National Cancer Institute®
Last Modified: January 1, 2002
UI - 10856105
AU - Kirkwood JM; Ibrahim JG; Sondak VK; Richards J; Flaherty LE; Ernstoff
TI - MS; Smith TJ; Rao U; Steele M; Blum RH High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.
SO - J Clin Oncol 2000 Jun;18(12):2444-58
AD - Department of Pathology, University of Pittsburgh Medical Center, PA 15213-2582, USA. email@example.com
PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFNalpha2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs). PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFNalpha2b (HDI) for 1 year and low-dose IFNalpha2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points. RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months' median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and 35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus Obs was 1.28 (P(2) =.05); for LDI versus Obs, it was 1.19 (P(2) =.17). By Cox analysis, the impact of HDI on RFS achieved significance (P(2) =.03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with Obs at this time. A major improvement in the median OS of patients in the E1690 Obs arm was noted in comparison with E1684 (6 years v 2.8 years). An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the Obs arm received IFNalpha-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. This study did not specify therapy at recurrence. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFNalpha2b at relapse from Obs than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690. CONCLUSION: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFNalpha2b that is dose-dependent and significant for HDI by Cox multivariable analysis.
UI - 11306232
AU - Helfand M; Mahon SM; Eden KB; Frame PS; Orleans CT
TI - Screening for skin cancer.
SO - Am J Prev Med 2001 Apr;20(3 Suppl):47-58
AD - Division of Medical Informatics and Outcomes Research, Evidence-based Practice Center, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA. firstname.lastname@example.org
CONTEXT: Malignant melanoma is often lethal, and its incidence in the United States has increased rapidly over the past 2 decades. Nonmelanoma skin cancer is seldom lethal, but, if advanced, can cause severe disfigurement and morbidity. Early detection and treatment of melanoma might reduce mortality, while early detection and treatment of nonmelanoma skin cancer might prevent major disfigurement and to a lesser extent prevent mortality. Current recommendations from professional societies regarding screening for skin cancer vary. OBJECTIVE: To examine published data on the effectiveness of routine screening for skin cancer by a primary care provider, as part of an assessment for the U.S. Preventive Services Task Force. DATA SOURCES: We searched the MEDLINE database for papers published between 1994 and June 1999, using search terms for screening, physical examination, morbidity, and skin neoplasms. For information on accuracy of screening tests, we used the search terms sensitivity and specificity. We identified the most important studies from before 1994 from the Guide to Clinical Preventive Services, second edition, and from high-quality reviews. We used reference lists and expert recommendations to locate additional articles. STUDY SELECTION: Two reviewers independently reviewed a subset of 500 abstracts. Once consistency was established, the remainder were reviewed by one reviewer. We included studies if they contained data on yield of screening, screening tests, risk factors, risk assessment, effectiveness of early detection, or cost effectiveness. DATA EXTRACTION: We abstracted the following descriptive information from full-text published studies of screening and recorded it in an electronic database: type of screening study, study design, setting, population, patient recruitment, screening test description, examiner, advertising targeted at high-risk groups or not targeted, reported risk factors of participants, and procedure for referrals. We also abstracted the yield of screening data including probabilities and numbers of referrals, types of suspected skin cancers, biopsies, confirmed skin cancers, and stages and thickness of skin cancers. For studies that reported test performance, we recorded the definition of a suspicious lesion, the "gold-standard" determination of disease, and the number of true positive, false positive, true negative, and false negative test results. When possible, positive predictive values, likelihood ratios, sensitivity, and specificity were recorded. DATA SYNTHESIS: No randomized or case-control studies have been done that demonstrate that routine screening for melanoma by primary care providers reduces morbidity or mortality. Basal cell carcinoma and squamous cell carcinoma are very common, but detection and treatment in the absence of formal screening are almost always curative. No controlled studies have shown that formal screening programs will improve this already high cure rate. While the efficacy of screening has not been established, the screening procedures themselves are noninvasive, and the follow-up test, skin biopsy, has low morbidity. Five studies from mass screening programs reported the accuracy of skin examination as a screening test. One of these, a prospective study, tracked patients with negative results to determine the number of patients with false-negative results. In this study, the sensitivity of screening for skin cancer was 94% and specificity was 98%. Several recent case-control studies confirm earlier evidence that risk of melanoma rises with the presence of atypical moles and/or many common moles. One well-done prospective study demonstrated that risk assessment by limited physical exam identified a relatively small (<10%) group of primary care patients for more thorough evaluation. CONCLUSIONS: The quality of the evidence addressing the accuracy of routine screening by primary care providers for early detection of melanoma or nonmelanoma skin cancer ranged from poor to fair. We found no studies that assessed the effectiveness of periodic skin examination by a clinician in reducing melanoma mortality. Both self-assessment of risk factors or clinician examination can classify a small proportion of patients as at highest risk for melanoma. Skin cancer screening, perhaps using a risk-assessment technique to identify high-risk patients who are seeing a physician for other reasons, merits additional study as a strategy to address the excess burden of disease in older adults.
