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NCI CANCERLIT® Search: Therapy of Melanoma - April 2002
National Cancer Institute®
Ultima Vez Modificado: 1 de abril del 2002
Table of Contents
1
UI - 11686036
AU - Benson C; Gore ME
TI -
Melanoma.
SO - Cancer Chemother Biol Response Modif 2001;19():629-38
AD - Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK.
2
UI - 11776490
AU - Zogakis TG; Bartlett DL; Libutti SK; Liewehr DJ; Steinberg SM; Fraker
TI -
DL; Alexander HR
Factors affecting survival after complete response to isolated limb
perfusion in patients with in-transit melanoma.
SO - Ann Surg Oncol 2001 Dec;8(10):771-8
AD - Surgery Branch and the Biostatistics and Data Management Section, Center
for Cancer Research, National Cancer Institute, Bethesda, Maryland
20892, USA.
BACKGROUND: Isolated limb perfusion (ILP) results in complete response
(CR) rates of 60% to 90% in patients with regionally advanced melanoma.
Survival after a CR may be influenced by various factors, particularly
out-of-field disease in iliac lymph nodes (ILN) identified during
lower-extremity ILP. We examined clinical and pathological parameters,
including ILN status and outcome, for patients with in-transit melanoma
(16 men and 34 women; median age, 57 years) with stage IIIA or IIIAB
melanoma had a CR to a 90-minute hyperthermic iliac ILP with melphalan
(10 mg/L limb volume, n = 20) or melphalan and tumor necrosis factor
(4-6 mg+/-200 microg interferon; n = 30). Clinical and pathological
parameters were analyzed by univariate and Cox proportional hazards
models to determine which were associated with survival or in-field
recurrence. RESULTS: The median in-field recurrence-free survival in the
cohort of 50 patients after a CR to ILP was 1.4 years, and the actuarial
5-year in-field recurrence-free survival was 30%. By univariate
analysis, there was a trend for improved outcome with female sex and
stage IIIA (vs. IIIAB) at initial diagnosis was associated with improved
survival after a CR to ILP (P = .056 and .012, respectively). Eleven
(22%) of 50 patients had positive ILNs identified and resected at ILP.
The probability of overall in-field recurrence was 70% after 4 years,
and there was no difference between those with or without positive ILNs;
median time to in-field recurrence was 13 and 19 months, respectively (P
= .62). Similarly, overall survival was not influenced by positive ILN
status (median [months]: +ILN, 69 vs. -ILN, 58; P = .68). Of note, Cox
models identified that the risk of death was significantly greater in
those with a history of prior systemic therapy (hazard ratio: 2.67 [95%
confidence interval, 1.17-6.11]; P = .02) and those with an in-transit
lesion size > or =1.4 cm2 (hazard ratio, 3.12 [95% confidence interval,
1.30-7.5]; P = .011). When these two variables were combined, there was
a highly significant association with shortened survival (P = .002 by
log-rank test). CONCLUSIONS: These data indicate that for patients
undergoing ILP and in whom positive ILNs are found and resected, ILP is
justified. In addition, patients who have a CR after ILP and have a
history of prior treatment or larger lesions should be considered for
adjuvant systemic therapy.
3
UI - 11783968
AU - Bishop JA; Corrie PG; Evans J; Gore ME; Hall PN; Kirkham N; Roberts DL;
TI -
Anstey AV; Barlow RJ; Cox NH; Melanoma Study Group; British Association
of Dermatologists
UK guidelines for the management of cutaneous melanoma.
SO - Br J Plast Surg 2002 Jan;55(1):46-54
AD - Genetic Epidemiology Division, ICRF Clinical Centre, St James's
University Hospital, Leeds, UK.
These guidelines for management of cutaneous melanoma present
evidence-based guidance for treatment, with identification of the
strength of evidence available at the time of preparation of the
guidelines, and a brief overview of epidemiological aspects, diagnosis
and investigation. To reflect the collaborative process for the UK, they
are subject to dual publication in the British Journal of Dermatology
and the British Journal of Plastic Surgery. Copyright 2002 The British
Association of Plastic Surgeons and the British Association of
Dermatologists.
4
UI - 11862432
AU - Quto b SS; Ng CE
TI -
Comparison of apoptotic, necrotic and clonogenic cell death and
inhibition of cell growth following camptothecin and X-radiation
treatment in a human melanoma and a human fibroblast cell line.
SO - Cancer Chemother Pharmacol 2002 Feb;49(2):167-75
AD - Ottawa Regional Cancer Centre, Ottawa, ON, K1H 1C4, Canada.
PURPOSE: We evaluated apoptotic, necrotic and clonogenic cell death and
inhibition of cell growth in a human melanoma cell line (Sk-Mel-3) and a
normal human fibroblast cell line (AG1522) following treatment with
camptothecin (CPT) or with concurrent CPT and X-radiation. MATERIALS AND
METHODS: Apoptotic and necrotic cell death was determined
morphologically by dual-staining (propidium iodide, acridine orange).
