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© 2001 American Society for Clinical Oncology 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 01/92ByFrom the Departments of Medicine, Hematology and Oncology, Radiation Oncology, and General Surgery, and Institute for Medical Informatics and Biomathematics, Westfälische-Wilhelms-Universität, Münster; Municipal Clinic, Department of Hematology/Oncology, and Pius-Hospital, Department of Radiooncology, Oldenburg; Department of Surgery, St-Antonius-Hospital, Kleve; Department of Medicine III–Großhadern, Ludwig-Maximilians-Universität, München; Department of Medicine/Gastroenterology and Oncology, Municipal Clinic, Dortmund; Departments of Medicine, Hematology and Oncology, and Radiation Oncology, Universität des Saarlands, Homburg; Departments of Gastroenterology and Radiation Oncology, Zentralklinikum, Augsburg; Department of Hematology/Oncology, Central Clinic, and Institute of Radiooncology, Minden; and Departments of Hematology/Oncology, Medical Clinic II, and Radiation Oncology, Christian-Albrechts-Universität, and Lymph Node Registry at the German Society of Pathology, Department of Hematopathology, Christian-Albrechts-Universität, Kiel, Germany. Address reprint requests to Peter Koch, MD, Medizinische Klinik A, Westfälische-Wilhelms-Universität, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany; email: prfkoch{at}aol.com
PURPOSE: The aim of the study was to obtain data on anatomic and histologic distribution, clinical features, and treatment results of patients with primary gastrointestinal non-Hodgkin’s lymphomas, particularly combined surgical and conservative treatment (CSCT) versus conservative treatment (CT) alone for primary gastric lymphoma (PGL) in localized stages. PATIENTS AND METHODS: Whether the treatment included surgery was left to the discretion of each participating center. Radiotherapy (Rx) and chemotherapy were stratified according to histologic grading, stage, and the inclusion or omission of surgery as follows: patients with low-grade PGL were treated with extended-field (EF) Rx (30 Gy). In case of residual tumor after surgery or in case of CT only (in stage IIE after six cycles of cyclophosphamide, vincristine, and prednisone), an additional boost of 10 Gy was given. All patients with high-grade PGL were treated with four (stage IE) or six (stage IIE) cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by EF Rx (stage IE) or involved-field (IF) Rx (stage IIE). Rx dosage corresponded to low-grade NHL. RESULTS: Between October 1992 and November 1996, 106 patients had CT only. The survival rate (SR) after 5 years was 84.4% and was influenced neither by patients’ characteristics nor by stage or histologic grade. Seventy-nine patients had CSCT. Their SR was 82.0%. Complete resection of the tumor (R0) was prognostic for the overall survival (P = .0165) as compared with incomplete resection. CONCLUSION: Although the study was not randomized, a stomach-conserving approach may be favored.
OPTIMAL MANAGEMENT of primary gastric lymphoma (PGL) in localized stages has been discussed in numerous reports in the literature over the past years. Whereas antibiotic treatment was quickly accepted for low-grade stage IE PGL of mucosa-associated lymphoid tissue (MALT) type following publications describing the regression of lymphoma after eradication of Helicobacter pylori,1-3 for the majority of PGL the discussion of resection or stomach preservation is still ongoing.4,5 Surgery, radiotherapy, and chemotherapy have been used alone or in various combinations. Although most authors stress the importance of tumor resection with or without additional therapy, this approach has been questioned in the last few years in favor of conservative treatment alone.6-13 The rarity of PGL (0.8 to 1.2 cases per 100,000 persons per year)14 led to mainly retrospective studies with only small patient numbers or studies that have been conducted over periods of up to two decades and more. They often are heterogeneous, combining different types of gastrointestinal lymphomas using varying histologic classifications, different staging systems, and different forms of therapy as detailed in part I of this report.15 It was to answer some of the open questions that we initiated a prospective multicenter study to accrue a maximum number of patients within as short a time as possible to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results for these diseases within a standardized diagnostic and therapeutic setting. This second part of the report addresses particularly the question of treatment results after combined surgical and conservative or conservative treatment alone for PGL patients in stages IE and IIE.
