Treatment Results in Localized Primary Gastric Lymphoma: Data of Patients Registered Within the German Multicenter Study (GIT NHL 02/96)
http://www.100md.com
《临床肿瘤学》
the Departments of Medicine –Hematology and Oncology–Radiation Oncology, and General Surgery, and Institute for Informatics and Biomathematics, Westf?lische-Wilhelms-Universit?t, Münster
Department of Gastroenterology, Zentralklinikum, Augsburg
Department of Hematology/Oncology, Municipal Clinic, and Department of Radiation Oncology, Pius-Hospital, Oldenburg
Departments of Medicine –Hematology and Oncology–and of Radiation Oncology, Ernst-Moritz-Arndt-Universit?t, Greifswald
Departments of Medicine –Hematology and Oncology and Radiation Oncology–Universit?t Rostock
Departments of Medicine –Hematology and Oncology, and Radiation Oncology, Universit?t des Saarlands, Homburg
Department of Radiation Oncology, Mutterhaus der Borrom?erinnen, Trier
Department of Radiation Oncology, Charité, Berlin
Lymph Node Registry at the German Society of Pathology, Department of Hematopathology, Universit?t von Schleswig-Holstein, Campus Kiel, Kiel, Germany
ABSTRACT
PURPOSE: In the prospective study 02/96 on primary GI lymphoma, we have collected data on histology, clinical features, and treatment results. In particular, in stages I and II localized primary gastric lymphoma (PGL), our objectives were to reduce treatment intensity and to confirm our hypothesis from study 01/92, which maintained that an organ-preserving approach is not inferior to primary surgery.
PATIENTS AND METHODS: Patients receiving radiotherapy and/or chemotherapy were stratified for histologic grade, stage, and whether surgery had been carried out or not (as decided by each participating center). Patients with aggressive PGL received six cycles of CHOP-14 (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by involved-field radiotherapy (40 Gy). Patients with indolent PGL (including patients experiencing treatment failure with antibiotic therapy for Helicobacter pylori) were treated with extended-field radiotherapy. The volume depended on stage. The irradiation dose was 30 Gy, followed by a boost of 10 Gy (the latter omitted after complete resection) to the tumor region.
RESULTS: Seven hundred forty-seven patients were accrued. Of these patients, 393 with localized PGL were treated with radiotherapy and/or chemotherapy only or additional surgery between December 1996 and December 2003. The survival rate at 42 months for patients treated with surgery was 86% compared with 91.0% for patients without surgery.
CONCLUSION: In this nonrandomized study (02/96), we reproduced the previous results of study 01/92 showing no disadvantage for an organ-preserving treatment. Therefore, primary stomach resection should be questioned.
INTRODUCTION
The inclusion of surgery, in contrast to an organ-conserving approach, in the treatment strategy for localized primary gastric lymphomas (PGL) has been controversial and extensively discussed in the literature. This discussion is reflected in the publications by Brands et al1 and de Jong et al.2 Only therapy with antibiotics for Helicobacter pylori–positive marginal-zone B-cell lymphoma (MZCL) in stage I has been accepted as standard.3,4
Although until recently data in the literature had been based on retrospective studies and analyses, in 2000, the first major prospective study on PGL was published by Fischbach et al,5 with the conclusion that resection remained the treatment of choice. Because our nonrandomized study (German Multicenter Study Group GIT NHL 01/92) comparing a conservative treatment approach with one including complete or partial resection of the stomach showed no advantage for surgery and because preliminary analysis of our second study (GIT NHL 02/96) seemed to confirm these earlier results, we expressed considerable doubts about the significance of surgery in treating PGL.6
The aim of GIT NHL 02/96 was to collect further data, such as histology, anatomic distribution, clinical features, and treatment results, in primary GI lymphomas.7 Because the numbers in advanced PGL and in intestinal lymphoma were too small to draw any conclusions, there was no change in treatment strategy in these entities. On the basis of the published data in localized PGL,6 we changed the objectives, first, to reduce the intensity of treatment without compromising results obtained in study 01/92 and, second, to confirm our hypothesis that surgery could be omitted because a stomach-conserving approach would improve the quality of life in PGL patients considerably. This report provides an interim analysis on 393 patients with localized PGL.
PATIENTS AND METHODS
Patients
This study was started on December 1, 1996, and was closed January 2004. Participating centers throughout Germany (see Appendix) reported every patient 18 years or older with a primary GI non-Hodgkin's lymphoma (NHL), which was defined according to Lewin et al.8 A patient had to present with GI symptoms of or have predominant lesions in the GI tract. There was no upper age limit. To allow a follow-up period of at least 6 months for this analysis, only patients with PGL in stages I and II, whose date of diagnosis was no later than December 1, 2003, were selected from the study cohort for this report. Furthermore, patients qualifying for primary antibiotic treatment of Helicobacter pylori (MZCL, stage I; H pylori positive) were included only after experiencing failure of the eradication.
This study was approved by the Ethics Committee of the University of Münster and by local ethics committees of the other participating centers. Written informed consent was obtained from all patients. According to the study protocol, patients who presented with second malignancies and/or had missing confirmation of histologic subtype by the central pathology review board and/or had comorbidity prohibiting adequate therapy were excluded from the evaluation of treatment.
Diagnostic and Staging Procedures
The diagnostic work-up included patient history and physical examination, blood work (such as lactate dehydrogenase [LDH], liver enzymes, alkaline phosphatase, creatinine, electrophoresis, immunoglobulins, and RBC and WBC counts), chest x-ray, radiologic and endoscopic evaluation with multiple biopsies of the upper and lower GI tract, computed tomography of the chest and abdomen, abdominal ultrasound evaluation, bone marrow biopsy, and examination of Waldeyer's ring. Endoscopic ultrasound was carried out in most patients.
Formalin-fixed biopsies were reviewed in most cases by the central pathologic board of the study (M.T. and R.P.), according to the classification by Isaacson et al9 and the revised Kiel classification.10 The biopsies were later reclassified according to the Revised European-American Lymphoma classification.11 Reviews of other hematologic pathologists collaborating in the review panel for German lymphoma studies were also accepted (see Appendix). Each biopsy was investigated immunohistochemically by staining for CD20 and CD3. Additionally, marginal-zone phenotype was proven by Ki-B3 negativity.12,13 Polymerase chain reaction–based amplifications of genes for immunoglobulin heavy chain or T-cell receptor chain were added to show monoclonal disease.
Patients were staged according to the Ann Arbor classification in its modification by Musshoff et al.14 In cases of tumor resection, the extent was analyzed retrospectively by one of the authors (J.B.) based on operating sheets and histopathologic certificates according to the International Union Against Cancer.15
Study Design and Treatment Strategy
Given the accrual rate of our study 01/92,7 the study committee decided against a randomized trial because expected numbers would not be sufficient for a valid statistical analysis. The decision to include surgery in the treatment strategy was left to each participating center, although patients were also accepted who underwent lymphoma resection and, only afterwards, were referred to a study center.
Patients who received radiotherapy and/or chemotherapy was stratified according to histologic grade of the lymphoma, stage of disease, and whether or not surgery had been carried out. In cases of primary surgery, further treatment was stratified according to the grade of resection (R0 v R1 or R2).
Indolent lymphomas. Operated patients with stage I disease received no further treatment after complete resection of the tumor (R0) and were just observed. Patients with microscopic (R1) or macroscopic (R2) rest in stage I were treated with reduced extended-field irradiation (instead of whole abdomen radiation, as in our first study6) to the upper and middle part of the abdomen, with the lower border of the treatment field including the fifth lumbar vertebra (30 Gy + 10 Gy boost to R1 or R2 regions). After complete resection (R0), patients with stage II disease received reduced extended-field irradiation (30 Gy), whereas after R1 or R2 resection, the target volume was the whole abdomen (30 Gy) followed by a boost irradiation of 10 Gy to the tumor region (but no mediastinal field, as in our first study). In nonoperated patients, the size of the extended field was also reduced to the upper and middle part of the abdomen (the lower border of the fifth lumbar vertebra) in stage I patients and was the total abdomen in stage II patients (30 Gy). The tumor region received a boost of 10 Gy.
