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ASCO 2001: CRITICAL COMMENTARIES PART 2 |
The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Correspondence: Jeffrey E. Gershenwald, M.D., Dept. of Surgical Oncology, Box 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-792-6936; FAX: 713-745-4926; e-mail: jgershen{at}mdanderson.org
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ABSTRACT |
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 Top Abstract Sentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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Key Words. Melanoma • Metastasis • Interferon • Sentinel node biopsy • Biochemotherapy • Chemoprevention • Vaccine
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SENTINEL LYMPH NODE BIOPSY |
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TopAbstractSentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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Study Design and Results
This study evaluated the predictors and patterns of failure in sentinel lymph node (SLN) positive patients from the M. D. Anderson Cancer Center sentinel node database. Overall, 186 of 1,119 patients (17%) had histologically positive SLNs; of these, 180 (97%) underwent formal lymph node dissection. After a median follow-up of 30 months, 37% developed recurrent melanoma. Among those patients who have thus far recurred, the majority (72%) developed distant metastasis as a first site of recurrence. In the multivariate analysis, ulceration (p = 0.001) and number of positive nodes (p = 0.001) were significant independent predictors of relapse-free survival (RFS) and disease-specific survival (DSS).
Predicting the Natural History of Melanoma After Tumor-Negative Sentinel Lymph Node Dissection. R Essner, DM Rose, M Kojima, Y Huynh, RR Turner, DL Morton (ABSTRACT 1397).
Study Design and Results
This study evaluated the natural history of melanoma after lymphatic mapping and negative sentinel lymphadenectomy in 517 patients from the John Wayne Cancer Institute database. At a median follow-up of 21 months, 53 (10%) patients had recurred in either the mapped nodal basin or at distant sites. Extensive pathologic analysis of SLNs from these patients revealed missed metastases in 13%. Multivariate analysis identified age and tumor thickness as predictors of DSS.
Commentary
The use of SLN biopsy to identify occult nodal metastasis in melanoma patients has increased dramatically over the past several years. Overall, these data support previous observations that pathologic SLN status in clinically node-negative patients is an important independent prognostic factor [1]. The data from M.D. Anderson document the prevalence of distant failure in the sentinel-node-positive population, and strongly support the stage III revisions to the American Joint Committee on Cancer (AJCC) melanoma staging system. These include the importance of the number of pathologically involved lymph nodes (rather than lymph node size in the current staging system), as well as the independent adverse prognostic impact of primary tumor ulceration, even among patients with stage III melanoma [2, 3].
In general, data from the John Wayne Cancer Institute support previous studies [4, 5] that demonstrate similar relatively low recurrence rates in sentinel-node-negative patients, as well as the underestimation of lymphatic disease when only routine histologic techniques are employed. One limitation, however, was the lack of inclusion of primary tumor ulceration in this analysis—ulceration is an important prognostic factor and is included in the new AJCC staging system [2, 3].
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TREATMENT OF HIGH-RISK AND METASTATIC MELANOMA |
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TopAbstractSentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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Interferon-
as Adjuvant Therapy for Melanoma: A Meta-Analysis of the Randomised Trials. K Wheatley, B Hancock, M Gore, S Suciu, A Eggermont (ABSTRACT 1394).
Pooled-Analysis of Four ECOG/Intergroup Trials of High-Dose Interferon Alpha-2b (HDI) in 1,916 Patients with High-Risk Resected Cutaneous Melanoma. JM Kirkwood, J Manola, J Ibrahim, VK Sondak, MS Ernstoff (ABSTRACT 1395).
Study Design and Results
In addition to an interim analysis of the Adjuvant Interferon in Melanoma-High Risk (AIM High) UK-sponsored randomized trial of low-dose extended-duration interferon (IFN), a large body of updated IFN data was presented in two large analyses of patients enrolled in various prospective clinical trials. The first study, AIM High, a UKCCCR randomized trial, compared the effect of long-term low-dose IFN (3 million units three times a week for 2 years or until recurrence) with observation on overall survival (OS) and disease-free survival (DFS) in patients with stage IIB or III resected melanoma. After a median follow-up of 1.33 years, there were no significant differences in OS or DFS between groups.
The next two studies consisted of a meta-analysis of randomized trials (n = 3,700) and a pooled analysis of primary data from the four Eastern Cooperative Oncology Group (ECOG)/Intergroup trials of high-dose IFN (n = 1,916). The meta-analysis noted clear benefit for high-dose IFN in terms of RFS, while the advantage was more modest for OS (odds ratio = 0.9, p = 0.05). Data from the ECOG database at an updated overall median follow-up of 3.5 years demonstrated: A) the survival impact of IFN was confined to regimens that incorporated both high-dose induction and high-dose subcutaneous maintenance; B) reduction of hazard was observed early; and C) RFS was sustained off treatment, in contrast to the more limited RFS prolongation reported by the low-dose trials.