Patients Only patients with PGL in stages IE and IIE, registered from October 1992 through November 1996, were evaluated for this analysis; however, those with Burkitt’s or lymphoblastic lymphomas were excluded because of a completely different conservative treatment strategy. All patients were part of the cohort described before.15 PGL was defined according to Lewin et al16: patients had to present the symptoms of or have predominant lesions in the stomach. According to the study protocol for evaluation of treatment, patients who were older than 75 years and/or presented with second malignancies, had missing confirmation of histologic subtype by central review, or had comorbidity prohibiting protocol therapy were excluded from study.
Diagnostic and Staging Procedures Formalin-fixed specimens were reviewed by the central pathologic board of the study (M.T. and R.P.) according to the classification by Isaacson et al17 and the revised Kiel classification.18 Each biopsy was investigated immunohistochemically by staining for CD20 and CD3. Additionally, marginal-zone phenotype was proven by Ki-B3. Polymerase chain reaction–based amplifications of genes for immunoglobulin heavy chain or T-cell receptor gamma chain were added to show monoclonal disease. Patients were staged according to the Ann Arbor classification in its modification by Musshoff.19 In cases of tumor resection, the extent was analyzed retrospectively by two of the authors (B.R. and J.B.) based on operating sheets and histopathologic certificates according to the International Union Against Cancer.20
Study Design and Treatment Strategy Therefore, whether therapy included surgery and conservative or conservative management only was left to the discretion of each participating center. This decision was made for all patients at each clinic, although patients whose stomach was resected and who were referred afterwards to a study center were also reported by the participating clinics, and their data were included in the study. Radiotherapy and/or chemotherapy was stratified according to histologic grading, stage of disease and the whether surgery had been carried out or not as follows: Low-grade lymphoma. After resection, patients in stages IE and IIE were treated by extended-field radiotherapy (EF Rx) with total-abdominal irradiation (30 Gy) and, in case of residual tumor, by an additional boost (10 Gy). Without resection, patients in stages IE and IIE received EF Rx (30 Gy + 10 Gy boost). In addition, in stage IIE, six cycles of COP (cyclophosphamide 500 mg/m2 on days 1 to 5; vincristine 1.4 mg/m2 [maximum, 2 mg] on day 1; prednisone 100 mg/m2 on days 1 to 5)21 preceded Rx for reduction of tumor load. High-grade NHL. Conservative treatment was unaffected by whether a resection had been performed or not. In stage IE, four cycles of CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [maximum, 2 mg] each on day 1, plus prednisone 100 mg on days 1 to 5)22 were followed by EF Rx (30 Gy + 10 Gy boost on tumor or residue). Patients in stage IIE received six cycles of CHOP and additional involved-field Rx (40 Gy). Written informed consent was obtained from all patients, and the study was approved by the Ethics Committee of the University of Münster. The recruitment period for the study was activated in October 1992 and ended in November 1996.
Follow-Up and Statistical Analysis Survival was measured from the first day of treatment; end points were defined as follows23: event-free survival (EFS; patients in complete or partial remission) was measured until any failure or death from any cause; overall survival (OS; all patients) was measured until death from any cause. Cause-specific survival (CSS; all patients) was measured until death related to NHL or 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. For the calculation of CSS patients, who died by causes not related to NHL, treatment, or by suspected late toxicity, were censored at the date of death. Survival fractions were calculated using the Kaplan-Meier product-limit method. For comparing survival curves, the log-rank test was used. P values were two-tailed. GraphPad Prism, version 3.0 (GraphPad Software, Inc, San Diego, CA), was used as software.
Patients Characteristics, Stage, and Histology From October 1992 throughout November 1996, 277 patients with PGL were accrued to the study and treated by medical, surgical, and/or radiotherapeutic departments (see Appendix). Thirty-nine did not correspond to the criteria for this analysis, as they were in stages IIIE and IVE (n = 30) or had Burkitt’s or lymphoblastic lymphoma as histologic subtype (n = 9).15 For assessment of treatment, 45 patients were excluded according to the study protocol (age > 75 years, n = 20; nonconfirmation of histologic subtype, n = 9; second malignancies, n = 12; comorbidity, n = 4). Another eight patients could not be evaluated for the following reasons: treatment by eradication of H pylori outside the study protocol, n = 4; insufficient data, n = 4. Thus 185 patients could be analyzed for treatment results. No patients were excluded because of treatment violation. The analysis of treatment results was carried out on an intent-to-treat basis. Pain was the main symptom at time of presentation in 80.5% of the patients, followed by loss of appetite (46.5%) and loss of weight (23.2%). The latter was not considered a "B" symptom but as a consequence of pain and loss of appetite. Night sweats and/or fever occurred in 25 patients (11.9%) (Table 1). The median duration from onset of symptoms to the final diagnosis was 93 days.