Inhibition of cell growth was determined from the number of cells
remaining in the culture dish following treatment. RESULTS: In Sk-Mel-3
cells: (a) after treatment with CPT alone, both apoptotic and necrotic
cell death increased significantly ( P<0.05) relative to untreated
controls; (b) after concurrent CPT and radiation treatment, however,
only the increase in necrotic cell death was significant ( P<0.05)
relative to cells receiving radiation alone; and (c) all assays of
cellular effects/cytotoxicities were consistent in showing that CPT,
given alone or with radiation, led to a substantial increase in cell
kill. In contrast, in AG1522 cells: (a) there were no significant
increases in apoptotic or necrotic cell death following either CPT alone
or concurrent CPT and radiation; and (b) the clonogenic assay measured
substantially higher cytotoxicities than the other assays. CONCLUSIONS:
Necrotic cell death was more important than apoptotic cell death during
concurrent CPT and radiation treatment in Sk-Mel-3 cells, but not in
AG1522 cells.
5
UI - 11900232
AU - Gibbs P; Anderson C; Pearlman N; LaClaire S; Becker M; Gatlin K;
TI -
O'Driscoll M; Stephens J; Gonzalez R
A phase II study of neoadjuvant biochemotherapy for stage III melanoma.
SO - Cancer 2002 Jan 15;94(2):470-6
AD - Oncology Department, Royal Melbourne Hospital, Parkville, Victoria,
Australia.
BACKGROUND: Phase II studies of biochemotherapy (combining
interleukin-2, interferon-alpha, and multiagent chemotherapy) have
reported high response rates and a significant number of durable
complete responses in patients with metastatic melanoma. METHODS: A
pilot Phase II study was performed to explore the safety and activity of
neoadjuvant biochemotherapy in patients with Stage III melanoma.
median age of the patients was 46 years (range, 19-70 years). Two cycles
of biochemotherapy were administered prior to and after complete lymph
node dissection. Each cycle was comprised of cisplatin, 20 mg/m2
intravenously (i.v.), on Days 1-4; vinblastine, 1.6 mg/m2 i.v., on Days
1-4; dacarbazine, 800 mg/m2 i.v., on Day 1; interleukin-2, 9 x 10(6)
IU/m2/day i.v. over 24 hours, on Days 1-4; and interferon-alpha, 5 x
10(6) IU/m2/day subcutaneously, on Days 1-5, every 3 weeks. Twelve
patients did not have measurable disease. All patients were evaluable
for toxicity and survival. RESULTS: Clinical responses were observed in
14 of 36 patients (38.9%) with measurable disease, including 13 partial
responses (36.1%) and 1 complete response (2.8%). Complete pathologic
responses were noted in 4 patients (11.1%). Toxicity, although severe,
was manageable and typically short-lived. There were no
treatment-related deaths reported. At a median follow-up of 31 months,
38 of the 48 patients (79.2%) were alive and 31 patients (64.6%)
remained free of disease progression. CONCLUSIONS: Neoadjuvant
biochemotherapy appears to have promising activity in patients with
Stage III melanoma. A larger multicenter study currently is underway to
explore this approach further.
6
UI - 11902528
AU - Nathan PD; Eisen TG
TI -
The biological treatment of renal-cell carcinoma and melanoma.
SO - Lancet Oncol 2002 Feb;3(2):89-96
AD - Medical Oncology at the Royal Free Hospital, London, UK.
Biological therapies are claiming a place in the routine management of
some solid tumours. In this review we focus on the biological treatment
of melanoma and renal-cell carcinoma, identifying the background to
current practice and areas of promise that may be in routine clinical
use in the near future. Melanomas and renal-cell carcinomas are
particularly resistant to chemotherapy and radiotherapy and are
characterised by the host immune response to the tumours. For this
reason there has been particular interest in the biological therapy of
these diseases. Biological therapies differ from chemotherapeutic
approaches in their mechanism of action, time to response, and
side-effect profiles. Although biological treatment has a long history,
it is only with recent advances in immunology and molecular biology that
progress has been made. In the next few years investigators expect to
build on their research experience with biotherapeutic agents to provide
tangible benefits for patients.
7
UI - 11870174
AU - Kilbridge KL; Cole BF; Kirkwood JM; Haluska FG; Atkins MA; Ruckdeschel
TI -
JC; Sock DE; Nease RF Jr; Weeks JC
Quality-of-life-adjusted survival analysis of high-dose adjuvant
interferon alpha-2b for high-risk melanoma patients using intergroup
clinical trial data.