Aggressive lymphomas (including all T-cell lymphomas). For all stages, patients received six cycles of CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [maximum 2 mg]) on day 1 and prednisone 100 mg on days 1 to 516 every 2 weeks (the number of cycles was reduced to four only after complete resection in surgically treated patients). If this regimen proved not to be feasible in time, filgrastim was administered after each cycle. Chemotherapy was followed by involved-field radiotherapy to the upper part of the abdomen with 40 Gy (or 30 Gy in case of complete resection).
Follow-Up and Statistical Analysis
Restaging after completion of treatment included diagnostic endoscopy and biopsies of the primarily involved site, including endoscopic ultrasound where available, abdominal and pelvic computed tomography scan and/or ultrasound, chest x-ray, blood work as described earlier, and clinical examination and patient history. Follow-up evaluations consisted of history, physical examination, chest x-ray, endoscopy, and abdominal ultrasound. Additional tests were carried out if necessary. Patients were examined every 3 months for at least 2 years and twice a year thereafter.
The date of this analysis was February 4, 2005. Response criteria and end points are reported according to published guidelines.17 Survival was measured from the first day of treatment; end points were defined as follows. Event-free survival (EFS; patients in complete or partial remission) was defined as time from first day of treatment to any failure or death from any cause. Overall survival (OS; all patients) was defined as time from first day of treatment to death from any cause. Cause-specific survival (CSS; all patients) was defined as time from first day of treatment to death either related to NHL or associated with treatment. Patients in remission or alive, depending on the kind of survival analysis, were censored at the last known date of follow-up evaluation and shown as tick marks on the survival curves. Survival fractions were calculated using the Kaplan-Meier product-limit method. The log-rank test was used for comparing survival curves. P values were calculated two tailed. GraphPad Prism version 3.0 (GraphPad, San Diego, CA) was used as the software.
RESULTS
Patient Characteristics, Stage, and Histology
December 1996 to February 2004, 747 patients with primary GI lymphomas were accrued to the study by medical, surgical, and/or radiotherapeutic departments throughout Germany (see Appendix). Of this cohort, all 520 patients with stages I and II PGL who were diagnosed before December 1, 2003 were selected to allow a follow-up period of at least 6 months after finishing treatment.
Fifty-seven patients were excluded from assessment of treatment according to the study protocol for the following reasons: preceding malignancies (n = 38), no confirmation of histologic subtype by the review board (n = 7), and comorbidity not allowing scheduled therapy (n = 12). A further 10 patients could not be evaluated because of their refusal of any treatment (n = 4), death before onset of treatment (n = 1), and treatment by monoclonal antibody because of patient decision (n = 2). Three patients were not correctly stratified for treatment. Fifty-five patients were treated successfully by antibiotics to eradicate H pylori.
Thus, 398 patients were available for this analysis of treatment results, which was carried out on an intent-to-treat basis. No patients were excluded because of treatment violation. Within this group, the following two cohorts can be differentiated: 335 patients received just conservative management (CM), whereas 63 patients underwent primary surgery followed by CM (S/CM); 60 of the S/CM patients were referred to a study center after surgery, and only three were recruited by a participating surgical clinic.
The median age of the patients was 63.2 years (range, 20.8 to 83.1 years), and 9.3% were older than 75 years. The female (n = 178) to male (n = 220) ratio was 1:1.2. The Karnofsky performance status was 90% (n = 136) or 100% (n = 197) in 90% of the patients. Serum LDH was elevated in only 61 patients (15.3%). In approximately 78% the patients, disease was limited either to the stomach (n = 229) or spread included only paragastric lymph nodes (n = 83). These data are listed in Table 1 and differentiated for patients after CM and S/CM. In most S/CM patients, the data on LDH and Karnofsky performance status were obtained after surgery. The higher percentage of stage II patients in the surgical cohort is a result of upstaging by laparotomy compared with noninvasive diagnostic procedures, as reported earlier by Maor at al.18
The distribution of histologic subtypes is displayed in Figure 1. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBCL]) accounted for the majority of PGL (59.5%). In 18.1% of DLBCL, a simultaneous small-cell component was demonstrated (43 of 237 patients); these lymphomas were classified by Isaacson et al9 as high-grade B-cell lymphoma of mucosa-associated lymphoid tissue with evidence of low-grade component. This subtype has no real equivalent in the Revised European-American Lymphoma classification11 or in its successor, the WHO classification,19 but it was subsumed to DLBCL and equated with other secondary DLBCL.20 However, two publications from the early 1990s by two pathologic groups stressed the importance of differentiation of so-called secondary high-grade lymphomas (SHGL).21,22
The actual frequency of SHGLs remains unclear because their diagnosis is highly dependent on the method by which the histopathologic specimens were obtained. The proportion of SHGLs in this study was 17.6% in resected lymphomas compared with 9.6% in endoscopic biopsies. This coexistence of large and small cells has been the rationale for a combined chemotherapy and radiotherapy approach in DLBCL within our study group.23,6
Extranodal MZCL (ie, low-grade lymphoma of mucosa-associated lymphoid tissue type9) accounted for 37.9% of lymphomas. Follicular and mantle-cell lymphomas were diagnosed in only a few patients, and there were only five T-cell lymphomas.
Histologic subtypes and their distribution according to stage are listed in Table 2. Survival rates are listed in Table 3, and the related survival curves are displayed in Figures 2 and 3.
Treatment
Three hundred ninety-three patients (excluding T-cell NHL) were evaluated for treatment; 84.3% of patients received CM (n = 332), and 61 patients (15.5%) received S/CM. Further analysis demonstrated that only three S/CM patients were accrued by a surgical study center that obviously preferred this approach for PGL. The remaining 58 patients were referred to a study center after complete or partial resection outside the study group. The median time of observation (MTO) was 42 months (range, 0.07 to 97.4 months), starting from the first day of treatment. As of the date of this analysis, 68 primary events (defined as progression, relapse, or death from any cause) have occurred.
Seven patients (none after surgery) had progressive disease. Only one patient responded to salvage therapy (high-dose chemotherapy with stem-cell transplantation) after progression and is still alive at 45 months after the second treatment. In six patients, the histologic diagnosis was DLBCL. In one patient with a primary MZCL, progression occurred immediately after the end of radiotherapy, and a DLBCL was diagnosed, suggesting an initial primary SHGL. LDH was elevated in two of seven patients. All but two patients had stage II disease.
In conservatively treated patients, 17 patients (5.1%) experienced relapse, with salvage therapy being successful in 13 patients. DLBCL (including SHGL) occurred at a higher frequency than MZCL (11 and six patients, respectively). LDH was elevated in four DLBCL patients. After surgical treatment, eight patients (six DLBCL patients) relapsed (13.1%); three are still alive after salvage therapy. Details of age, histologic subtype, and level of LDH are listed in Tables 4 and 5.
Death related to treatment or late effects occurred in 11 patients (two after surgery). A further 25 patients died from other causes after a median time of 40.8 months (range, 2.4 to 85.0 months).
Because there are no significant differences in the survival curves of patients with DLBCL and patients with additional small-cell components (Figs 2 and 3), both were grouped together comparing aggressive and indolent lymphomas. OS for combined stages I and II is shown in Figure 4. There was no significant difference between both subtypes under the chosen treatment strategy. Survival rates at the MTO (ie, 42 months) according to patient characteristics are listed in Table 6.