The median age of the patients was 59.8 years. The female to male ratio was 1:1.3. More than 90% of the patients had a Karnofsky performance status of 90% or 100%. Elevated LDH, which is associated with a worse prognosis (at least in high-grade nodal NHL), was found in only 19 cases (10.2%). In more than half of the patients, the disease was limited to the stomach (stage IE), and in just 16.8%, more than regional lymph nodes were involved (stage II2E). Details are given in Table 2. Invading growth into neighboring organs was found in nearly 11% of the cases. It was more frequent in high-grade than in low-grade lymphomas (15.8% and 6.0%, respectively) (Table 3).
We were able to demonstrate that the recommendation by Musshoff et al24 to divide stage IIE into stage II1E (involvement of regional lymph nodes only) and stage II2E reflects a significant difference in EFS (P = .0016) as well as in OS (P = .0110) (Fig 1).
Low-grade MALT-type lymphoma (ie, marginal-zone lymphoma in the Revised European-American Lymphoma classification25) accounted for 44.3%. Only two cases with mantle-cell lymphoma were diagnosed. High-grade subtypes account for the majority of gastric lymphomas (54.6%), in which a simultaneous low-grade component (SLGC) showing the typical features of low-grade MALT-type lymphoma could be demonstrated in 31.7% of the cases (Fig 2). This indicates that they also originate in the marginal zone (secondary high grade).
The distribution of histologic subtypes according to stage is listed in Table 4. In contrast to nodal NHL, the majority of low-grade gastric lymphomas are in stage IE, whereas high-grade as well as secondary high-grade NHL show a higher fraction in stages II1E and II2E. They also have a higher tendency to invade neighboring organs as mentioned above (Table 3).
EFS in high-grade lymphoma with a SLGC in combined stages IE and IIE was significantly worse as compared with low- and high-grade NHL (P = .0011 and P = .0031, respectively), although there was only a trend concerning OS (P = .0864 and P = .3389, respectively) (Fig 3).
Treatment Conservative treatment only was performed in 106 patients, whereas for 79 patients, complete or partial resection in combination with radio- and/or chemotherapy was carried out. Histologically proven lymphoma was the indication to operate in 52 cases in centers, which had decided for surgery (65.8%). Other reasons were uncertain histology (n = 15), clinician’s assumption of malignant growth (n = 5), bleeding or perforation (n = 6), and ulcer (n = 1). The MTO was 52 months from the onset of treatment (range, 0 to 92 months). In patients alive, MTO was 56 months, with a range of 10 to 92 months. Thirty-four primary events, defined as progression, relapse, or death owing to any cause, have been observed. Progressive disease occurred in three patients, who responded to no other therapy. Thirteen patients experienced relapse, but salvage therapy was successful in 10 cases. Eighteen patients died. An independent review (M. Engelhard and C. Tirier) considered 11 deaths related to treatment (during or within 8 weeks after therapy) or late effects (up to 4 years after therapy), whereas in seven patients, other causes were obvious (second malignancies, n = 2; cardiac dysfunctions, n = 4; status asthmaticus, n = 1; occurrence 30.4 to 57.9 months after end of treatment). Only one patient died after perforation during chemotherapy. There were no major complications caused by bleeding. There was a striking difference in the pattern of relapse depending on whether surgery had been performed or just conservative treatment. After partial or complete resection, three of six patients had a systemic relapse, two of six had a local recurrence, and in one patient, there was a nodal relapse. Three relapses were fatal. In conservatively treated patients, seven lymphomas relapsed locally, and salvage treatment, which consisted of eradication of H pylori, administration of chlorambucil, or surgery, was successful in all cases. The median time in second complete remission (CR) for relapsed conservatively treated patients was 1,316 days (range, 219 to 1,996 days; one patient died after 219 days in CR during dialysis). Survival curves of both treatment groups are displayed in Figs 4 and 5. Survival proportions at 5 years according to patients’ characteristic are listed in Table 5. In conservatively treated patients, neither age more than 60 years, performance status, elevated LDH, stage, nor histologic grading influenced EFS or OS. In patients treated by surgery, age over 60 years influenced EFS negatively (P = .0189). Karnofsky performance status of less than 100% (stated 2 to 4 weeks after surgery) and elevated LDH were both predictive for EFS and OS (Table 5).
