-producing tumor cells were well tolerated by patients and led
to the activation of an antitumor immune response in some patients.
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Hypopigmentation Associated With an Adenovirus-Mediated gp100/MART-1-Transduced
Dendritic Cell Vaccine for Metastatic Melanoma.
Tsao H, Millman P, Linette GP, Hodi FS, Sober AJ,
Goldberg MA, Haluska FG.
Department of Dermatology, Bartlett 622, 48 Blossom
St, Massachusetts General Hospital, Boston, MA 02114.
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Arch Dermatol 2002 Jun;138(6):799-802 Abstract quote
BACKGROUND: Reports of vitiligo associated with metastases and rare
cases of spontaneous regression of disease have fueled enthusiasm for
immunologic approaches to the treatment of advanced melanoma. More recent
strategies have focused on using antigen-presenting dendritic cells
as vaccines.
OBSERVATIONS: We observed 3 cases of leukoderma associated with a novel
adenovirus-mediated gp100/MART-1-transduced dendritic cell (MART indicates
melanoma antigen recognized by T cells). All 3 patients had advanced
metastatic melanoma. Despite the development of this leukodermic response,
all patients experienced disease progression while under treatment.
CONCLUSION: We provide the initial evidence for effective induction
of a leukodermic response with a gp100/MART-1-transduced dendritic cell
vaccine.
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