SO - J Clin Oncol 2002 Mar 1;20(5):1311-8
AD - Department of Health Evaluation Sciences, University of Virginia Health
System, Charlottesville, VA 22908-0821, USA. kk4h@virginia.edu
PURPOSE: High-dose adjuvant interferon alpha-2b (IFN alpha 2b) 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
IFN alpha 2b 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
IFN alpha 2b 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, IFN
alpha 2b 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 IFN alpha 2b 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 IFN alpha 2b 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 IFN
alpha 2b toxicity than on the utility for melanoma recurrence. Cancer
patients probably have higher utilities for IFN alpha 2b toxicity than
members of the general population and will tend to favor IFN alpha 2b
treatment as a result.
8
UI - 11888868
AU - Lindner P; Doubrovsky A; Kam PC; Thompson JF
TI -
Prognostic factors after isolated limb infusion with cytotoxic agents
for melanoma.
SO - Ann Surg Oncol 2002 Mar;9(2):127-36
AD - Sydney Melanoma Unit, Royal Prince Alfred Hospital, USA.
BACKGROUND: Isolated limb perfusion (ILP) with cytotoxic agents is a
remarkably effective but complex technique used to treat locally
recurrent and metastatic melanoma confined to a limb. Isolated limb
infusion (ILI), essentially a low-flow ILP performed without oxygenation
via percutaneous catheters, has been developed as a simpler alternative.
METHODS: The outcome in 135 patients treated by ILI was reviewed.
RESULTS: The overall response rate in the treated limb was 85% (complete
response [CR] rate 41%, partial response rate 44%). Median response
duration response was 16 months (24 months for patients with CR). Median
patient survival was 34 months. In those with a CR, the median survival
was 42 months. CR rate and survival time decreased with increasing
disease stage. Patients aged >70 years had a better overall response
than younger patients. On multivariate analysis, factors associated with
an improved outcome were a lower stage of disease, a final limb
temperature >37.8 degrees C, and a tourniquet time >40 minutes.
CONCLUSIONS: The frequency and duration of responses after ILI were
comparable to those achieved by conventional ILP. The ILI technique is
particularly useful for older patients who might not be considered
suitable for conventional ILP.
9
UI - 11567700
AU - Cascinelli N; Belli F; MacKie RM; Santinami M; Bufalino R; Morabito A
TI -
Effect of long-term adjuvant therapy with interferon alpha-2a in
patients with regional node metastases from cutaneous melanoma: a
randomised trial.
SO - Lancet 2001 Sep 15;358(9285):866-9
AD - National Cancer Institute, Via G Venezian 1, 20133, Milan, Italy.
who-melanoma@istitutotumori.mi.it
BACKGROUND: Less than half of patients with melanoma that has spread to
local draining regional lymph nodes (stage III melanoma) live with no
disease for 5 years or longer after surgery. We aimed to see whether
interferon alpha-2a increased survival prospects in these patients.
METHODS: 444 patients from 23 centres in the WHO Melanoma Programme had
complete lymphadenectomy for pathologically proven regional nodal spread
of melanoma and were randomly assigned to receive either 3 MU
subcutaneously of recombinant interferon alpha-2a three times a week for
3 years, or to observation alone after surgery. Patients were stratified
by centre, nodes with macroscopic or microscopic melanoma, number of
affected nodes, and nodal metastatic spread. Treatment was continued for
3 years or until first sign of relapse. FINDINGS: 424 patients entered
the study. 5-year disease-free survival of those who had surgery plus
interferon alpha-2a was 27.5% (95% CI 21.7-33.6); for those who received
surgery alone, survival was 28.4% (22.5-34.6) (p=0.50). Neither
Kaplan-Meier cumulative survival rates, nor multivariate analysis of
survival, showed a difference between those who had surgery and
interferon alpha-2a (35%, 95% CI 29-42) and those who had surgery alone
(37%, 31-44). INTERPRETATION: Patients with melanoma that has spread to
the local draining regional lymph nodes tolerate well 3 MU of interferon
alpha-2a given subcutaneously three times a week for 3 years, but this
treatment does not improve either disease-free or overall survival.
10
UI - 11918944
AU - Kirkwood JM; Ibrahim JG; Sondak VK; Ernstoff MS; Ross M
TI -
Interferon alfa-2a for melanoma metastases.
SO - Lancet 2002 Mar 16;359(9310):978-9
11
UI - 11919239
AU - Lens MB; Dawes M
TI -
Interferon alfa therapy for malignant melanoma: a systematic review of
randomized controlled trials.
SO - J Clin Oncol 2002 Apr 1;20(7):1818-25
AD - Center for Evidence-Based Medicine, University of Oxford, Oxford, United
Kingdom. markolens@aol.com
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.
12
UI - 11891956
AU - Patel SG; Prasad ML; Escrig M; Singh B; Shaha AR; Kraus DH; Boyle JO;
TI -
Huvos AG; Busam K; Shah JP
Primary mucosal malignant melanoma of the head and neck.
SO - Head Neck 2002 Mar;24(3):247-57
AD - Head and Neck Service, Memorial Sloan-Kettering Cancer Center, 1275 York
Avenue, New York, New York 10021, USA. shahj@mskcc.org
INTRODUCTION: The relative rarity of mucosal melanomas of the head and
neck (MMHN) has made analysis of treatment approaches difficult.