UI - 11417749
AU - Dreau D; Foster M; Hogg M; Swiggett J; Holder WD; White RL
TI - Angiogenic and immune parameters during recombinant interferon-alpha2b adjuvant treatment in patients with melanoma.
SO - Oncol Res 2001;12(5):241-51
AD - Department of General Surgery Research, Carolinas Medical Center, Charlotte, NC 28203, USA. email@example.com
As an adjuvant therapy for patients with high risk of recurrent melanoma, high-dose interferon (IFN)-alpha2b therapy has been shown to have some efficacy. We examined 22 patients with resected melanoma who were treated with repeated injections of recombinant IFN-alpha2b during the treatment. Both angiogenic and immune parameters were measured. White blood cells (WBCs) and lymphocyte numbers, lymphocyte subpopulations, serum concentrations of IFN-alpha and anti-IFN-alpha antibodies, and the serum vascular endothelial growth factor (VEGF), interleukin (IL)-8, and basis fibroblast growth factor (bFGF) concentrations were determined over time in resected, recurrence-free patients with American Joint Committee on Cancer (AJCC) stage III melanoma with one or less (LN+ < or = 1, n = 7) or more than one (LN+ > 1, n = 8) lymph nodes involved, and AJCC stage IV resected disease (n = 7). Follow-up and recurrence-free intervals were longer in stage III (LN+ < or = 1) patients compared with stage IV patients (P < 0.05). The number of WBCs and lymphocytes decreased during the treatment for all patient groups (P < 0.001). In addition, percentages of CD8 and CD20 were higher in stage IV patients than in stage III (LN+ > 1) and stage III (LN+ < or = 1) patients at the beginning of therapy (P < 0.05). A significant increase in the percentage of CD20+ cells, mostly B lymphocytes, was observed in the stage III (LN+ > 1) and stage III (LN+ < or = 1) patients over time but not in stage IV patients (P < 0.001). Low IL-8 and bFGF concentrations at the beginning of therapy were associated with significantly longer recurrence-free survival (P < 0.05). These results warrant a larger trial to determine if the differences observed in patients before treatment can provide prognostic markers in patients receiving IFN-alpha2b therapy.
UI - 11440180
AU - Drzewiecka A; Urbanska K; Matuszak Z; Pineiro M; Arnaut LG; Habdas J;
TI - Ratuszna A; Stochel G Tritolylporphyrin dimer as a new potent hydrophobic sensitizer for photodynamic therapy of melanoma.
SO - Acta Biochim Pol 2001;48(1):277-82
AD - Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
We report the synthesis, photochemical and photophysical properties and preliminary studies on biological effect of a new tritolylporphyrin dimer (T-D). Absorption and emission properties of T-D suggest its possible use in photodynamic therapy. T-D is capable of singlet oxygen production with 0.8 quantum yield. It also has a high photostability. The photodynamic properties of the dimer were examined following the growth of SKMEL 188 (human melanoma) cells irradiated with red light (cut off < 630 nm). The surviving fraction of the cells decreased about 3-fold (vs. non-irradiated cells) for an 81 J/cm dose. Our results suggest that tritolylporphyrine dimer T-D may be an interesting hydrophobic sensitizer for photodynamic therapy.
UI - 11418308
AU - Dillman RO; DeLeon C; Beutel LD; Barth NM; Schwartzberg LS; Spitler LE;
TI - Garfield DH; O'Connor AA; Nayak SK Short-term autologous tumor cell lines for the active specific immunotherapy of patients with metastatic melanoma.
SO - Crit Rev Oncol Hematol 2001 Jul-Aug;39(1-2):115-23
AD - Hoag Cancer Center, One Hoag Drive, Building 41, Newport Beach, CA 92658, USA. firstname.lastname@example.org
We established short-term cell lines for 108/170 (64%) patients with metastatic melanoma. Tumor cell numbers were expanded to 10(8), then cells were irradiated, aliquoted, and cryopreserved for clinical use. Vaccines have been used to treat 69 patients with clinical follow up for 33 who had measurable metastatic disease at the time vaccine therapy was initiated (METS), and 33 who had no evidence of disease (NED) at the time of vaccine therapy following surgical resection of metastases. The protocol called for a baseline test of delayed tumor hypersensitivity (DTH), three weekly injections, a repeat of the DTH test, then monthly injections for an additional 5 months. Objective tumor responses were noted in 3/26 (12%) patients who received a minimum of three vaccinations, one complete, and two partial, with survivals of 36, 46+, and 78+ months. Only 6/64 (9.4%) had a positive DTH (>10 mm) at baseline, including three METS, all of whom progressed within 4 months and died within a year, and three who are still NED after more than 5 years. Conversion of DTH from negative to positive was documented in 18/44 (41%) patients who were tested at week 0 and 4. At a median follow up of greater than 5 years, the median overall survival (OS) was 40 months for "NED" with a 5-year survival rate of 39%, and 8.6 months with a 5-year survival rate of 10% for "METS" The 18 patients who had conversion of their DTH had a median event-free survival (EFS) of 15.8 months and 5-year EFS of 32% compared to 4.2 months and 9% for the 26 non-converters (P=0.012, two-tailed, log-rank test). Among patients who were NED when treatment started, the 12 patients whose DTH converted had a median overall survival of 61.4 months with 5-year survival of 63% compared to 9.7 months and 0% for the 13 non-converters (P=0.0026). This treatment approach is feasible, produces minimal toxicity, and is associated with long-term survival in a significant subset of patients.
