Sentinel-Node Technique Will Change the Design of Clinical Trials in Malignant Melanoma
Authors: Lutz Kretschmer, Christine Neumann, Brett Coldiron, Scott Dinehart, John M. Kirkwood, Sanjiv S. Agarwala, Joseph Ibrahim, Judith Manola, Vernon K. Sondak, Marc S. Ernstoff, Merrick K. Ross
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.8.2208 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11956283 Sentinel-Node Technique Will Change the Design of Clinical Trials in Malignant Melanoma Lutz KretschmerxLutz KretschmerSearch for articles by this author , Christine NeumannxChristine NeumannSearch for articles by this author Brett ColdironxBrett ColdironSearch for articles by this author , Scott DinehartxScott DinehartSearch for articles by this author John M. KirkwoodxJohn M. KirkwoodSearch for articles by this author , Sanjiv S. AgarwalaxSanjiv S. AgarwalaSearch for articles by this author , Joseph IbrahimxJoseph IbrahimSearch for articles by this author , Judith ManolaxJudith ManolaSearch for articles by this author , Vernon K. SondakxVernon K. SondakSearch for articles by this author , Marc S. ErnstoffxMarc S. ErnstoffSearch for articles by this author , Merrick K. RossxMerrick K. RossSearch for articles by this author Show More University of Gottingen, Gottingen, GermanyCincinnati, OHArkansas Cancer Research Center, Little Rock, ARUniversity of Pittsburgh Medical Center, Pittsburgh, PADana-Farber Cancer Institute, Boston, MAUniversity of Michigan, Ann Arbor, MIDartmouth-Hitchcock Medical Center, Lebanon, NHM.D. Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.2002.20.8.2208 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologySentinel-Node Technique Will Change the Design of Clinical Trials in Malignant Melanoma15042002Response15042002To the Editor:We have reviewed the article by Kirkwood et al1 with great interest. We note that there isn’t a balance between the two arms of the study with respect to Breslow’s measurement data. Specifically, there are fewer numbers of patients with very thin (< 0.75 mm) melanomas randomized to the CMK vaccine arm of the study versus a larger number of patients with thin melanomas that were randomized to the high-dose interferon alfa-2b (HDI) arm. Because Breslow’s measurement is a significant prognostic factor, a significant bias might have been given to the HDI group, particularly the node-negative subset. It seems, from the survival charts, that the N0 group, where this maldistribution occurred, was also the group with the most dramatic benefit from interferon therapy. In fact, it seems that the N0 group was the only group that showed statistically significant improvement in relapse-free survival (RFS) and overall survival (OS).In addition, it is stated that an analysis of RFS and OS in all three trials (E1684, E1690, and E1694), indicated that the benefit associated with HDI improved with each successive trial. It follows then that the vaccine group in E1694 should have had an improved OS and RFS when compared with observation groups of the other two studies (E1690 and E1684). Because this was not the case, this suggests to us that there may have been a detrimental effect on OS and RFS produced by the vaccine. These two observations are deserving of further explanation and may invalidate some of the conclusions of the study.In Reply:We would like to respond to the above letters in regard to our article.1 First, Drs Kretschmer and Neumann erroneously conclude from our article that “only the subset of T4N0M0 patients benefited significantly from HDI treatment,” and that “because ulceration in trial E1694 was not included in the multivariate analysis, imbalances in ulceration might have accounted for the benefit observed with high-dose interferon alfa-2b in Intergroup trial E1694.”The impact of high-dose interferon alfa-2b (HDI) upon relapse interval and survival in Intergroup study E1694 was significant for the study as a whole, both when analyzed using the intent-to-treat population and the eligible population (P = .0015 and P = .009 for relapse-free survival and overall survival, respectively, in eligible patients). The analysis of subsets according to the stage stratification subgroups was only performed as a secondary analysis, after achieving significance in the overall study for survival benefit and relapse-interval prolongation. Subsets were analyzed to explore the possibility of a differential impact of therapy according to stage groups into which patients were stratified at entry to this study. The most significant impact of HDI was observed in patients with T4N0M0 disease, where prolongation of relapse-free survival achieved significance when analyzed for the subset apart from the trial as a whole. The benefit of HDI was also seen in each of the other stratification groups with one, two to three, or ≥ four nodes involved. Although these subsets did not yield significance when analyzed independently, the trial was not designed with a sample size large enough to address each individual subset with a high degree of statistical power. This subset analysis may provoke speculation that the benefit of HDI is the greatest in patients with the lowest burden of disease. However, it must be noted that the greatest impact of HDI observed in the pivotal E1684 study2 was found in patients with one lymph node involved by tumor (Smith T, et al, unpublished data); and the impact of HDI in E16903 was greatest in patients with two to three nodes involved; thus, the differential subset benefit in the patients without known nodal involvement (T4N0M0) for E1694 must be interpreted with caution, despite the fact that this is the largest trial of HDI. The aggregate of our experience suggests that the impact of HDI is more likely to be homogeneous across the subsets of disease stage and may be more appropriately considered as a relative risk reduction