In CM patients, age greater than 60 years was not a prognostic factor for EFS, but it was for OS because death from other causes influenced this age group more. A Karnofsky performance status less than 100% influenced both EF and OS. The influence of LDH was only marginal for OS. EFS was statistically worse in stage II patients. Probably because of observation time, this could not be shown for OS. In S/CM patients, no parameter influenced OS. Because LDH and performance status were documented mainly 2 to 4 weeks after surgery, the results for EFS have to be looked at with caution. The survival curves for both treatment groups are displayed in Figures 5 (CM) and 6 (S/CM). Because of the number of deaths not related to lymphoma or its treatment, CSS was also calculated.
DISCUSSION
Many single reports and reviews1,24 on the appropriate treatment strategy for PGL favored the inclusion of primary resection as first choice of treatment. This view was supported by the publication of the first major prospective study on PGL by Fischbach et al,5 which accrued sufficient numbers of patients to generate convincing results. With a median follow-up time of 17.5 months, the reported survival rates at 2 years from 89% to 96% for low-grade lymphomas ranged and from 83% to 88% for high-grade lymphomas. Nevertheless, the authors concluded their discussion with the comment that only by means of a randomized study could final recommendations for the best treatment strategy be reached.
When designing our first study GIT NHL 01/92, the study committee decided against a randomization because they were confronted with the conflicting opinions of physicians on the importance of surgery, which would endanger sufficient accrual of patients. Instead, we decided on a study design with two nonrandomized treatment arms. The reported results showed no advantage for either approach after 55 months of MTO, which, at that time, led to our assumption that a stomach-conserving approach might be favored, although a bias towards selecting patients had to be kept in mind.6 In addition, our data were not inferior to those published by Fischbach et al.5
Early analysis of study 01/92 encouraged a follow-up study design, which again was not randomized because the statistical test would be on equivalence, demanding an accrual rate that could not be reached in reasonable time. Instead, the following two aims were formulated. First, we wanted to reduce treatment intensity to improve quality of life for the patients without compromising the results achieved so far. This was done by reducing toxicity by using antibiotic treatment of H pylori for qualified patients (MZCL stage I patients; positive proof of H pylori) and by carefully reducing the chemotherapy and/or radiation fields. Although this goal seems to be reached in our interim analysis, a detailed report of these data would be too early because, in our opinion, an MTO of at least 4 years after the closure of the study is required, especially for indolent lymphoma. However, the second goal, which was to confirm our hypothesis that surgery offers no advantage in treating PGL patients, has been reached. The results of study 01/92 (MTO, 96 months) could be reproduced, even though there was no upper age limit in study 02/96 (age limit of 75 years in 01/96) and treatment intensity was reduced, especially in indolent lymphomas (Fig 7).
Thus, the results of an organ-preserving approach are not inferior to the data reported by Fischbach et al,5 when surgery was the primary goal. The same is the case for the S/CM cohorts in our two consecutive studies (Fig 7). In addition, the data by Sonnen et al,25 which were published primarily in 1994, were updated after 10 years.26 In this likewise nonrandomized comparison, the authors saw no difference between S/CM and CM, reporting failure-free survival rates of 93% and 91%, respectively, and a disease-free survival rate of 93% for both groups at 5 years. The safety of an organ-preserving treatment in stage I and II MZCL alone either by eradication of H pylori or by radiation was stressed by the results of a prospective study presented at the 40th Annual Meeting of the American Society of Clinical Oncology.27 In a randomized study on gastric DLBCL by Avilés et al,28 results after chemotherapy or combined surgery and chemotherapy (10-year survival rates, 96% and 91%, respectively; not significant) were significantly superior (P < .001) to surgery alone (10-year survival rate, 54%) or surgery in combination with radiotherapy (10-year survival rate, 53%).The same authors also published their treatment results in MZCL of the stomach after surgery, chemotherapy, or radiotherapy, with no difference in survival rates at 10 years.29
In his monograph on malignant lymphoma, Aisenberg30 stated in 1991 that, for treating gastric lymphoma, "until definitive data from multi-institutional studies become available, many treatment decisions must be based on common sense and prior nonrandomized, retrospective experience." These studies are now available. Three are prospective nonrandomized studies, but comparing the results, no advantage for primary resection in PGL could be demonstrated. In addition, two randomized studies published by Avilés et al28,29 confirmed our hypothesis that surgery could be omitted from treatment of PGL.6
As a result of these considerations, the main competing study groups in Germany joined together as the German Study Group on Gastrointestinal Lymphoma (DSGL), whose first protocol DSGL 01/2003 addresses improvements in conservative treatment for localized PGL by carefully reducing treatment intensity in two ways. First, for H pylori–negative MZCL, there is a consequent further reduction of radiation volume to involved field, which has been advocated before but based on small numbers only (17 and 15 patients).31,32 Second, for gastric DLBCL patients in the current study, CHOP chemotherapy was reduced from six to four cycles in combination with rituximab followed by involved-field radiotherapy. Another goal is to collect enough data to look for prognostic factors, which have yet to be formulated for CM in PGL. Our newly founded study group recommends surgery only when perforation, bleeding, or obstruction occur, which cannot be managed by conservative treatment.