Advances in diagnostic techniques and treatment interventions have had
obvious impact on outcomes in cutaneous melanoma, but the effects on
outcome in MMHN remain undefined. This study aims to assess the outcome
and identify clinical and histologic prognostic indicators in a recent
cohort of patients with MMHN treated at a single institution. METHODS:
The clinical records of 59 patients with the diagnosis of MMHN treated
at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1978 and 1998
were retrospectively reviewed. Pathologic material on each of these
patients was prospectively reviewed by at least two pathologists (MP,
KB, or AH) for confirmation of diagnosis and assessment of histologic
variables. Survival was calculated by the Kaplan-Meier method. Clinical
(patient demographics, tumor characteristics, and treatment) and
histologic data (tumor thickness, melanosis, melanoma in situ, vascular
invasion, and multifocality) were analyzed for impact on outcome by both
univariate and multivariate analyses. RESULTS: Thirty-five patients
(59%) had sinonasal tumors (SNMM), whereas 24 (41%) had oral (ORMM)
tumors. Forty-seven patients (79.6%) were staged as stage I, 8 (13.6%)
as stage II, and 4 (6.8%) were classified as stage III. Regional
lymphatic metastases at presentation were more frequent in ORMM compared
with SNMM (25% vs 6%, p =.05). Surgery was used in all patients.
Adjuvant radiation therapy was used more frequently in the SNMM group
compared with the ORMM group (40% vs 17%, p =.04). The rates of local
failure for ORMM and SNMM were 51% and 50%, nodal failure rates were 42%
and 20%, and distant failure rates were 67% and 40%, respectively (p =
NS). With a median follow-up of 20 months, the 5-year disease-specific
survival rate was 44% (40% for ORMM vs 47% for SNMM, p = NS).
Significant prognostic factors for disease-specific survival on
univariate analysis included advanced clinical stage at presentation,
tumor thickness greater than 5 mm, presence of vascular invasion, and
development of nodal and distant metastases. On multivariate analysis,
however, regional nodal failure lost significance. CONCLUSIONS: Clinical
stage at presentation, tumor thickness greater than 5 mm, vascular
invasion on histologic studies, and development of distant failure are
the only independent predictors of outcome in MMHN. Copyright 2002 Wiley
Periodicals, Inc.
13
UI - 11874503
AU - Schadendorf D
TI -
The use of histamine in cancer immunotherapy.
SO - J Invest Dermatol 2002 Mar;118(3):560-1
14
UI - 11920589
AU - Jager E; Hohn H; Necker A; Forster R; Karbach J; Freitag K; Neukirch C;
TI -
Castelli C; Salter RD; Knuth A; Maeurer MJ
Peptide-specific CD8+ T-cell evolution in vivo: response to peptide
vaccination with Melan-A/MART-1.
SO - Int J Cancer 2002 Mar 20;98(3):376-88
AD - Medizinische Klinik II, Hamatologie-Onkologie, Krankenhaus Nordwest,
Frankfurt, Germany.
Monitoring of CD8+ T-cell responses in cancer patients during peptide
vaccination is essential to provide useful surrogate markers and to
demonstrate vaccine efficacy. We have longitudinally followed CD8+
T-cell responses in 3 melanoma patients who were immunized with peptides
derived from Melan-A/MART-1. Recombinant HLA-A2 tetramers loaded with
the naturally presented Melan-A/MART-1 nonamer peptide (AAGIGILTV) and
the Melan-A/MART-1 analog (ELAGIGILTV) were used in combination with
phenotypical analysis for different T-cell subsets including naive T
cells, effector T cells, "true memory" T cells and "memory effector" T
cells, based on CD45RA/RO and CCR7-expression. At least in a single
patient, T cells binding to the AAGIGILTV epitope were detected in
naive, precursor (CD45RA+/CCR7+) CD8+ T cells, and CD8+ T cells binding
to the analog ELAGIGILTV peptide were identified in the terminally
differentiated (CD45RA+/CCR7-) T-cell subset. Molecular and functional
analysis of tetramer-binding T cells revealed that the T-cell receptor
(TCR) repertoire was oligo/polyclonal in AAGIGILTV-reactive T cells, but
different and restricted to a few TCR clonotypes in ELAGIGILTV-reactive
T cells prior to vaccination. The TCR repertoire reactive with
Melan-A/MART-1 peptide epitopes was broadened during vaccination and
exhibited a different profile of cytokine release after specific
stimulation: tetramer-binding T cells from 2/3 patients secreted
granulocyte/macrophage colony-stimulating factor (GM-CSF) and
interferon-gamma but not interleukin-2 (IL-2) in response to
Melan-A/MART-1 peptides. In the third patient, tetramer-binding T cells
secreted IL-2 exclusively. Our results show that T-cell responses to
peptide vaccination consist of different T-cell subsets associated with
different effector functions. Complementary analysis for TCR CDR3 and
cytokine profiles may be useful to define the most effective CD8+ T-cell
population induced by peptide vaccination. Copyright 2002 Wiley-Liss,
Inc.