of 33% for both relapse and mortality, as calculated from the hazard function data in the largest E1694 study.1Kretschmer and Neumann also posit that ulceration might have been unequally distributed between the GMK and HDI therapy groups, and that, especially in the T4N0M0 patients, this might have related to the outcome of our study. The results of E1694 have in fact been analyzed according to ulceration, as published in Table 1 of our article.1 There is no statistically significant difference in the frequency of ulceration among recipients of GMK (138 of 353 patients, 19.6%) and the frequency of ulceration among recipients of HDI (150 of 351 patients, 21.31%); if anything, the distribution favored the vaccine arm. The published Cox multivariate analyses of E1694 related to factors for which we had generally complete data; for ulceration, there were 20% of cases in which this variable was not available, and for this reason, ulceration was not included in the multivariable analysis as published. The impact of ulceration in the E1694 trial is significant (P = .0001) for both eligible and intent-to-treat analyses. Thus, although ulceration played no part in the trial differences related to interferon, ulceration is an important prognostic factor overall in the study.Secondly, Drs Coldiron and Dinehart raise additional concerns regarding two aspects of the E1694 trial; “there is no (sic) balance between the two arms of the E1694 trial, with respect to Breslow’s depth,” and “the benefit associated with HDI has improved with each successive trial [E1684, E1690, and E1694], and it follows that the vaccine group in E1694 should have had an improved OS and RFS when compared with observation groups of the two [earlier] studies E1684 and E1690. . . because this was not the case, there may have been a detrimental effect on OS and RFS produced by the vaccine.”The arms are quite balanced with respect to the Breslow thickness categories overall (with a two-sided P value comparing the two arms over all four categories of .1430). For the Breslow category T1 (Breslow ≥ 1 mm; the two-sided P value comparing proportions between the two arms = .025), there is an imbalance, but the importance of Breslow’s thickness (T1) is overshadowed by the presence of nodal metastatic disease in 77% of eligible patients who entered this trial. As Drs Coldiron and Dinehart note, the chief concern regarding potential effects of imbalances in Breslow’s thickness would relate to the patients who had no known nodal metastatic disease at entry to E1694 (N = 0). These data are presented using the newly adopted American Joint Committee on Cancer criteria in Tables 1 and 2. E1694 Patient Distribution by Breslow Thickness According to the Newly Formulated AJCC 2002 Categories of T Stage for All Patients E1694 Patient Distribution by Breslow Thickness According to the Newly Formulated AJCC 2002 Categories of T Stage for All PatientsTreatmentBreslow Depth by AJCC 2002 Category for E1694 (all patients)T1T2T3T4TotalNo.%No.%No.%No.%No.%NOTE. Breslow depth missing, n = 121.Abbreviation: AJCC, American Joint Committee on Cancer.GMK435.79512.58911.715420.338150.2HDI648.48110.78511.214819.537849.8Total10714.117623.217422.930239.8759100 E1694 Patient Distribution by Breslow Thickness According to the Newly Formulated AJCC 2002 Categories of T Stage for Node-Negative Patients E1694 Patient Distribution by Breslow Thickness According to the Newly Formulated AJCC 2002 Categories of T Stage for Node-Negative PatientsTreatmentBreslow Depth by AJCC 2002 Category for E1694 (N0, node-negative patients only)T1T2T3T4TotalNo.%No.%No.%No.%No.%NOTE. Breslow depths missing, n = 8.GMK10.521.031.59247.49850.5HDI10.521.021.09146.99649.5Total21.042.152.618394.3194100Finally, with respect to the comparison of outcomes between trials, it is not possible to conclude that GMK had a detrimental effect on the outcome of patients in E1694. In fact, all information that is available to date from our pooled analyses of all trials that have tested HDI and GMK suggest that there was no adverse impact of GMK. The comparisons of GMK with observation across trials are not valid because they were performed across studies with differing known and unknown prognostic factors. The analysis of outcome for patients who responded with the production of antibody at a titer of 1:80 or greater by day 29 reveals, if anything, a trend to more favorable outcome, albeit significantly less than that for the impact of HDI in the Intergroup E1694 trial. Moreover, there was no evidence of any detrimental effect of vaccination with GM2 ganglioside plus BCG in a prior randomized trial.4 Finally, because HDI significantly improved relapse-free survival in two prior trials compared with observation in a magnitude similar to the E1694 trial, if there were a detrimental effect of GMK on survival, it occurred without resulting in a disproportionate number of relapses, a highly implausible result.REFERENCE1. Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS vaccine in patients with resected stage IIB-III melanoma: Results of Intergroup Trial E1694/S9512/C509801. J Clin Oncol 19:: 2370,2001-2380, Link, Google Scholar1. Kirkwood JM, Ibrahim JG, Sosman JA, et al: 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. J Clin Oncol 19:: 2370,2001-2380, Link, Google Scholar2. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14:: 7,1996-17, Link, Google Scholar3. Kirkwood JM, Ibrahim JG, Sondak VK, et al: High- and low-dose interferon alfa-2b in high-risk melanoma: First analysis of Intergroup Trial E1690/S9111/C9190. J Clin Oncol 18:: 2444,2000-2458, Link, Google Scholar4. Livingston PO, Wong GYC, Adluri S, et al: Improved survival in stage III melanoma patients with GM2 antibodies: A randomized trial of adjuvant vaccination with GM2 ganglioside. 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