UI - 11485637
AU - Kaufman HL; DeRaffele G; Divito J; Horig H; Lee D; Panicali D; Voulo M
TI - A phase I trial of intralesional rV-Tricom vaccine in the treatment of malignant melanoma.
SO - Hum Gene Ther 2001 Jul 20;12(11):1459-80
AD - Abert Einstein Cancer Center, Bronx, New York 10461, USA. email@example.com
UI - 11504282
AU - Sondak VK
TI - Adjuvant therapy for melanoma.
SO - Cancer J 2001 Jul-Aug;7 Suppl 1():S24-7
AD - Division of Surgical Oncology, University of Michigan Medical School, Ann Arbor, USA.
Patients with deep primaries (> or = 4 mm) or regional lymph node involvement often require adjuvant therapy in addition to surgery to successfully treat melanoma. Various adjuvant strategies are reviewed. Randomized trials of IFN-alpha adjuvant therapy have demonstrated statistically significant improvements in disease-free and overall survival rates, leading to approval by the United States Food and Drug Administration of the use of 1 year of intensive IFN-alpha2b following surgical resection of high-risk disease. A study comparing high-dose IFN with the ganglioside vaccine GMK was terminated early when the Data Safety Monitoring Committee concluded that the high-dose IFN treatment arm was associated with highly significantly improved relapse-free and overall survival. Studies of IFN-alpha in stage I and II melanoma are reviewed. Dose and schedule issues in the use of IFN-alpha are addressed. In addition to adjuvant therapy with IFN-alpha, various other treatment strategies appear promising. Adjuvant vaccine therapy may be useful for treatment of cutaneous melanoma. Polyvalent melanoma vaccines are discussed as a potential adjuvant therapy. Finally, nonrandomized preliminary studies suggest that postoperative radiation to the neck or axilla after radical lymph node dissection may decrease regional recurrence rates in node-positive patients, supporting the selective use of radiation therapy for melanoma.
UI - 11555334
AU - Weinstock MA
TI - Sunscreen use can reduce melanoma risk.
SO - Photodermatol Photoimmunol Photomed 2001 Oct;17(5):234-36; discussion 236-7
AD - Dermatoepidemiology Unit, V.A. Medical Center 11-D, 830 Chalkstone Avenue, Providence, RI 02908, USA. firstname.lastname@example.org
UI - 11564919
AU - Mercier GA; Alavi A; Fraker DL
TI - FDG positron emission tomography in isolated limb perfusion therapy in patients with locally advanced melanoma: preliminary results.
SO - Clin Nucl Med 2001 Oct;26(10):832-6
AD - Division of Nuclear Medicine, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
PURPOSE: Isolated limb perfusion (ILP) with high-dose chemotherapy and tumor necrosis factor is being tested in clinical trials as a treatment for locally advanced extremity melanoma. The authors investigated the ability of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) to determine the true extent of disease in patients with this condition, whose distribution of lesions differs from that seen in previous studies. METHODS: Nine patients with locally advanced melanoma were selected for imaging of the entire body and extremities using FDG PET from a group of participants in a clinical trial of ILP with melphalan +/- tumor necrosis factor. Scans were obtained without attenuation correction. Post-treatment scans were obtained in three patients 1 month after ILP. The findings in the FDG-PET scans were compared with those of a standard protocol (SP) that included anatomic images and physical examinations. RESULTS: Eighty lesions (74 malignant, 6 benign) were detected with FDG PET and the SP combined. Only malignant lesions were detected by both methods in the perfused limbs. Of the malignant lesions, FDG PET detected 65 lesions (sensitivity rate, 88%). In contrast, 48 lesions were detected with the SP (sensitivity rate, 65%). Twenty-six malignant lesions were seen only with FDG PET (35%), whereas nine malignant lesions were seen only with SP (12%). The six benign lesions included three false-positive mediastinal lymph nodes in one patient. The accuracy rates of FDG PET and the SP were 83% and 65%, respectively. These results are comparable to those seen in previous studies with patients who had disease confined primarily to the torso. All post-therapy FDG-PET scans showed a reduction in the number of visualized limb lesions, and diffuse uptake throughout the perfused limbs. The diffuse uptake correlated with post-therapy limb inflammation. CONCLUSIONS: Non-attenuation-corrected FDG PET is more sensitive than the SP in detecting the extent of disease in candidates for ILP. The FDG uptake associated with post-therapy inflammation may reduce the contrast resolution of this technique and must be evaluated further.