The extent of tumor resection also proved to be prognostic. After complete resection (R0), the survival proportions for EFS and OS at 5 years were both 91.5% (SEM, 4.1) as compared with 68.8% (SEM, 9.4) in EFS and 91.5% (SEM, 8.8) in OS after incomplete resection (Fig 6). Adjusting this analysis for histologic subtypes, the results in part had just a borderline significance because of small subsets.
Because the median age in patients with PGL was 59.8 years, we also evaluated the CSS, excluding all patients whose death was considered neither as being caused by the lymphoma nor related to the treatment. These exclusions were performed by an external review to avoid any bias. The last death to be registered in the conservative treatment group occurred after approximately 51 months following repeated surgery for perforations in the small bowel, which might be related to radiotherapy. In the group treated by combined surgical and conservative management, the last patient died after approximately 32 months because of progressive disease after relapse (Fig 7).
For the last 20 years, the question of the appropriate treatment strategy for PGL has generated many arguments and contradictory reports regarding whether surgery was still the first choice of treatment (see review in Crump et al5). Based on a questionnaire mailed to leading institutions interested in the management of PGL, de Jong et al4 came to the conclusion that hematologically oriented groups preferred conservative treatment (eight of 10), in contrast to gastroenterology-oriented groups, which were more inclined to choose a surgical approach (five of seven). Confronted with similar conflicting opinions in physicians, the writing committee of our study had decided to design two prospective studies within one rather than strive for a randomization between surgical and nonsurgical treatment strategies. Acceptance of this concept was quite satisfying, resulting in an accrual of 371 patients with primary gastrointestinal lymphomas as detailed in part I of this report.15 A total of 185 patients with gastric lymphoma in stages IE and IIE could be evaluated for treatment results. Their symptoms at diagnosis (Table 1), clinical features (Table 2), and histologic subtypes (Table 3) did not differ much from the whole cohort with PGL described in part I of this report.15 Only LDH was less elevated (10% as compared with 20%). Diagnosis of lymphoma by biopsy was possible in approximately 90% of the patients, although sometimes repeated endoscopies were necessary, and often the histologic subtype was determined only after consulting the central pathologic board of the study. That was the case especially when SLGCs in high-grade NHL were diagnosed according to the classification of Isaacson et al.17 In contrast, the diagnosis of a low-grade lymphoma overlooking simultaneous large cells occurred just three times. In the literature, correct diagnosis by endoscopic biopsy was reported in 98.5% in a single-center study26 as compared with 62% in a prospective multicenter study.7 To our knowledge, there is no published major prospective study applying the classification of Isaacson et al17 especially with regard to SLGCs in high-grade lymphomas, but this was done in two retrospective analyses based on resection specimens.27,28 Both studies reported a significantly higher survival rate (SR) at 5 years for low-grade lymphoma (91%27 and 71%,28 respectively) as compared with high-grade NHL (56%27 and 42%,28 respectively), although their results for patients with SLGC in high-grade lymphomas were contradictory. In the report by Cogliatti et al,27 the SR in these patients was 73% at 5 years, with no difference as compared with high-grade NHL at 10 years. In the publication by Radaszkiewicz et al,28 there was no difference in the SR between low- and secondary high-grade NHL. In our study, we saw no difference in SR of low- and high-grade lymphoma in EFS and OS (Fig 3), but EFS was significantly worse for patients with SLGCs in high-grade lymphomas, whereas for OS there was only a trend. An explanation for these divergent results might be nonuniform treatment strategies in the cited studies or a different grading system for secondary high-grade lymphomas. There is a demand for an exact classification.29,30 In the analysis of treatment results (Figs 4 through 7), the histologic subtype was disregarded for the following reasons: (1) we saw no influence in OS (Fig 4; Table 5), and (2) because in most cases the histologic diagnosis was made on biopsies, the rate of undetected SLGC in high-grade lymphomas remains questionable. EFS and OS in patients are shown in Fig 5 for stages IE and IIE. The SR at 5 years for the combined stages are 78.9% (SEM, 4.9; EFS) and 82.0% (SEM, 4.5; OS) (Table 5). These data are difficult to compare with the only other major prospective multicenter study published to our knowledge, because of different ways of reporting subgroups.7 Sano et al31 reported an SR at 5 years of 80.5% for stages IE and IIE in a single-center study, which is comparable to the results published in recent reviews.5,32 The results reported by Ruskoné-Fourmestraux et al7 underline the importance of a complete resection. For high-grade NHL, the 5-year OS was 100% after radical resection followed by chemotherapy as compared with 56% when the lymphoma was not resected or was incompletely resected. That confirms the review of the literature by Azab et al.33 In our study, the extent of resection was also prognostic. EFS and OS were significantly better after complete removal of the tumor (P = .0079 and P = .0165, respectively) (Fig 6). The SR at 5 years was 91.4% (SEM, 4.1).