Appendix
The following individuals and centers participated in the study: Klinik für Strahlentherapie der Universit?t (R. Mager), Luisenhospital (W. Berges), Aachen; St Franziskus-Hospital (E. Jacobi), Ahlen; Klinikum St Marien (L. Fischer von Weikersthal, W. Berberich), Amberg; St Nikolaus-Stiftshospital (A. Steinmetz), Andernach; Marienhospital (F.-J. Altenwerth), Arnsberg; Zentralklinikum (P. Probst; A.-C. Voss), Augsburg; Kreiskrankenhaus (D. Unverferth, F. Püschel), Aurich; Stadtkrankenhaus (J. Gensicke), Bad Arolsen; Gemeinschaftspraxis (P. Harms), Bad Oeynhausen; Humaine Klinikum (D. Schultze, P. Nowakowski), Bad Saarow; St Elisabeth-Hospital (N. Nikolaides) Beckum; Helios-Klinikum/Robert-R?ssle-Klinik (Th. Benter), Universit?tsklinikum Charite (O. Sezer, M. Hinkelbein), Helios-Klinikum/Buch (T. Gottstein), H?matologisch/Onkologische Fachpraxis (A. Kirsch), Berlin; Franziskus-Hospital (F. Jentsch, B. Angrick), St?dtische Kliniken (J. Feldkamp, P. Hirnle), Bielefeld; Medizinische Universit?ts-Poliklinik (S. Fronhoffs), Bonn; Marienhospital (E. Musch), Bottrop; ZKH Bremen-Nord (B. Rühlmann), Ev. Diakonie-Krankenhaus (K.-H. Pflüger), ZKH, Klinik für Strahlentherapie (S. Staar) Bremen; Lukas Krankenhaus (F. M?ller-Fa?bender), Bünde; Allgemeines Krankenhaus (F. Marquard, D. Schnalke), Celle; St-Vincenz-Hospital (Th.Y. Padel), Coesfeld; Kreiskrankenhaus (W. Thier), Dormagen; St-Johannes-Hospital (M. Nahler), Knappschafts-Krankenhaus (H.-G. Wehmeyer), Dortmund; Marien-Hospital (A. Schütte), Düsseldorf; Hans-Susemihl-Krankenhaus (H. Becker), Emden; St-Antonius-Hopital (R. Fuchs), Eschweiler; Universit?tsklinikum (M. Engelhard), Alfried-Krupp-Krankenhaus (F. Guntrum), Kliniken Essen-Mitte (M. Stahl), Ev.Krankenhaus Lutherhaus (C. Ko?ler-Wiesweg), Kliniken Essen Süd (C. Tirier), Essen; Diakonissenkrankenhaus (T. Koch), St Franziskus-Hospital (H.-J. Brodersen, S. Hartwigsen), Flensburg; Evangelisches Diakoniekrankenhaus (U. Brand), Onkologische Schwerpunktpraxis (N. Marschner), Freiburg; St?dtisches Klinikum (H.-G. H?ffkes, H. H?u?ler-Mischlich), Fulda; Georg-August-Universit?t (W. Jung, H. Schmidtberger, T. Armbrust), G?ttingen; E.-M.-Arndt-Universit?t (C. Hirt, R. Breitsprecher), Greifswald; Internistische Gemeinschaftspraxis (E. Eschenburg), Güstrow; Fachpraxis H?atologie/Onkologie (S.B. R?sel), Gütersloh; St Salvator-Krankenhaus (I. Hausbrandt, U. Schippan), Halberstadt; Krankenhaus St Elisabeth/St Barbara (E. Fa?hauer), M.-Luther-Universit?t (I. Kühne, J. Dunst), Praxis für Strahlentherapie (C. Eckstein), Halle; Allgemeines Krankenhaus Altona (D. Braumann), Allgemeines Krankenhaus St Georg (R. Sonnen; M. Busch), Praxis für Strahlentherapie (D. Carstens), Hamburg; St Marien-Hospital (R. Jany, H. Dürk), Fachpraxis H?matologie/Onkologie (H. Weischer), St Barbara Klinik (W. Frontzek), Hamm; St?dtisches Krankenhaus Siloah (H. Kirchner, A. Wildfang), Henriettenstiftung (F. Glüer-Fuchs), Praxis für Strahlentherapie (W. Brenneisen), Hannover; H?mato/Onkolog. Fachpraxis (W. Grimm), Harrislee; Praxis f. Strahlentherapie (A. Lüddeke), Hildesheim; Universit?tskliniken des Saarlandes (R. Schmits, C. Rübe, C. Moser), Homburg/Saar; St?dtisches Klinikum (M. Haag, M.-L. Sautter-Bihl), Karlsruhe; St?dtische Kliniken (E.-U. Steinhauer), Kassel; Klinikum Kempten-Oberallg?u (O. Prümmer, U. Zimmerman), Kempten; Christian-Albrechts-Universit? (C. Pott, R. Bartsch, J. Schultze), Kiel; St-Antonius-Hospital (B. Reers, V. Runde), Kleve; St?dtisches Klinikum Kemperhof (H. Nolte, A. Schendera), Koblenz; Universit?t zu K?ln (M. Reiser; R.-P. Müller), St Elisabeth-Krankenhaus (J. Benz), Krankenhaus der Augustinerinnen (A. Tschenne), H?matolog./Onkolog. Fachpraxis (S. Schmitz), K?ln; St?dtische Kliniken (T. Frieling, U. Schulz), Krankenhaus Maria-Hilf (U. Peters), Krefeld; Klinikum Landshut (A. Holstege, H.-J. Wypior), Landshut; St?dtisches Klinikum (R. Jakobs, A. Neu), Ludwigshafen; Kreiskrankenhaus (L.M. Ahlemann), Lüdenscheid; Evangelisches Krankenhaus (C. Winkelmann), Lutherstadt Wittenberg; Otto-von-Guericke-Universit?t (A. Franke, G. Gademann), Magdeburg; Klinikum (H. Bodenstein), Praxis für Strahlentherapie (A. Junker), Minden; Kliniken Maria Hilf (I. Stumpfe, J. Hoffmanns), H?amtologisch/Onkologische Praxis (U. Grabenhorst), M?nchengladbach; Evangelisches Krankenhaus (J. Freise, P. Schuster), St Marienhospital (M. Schweickert), Mülheim; Universit?ts-Klinikum Gro?hadern (N. Lang, R. Wilkewski), München; Universit?ts-Klinik (P. Koch, G. Reinartz, J. Brockmann), Franziskus-Hospital (A. Bremer), Onkologische Fachpraxis (J. Wehmeyer), Münster; Klinikum Neubrandenburg (H.-U. Brand), Neubrandenburg; Lukas-Krankenhaus (W.D. Maier, H. Grauthoff), Neuss; H?matologisch/Onkologische Fachpraxis (S. Detken), Northeim; Klinikum Oldenburg (F. del Valle; M. Schmidt-Lauber), Pius-Hospital (A. Temmesfeld, H. Clasen), Oldenburg; Paracelsus-Klinik (O.M. Koch, W. Wagner), Osnabrück; Brüderkrankenhaus St Josef (G. Lubinski-de Lange), Paderborn; Klinikum Südstadt (P. Ketterer), Universit?tsklinik (M. Freund, R. Fietkau), Rostock; Martin-Luther-Krankenhaus (G. Paetzmann), Schleswig; Klinikum Schwerin (R. Subert, S. Knaack), Schwerin; St. Marien-Krankenhaus (P. Fritz), Siegen; Johanniter-Krankenhaus (G. Müller; J. Bahnsen), Stendahl; Diakonissenkrankenhaus (J. Kaesberger), Stuttgart; Klinikum Traunstein (I. Kleff, H.-G. Biedermann), Traunstein; Mutterhaus der Borrom?erinnen (M.R. Clemens; E. Freitag), Krankenhaus der Barmherzigen Brüder (H. Kirchen), Trier; St. Marienhospital (J. Diers), Praxis für Strahlentherapie (C. Stallmann), Vechta; Müritz-Klinikum (K. Knieling), Waren; Asklepios-Kreiskrankenhaus (A. Bornschein), Wei?enfels; Harz-Klinikum (G. Wilhelm), Praxis für Strahlentherapie (D. Haessner), Wernigerode; and Heinrich-Braun-Krankenhaus (U. Zschille, J. St?ltzner), Zwickau, Germany.
The following are members of the review board for German lymphoma studies: A.C. Feller (Lübeck); M.-L. Hansmann (Frankfurt); P. M?ller (Ulm); H.K. Müller-Hermelink (Würzburg), R. Parwaresch (Kiel), and H. Stein (Berlin).
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank M. Bertels for her excellent secretarial assistance.