15
UI - 11920592
AU - Scheibenbogen C; Sun Y; Keilholz U; Song M; Stevanovic S; Asemissen AM;
TI -
Nagorsen D; Thiel E; Rammensee HG; Schadendorf D
Identification of known and novel immunogenic T-cell epitopes from tumor
antigens recognized by peripheral blood T cells from patients responding
to IL-2-based treatment.
SO - Int J Cancer 2002 Mar 20;98(3):409-14
AD - Medizinische Klinik III, Hematology, Oncology and Transfusion Medicine,
Universitaetsklinikum Benjamin Franklin, Freie Universitat Berlin,
Berlin, Germany. scheibenbogen@ukfb.fu-berlin.de
In previous studies CD8+ T cells specific for melanocyte antigens have
been frequently found in melanoma patients responding to interleukin-2
(IL-2)-based therapies. In our study we analyzed the suitability of
using circulating T cells from melanoma patients with clinical response
after IL-2-based therapy to identify novel T-cell epitopes from defined
tumor antigens. Using unstimulated peripheral blood mononuclear cells
and the interferon-gamma (IFN-gamma) ELISPOT assay, we studied CD8(+)
T-cell responses against 5 peptides from the tumor antigen tyrosinase
(Tyr) selected by epitope prediction using an HLA-A1-binding computer
algorithm. T cells specifically secreting IFN-gamma in response to 3 of
these 5 peptides, namely, Tyr (454-463), Tyr (146-156) and Tyr
(243-251), could be detected in 4 of 4 HLA-A1-positive patients with
clinical response. In contrast, no T-cell responses against these
peptides were seen in 6 HLA-A1-positive melanoma patients with
progressive disease and in 8 healthy subjects. We could generate
specific cytotoxic T lymphocytes (CTL) against Tyr (454-463) using
peptide-pulsed autologous dendritic cells as antigen-presenting cells.
The induced CTLs efficiently killed melanoma cells that express HLA-A1
and tyrosinase. The peptides Tyr (146-156) and Tyr (243-251) had
recently been identified as CTL epitopes by other groups. Further ex
vivo characterization of the T cells reactive against the novel epitope
Tyr (454-463) in 1 patient by multicolor flow cytometry showed specific
CD3+/CD8+/IFN-gamma+ T cells with frequencies of up to 0.41% of the
CD3+/CD8+ T-cell population. Most of this T-cell population also
expressed granzyme B. Our data confirm that in patients with tumor
regressions induced by immunotherapy or chemoimmunotherapy circulating T
cells reactive with tyrosinase epitopes can frequently be detected.
Peripheral blood T cells from such patients are a valuable source for
screening peptides selected by epitope prediction This strategy
facilitates the rapid identification of immunogenic T-cell epitopes that
are probable targets of immune-mediated tumor rejection. Copyright 2002
Wiley-Liss, Inc.
16
UI - 11896110
AU - Ridolfi R; Chiarion-Sileni V; Guida M; Romanini A; Labianca R; Freschi
TI -
A; Lo Re G; Nortilli R; Brugnara S; Vitali P; Nanni O; Italian Melanoma
Intergroup
Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and
interferon alpha-2b in advanced melanoma outpatients: results from an
Italian multicenter phase III randomized clinical trial.
SO - J Clin Oncol 2002 Mar 15;20(6):1600-7
AD - Department of Medical Oncology, Pierantoni Hospital, Forli.
PURPOSE: Phase II and III studies have shown that the addition of
interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in
multiagent chemotherapy (CT) for advanced melanoma increases overall
response (OR), albeit without clear evidence of an improvement in
overall survival (OS). Treatment with high-dose IL-2 can cause severe
toxicity and is normally administered in an inpatient setting. We
conducted a multicenter prospective randomized clinical trial in
outpatients with metastatic melanoma to compare CT with biochemotherapy
(bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS
AND METHODS: One hundred seventy-six eligible patients with advanced
melanoma were randomized to receive CT (cisplatin and dacarbazine with
or without carmustine every 21 days) or bioCT comprising the same CT
regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN
alpha-2b three times a week, both for six cycles. RESULTS: At a median
follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus
11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs
(20.2%) (three complete responders [CRs] and 15 partial responders
[PRs]) were observed according to World Health Organization criteria. In
the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P
=.70) were recorded. Treatment-related toxicity was fairly similar in
both arms. CONCLUSION: The addition of low-dose immunotherapy did not
produce a statistically significant advantage in OS, time to
progression, or OR. However, the 11-month median OS in the bioCT arm
does not differ greatly from the best results with high-dose
IL-2-containing regimens reported in the literature. Furthermore, our
treatment schedule was carried out on outpatients and had an acceptable
level of toxicity.