Commentary
The meta-analyses presented at the American Society of Clinical Oncology (ASCO) revealed that low-dose IFN regimens are felt to be ineffective as they have neither convincingly nor consistently achieved DFS and OS gains. However, Kirkwood et al. have presented strong data supporting a sustained survival impact for patients receiving high-dose IFN in at least two randomized trials, E1684 and E1690, and for improved DFS in all four ECOG high-dose IFN studies. The observation that other studies have been unable to consistently confirm the OS benefits suggests that the advantage may be modest. It is also important to recognize that data from patients enrolled in other IFN trials at various dosing levels remain immature. Further follow-up is warranted from these important trials, including E1694 (median follow-up 2.1 years), EORTC 18952 (median follow-up 1.9 years), and the AIM High study (median follow-up 1.33 years).
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BIOCHEMOTHERAPY |
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TopAbstractSentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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-2b (IFN) in Patients with Metastatic Melanoma. MB Atkins, JA Gollob, JW Mier, DF McDermott, L Tutin, P Sorokin, JA Sosman (ABSTRACT 1391). Updated Results of Maintenance Biotherapy with IL-2 and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) for Patients with Metastatic Melanoma. SJ O'Day, PD Boasberg, TS Kristedja, MA Martin, S Stern, R Deck, P Ames, P Fournier, K Shinn, G Gammon (ABSTRACT 1405).
Study Design and Results
Concurrent biochemotherapy has been shown to be an active regimen for patients with metastatic melanoma [6]. Based on the observed activity of the dacarbazine (DTIC) metabolite, temozolomide, in central nervous system (CNS) neoplasia, Atkins et al. treated 48 patients with advanced metastatic melanoma (65% stage M1C by the newly revised AJCC staging system criteria) using a concurrent biochemotherapy regimen wherein i.v. DTIC (800 mg/m2) on day 1 was replaced by oral temozolomide (150 mg/m2/day given on days 1-4). One objective of the study was to assess the frequency of CNS relapse. With a short median follow-up of 414 days, the overall response rate was 47% with seven complete remissions (CR) and a median response duration of only 6 months. With respect to primary endpoints, two (9%) responders initially relapsed in the CNS while six other responders relapsed in the CNS subsequent to systemic relapse elsewhere. Thus far, eight responders (36%) have relapsed in the CNS compared with 63% of responders treated with a previously studied DTIC-containing regimen [7].
O'Day et al. sought to increase the frequency of durable response after biochemotherapy by exploring a novel maintenance strategy using IL-2 and GM-CSF. In this study, 52 patients with metastatic melanoma underwent a regimen of daily outpatient injection of low-dose IL-2 (1 MIU/m2) and GM-CSF (125 µg/m2), with intermittent pulses of inpatient high-dose decrescendo IL-2. When compared with 55 historical controls with a comparable response profile to biochemotherapy alone in the same institution, median time to progression was reported to be 10.7 months with maintenance therapy versus 7.7 months without maintenance therapy and median overall survival was 18.9 months versus 13 months, respectively.
Commentary
At last year's ASCO meeting, Eton et al. reported on a randomized phase III trial of 190 patients comparing biochemotherapy with cisplatin, vinblastine, and dacarbazine (CVD) alone [8]. Compared with CVD alone, the biochemotherapy arm doubled response rate and time to treatment failure. In addition, biochemotherapy was associated with a significant, though modest, survival benefit. Since major response rates of 40%-60% have been observed, biochemotherapy can be considered an effective induction regimen. Despite advances in response induction, early progression and CNS relapse continue to present formidable challenges in need of new approaches. Maintenance biotherapy was studied to increase the durability of responses, and temozolomide was used instead of DTIC in order to reduce the incidence of brain metastases. Though the results presented for both strategies were hopeful, these data represent preliminary findings in uncontrolled small trial settings and must survive not only a test of time, but also perhaps multicenter assessment in phase III clinical trials before being incorporated into the standard of care for metastatic melanoma.
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OTHER ABSTRACTS |
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TopAbstractSentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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Temozolomide (TMZ) and Whole-Brain Irradiation (WBI) in Melanoma (Mel) Metastatic to the Brain (CNS): A Phase II Cytokine Working Group Trial. KA Margolin, JA Thompson, JI Clark, L Flaherty, M Atkins, J Sosman, G Weiss, M Ernstoff, J Weber, JP Dutcher, J Smith (ABSTRACT 1432).