NOTES
Supported by Amgen and Hoffmann-LaRoche AG, Germany.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Koch P, del Valle F, Berdel WE, et al: Primary gastrointestinal non-Hodgkin's lymphoma II: Combined surgical and conservative or conservative management only in localized gastric lymphoma—Results of the prospective German multicenter study (GIT NHL 01/92). J Clin Oncol 19:3874-3883, 2001
Koch P, del Valle F, Berdel WE, et al: Primary gastrointestinal non-Hodgkin's lymphoma I: Anatomical and histological distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study (GIT NHL 01/92). J Clin Oncol 19:3861-3873, 2001
Lewin KJ, Ranchod M, Dorfman RF: Lymphomas of the gastrointestinal tract: A study of 117 cases presenting with gastrointestinal disease. Cancer 42:693-707, 1978
Isaacson PG, Spencer J, Wright DH: Classifying primary gut lymphomas. Lancet 2:1148-1149, 1988
Stansfeld AG, Diebold J, Noel H, et al: Updated Kiel classification for lymphomas. Lancet 1:292-293, 1988
Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994
Van Krieken JH, von Schilling C, Pluin PM, et al: Splenic marginal zone lymphocytes and related cells in the lymph node: A morphologic and immunohistochemical study. Hum Pathol 20:1225-1227, 1989
Stein K, Hummel M, Korbjuhn P, et al: Monocytoid B cells are distinct from marginal zone cells and commonly derive from unmutated naive B cells and less frequently from postgerminal center B cells by polyclonal transformation. Blood 94:2800-2808, 1999
Musshoff K, Schmidt-Vollmer H: Prognosis of non-Hodgkin's lymphomas with special emphasis on the staging classification. Z Krebsforsch 83:323-341, 1975
Hermanek P, Scheibe O, Spiessl B, et al: (eds): TNM Classification of Malignant Tumors. New York, NY, Springer, 1992
Bagley CM, DeVita VT, Berad CW, et al: Advanced lymphosarcoma: Intensive cyclical combination chemotherapy with cyclophosphamide, vincristine, and prednisone. Ann Intern Med 76:227-234, 1972
Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253, 1999
Maor MH, Velasquez WS, Fuller LM, et al: Stomach conservation in stages IE and IIE gastric non-Hodgkin's lymphoma. J Clin Oncol 8:266-271, 1990
Jaffe ES, Harris NL, Stein H, et al: (eds): World Health Organization Classifications of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001
Gatter KC, Warnke RA: Diffuse large B-cell lymphoma, in Jaffe ES, Harris NL, Stein H, et al (eds): World Health Organization Classifications of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001, pp 171-174
Cogliatti SB, Schmid U, Schumacher U, et al: Primary B-cell gastric lymphoma: A clinicopathological study of 145 patients. Gastroenterology 101:1159-1170, 1991
Radaszkiewicz T, Dragosics B, Bauer P: Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue: Factors relevant to prognosis. Gastroenterology 102:1628-1638, 1992
Koch P, Berdel WE, Willich N, et al: Grading in marginal-zone lymphomas. J Clin Oncol 18:2788-2789, 2000
Crump M, Gospodarowicz M, Shepherd FA: Lymphoma of the gastrointestinal tract. Semin Oncol 26:324-337, 1999
Sonnen R, Calavrezos A, Grimm HA, et al: Kombinierte konservative behandlung von lokalisierten magenlymphomen. Dtsch Med Wochenschr 119:863-868, 1994
Schmidt W-P, Schmitz N, Sonnen R: Conservative management of gastric lymphoma: The treatment option of choice. Leuk Lymphoma 45:1847-1852, 2004
Mera K, Ohtsu A, Nakamura S, et al: Non-surgical treatment for localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma: Preliminary results of a multicenter prospective study in Japan. J Clin Oncol 22:572S, 2004 (suppl 14S)
Avilés A, Nambo MJ, Neri N, et al: The role of surgery in primary gastric lymphoma: Results of a controlled clinical trial. Ann Surg 240:44-50, 2004
Aviles A, Nambo MJ, Neri N, et al: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: Results of a controlled clinical trial. Med Oncol 22:57-62, 2005
Aisenberg AC: Malignant Lymphoma: Presentation, Natural History, and Treatment. Malvern, PA, Lea & Febiger, 1991
Schechter NR, Portlock CS, Yahalom J: Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 16:1916-1921, 1998
Tsang RW, Gospodarowicz M, Pintilie M, et al: Stage I and II MALT lymphoma: Results of treatment with radiotherapy. Int J Radiat Oncol Biol Phys 50:1258-1264, 2001(Peter Koch, Andreas Probs)
Department of Gastroenterology, Zentralklinikum, Augsburg
Department of Hematology/Oncology, Municipal Clinic, and Department of Radiation Oncology, Pius-Hospital, Oldenburg
Departments of Medicine –Hematology and Oncology–and of Radiation Oncology, Ernst-Moritz-Arndt-Universit?t, Greifswald
Departments of Medicine –Hematology and Oncology and Radiation Oncology–Universit?t Rostock
Departments of Medicine –Hematology and Oncology, and Radiation Oncology, Universit?t des Saarlands, Homburg
Department of Radiation Oncology, Mutterhaus der Borrom?erinnen, Trier
Department of Radiation Oncology, Charité, Berlin
Lymph Node Registry at the German Society of Pathology, Department of Hematopathology, Universit?t von Schleswig-Holstein, Campus Kiel, Kiel, Germany
ABSTRACT
PURPOSE: In the prospective study 02/96 on primary GI lymphoma, we have collected data on histology, clinical features, and treatment results. In particular, in stages I and II localized primary gastric lymphoma (PGL), our objectives were to reduce treatment intensity and to confirm our hypothesis from study 01/92, which maintained that an organ-preserving approach is not inferior to primary surgery.
PATIENTS AND METHODS: Patients receiving radiotherapy and/or chemotherapy were stratified for histologic grade, stage, and whether surgery had been carried out or not (as decided by each participating center). Patients with aggressive PGL received six cycles of CHOP-14 (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by involved-field radiotherapy (40 Gy). Patients with indolent PGL (including patients experiencing treatment failure with antibiotic therapy for Helicobacter pylori) were treated with extended-field radiotherapy. The volume depended on stage. The irradiation dose was 30 Gy, followed by a boost of 10 Gy (the latter omitted after complete resection) to the tumor region.
RESULTS: Seven hundred forty-seven patients were accrued. Of these patients, 393 with localized PGL were treated with radiotherapy and/or chemotherapy only or additional surgery between December 1996 and December 2003. The survival rate at 42 months for patients treated with surgery was 86% compared with 91.0% for patients without surgery.
CONCLUSION: In this nonrandomized study (02/96), we reproduced the previous results of study 01/92 showing no disadvantage for an organ-preserving treatment. Therefore, primary stomach resection should be questioned.
INTRODUCTION
The inclusion of surgery, in contrast to an organ-conserving approach, in the treatment strategy for localized primary gastric lymphomas (PGL) has been controversial and extensively discussed in the literature. This discussion is reflected in the publications by Brands et al1 and de Jong et al.2 Only therapy with antibiotics for Helicobacter pylori–positive marginal-zone B-cell lymphoma (MZCL) in stage I has been accepted as standard.3,4
Although until recently data in the literature had been based on retrospective studies and analyses, in 2000, the first major prospective study on PGL was published by Fischbach et al,5 with the conclusion that resection remained the treatment of choice. Because our nonrandomized study (German Multicenter Study Group GIT NHL 01/92) comparing a conservative treatment approach with one including complete or partial resection of the stomach showed no advantage for surgery and because preliminary analysis of our second study (GIT NHL 02/96) seemed to confirm these earlier results, we expressed considerable doubts about the significance of surgery in treating PGL.6
The aim of GIT NHL 02/96 was to collect further data, such as histology, anatomic distribution, clinical features, and treatment results, in primary GI lymphomas.7 Because the numbers in advanced PGL and in intestinal lymphoma were too small to draw any conclusions, there was no change in treatment strategy in these entities. On the basis of the published data in localized PGL,6 we changed the objectives, first, to reduce the intensity of treatment without compromising results obtained in study 01/92 and, second, to confirm our hypothesis that surgery could be omitted because a stomach-conserving approach would improve the quality of life in PGL patients considerably. This report provides an interim analysis on 393 patients with localized PGL.
PATIENTS AND METHODS
Patients
This study was started on December 1, 1996, and was closed January 2004. Participating centers throughout Germany (see Appendix) reported every patient 18 years or older with a primary GI non-Hodgkin's lymphoma (NHL), which was defined according to Lewin et al.8 A patient had to present with GI symptoms of or have predominant lesions in the GI tract. There was no upper age limit. To allow a follow-up period of at least 6 months for this analysis, only patients with PGL in stages I and II, whose date of diagnosis was no later than December 1, 2003, were selected from the study cohort for this report. Furthermore, patients qualifying for primary antibiotic treatment of Helicobacter pylori (MZCL, stage I; H pylori positive) were included only after experiencing failure of the eradication.
This study was approved by the Ethics Committee of the University of Münster and by local ethics committees of the other participating centers. Written informed consent was obtained from all patients. According to the study protocol, patients who presented with second malignancies and/or had missing confirmation of histologic subtype by the central pathology review board and/or had comorbidity prohibiting adequate therapy were excluded from the evaluation of treatment.
Diagnostic and Staging Procedures
The diagnostic work-up included patient history and physical examination, blood work (such as lactate dehydrogenase [LDH], liver enzymes, alkaline phosphatase, creatinine, electrophoresis, immunoglobulins, and RBC and WBC counts), chest x-ray, radiologic and endoscopic evaluation with multiple biopsies of the upper and lower GI tract, computed tomography of the chest and abdomen, abdominal ultrasound evaluation, bone marrow biopsy, and examination of Waldeyer's ring. Endoscopic ultrasound was carried out in most patients.