17
UI - 11719634
AU - Cohen L; de Moor C; Devine D; Baum A; Amato RJ
TI -
Endocrine levels at the start of treatment are associated with
subsequent psychological adjustment in cancer patients with metastatic
disease.
SO - Psychosom Med 2001 Nov-Dec;63(6):951-8
AD - Department of Behavioral Science, The University of Texas M. D. Anderson
Cancer Center, Houston, TX 77030, USA. lcohen@mdanderson.org
OBJECTIVE: This study examined the association between hormonal profiles
at the start of cancer treatment and subsequent psychological
symptomatology. METHODS: Twenty-seven patients with metastatic renal
cell carcinoma and 18 patients with metastatic melanoma completed three
assessments during the course of treatment: at the start of treatment
(baseline), at the end of treatment (3 weeks after baseline), and at a
follow-up appointment 1 month later. Cortisol, norepinephrine, and
epinephrine levels were measured at baseline using 15-hour urine
samples. At each assessment, patients completed the Impact of Event
Scale (IES) and the Brief Symptom Inventory (BSI). RESULTS: Patients
reported moderate levels of distress throughout treatment as measured by
the IES and BSI. Norepinephrine levels at the start of treatment were
positively associated with IES total scores at the end of treatment and
at follow-up, and cortisol levels were positively associated with IES
total scores at follow-up after adjusting for baseline IES and overall
distress scores. Norepinephrine levels were also positively associated
with depression scores at follow-up, and cortisol levels were positively
associated with depression scores at the end of treatment and at
follow-up after adjusting for baseline depression and overall distress
scores. CONCLUSIONS: Hormonal profiles at the start of cancer treatment
are associated with subsequent psychological adjustment.
18
UI - 11773161
AU - Agarwala SS; Glaspy J; O'Day SJ; Mitchell M; Gutheil J; Whitman E;
TI -
Gonzalez R; Hersh E; Feun L; Belt R; Meyskens F; Hellstrand K; Wood D;
Kirkwood JM; Gehlsen KR; Naredi P
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.
SO - J Clin Oncol 2002 Jan 1;20(1):125-33
AD - Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop
Street, Pittsburgh, PA 15213-2582, USA. agarwalass@msx.upmc.edu
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.
19
UI - 11896085
AU - Urba WJ; Alvord WG
TI -
Are all hypotheses generated before data analysis prospective?
SO - J Clin Oncol 2002 Mar 15;20(6):1431-3
20
UI - 11912825
AU - Robinson JK
TI -
Early detection and treatment of melanoma: update 2000.
SO - Dermatol Nurs 2000 Dec;12(6):397-402, 441-2
AD - Loyola University Chicago, Maywood, IL, USA.
Risk factors for the development of melanoma, early detection, biopsy
technique, and treatment recommendations are discussed. Survival depends
upon the stage at the time of diagnosis; thus, early detection of thin
melanoma limited to the skin's surface enhances survival.
21
UI - 11926952
AU - Lens MB; Dawes M; Goodacre T; Newton-Bishop JA
TI -
Elective lymph node dissection in patients with melanoma: systematic
review and meta-analysis of randomized controlled trials.
SO - Arch Surg 2002 Apr;137(4):458-61
AD - Centre for Evidence-Based Medicine, University of Oxford Nuffield
Department of Clinical Medicine, the Oxford Radcliffe National Health
Service Trust, Oxford OX3 9DU, England. markolens@aol.com
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
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.
22
UI - 11917943
AU - Jelic S; Babovic N; Stamatovic L; Kreacic M; Matkovic S; Popov I
TI -
Vinblastin-carboplatin for metastatic cutaneous melanoma as first-line
chemotherapy and in dacarbazine failures: a single-center study.
