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Journal of Clinical Oncology, Vol 22, No 3 (February 1), 2004: pp. 574-575 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.275
In Reply:Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Universitätsklinikum Charite, Berlin, Germany The comments by Fazio and Öberg, as well as by Völter and Peschel are well taken. We agree with the general call for even larger clinical trials in international, prospective, randomized, multicenter settings studying homogeneous patient populations. Despite this, however, daily clinical reality shows—as exemplified also by the only three published prospective randomized trials—a rather sluggish willingness of every major center to participate in national and international clinical trials [1-3]. One explanation (among others) for the generally low recruitment is the low incidence of this tumor entity. Additional reasons are the lack of well-matched patient subgroups, including a comparable tumor stage and grading, primary tumor localization, functionality, and pretreatment before study entry. Therefore, the generation of evidence-based data in this area of clinical research is strongly dependent on the active collaboration of leading centers. Initially, our study was launched as an international multicenter trial with the intention to include 105 patients in a timely manner. However, on the basis of our stringent inclusion and exclusion criteria, such as the demand for almost no pretreatment (except surgery and less than 1 month of biotherapy) together with a required documented tumor progression before study entry, a lower-than-expected recruitment rate was observed. Despite this, however, we still obtained valid data for a patient number so far unmatched by other studies in this setting [1]. To date, our study also remains the only published prospective randomized clinical trial comparing the two medical treatment options for neuroendocrine tumors of the gastroenteropancreatic system with somatostatin analogues or/and interferon alfa.
Until now, as indicated also by Fazio and Öberg and by Völter and Peschl, a large number of retrospective, mainly monocentric studies have been published (reviewed in Hejna et al [4]). All of these retrospective studies have been hampered by the fact that patients were variably pretreated, had a variable tumor load, often had different sites of tumor primaries, and were treated partly for only short periods ( On the basis of the reported dose-dependent antiproliferative effects of lanreotide and octreotide [6-8], higher doses of lanreotide (3 x 1 mg/d) were used in our study to optimize antiproliferative efficacy. Interestingly, side effects were almost identical to those after standard doses in our study. In addition, assuming an identical clinical efficacy of lanreotide and octreotide—as also suggested by Völter and Peschel—a lower antiproliferative effect, as expected, was still observed. Regarding control of functionality, our data demonstrate symptom reduction in 29 patients with functional metastatic neuroendocrine tumor disease, as expected (Fig 5 in [1]). As stated in Results, statistical significance was only observed in the combination arm. This observation may argue for an additive effect of the two biotherapeutic agents used, at least for the control of symptoms. However, as we pointed out, control of symptoms was not the primary objective of our study. Clearly, future studies will have to address this point in more detail. We also agree with Fazio and Öberg and with Völter and Peschel that our study population was not homogenous. In this context, the rather large proportion of foregut neuroendocrine tumors (45%) may have affected the overall outcome of the studied population, as we also indicated in our article. Despite this, however, on the basis of the large number of patients studied (including those with midgut tumors; n = 30) together with the randomization protocol and the required therapy naivety, we have still analyzed a larger patient cohort than is given in most previous retrospective studies. To our knowledge, our study also represents the first in the field fulfilling Consolidated Standards of Reporting Trials criteria [9]. As to the use of WHO criteria for radiologic evaluation, we certainly applied these in the use of computed tomography scanning. In addition, ultrasound was used in parallel as a convenient screening method for follow-up. We also agree with the statement that radiologic blinding was not only used in our study. However, as cited by Völter and Peschel, few studies have so far been performed in this setting. Because of the small number of octreoscan-negative patients combined with the lack of statistical power, we refrained from a more detailed analysis of this subgroup, leading only to a casuistic description, as is often done. We are aware of the fact that a negative octreoscan does not exclude expression of somatostatin receptors other than sstr2 and 5 [10,11]. Accordingly, this fact is mentioned in the Discussion of our article. In summary, we are convinced that additional, carefully developed study protocols focusing on specific subgroups (such as functional neuroendocrine tumors of the midgut; that is, with carcinoid syndrome or nonfunctional pancreatic tumors), including comparable tumor stages and grading, are required. In this way, previous "odysseys" [12] in the ocean of small tumors with small retrospective studies will lead us—it is hoped—to the land of evidence-based medicine. In this context, a close interaction between leading centers represents a sine qua non condition to achieve meaningful clinical data. Authors’ Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: B. Wiedenmann, Intersan. REFERENCES
1. Faiss S, Pape UF, Böhmig M, et al: Prospective, randomized multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors: The International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 21: 2689-2696, 2003 2. Frank M, Klose KJ, Wied M, et al: Combination therapy with octreotide and alpha-interferon. Am J Gastroenterol 94: 1381-1387, 1999[Medline] 3. Kölby L, Persson G, Franzen S, et al: Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg 90: 687-693, 2003[CrossRef][Medline]
4. Hejna M, Schmidinger M, Raderer M: The clinical role of somatostatin analogues as antineoplastic agents: Much ado about nothing?. Ann Oncol 13: 653-668, 2002 5. Öberg K: Carcinoid tumors: Molecular genetics, tumor biology, and update of diagnosis and treatment. Curr Opin Oncol 14: 38-45, 2002[CrossRef][Medline] 6. Anthony L, Johnson D, Hande K, et al: Somatostatin analogue phase I trials in neuroendocrine neoplasms. Acta Oncol 32: 217-223, 1993[Medline]
7. Eriksson B, Renstrup J, Iman H, et al: High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: Clinical and biological effects. Ann Oncol 8: 1041-1044, 1997 8. Faiss S, Rath U, Mansmann U, et al: Ultra-high-dose lanreotide treatment in patients with metastatic neuroendocrine gastroenteropancreatic tumors. Digestion 60: 469-476, 1999[CrossRef][Medline] 9. Moher D, Schultz KF, Altman DG: The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. Lancet 357: 1191-1194, 2001[CrossRef][Medline]
10. John M, Meyerhof W, Richter D, et al: Positive somatostatin receptor scintigraphy correlates with the presence of somatostatin receptor subtype 2. Gut 38: 33-39, 1996 11. Jonas S, John M, Boese-Landgraf J, et al: Somatostatin receptor subtypes in neuroendocrine tumor cell lines and tumor tissues. Langenbecks Arch Chir 380: 90-95, 1995[Medline]
12. Moertel CG: Karnofsky memorial lecture: An odyssey in the land of small tumors. J Clin Oncol 5: 1502-1522, 1987 Related Article
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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3 months) and with dosages varying by more than one order of magnitude (in the case of somatostatin analogs). Therefore, it is not surprising that the reported antiproliferative effects of somatostatin analog and/or interferon alfa alone or in combination range from approximately 15% to 50% [