Formalin-fixed biopsies were reviewed in most cases by the central pathologic board of the study (M.T. and R.P.), according to the classification by Isaacson et al9 and the revised Kiel classification.10 The biopsies were later reclassified according to the Revised European-American Lymphoma classification.11 Reviews of other hematologic pathologists collaborating in the review panel for German lymphoma studies were also accepted (see Appendix). Each biopsy was investigated immunohistochemically by staining for CD20 and CD3. Additionally, marginal-zone phenotype was proven by Ki-B3 negativity.12,13 Polymerase chain reaction–based amplifications of genes for immunoglobulin heavy chain or T-cell receptor chain were added to show monoclonal disease.
Patients were staged according to the Ann Arbor classification in its modification by Musshoff et al.14 In cases of tumor resection, the extent was analyzed retrospectively by one of the authors (J.B.) based on operating sheets and histopathologic certificates according to the International Union Against Cancer.15
Study Design and Treatment Strategy
Given the accrual rate of our study 01/92,7 the study committee decided against a randomized trial because expected numbers would not be sufficient for a valid statistical analysis. The decision to include surgery in the treatment strategy was left to each participating center, although patients were also accepted who underwent lymphoma resection and, only afterwards, were referred to a study center.
Patients who received radiotherapy and/or chemotherapy was stratified according to histologic grade of the lymphoma, stage of disease, and whether or not surgery had been carried out. In cases of primary surgery, further treatment was stratified according to the grade of resection (R0 v R1 or R2).
Indolent lymphomas. Operated patients with stage I disease received no further treatment after complete resection of the tumor (R0) and were just observed. Patients with microscopic (R1) or macroscopic (R2) rest in stage I were treated with reduced extended-field irradiation (instead of whole abdomen radiation, as in our first study6) to the upper and middle part of the abdomen, with the lower border of the treatment field including the fifth lumbar vertebra (30 Gy + 10 Gy boost to R1 or R2 regions). After complete resection (R0), patients with stage II disease received reduced extended-field irradiation (30 Gy), whereas after R1 or R2 resection, the target volume was the whole abdomen (30 Gy) followed by a boost irradiation of 10 Gy to the tumor region (but no mediastinal field, as in our first study). In nonoperated patients, the size of the extended field was also reduced to the upper and middle part of the abdomen (the lower border of the fifth lumbar vertebra) in stage I patients and was the total abdomen in stage II patients (30 Gy). The tumor region received a boost of 10 Gy.
Aggressive lymphomas (including all T-cell lymphomas). For all stages, patients received six cycles of CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [maximum 2 mg]) on day 1 and prednisone 100 mg on days 1 to 516 every 2 weeks (the number of cycles was reduced to four only after complete resection in surgically treated patients). If this regimen proved not to be feasible in time, filgrastim was administered after each cycle. Chemotherapy was followed by involved-field radiotherapy to the upper part of the abdomen with 40 Gy (or 30 Gy in case of complete resection).
Follow-Up and Statistical Analysis
Restaging after completion of treatment included diagnostic endoscopy and biopsies of the primarily involved site, including endoscopic ultrasound where available, abdominal and pelvic computed tomography scan and/or ultrasound, chest x-ray, blood work as described earlier, and clinical examination and patient history. Follow-up evaluations consisted of history, physical examination, chest x-ray, endoscopy, and abdominal ultrasound. Additional tests were carried out if necessary. Patients were examined every 3 months for at least 2 years and twice a year thereafter.
The date of this analysis was February 4, 2005. Response criteria and end points are reported according to published guidelines.17 Survival was measured from the first day of treatment; end points were defined as follows. Event-free survival (EFS; patients in complete or partial remission) was defined as time from first day of treatment to any failure or death from any cause. Overall survival (OS; all patients) was defined as time from first day of treatment to death from any cause. Cause-specific survival (CSS; all patients) was defined as time from first day of treatment to death either related to NHL or associated with treatment. Patients in remission or alive, depending on the kind of survival analysis, were censored at the last known date of follow-up evaluation and shown as tick marks on the survival curves. Survival fractions were calculated using the Kaplan-Meier product-limit method. The log-rank test was used for comparing survival curves. P values were calculated two tailed. GraphPad Prism version 3.0 (GraphPad, San Diego, CA) was used as the software.
RESULTS
Patient Characteristics, Stage, and Histology
December 1996 to February 2004, 747 patients with primary GI lymphomas were accrued to the study by medical, surgical, and/or radiotherapeutic departments throughout Germany (see Appendix). Of this cohort, all 520 patients with stages I and II PGL who were diagnosed before December 1, 2003 were selected to allow a follow-up period of at least 6 months after finishing treatment.
Fifty-seven patients were excluded from assessment of treatment according to the study protocol for the following reasons: preceding malignancies (n = 38), no confirmation of histologic subtype by the review board (n = 7), and comorbidity not allowing scheduled therapy (n = 12). A further 10 patients could not be evaluated because of their refusal of any treatment (n = 4), death before onset of treatment (n = 1), and treatment by monoclonal antibody because of patient decision (n = 2). Three patients were not correctly stratified for treatment. Fifty-five patients were treated successfully by antibiotics to eradicate H pylori.
Thus, 398 patients were available for this analysis of treatment results, which was carried out on an intent-to-treat basis. No patients were excluded because of treatment violation. Within this group, the following two cohorts can be differentiated: 335 patients received just conservative management (CM), whereas 63 patients underwent primary surgery followed by CM (S/CM); 60 of the S/CM patients were referred to a study center after surgery, and only three were recruited by a participating surgical clinic.
The median age of the patients was 63.2 years (range, 20.8 to 83.1 years), and 9.3% were older than 75 years. The female (n = 178) to male (n = 220) ratio was 1:1.2. The Karnofsky performance status was 90% (n = 136) or 100% (n = 197) in 90% of the patients. Serum LDH was elevated in only 61 patients (15.3%). In approximately 78% the patients, disease was limited either to the stomach (n = 229) or spread included only paragastric lymph nodes (n = 83). These data are listed in Table 1 and differentiated for patients after CM and S/CM. In most S/CM patients, the data on LDH and Karnofsky performance status were obtained after surgery. The higher percentage of stage II patients in the surgical cohort is a result of upstaging by laparotomy compared with noninvasive diagnostic procedures, as reported earlier by Maor at al.18
The distribution of histologic subtypes is displayed in Figure 1. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBCL]) accounted for the majority of PGL (59.5%). In 18.1% of DLBCL, a simultaneous small-cell component was demonstrated (43 of 237 patients); these lymphomas were classified by Isaacson et al9 as high-grade B-cell lymphoma of mucosa-associated lymphoid tissue with evidence of low-grade component. This subtype has no real equivalent in the Revised European-American Lymphoma classification11 or in its successor, the WHO classification,19 but it was subsumed to DLBCL and equated with other secondary DLBCL.20 However, two publications from the early 1990s by two pathologic groups stressed the importance of differentiation of so-called secondary high-grade lymphomas (SHGL).21,22
The actual frequency of SHGLs remains unclear because their diagnosis is highly dependent on the method by which the histopathologic specimens were obtained. The proportion of SHGLs in this study was 17.6% in resected lymphomas compared with 9.6% in endoscopic biopsies. This coexistence of large and small cells has been the rationale for a combined chemotherapy and radiotherapy approach in DLBCL within our study group.23,6
Extranodal MZCL (ie, low-grade lymphoma of mucosa-associated lymphoid tissue type9) accounted for 37.9% of lymphomas. Follicular and mantle-cell lymphomas were diagnosed in only a few patients, and there were only five T-cell lymphomas.
Histologic subtypes and their distribution according to stage are listed in Table 2. Survival rates are listed in Table 3, and the related survival curves are displayed in Figures 2 and 3.