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MELANOMA CHEMOPREVENTION |
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TopAbstractSentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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Study Design and Results
Lovastatin, an HMG-CoA reductase inhibitor, inhibits the synthesis of mevalonic acid, a key precursor in cholesterol biosynthesis. The recently completed Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS) trial was not "oncologic" in design, but rather evaluated the efficacy of lovastatin for preventing coronary events in 6,605 individuals with average cholesterol levels and without known coronary artery disease. The study demonstrated a 37% risk reduction of first coronary event in the lovastatin group compared with placebo (p < 0.001) [9]. Interestingly, analysis of the safety data demonstrated a significantly decreased incidence of new melanomas in the lovastatin arm compared with the placebo arm (27/3,301 versus 14/3,304; p = 0.04). There was no difference in the incidence of cancers of the prostate, colon, lung, bladder, breast, or lymph nodes. In addition, among the 41 participants who developed melanoma, there was a trend, although not statistically significant, toward earlier stage at diagnosis in the lovastatin group.
Commentary
Despite progress in cancer chemoprevention over the past several years and the increasing incidence of melanoma, none of 15 large-scale, randomized, prospective clinical trials specifically address melanoma [10]. In addition to its potential as a chemopreventive agent, lovastatin has been shown to have antitumor effects in several animal models [11], suggesting that its use with conventional antitumor regimens may be worth exploring.
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VACCINE THERAPY |
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TopAbstractSentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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Clinical and Immunological Results of Vaccination with Autologous Heat-Shock Protein Peptide Complex-96 (HSPPC-96) in Metastatic Melanoma. G Parmiani, F Belli, A Testori, M Maio, MR Sertoli, G Andreola, G Gallino, C Lombardo, G Tragni, I Lazzari, A Marchianò, A Cova, L Ascani, E Lamaj, C Santantonio, G Scita, P Queirolo, F Cafiero, R Camerini, JJ Lewis, PK Srivastava, L Rivoltini (ABSTRACT 1006).
Study Design and Results
The study by Sosman et al. was designed as a prospective correlative study of SWOG Trial 9035, a phase III study in which patients with intermediate-thickness (1.5-4.0 mm or Clark level IV), clinically or pathologically node-negative melanoma were randomized (n = 689) to receive either an allogeneic melanoma cell lysate plus an immunologic adjuvant for two years or observation. This study was designed to prospectively evaluate previously observed associations between HLA Class I type and response to this vaccine in stage IV patients (i.e., greater response rate in patients with 2-3 versus 0-1 of the following alleles: HLA-A2, A28, B44, B45, and C3) in the adjuvant setting [12]. Serologic HLA typing revealed that among vaccinated patients, those with 2-3 alleles, particularly HLA-A2 and C3, had a superior DFS than those in the observation arm (4-year DFS 87% versus 64%, p = 0.0001) or 0-1 HLA matches (4-year DFS 87% versus 64%, p = 0.004).
In the second study, Parmiani et al. vaccinated 45 metastatic (AJCC stage IV) melanoma patients with HSPPC-96: 11 with no evidence of disease after surgery and 34 with measurable disease after resection for tumor procurement and vaccine production. Interestingly, among the 34 patients with indicator lesions measurable after surgery, two CRs lasting over a year were noted, one in a patient with in-transit disease and another in a patient with a splenic defect. Among the 11 patients treated in the adjuvant setting, the median DFS was 300 days (range, 66 to 536+ days). No grade III or IV toxicities were noted. Using the ELISPOT assay, a melanoma-specific T cell-mediated immune reaction was noted in some responders.
Commentary
In the first study, preliminary results of SWOG 9035 presented earlier this year [13] revealed a nonsignificant improvement in DFS for eligible patients randomized to receive vaccine and a statistically significant difference between the treatment and control groups. It is particularly interesting that differences in genotype were able to at least partially explain response to therapy, and provide support for the concept of targeted vaccine therapy in melanoma. These data indicate the melanoma cell lysate used generates peptides that bind to specific HLA molecules. Identification of specific components of this lysate responsible for the observed responses may point toward how to focus this vaccine strategy further.
In the second study, Parmiani's encouraging preliminary results using the novel vaccine strategy developed by Srivastava and colleagues yielded two CRs among 34 patients with stage IV disease. Only a modest induced cellular immune response was detected in the responders using the sensitive ELISPOT assay [14]. Interestingly, an immune response was detected against a specific known melanoma peptide after vaccination in the responding patients but not in nonresponding patients. It has not yet been determined whether the ELISPOT assay examining peripheral blood T cells is useful to monitor immune responses that may occur in lymph nodes or in the tumor itself. Nonetheless, based on the observed activity in this study, this autologous tumor-derived vaccine strategy will be further analyzed in multi-institutional studies.
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REFERENCES |
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TopAbstractSentinel Lymph Node BiopsyTreatment of High-Risk and...BiochemotherapyOther AbstractsMelanoma ChemopreventionVaccine TherapyReferences |
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