UI - 11596037
AU - Joukhadar C; Klein N; Mader RM; Schrolnberger C; Rizovski B; Heere-Ress
TI - E; Pehamberger H; Strauchmann N; Jansen B; Muller M Penetration of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide into cutaneous metastases of human malignant melanoma.
SO - Cancer 2001 Oct 15;92(8):2190-6
AD - Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna Medical School, Vienna, Austria.
BACKGROUND: Dacarbazine has been on the market for approximately 3 decades but remains the most effective single agent available for the therapy of metastatic malignant melanoma (MMM). Most MMMs, however, respond poorly to dacarbazine therapy. Apart from tumor resistance at a molecular level, several studies support the notion that therapeutic failure in tumor therapy also might be attributed to an impaired transcapillary drug transfer. METHODS: On the basis of this hypothesis, the authors measured intratumor transcapillary transfer rates of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide (AIC) by in vivo microdialysis after intravenous administration of dacarbazine at doses of 200 mg/m(2) to 1000 mg/m(2) (n = 7) in patients suffering from MMM. RESULTS: For all doses, area under the concentration curve (AUC) values for dacarbazine and AIC were not significantly different between plasma and tumor interstitium with AUC(tumor)/AUC(plasma) ratios of 0.97 +/- 0.08 (mean +/- standard error of the mean) for dacarbazine and 0.76 +/- 0.22 for AIC. AUC(0-240) values for dacarbazine and AIC measured in plasma correlated closely with corresponding AUC(0-240)values measured in the interstitium of MMMs with values of r(s) = 0.82 (P = 0.042) and r(s) = 0.90 (P = 0.037), respectively. CONCLUSIONS: The results of this study indicate favorable tumor penetration characteristics of dacarbazine and its active metabolite AIC. The relative lack of response to antineoplastic therapy with dacarbazine, thus might be explained by resistance of melanoma cells at a molecular level rather than by an inability of dacarbazine and AIC to penetrate into the interstitium of MMM. Copyright 2001 American Cancer Society.
UI - 11595689
AU - Slingluff CL Jr; Yamshchikov G; Neese P; Galavotti H; Eastham S;
TI - Engelhard VH; Kittlesen D; Deacon D; Hibbitts S; Grosh WW; Petroni G; Cohen R; Wiernasz C; Patterson JW; Conway BP; Ross WG Phase I trial of a melanoma vaccine with gp100(280-288) peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes.
SO - Clin Cancer Res 2001 Oct;7(10):3012-24
AD - Department of Surgery, University of Virginia, Charlottesville, 22908, USA. email@example.com
A melanoma vaccine composed of HLA-A2-restricted peptide YLEPGPVTA (gp100(280)), with or without a modified T-helper epitope from tetanus toxoid AQYIKANSKFIGITEL, has been evaluated in a Phase I trial to assess safety and immunological response. The vaccines were administered s.c. in either of two adjuvants, Montanide ISA-51 or QS-21, to 22 patients with high-risk resected melanoma (stage IIB-IV). Local and systemic toxicities were mild and transient. We detected CTL responses to the gp100(280) peptide in peripheral blood in 14% of patients. Helper T-cell responses to the tetanus helper peptide were detected in 79% of patients and had a Th1 cytokine profile. One patient with a CTL response to gp100 had a recurrence in a lymph node 2 years later; her nodes contained CD8+ cells reactive to gp100(280) (0.24%), which proliferated in response to peptide. The overall survival of patients is 75% (95% confidence interval, 57-94%) at 4.7 years follow-up, which compares favorably with expected survival. Four of 14 patients who completed at least six vaccines subsequently developed metastases, all of which were solitary and surgically resectable. They remain alive and clinically free of disease at last follow-up. Data from this trial demonstrate immunogenicity of the gp100(280) peptide and suggest that immune responses may persist long-term in some patients. The frequency and magnitude of the CTL response may be improved with more aggressive vaccination regimens. Although this Phase I study was not intended to evaluate clinical benefit, the excellent survival of patients on this protocol suggests the possibility of a benefit that should be assessed in future studies.
UI - 11605226
AU - Ryuto M; Higaki Y; Tomita K
TI - [Clinical analysis of 16 cases of malignant head and neck melanoma]
SO - Nippon Jibiinkoka Gakkai Kaiho 2001 Sep;104(9):859-65
AD - Division of Head and Neck, National Kyushu Cancer Center, Fukuoka.
Subjects were 16 patients--5 men and 11 women aged 46-82 years (mean: 61 years)--with malignant melanoma of the head and neck treated at our clinic from 1972 to 1988. Histologically, 1 subjects was amelanotic and 15 melanotic type. Primary lesions were 10 involving the nasal cavity, 2 the paranasal sinus, 2 the gingiva, 1 the lip, and 1 primary unknown. They were treated with or without multimodal surgery, radiation, chemotherapy, and immunotherapy. Of 12 treated using local surgery, local recurrence was seen in 6 in 7 areas. Two-year survival was 44% and 5-year survival 22%. The prognosis of malignant head and neck melanoma is poor but has gradually improved due to preoperative decisions on disease spread and the introduction of multimodal therapy.