Treatment
Three hundred ninety-three patients (excluding T-cell NHL) were evaluated for treatment; 84.3% of patients received CM (n = 332), and 61 patients (15.5%) received S/CM. Further analysis demonstrated that only three S/CM patients were accrued by a surgical study center that obviously preferred this approach for PGL. The remaining 58 patients were referred to a study center after complete or partial resection outside the study group. The median time of observation (MTO) was 42 months (range, 0.07 to 97.4 months), starting from the first day of treatment. As of the date of this analysis, 68 primary events (defined as progression, relapse, or death from any cause) have occurred.
Seven patients (none after surgery) had progressive disease. Only one patient responded to salvage therapy (high-dose chemotherapy with stem-cell transplantation) after progression and is still alive at 45 months after the second treatment. In six patients, the histologic diagnosis was DLBCL. In one patient with a primary MZCL, progression occurred immediately after the end of radiotherapy, and a DLBCL was diagnosed, suggesting an initial primary SHGL. LDH was elevated in two of seven patients. All but two patients had stage II disease.
In conservatively treated patients, 17 patients (5.1%) experienced relapse, with salvage therapy being successful in 13 patients. DLBCL (including SHGL) occurred at a higher frequency than MZCL (11 and six patients, respectively). LDH was elevated in four DLBCL patients. After surgical treatment, eight patients (six DLBCL patients) relapsed (13.1%); three are still alive after salvage therapy. Details of age, histologic subtype, and level of LDH are listed in Tables 4 and 5.
Death related to treatment or late effects occurred in 11 patients (two after surgery). A further 25 patients died from other causes after a median time of 40.8 months (range, 2.4 to 85.0 months).
Because there are no significant differences in the survival curves of patients with DLBCL and patients with additional small-cell components (Figs 2 and 3), both were grouped together comparing aggressive and indolent lymphomas. OS for combined stages I and II is shown in Figure 4. There was no significant difference between both subtypes under the chosen treatment strategy. Survival rates at the MTO (ie, 42 months) according to patient characteristics are listed in Table 6.
In CM patients, age greater than 60 years was not a prognostic factor for EFS, but it was for OS because death from other causes influenced this age group more. A Karnofsky performance status less than 100% influenced both EF and OS. The influence of LDH was only marginal for OS. EFS was statistically worse in stage II patients. Probably because of observation time, this could not be shown for OS. In S/CM patients, no parameter influenced OS. Because LDH and performance status were documented mainly 2 to 4 weeks after surgery, the results for EFS have to be looked at with caution. The survival curves for both treatment groups are displayed in Figures 5 (CM) and 6 (S/CM). Because of the number of deaths not related to lymphoma or its treatment, CSS was also calculated.
DISCUSSION
Many single reports and reviews1,24 on the appropriate treatment strategy for PGL favored the inclusion of primary resection as first choice of treatment. This view was supported by the publication of the first major prospective study on PGL by Fischbach et al,5 which accrued sufficient numbers of patients to generate convincing results. With a median follow-up time of 17.5 months, the reported survival rates at 2 years from 89% to 96% for low-grade lymphomas ranged and from 83% to 88% for high-grade lymphomas. Nevertheless, the authors concluded their discussion with the comment that only by means of a randomized study could final recommendations for the best treatment strategy be reached.
When designing our first study GIT NHL 01/92, the study committee decided against a randomization because they were confronted with the conflicting opinions of physicians on the importance of surgery, which would endanger sufficient accrual of patients. Instead, we decided on a study design with two nonrandomized treatment arms. The reported results showed no advantage for either approach after 55 months of MTO, which, at that time, led to our assumption that a stomach-conserving approach might be favored, although a bias towards selecting patients had to be kept in mind.6 In addition, our data were not inferior to those published by Fischbach et al.5
Early analysis of study 01/92 encouraged a follow-up study design, which again was not randomized because the statistical test would be on equivalence, demanding an accrual rate that could not be reached in reasonable time. Instead, the following two aims were formulated. First, we wanted to reduce treatment intensity to improve quality of life for the patients without compromising the results achieved so far. This was done by reducing toxicity by using antibiotic treatment of H pylori for qualified patients (MZCL stage I patients; positive proof of H pylori) and by carefully reducing the chemotherapy and/or radiation fields. Although this goal seems to be reached in our interim analysis, a detailed report of these data would be too early because, in our opinion, an MTO of at least 4 years after the closure of the study is required, especially for indolent lymphoma. However, the second goal, which was to confirm our hypothesis that surgery offers no advantage in treating PGL patients, has been reached. The results of study 01/92 (MTO, 96 months) could be reproduced, even though there was no upper age limit in study 02/96 (age limit of 75 years in 01/96) and treatment intensity was reduced, especially in indolent lymphomas (Fig 7).
Thus, the results of an organ-preserving approach are not inferior to the data reported by Fischbach et al,5 when surgery was the primary goal. The same is the case for the S/CM cohorts in our two consecutive studies (Fig 7). In addition, the data by Sonnen et al,25 which were published primarily in 1994, were updated after 10 years.26 In this likewise nonrandomized comparison, the authors saw no difference between S/CM and CM, reporting failure-free survival rates of 93% and 91%, respectively, and a disease-free survival rate of 93% for both groups at 5 years. The safety of an organ-preserving treatment in stage I and II MZCL alone either by eradication of H pylori or by radiation was stressed by the results of a prospective study presented at the 40th Annual Meeting of the American Society of Clinical Oncology.27 In a randomized study on gastric DLBCL by Avilés et al,28 results after chemotherapy or combined surgery and chemotherapy (10-year survival rates, 96% and 91%, respectively; not significant) were significantly superior (P < .001) to surgery alone (10-year survival rate, 54%) or surgery in combination with radiotherapy (10-year survival rate, 53%).The same authors also published their treatment results in MZCL of the stomach after surgery, chemotherapy, or radiotherapy, with no difference in survival rates at 10 years.29
In his monograph on malignant lymphoma, Aisenberg30 stated in 1991 that, for treating gastric lymphoma, "until definitive data from multi-institutional studies become available, many treatment decisions must be based on common sense and prior nonrandomized, retrospective experience." These studies are now available. Three are prospective nonrandomized studies, but comparing the results, no advantage for primary resection in PGL could be demonstrated. In addition, two randomized studies published by Avilés et al28,29 confirmed our hypothesis that surgery could be omitted from treatment of PGL.6
As a result of these considerations, the main competing study groups in Germany joined together as the German Study Group on Gastrointestinal Lymphoma (DSGL), whose first protocol DSGL 01/2003 addresses improvements in conservative treatment for localized PGL by carefully reducing treatment intensity in two ways. First, for H pylori–negative MZCL, there is a consequent further reduction of radiation volume to involved field, which has been advocated before but based on small numbers only (17 and 15 patients).31,32 Second, for gastric DLBCL patients in the current study, CHOP chemotherapy was reduced from six to four cycles in combination with rituximab followed by involved-field radiotherapy. Another goal is to collect enough data to look for prognostic factors, which have yet to be formulated for CM in PGL. Our newly founded study group recommends surgery only when perforation, bleeding, or obstruction occur, which cannot be managed by conservative treatment.