SO - Med Oncol 2001;18(3):189-95
AD - Institute for Oncology and Radiology of Serbia, Department of Medical
Oncology, Belgrade, Yugoslavia. jelics@ncrc.ac.yu
First-line treatments of metastatic melanoma are usually decarbazine
(DTIC) and/or alpha-interferon based, with response rates in the range
of at most 20-30%. In this study, initiated, in fact, by a temporary
DTIC shortage in the country, we have assessed the efficacy and toxicity
of a vinblastine-carboplatin regimen for metastatic melanoma. The
regimen was subsequently applied in two cohorts of patients: a
chemotherapy-naive one and in DTIC failures (because the regimen was
claimed non-cross-resistant). The regimen contained 6 mg/m2 vinblastine
on d 1 and 450 mg/m2 carboplatin on d 1 for 3 wk. In the
chemotherapy-naive cohort, 50 patients were included, 29 males and 21
females, median age 54 yr (range: 33-68), performance status 0+1 for 26
patients and 2+3 for 24 patients. Forty-eight patients were evaluable
for activity. The response was the following: complete response (CR),
1/48 (2%); partial response (PR), 13/48 (27%); stable disease (SD),
20/48 (42%); progressive disease (PD), 14/48 (29%). The overall response
rate was 14/48 (29%). The median response duration was 7 mo (range:
3-14); the median time to progression was 4 mo (range: 2-14). Toxicity
included granulocytopenia and thrombocytopenia grade IV in 3/50 patients
and nausea grade II in 8/50 patients. In the DTIC-failures cohort, 58
patients were included, 38 males and 20 females, median age 51 yr
(range: 20-65), performance status 0+1 for 25 patients and 2+3 for 33
patients. All 58 patients were evaluable for activity. The response was
the following: CR 3/58 (5%), PR 4/58 (7%), SD 10/58 (17%), PD 41/58
(71%). The overall response rate was 7/58 (12%). The median response
duration was 11 mo (range: 3-24); the median time to progression was 4
mo (range: 2-24). Toxicities included granulocytopenia grade IV in 4/58
patients and nausea grade II in 4/58 patients. Thus, despite the fact
that the regimen achieved a response rate comparable to DTIC in a
first-line setting, the lack of cross-resistance did not prevent it from
being of limited activity in DTIC failures, although, even in this
group, several long-lasting responses and stabilizations were noted.
23
UI - 11903242
AU - Barlow RJ; White CR; Swanson NA
TI -
Mohs' micrographic surgery using frozen sections alone may be unsuitable
for detecting single atypical melanocytes at the margins of melanoma in
situ.
SO - Br J Dermatol 2002 Feb;146(2):290-4
AD - Department of Dermatology, Oregon Health Sciences University, Portland,
OR, USA. rhea.mills@gstt.sthames.nhs.uk
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.
24
UI - 11920783
AU - Kroon BB; Noorda EM; Vrouenraets BC; Nieweg OE
TI -
Isolated limb perfusion for melanoma.
SO - J Surg Oncol 2002 Apr;79(4):252-5
AD - The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital,
Amsterdam, The Netherlands. bkroon@nki.nl
25
UI - 11894998
AU - Willemsen R A; Debets R; Hart E; Hoogenboom H R; Bolhuis R L; Chames P
TI -
A phage display selected fab fragment with MHC class I-restricted
specificity for MAGE-A1 allows for retargeting of primary human T
lymphocytes.
SO - Gene Ther 2001 Nov;8(21):1601-8
AD - Department of Clinical and Tumor Immunology, Academic Hospital
Rotterdam/Daniel den Hoed Cancer Center, The Netherlands.
The clinical benefit of adoptive transfer of MHC-restricted cytotoxic T
lymphocytes(CTL) for the treatment of cancer is hampered by the low
success rate to generate antitumor CTLs. To bypass the need for
tumor-specific CTL, we developed a strategy that allows for grafting of
human T lymphocytes with MHC-restricted antigen specificity using in
vitro selected human Fab fragments fused to the Fc(epsilon)RI-gamma
signaling molecule. Retroviral introduction of a Fab-based chimeric
receptor specific for MAGE-A1/HLA-A1 into primary human T lymphocytes
resulted in binding of relevant peptide/MHC complexes. Transduced T
lymphocytes responded to native MAGE-A1/HLA-A1POS target cells by
specific cytokine production and cytolysis. Therefore,
peptide/MHC-specific Fab fragments represent new alternatives to TCR to
confer human T lymphocytes with tumor specificity, which provides a
promising rationale for developing immunogene therapies.
26
UI - 11839253
AU - Hamilton S; Odili J; Gundogdu O; Wilson GD; Kupsch JM
TI -
Improved production by domain inversion of single-chain Fv antibody
fragment against high molecular weight proteoglycan for the
radioimmunotargeting of melanoma.
SO - Hybrid Hybridomics 2001;20(5-6):351-60
AD - RAFT Institute of Plastic Surgery and Cancer Research Trust, Mount
Vernon Hospital, Northwood, Middlesex HA6 2RN, UK.
Melanoma is among the few cancers with rising incidence. Currently there
is no effective treatment for metastatic disease, but improved detection
of melanoma has the potential to benefit the management of patients with
early disease. Radioimmunodection by imaging with single-chain Fv (scFv)
antibody fragments is one such emerging diagnostic method. However, the
amount of scFv that can be produced at a scale suitable for use in
patients is limiting. We have previously shown that the bacterial
expression of a scFv derived from a monoclonal antibody (MAb) specific
for melanoma-associated proteoglycan can be increased by light chain
shuffling. In this report we show that a further increase in expression
yield can be obtained by reversing the usual V(H)-V(L) orientation of
scFvs to V(L)-V(H). Such seemingly minor changes have previously been
reported to have unexpected effects on the in vitro and in vivo binding
properties of recombinant antibodies. Our results show that reversal of
the V domain orientation of the scFv improves expression by 150% without
an adverse effect on melanoma binding in vitro and tumor targeting in
vivo. Therefore, our results show that alteration of V domain
orientation can improve the production yield of clinically useful
antibody fragments. When used in combination with other antibody
engineering approaches for increased antibody production changing the
domain orientation is a simple strategy to achieve significant
improvements in the production of scFvs for tumor radioimmunodetection
for patient studies.