UI - 11603540
AU - Payne WG; Kearney R; Wells K; Blue M; Walusimbi M; Mosiello G; Cruse CW;
TI - Reintgen D Desmoplastic melanoma.
SO - Am Surg 2001 Oct;67(10):1004-6
AD - Department of Surgery, University of South Florida, Tampa, USA.
Desmoplastic melanoma is an uncommonly encountered variant of malignant melanoma. Three histological subtypes exist: desmoplastic, neurotropic, and neural transforming. Desmoplastic melanoma commonly presents in conjunction with existing melanocytic lesions or as an amelanotic firm nodule. Local recurrences are common. Thirty patients over a 6-year period were treated at our institution for desmoplastic melanoma. All lesions were treated with local excision. Local recurrence occurred in seven patients (23%) and was treated by aggressive re-excision in each instance. Clinical regional metastasis (lymph nodal basins) were detected in two patients (6%). Distant metastasis (lung) developed in two patients (6%). Twenty-three patients (76%) were found to have desmoplastic subtype, whereas five (17%) had neurotropic subtype. Six patients (20%) had associated pigmented melanotic lesions. Average length of follow-up has been 18 months. Overall survival is 96 per cent. Presentations and histologic diagnosis can sometimes be difficult and misleading. Treatment is aggressive local excision with follow-up necessary to detect resectable recurrent lesions.
UI - 11641093
AU - Lejeune FJ; Kroon BB; Di Filippo F; Hoekstra HJ; Santinami M; Lienard D;
TI - Eggermont AM Isolated limb perfusion: the European experience.
SO - Surg Oncol Clin N Am 2001 Oct;10(4):821-32, ix
AD - Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. firstname.lastname@example.org
Isolated limb perfusion (ILP) is a method of cancer treatment allowing the administration of high doses of anticancer agents in a limb surgically isolated from systemic circulation. By using continuous leakage monitoring and using the drug melphalan, a high complete remission rate is obtained in patients with melanoma. In patients with sarcomas, ILP with tumor necrosis factor and melphalan represents a neoadjuvant treatment for limb-sparing surgery. This treatment is the first demonstration of an active anti-angiogenic regimen in the clinic.
UI - 11641099
AU - Santinami M; Maurichi A; Patuzzo R; Pennacchioli E; Cascinelli N
TI - Impact of clinical trials on the treatment of melanoma.
SO - Surg Oncol Clin N Am 2001 Oct;10(4):935-47, xi
AD - Department of Surgery, Instituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Today the role of clinical trials is being challenged and it seems that this investigative tool does not keep in step with the rhythms imposed by the progress of scientific knowledge and the expectations of the public and media. From the 1970's to the 1990's, however, clinical trials have been the most important way for clinical researchers to find answers to therapeutic questions.
UI - 11675517
AU - Gershenwald JE
TI - Melanoma.
SO - Oncologist 2001;6(5):402-6
AD - The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. email@example.com
The presentations at the American Society of Clinical Oncology 2001 meeting reported or updated the results of phase I, II, and III randomized trials and also reported important meta-analyses and retrospective studies impacting on the management of patients with melanoma. In the treatment of early stage melanoma, the prognostic significance of pathologic status of sentinel lymph nodes was affirmed. With respect to regional nodal involvement (American Joint Committee on Cancer [AJCC] stage III), investigators presented the interim results of the United Kingdom randomized low-dose interferon (IFN) trial, and up-to-date meta-analyses of several IFN trials including a pooled analysis of the Eastern Cooperative Oncology Group trials evaluating interferon in the adjuvant setting. In the advanced disease setting (AJCC stage IV), several studies elucidated the pros and cons of biochemotherapy in patients with metastatic melanoma, with an emphasis on seeking to improve response in the central nervous system and durability of response in general. Thought provoking was new data regarding the potential for lovastatin to act as a chemopreventive agent for melanoma. Translational studies were presented, one supporting the importance of HLA-typing in developing targeted vaccine therapy. Finally, the results of a novel experimental melanoma vaccine were presented using autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96).
UI - 11677100
AU - Eggermont AM
TI - The role interferon-alpha in malignant melanoma remains to be defined.