Appendix
The following individuals and centers participated in the study: Klinik für Strahlentherapie der Universit?t (R. Mager), Luisenhospital (W. Berges), Aachen; St Franziskus-Hospital (E. Jacobi), Ahlen; Klinikum St Marien (L. Fischer von Weikersthal, W. Berberich), Amberg; St Nikolaus-Stiftshospital (A. Steinmetz), Andernach; Marienhospital (F.-J. Altenwerth), Arnsberg; Zentralklinikum (P. Probst; A.-C. Voss), Augsburg; Kreiskrankenhaus (D. Unverferth, F. Püschel), Aurich; Stadtkrankenhaus (J. Gensicke), Bad Arolsen; Gemeinschaftspraxis (P. Harms), Bad Oeynhausen; Humaine Klinikum (D. Schultze, P. Nowakowski), Bad Saarow; St Elisabeth-Hospital (N. Nikolaides) Beckum; Helios-Klinikum/Robert-R?ssle-Klinik (Th. Benter), Universit?tsklinikum Charite (O. Sezer, M. Hinkelbein), Helios-Klinikum/Buch (T. Gottstein), H?matologisch/Onkologische Fachpraxis (A. Kirsch), Berlin; Franziskus-Hospital (F. Jentsch, B. Angrick), St?dtische Kliniken (J. Feldkamp, P. Hirnle), Bielefeld; Medizinische Universit?ts-Poliklinik (S. Fronhoffs), Bonn; Marienhospital (E. Musch), Bottrop; ZKH Bremen-Nord (B. Rühlmann), Ev. Diakonie-Krankenhaus (K.-H. Pflüger), ZKH, Klinik für Strahlentherapie (S. Staar) Bremen; Lukas Krankenhaus (F. M?ller-Fa?bender), Bünde; Allgemeines Krankenhaus (F. Marquard, D. Schnalke), Celle; St-Vincenz-Hospital (Th.Y. Padel), Coesfeld; Kreiskrankenhaus (W. Thier), Dormagen; St-Johannes-Hospital (M. Nahler), Knappschafts-Krankenhaus (H.-G. Wehmeyer), Dortmund; Marien-Hospital (A. Schütte), Düsseldorf; Hans-Susemihl-Krankenhaus (H. Becker), Emden; St-Antonius-Hopital (R. Fuchs), Eschweiler; Universit?tsklinikum (M. Engelhard), Alfried-Krupp-Krankenhaus (F. Guntrum), Kliniken Essen-Mitte (M. Stahl), Ev.Krankenhaus Lutherhaus (C. Ko?ler-Wiesweg), Kliniken Essen Süd (C. Tirier), Essen; Diakonissenkrankenhaus (T. Koch), St Franziskus-Hospital (H.-J. Brodersen, S. Hartwigsen), Flensburg; Evangelisches Diakoniekrankenhaus (U. Brand), Onkologische Schwerpunktpraxis (N. Marschner), Freiburg; St?dtisches Klinikum (H.-G. H?ffkes, H. H?u?ler-Mischlich), Fulda; Georg-August-Universit?t (W. Jung, H. Schmidtberger, T. Armbrust), G?ttingen; E.-M.-Arndt-Universit?t (C. Hirt, R. Breitsprecher), Greifswald; Internistische Gemeinschaftspraxis (E. Eschenburg), Güstrow; Fachpraxis H?atologie/Onkologie (S.B. R?sel), Gütersloh; St Salvator-Krankenhaus (I. Hausbrandt, U. Schippan), Halberstadt; Krankenhaus St Elisabeth/St Barbara (E. Fa?hauer), M.-Luther-Universit?t (I. Kühne, J. Dunst), Praxis für Strahlentherapie (C. Eckstein), Halle; Allgemeines Krankenhaus Altona (D. Braumann), Allgemeines Krankenhaus St Georg (R. Sonnen; M. Busch), Praxis für Strahlentherapie (D. Carstens), Hamburg; St Marien-Hospital (R. Jany, H. Dürk), Fachpraxis H?matologie/Onkologie (H. Weischer), St Barbara Klinik (W. Frontzek), Hamm; St?dtisches Krankenhaus Siloah (H. Kirchner, A. Wildfang), Henriettenstiftung (F. Glüer-Fuchs), Praxis für Strahlentherapie (W. Brenneisen), Hannover; H?mato/Onkolog. Fachpraxis (W. Grimm), Harrislee; Praxis f. Strahlentherapie (A. Lüddeke), Hildesheim; Universit?tskliniken des Saarlandes (R. Schmits, C. Rübe, C. Moser), Homburg/Saar; St?dtisches Klinikum (M. Haag, M.-L. Sautter-Bihl), Karlsruhe; St?dtische Kliniken (E.-U. Steinhauer), Kassel; Klinikum Kempten-Oberallg?u (O. Prümmer, U. Zimmerman), Kempten; Christian-Albrechts-Universit? (C. Pott, R. Bartsch, J. Schultze), Kiel; St-Antonius-Hospital (B. Reers, V. Runde), Kleve; St?dtisches Klinikum Kemperhof (H. Nolte, A. Schendera), Koblenz; Universit?t zu K?ln (M. Reiser; R.-P. Müller), St Elisabeth-Krankenhaus (J. Benz), Krankenhaus der Augustinerinnen (A. Tschenne), H?matolog./Onkolog. Fachpraxis (S. Schmitz), K?ln; St?dtische Kliniken (T. Frieling, U. Schulz), Krankenhaus Maria-Hilf (U. Peters), Krefeld; Klinikum Landshut (A. Holstege, H.-J. Wypior), Landshut; St?dtisches Klinikum (R. Jakobs, A. Neu), Ludwigshafen; Kreiskrankenhaus (L.M. Ahlemann), Lüdenscheid; Evangelisches Krankenhaus (C. Winkelmann), Lutherstadt Wittenberg; Otto-von-Guericke-Universit?t (A. Franke, G. Gademann), Magdeburg; Klinikum (H. Bodenstein), Praxis für Strahlentherapie (A. Junker), Minden; Kliniken Maria Hilf (I. Stumpfe, J. Hoffmanns), H?amtologisch/Onkologische Praxis (U. Grabenhorst), M?nchengladbach; Evangelisches Krankenhaus (J. Freise, P. Schuster), St Marienhospital (M. Schweickert), Mülheim; Universit?ts-Klinikum Gro?hadern (N. Lang, R. Wilkewski), München; Universit?ts-Klinik (P. Koch, G. Reinartz, J. Brockmann), Franziskus-Hospital (A. Bremer), Onkologische Fachpraxis (J. Wehmeyer), Münster; Klinikum Neubrandenburg (H.-U. Brand), Neubrandenburg; Lukas-Krankenhaus (W.D. Maier, H. Grauthoff), Neuss; H?matologisch/Onkologische Fachpraxis (S. Detken), Northeim; Klinikum Oldenburg (F. del Valle; M. Schmidt-Lauber), Pius-Hospital (A. Temmesfeld, H. Clasen), Oldenburg; Paracelsus-Klinik (O.M. Koch, W. Wagner), Osnabrück; Brüderkrankenhaus St Josef (G. Lubinski-de Lange), Paderborn; Klinikum Südstadt (P. Ketterer), Universit?tsklinik (M. Freund, R. Fietkau), Rostock; Martin-Luther-Krankenhaus (G. Paetzmann), Schleswig; Klinikum Schwerin (R. Subert, S. Knaack), Schwerin; St. Marien-Krankenhaus (P. Fritz), Siegen; Johanniter-Krankenhaus (G. Müller; J. Bahnsen), Stendahl; Diakonissenkrankenhaus (J. Kaesberger), Stuttgart; Klinikum Traunstein (I. Kleff, H.-G. Biedermann), Traunstein; Mutterhaus der Borrom?erinnen (M.R. Clemens; E. Freitag), Krankenhaus der Barmherzigen Brüder (H. Kirchen), Trier; St. Marienhospital (J. Diers), Praxis für Strahlentherapie (C. Stallmann), Vechta; Müritz-Klinikum (K. Knieling), Waren; Asklepios-Kreiskrankenhaus (A. Bornschein), Wei?enfels; Harz-Klinikum (G. Wilhelm), Praxis für Strahlentherapie (D. Haessner), Wernigerode; and Heinrich-Braun-Krankenhaus (U. Zschille, J. St?ltzner), Zwickau, Germany.
The following are members of the review board for German lymphoma studies: A.C. Feller (Lübeck); M.-L. Hansmann (Frankfurt); P. M?ller (Ulm); H.K. Müller-Hermelink (Würzburg), R. Parwaresch (Kiel), and H. Stein (Berlin).
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank M. Bertels for her excellent secretarial assistance.
NOTES
Supported by Amgen and Hoffmann-LaRoche AG, Germany.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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