27
UI - 11331315
AU - Kirkwood JM; Ibrahim JG; Sosman JA; Sondak VK; Agarwala SS; Ernstoff MS;
TI -
Rao U
High-dose interferon alfa-2b significantly prolongs relapse-free and
overall survival compared with the GM2-KLH/QS-21 vaccine in patients
with resected stage IIB-III melanoma: results of intergroup trial
E1694/S9512/C509801.
SO - J Clin Oncol 2001 May 1;19(9):2370-80
AD - Division of Hematology-Oncology and Department of Pathology, Department
of Medicine, University of Pittsburgh Cancer Institute Melanoma Center,
University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA.
jmk@jiimmy.harvard.edu
PURPOSE: Vaccine alternatives to high-dose interferon alfa-2b therapy
(HDI), the current standard adjuvant therapy for high-risk melanoma, are
of interest because of toxicity associated with HDI. The GM2 ganglioside
is a well-defined melanoma antigen, and anti-GM2 antibodies have been
associated with improved prognosis. We conducted a prospective,
randomized, intergroup trial to evaluate the efficacy of HDI for 1 year
versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and
administered with QS-21 (GMK) for 96 weeks (weekly x 4 then every 12
weeks x 8). PATIENTS AND METHODS: Eligible patients had resected stage
IIB/III melanoma. Patients were stratified by sex and number of positive
nodes. Primary end points were relapse-free survival (RFS) and overall
survival (OS). RESULTS: Eight hundred eighty patients were randomized
(440 per treatment group); 774 patients were eligible for efficacy
analysis. The trial was closed after interim analysis indicated
inferiority of GMK compared with HDI. For eligible patients, HDI
provided a statistically significant RFS benefit (hazard ratio [HR] =
1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus
HDI. Similar benefit was observed in the intent-to-treat analysis (RFS
HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in
all subsets of patients with zero to > or = four positive nodes, but the
greatest benefit was observed in the node-negative subset (RFS HR =
2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2
(ie, titers > or = 1:80) at days 29, 85, 365, and 720 were associated
with a trend toward improved RFS and OS (P2 = .068 at day 29).
CONCLUSION: This trial demonstrated a significant treatment benefit of
HDI versus GMK in terms of RFS and OS in melanoma patients at high risk
of recurrence.
28
UI - 11956264
AU - Eton O; Legha SS; Bedikian AY; Lee JJ; Buzaid AC; Hodges C; Ring SE;
TI -
Papadopoulos NE; Plager C; East MJ; Zhan F; Benjamin RS
Sequential biochemotherapy versus chemotherapy for metastatic melanoma:
results from a phase III randomized trial.
SO - J Clin Oncol 2002 Apr 15;20(8):2045-52
AD - Department Melanoma/Sarcoma, The University of Texas M.D. Anderson
Cancer Center, Houston, TX 77030, USA. oeton@mdanderson.org
PURPOSE: The addition of cytokines to chemotherapy has produced
encouraging results in advanced melanoma. In this phase III trial, we
compared the effects of chemotherapy (cisplatin, vinblastine, and
dacarbazine [CVD]) with those of sequential biochemotherapy consisting
of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS:
Metastatic melanoma patients who had not previously received
chemotherapy were stratified by prognostic factors and given
chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1
and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25).
Biochemotherapy involved CVD with vinblastine reduced 25% plus
interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20,
and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days
5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks.
RESULTS: Among 190 patients enrolled, 91 were assessable for
biochemotherapy and 92 for chemotherapy. Ten percent of the patients
were alive a median of 52 months from start of therapy. Response rates
were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six
patients given biochemotherapy and two given chemotherapy had complete
responses. Median time to progression (TTP) was 4.9 months for
biochemotherapy and 2.4 months for chemotherapy (P =.008); median
survival was 11.9 and 9.2 months, respectively (P =.06). The influence
of treatment on TTP and survival was confirmed in multivariate analyses
with other prognostic factors not included in the original
stratification. Biochemotherapy produced substantially more
constitutional, hemodynamic, and myelosuppressive toxic effects.
CONCLUSION: Cytokines substantially augment the antitumor activity of
chemotherapy at the expense of considerable toxicity in patients with
metastatic melanoma.
29
UI - 11956265
AU - Rao UN; Ibrahim J; Flaherty LE; Richards J; Kirkwood JM
TI -
Implications of microscopic satellites of the primary and extracapsular
lymph node spread in patients with high-risk melanoma: pathologic
corollary of Eastern Cooperative Oncology Group Trial E1690.
SO - J Clin Oncol 2002 Apr 15;20(8):2053-7
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