SO - Eur J Cancer 2001 Nov;37(17):2147-53
AD - Department of Surgical Oncology, Erasmus University Medical Center--Daniel den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA Rotterdam, The Netherlands. firstname.lastname@example.org
Interferon-alpha (IFNalpha) is a pleiotropic cytokine with various direct and indirect inflammatory response modulating activities. Some of these activities may have direct or indirect antitumour effects. For such a wide range of biological activities, the dose for optimal biological activity may differ greatly from the maximally tolerated dose as different effects are mediated by different concentrations of IFNalpha. Because of its immunomodulatory effects, it has been extensively studied in melanoma patients. Little antitumour activity has been demonstrated in metastatic stage IV melanoma, with overall response rates of 10-15%, which were not dose-related. Yet, IFNalpha has been widely studied in the adjuvant setting for stage II and III disease. Many trials have been underpowered, have used very heterogeneously mixed patient populations, a wide variety of doses and treatment schedules, and have suffered from early and unplanned analyses. Mature data are still pending in some 3000 patients of the overall approximately 6000 patients that participated in the adjuvant trials. A meta-analysis has demonstrated a similar impact on relapse-free survival across various dose ranges of IFNalpha, but no significant impact on overall survival (OS). In light of the lack of impact on OS and the considerable to serious dose-dependent toxicity of IFNalpha, we do not have a clearly dose- and schedule-defined role for IFNalpha in the adjuvant setting and have no evidence for a benefit of IFNalpha in stage IV melanoma. For the adjuvant setting, the main question: efficacy of very toxic high dose therapy versus efficacy of non-toxic long-term treatment will be answered by the mature data from the large US-Intergroup high-dose and EORTC intermediate-dose and long-term maintenance therapy trials.
UI - 11688150
AU - Kampgen E; Becker J; Brocker EB
TI - [Cell therapy with dendritic cells]
SO - Internist (Berl) 2001 Oct;42(10):1314-20
AD - Universitat Wurzburg, Klinik und Poliklinik fur Haut- und Geschlechtskrankheiten, Josef-Schneider-Strasse 2, 97080 Wurzburg. Kaempgenemail@example.com
UI - 11693798
AU - Bajetta E; Del Vecchio M; Vitali M; Martinetti A; Ferrari L; Queirolo P;
TI - Sertoli MR; Cainelli T; Cellerino R; Cascinelli N A feasibility study using polychemotherapy (cisplatin + vindesine + dacarbazine) plus interferon-alpha or monochemotherapy with dacarbazine plus interferon-alpha in metastatic melanoma.
SO - Tumori 2001 Jul-Aug;87(4):219-22
AD - Unit of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. firstname.lastname@example.org
AIMS AND BACKGROUND: This trial evaluated the feasibility and tolerability of an immunochemotherapeutic approach that uses cisplatin, vindesine, and dacarbazine (DTIC), or only DTIC, in combination with interferon alpha-2a (IFN-alpha), in patients with metastatic melanoma, considering the significant toxicity of several different regimens used patients (50 of whom were assessable) entered a multicentric trial and were randomized to receive cisplatin (30 mg/m2 daily for 3 days) + vindesine (2.5 mg/m2 only day 1) + DTIC (250 mg/m2 daily for 3 consecutive days) + IFN-alpha (3 MIU i.m. 3x/wk continuously) (CVD arm) versus DTIC (800 mg/m2 day 1) + IFN-alpha (3 MIU i.m. 3x/wk continuously) (DTIC arm). The chemotherapy was recycled every 21 days. Patient reevaluation was performed every two cycles, and the treatment was continued in case of objective response or stabilization of disease. RESULTS: We observed 3 complete responses, 2 partial responses and 5 stable diseases in the CVD arm, and 2 partial responses and 4 stabilizations of disease in the DTIC arm. CONCLUSIONS: We conclude that these chemotherapeutic regimens are well tolerated regimens with modest toxicity. Future trials will be conducted associating the CVD regimen with biological response modifiers (IFN, IL-2) in order to improve the results.
UI - 11693825
AU - Morton DL
TI - Cytoreductive surgery and adjuvant immunotherapy in the management of metastatic melanoma.
SO - Tumori 2001 Jul-Aug;87(4):S57-9
AD - Roy E Coats Research Laboratories, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. email@example.com
UI - 11693827
AU - Eggermont AM
TI - Frontiers in adjuvant therapy in stage II-III melanoma.
SO - Tumori 2001 Jul-Aug;87(4):S60-3
AD - Department of Surgical Oncology. University Hospital Rotterdam, Daniel Den Hoed Cancer Center Rotterdam, The Netherlands. firstname.lastname@example.org
UI - 11698460
AU - Blanchet JS; Valmori D; Dufau I; Ayyoub M; Nguyen C; Guillaume P;
TI - Monsarrat B; Cerottini JC; Romero P; Gairin JE A new generation of Melan-A/MART-1 peptides that fulfill both increased immunogenicity and high resistance to biodegradation: implication for molecular anti-melanoma immunotherapy.
SO - J Immunol 2001 Nov 15;167(10):5852-61
AD - Laboratoire d'ImmunoPharmacologie Structurale, Institut de Pharmacologie et Biologie Structurale, Centre National de la Recherche Scientifique, Toulouse, France.
Intense efforts of research are made for developing antitumor vaccines that stimulate T cell-mediated immunity. Tumor cells specifically express at their surfaces antigenic peptides presented by MHC class I and recognized by CTL. Tumor antigenic peptides hold promise for the development of novel cancer immunotherapies. However, peptide-based vaccines face two major limitations: the weak immunogenicity of tumor Ags and their low metabolic stability in biological fluids. These two hurdles, for which separate solutions exist, must, however, be solved simultaneously for developing improved vaccines. Unfortunately, attempts made to combine increased immunogenicity and stability of tumor Ags have failed until now. Here we report the successful design of synthetic derivatives of the human tumor Ag Melan-A/MART-1 that combine for the first time both higher immunogenicity and high peptidase resistance. A series of 36 nonnatural peptide derivatives was rationally designed on the basis of knowledge of the mechanism of degradation of Melan-A peptides in human serum and synthesized. Eight of them were efficiently protected against proteolysis and retained the antigenic properties of the parental peptide. Three of the eight analogs were twice as potent as the parental peptide in stimulating in vitro Melan-specific CTL responses in PBMC from normal donors. We isolated these CTL by tetramer-guided cell sorting and expanded them in vitro. The resulting CTL efficiently lysed tumor cells expressing Melan-A Ag. These Melan-A/MART-1 Ag derivatives should be considered as a new generation of potential immunogens in the development of molecular anti-melanoma vaccines.
UI - 11710284
AU - Akimov MA; Gershanovich ML
TI - [Clinical evaluation of the efficacy of modern first, second, and third line regimes of chemotherapy in patients with disseminated cutaneous melanoma]
SO - Vopr Onkol 2001;47(4):428-35
AD - N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St. Petersburg.
The effectiveness and side-effects of various chemotherapy (CT) regimens were compared in 157 patients (74 males and 80 females, aged 23-79) with disseminated skin melanoma (DSM). Most cases had multiple metastases to the skin and subcutaneous fat tissue, regional lymph nodes (59-69%), lung (14-38%) and liver (13-36%); to other sites--82 (52%). Total response in the dacarbazine (DTIC) group was 18% (complete--5, partial--13 and stabilization--29%). DTIC was employed as first-line treatment in 71%. DBDT (cisplatin, DTIC, BCNU, tamoxifen) was used in 42 patients: as first-line--13 (31%), second-line--21 (50%) and third-line (following the first two regimens in cases refractory to treatment or those with response-based evidence of tumor progression)--8 (19%). In DBDT-treated patients, total response was 29% (complete--7, partial 22 and stabilization--38%). Similar results were recorded in the group where 69% were given CT as second- and third-line treatment. The effect of CVD (cisplatin, vinblastin, DTIC) was much the same as that of DTIC alone but was followed by a higher incidence of myelodepression and anemia. Combined treatment with prospidin+ CCNU + BCNU seems to offer more advantage.
UI - 11715595
AU - Claassen AT; van Berlo CL; Coebergh JW
TI - [Melanoma of the skin: excision policy and pathology report writing in the 'Integraal Kankercentrum Zuid' region is in accordance with the guideline in slightly more than half of the patients]
SO - Ned Tijdschr Geneeskd 2001 Oct 27;145(43):2079-83
AD - St. Maartens Gasthuis, afd. Chirurgie, Venlo. email@example.com
OBJECTIVE: To determine the extent to which the guidelines for cutaneous melanoma had been implemented in the diagnostic and treatment approach of general hospitals. DESIGN: Retrospective, descriptive. METHOD: Patients were selected via the cancer registration system of the 'Integraal Kankercentrum Zuid' (Integral Cancer Centre South, the Netherlands). They were submitted through the pathology laboratory by 1 of the 16 general hospitals in the region. Data was collected from the pathology (PA) reports of the 573 patients for whom a cutaneous melanoma was diagnosed in 1988, 1993 and 1997. The treatment policy and the PA reports were compared with the recommendations in the guidelines concerned and the revised versions of these published in 1985, 1990 and 1997. The patients studied were 212 men (37%) and 361 women (63%) with an average age of 51 years (range 13-96). RESULTS: A diagnostic excision was performed in 485/573 patients (85%). Invasiveness was assessed in 99% of the preparations; in 14% a melanoma was encountered in situ. Invasive melanomas were less often seen in the head and neck region than on the trunk or limb. Thickness of the tumour was not determined in 8% of all 493 invasive tumours and in 19% the pathology report did not state whether the diagnostic biopsy was performed radically. In accordance with the guidelines, diagnostic excision biopsy was first performed in 59% of patients with a subsequent re-excision if necessary; 77% of the PA reports satisfied the fundamental recommendations from the guidelines. For 55% of the patients the diagnostic and therapeutic procedures as well as the pathology report were completed in accordance with the guideline recommendations. Modest improvement occurred over time. CONCLUSION: The excision and re-excision policies as well as the pathology report writing concurred with the recommendations in the consensus for cutaneous melanoma in slightly more than half of the patients who were diagnosed within the IKZ region in the years 1988, 1993 and 1997.
UI - 11712820
AU - Nieboer P; Mulder NH; Van Der Graaf WT; Willemse PH; Hospers GA
TI - Dacarbazine DTIC and carboplatin as an outpatient treatment for disseminated malignant melanoma.
SO - Anticancer Res 2001 Jul-Aug;21(4B):3115-6
AD - Department of Medical Oncology, University Hospital Groningen, The Netherlands.
Occasionally long-term survival in disseminated melanoma can be obtained through chemotherapy. We treated 22 patients with disseminated melanoma with an outpatient regimen consisting of dacarbazine (DTIC) and carboplatin. Three patients had a complete response lasting 4+, 9 and 9 months (survival 4+, 10 and 16 months), respectively; 3 patients had a partial response lasting 4, 6 and 8 months (survival 6+, 11+ and 14 months), respectively. Overall response was 27% (95% confidence interval 11-50%). Toxicity was relatively mild and mainly due to nausea. In 3 patients the dose of carboplatin was reduced because of grade 4 haematological toxicity. This described easy outpatient regimen shows comparable results as other polychemotherapeutic regimens in disseminated melanoma, but with a relatively mild toxicity profile.
UI - 11727535
AU - Wang E; Phan GQ; Marincola FM
TI - T-cell-directed cancer vaccines: the melanoma model.
SO - Expert Opin Biol Ther 2001 Mar;1(2):277-90
AD - Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 2B42, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Significant advances in the understanding of the molecular basis for tumour/host interactions in humans have occurred in the last decade through studying patients with metastatic melanoma. This disease is characterised by its tendency to be modulated by immunologic factors. Furthermore, immunologic manipulation of the host with various systemic agents, in particular IL-2, frequently affects this natural phenomenon and can lead to complete rejection of cancer. By studying the cellular immunology occurring in patients undergoing immunotherapy, several tumour antigens (TA) and their epitopes recognised by human leukocyte antigen (HLA) class I-restricted cytotoxic T-lymphocytes (CTL) have been identified. Most of these TA are non-mutated molecules expressed by the majority of melanoma in vivo and most melanoma cell lines. In addition, unique minimal epitopic sequences play an immunodominant role in the context of specific HLA class I alleles. Since melanoma lesions from different patients often share expression of the same TA, and a minimal peptide sequence from a TA can cause immunologic changes in multiple patients, interest has grown in the development of TA-specific vaccines suitable for broad patient populations. Repeated in vitro stimulation of peripheral blood mononuclear cells (PBMC) with TA-derived epitopes can induce a high frequency of TA-reactive T-cells in melanoma patients. The same epitopes can also enhance TA-specific T-cell reactivity in vivo when administered subcutaneously in combination with Incomplete Freund's Adjuvant (IFA). Epitope-based vaccinations, however, have not shown strong clinical efficacy unless combined with IL-2 administration. Attempts to increase the efficacy of these vaccines have combined specialised antigen-presenting cells or the administration of whole TA through DNA- or RNA-based vaccines with the intention of increasing antigen presentation and processing. Save for scattered reports, however, the success of these approaches has been limited and T-cell-directed vaccination against cancer remains at a paradoxical standstill whereby anticancer immunisation can be induced but it is not sufficient, in most cases, to induce tumour regression. Using melanoma as the standard model for immunotherapy, we will review various methods of T-cell-directed vaccination, the monitoring and analysis of the resulting immune response, and several clinical trials in which cancer vaccines have successfully induced immunisation.
UI - 11727521
AU - Marchand M; Brichard V; van Baren N; Coulie PG
TI - Biological and clinical developments in melanoma vaccines.
SO - Expert Opin Biol Ther 2001 May;1(3):497-510
AD - Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 74, BP 7459, B-1200 Brussels, Belgium. firstname.lastname@example.org
The identification of antigens recognised on human tumours by autologous T-lymphocytes has opened the way for vaccination strategies involving defined tumour antigens. These vaccinations are therapeutic, i.e. they involve patients with detectable disease. Tumour regressions have been observed in a minority of melanoma patients in Phase I/II trials. Some of these regressions have been complete and long lasting. Improving the efficacy of therapeutic vaccines will critically depend on their capacity to trigger a robust immune response, on the development of appropriate methods to monitor these antitumour immune responses to vaccination and on a better understanding of the mechanisms used by tumours to escape immune attack. Finally, the initiation of large randomised Phase III trials will determine the impact of these vaccines on melanoma treatment.
UI - 11718143
AU - Anonymous
TI - Special report: vaccines for the treatment of malignant melanoma.
SO - Tecnologica MAP Suppl 2001 Apr 13;():19-20
This Special Report is a summary of the background for an evidence-based analysis of the phase I/II clinical trial data supporting currently open or recently closed phase III trials of melanoma vaccine therapy. It does not attempt to address the question as to whether the TEC criteria are met. Note, however, that since no melanoma vaccine as yet has FDA