In patients who underwent surgery, EFS and OS were significantly negatively influenced by age ( EFS and OS in patients after conservative treatment only are shown in Fig 4 for stages IE and IIE. The SR at 5 years for the combined stages is 78.7% (SEM, 4.6; EFS) and 84.0% (SEM, 4.2; OS) (Table 5). From a retrospective single-center study, an SR at 5 years of 92% was reported for the CSS, which is comparable to our data (Fig 7).9 Schechter et al34 treated low-grade lymphoma with radiation alone. At a median follow-up time of 27 months from completion of radiotherapy, EFS was 100%. The median age of our patients was 59.8 years at the time of diagnosis (range, 20.5 to 75.0 years). With a longer follow-up, death by causes other than lymphoma or treatment complication is to be expected. We therefore thought it justified to analyze the CSS of both treatment groups and excluded those patients as detailed above (Fig 7). The last death caused by lymphoma occurred after 14 months in the conservatively treated group and after 31 months in the patients treated by surgery and conservative approach, each after failure of salvage therapy. Another death, which happened after 51 months, was thought to be treatment-related. The patient developed a malabsorption-like syndrome approximately 12 months earlier and died after repeated operations for perforations of the small intestine. According to histologic subtypes, the last relapses occurred in high-grade, low-grade, and high-grade with SLGC after 11, 52, and 68 months, respectively. Although both treatment groups in our study were not randomized, we think with due caution that a comparison is justified. There were no differences in EFS or OS. If surgery is considered, one has to keep in mind that in patients whose lymphoma was not resected radically, prognosis is significantly worse than after conservative treatment only (P = .0364), and that the extent of resection can only be judged afterwards. On the other hand, relapses, which occurred after chemotherapy and/or radiation only, were localized in the stomach and therefore could be treated easier than in case of a systemic relapse. With respect to our data, the conservative treatment of primary gastric lymphoma is an alternative to the established and long-favored surgical approach. Comparing survival between patients who underwent surgery as part of their treatment strategy or were treated conservatively revealed no significant differences (P = .1796). However, because this is a nonrandomized study, results should be interpreted with due caution. Preserving the stomach is an improvement in quality of life for patients. In our follow-up study (GIT NHL 02/96), we tried to reduce toxicity on the one hand by introducing antibiotic treatment to eradicate H pylori and on the other by carefully reducing chemotherapy and/or radiation fields. Preliminary results in 179 assessable patients so far seem to confirm the data of this report. In the design of a third-generation study by the now combined German gastrointestinal study groups, surgery will not be routinely incorporated any longer but will be reserved for use in emergency situations, such as macroscopic bleeding or perforation.
Zentralklinikum (K. Füger, A. Probst), Krankenhauszweckverband (G. Jaenke), Augsburg; Kreiskrankenhaus (D. Unverferth), Aurich; Stadtkrankenhaus (P. Dravoj), Bad Arolsen; Paracelsus Klinik (H. Hohl), Bad Ems; Evangelisches Krankenhaus (R. Zahn), Bad Gandersheim; Gemeinschaftspraxis (P. Harms), Bad Oeynhausen; Vinzenz -Palotti-Hospital (S. Korsten), Bergisch Gladbach; Universitätsklinikum Charité (K. Possinger, S. Koswig), Robert-Rössle-Klinik (T. Benter), Berlin; Franziskus Hospital (B. Angrick, F. Jentsch, J.O. Jost), Städtische Kliniken (M. Sure), Städtische Kliniken Rosenhöhe (U. Junge), Bielefeld; St Josefs-Hospital der Universitätskliniken (M. Kißler), Bochum; Malteser Krankenhaus (A. Löffler), Universitätsklinik (H. Vetter), Bonn; Marienhospital (E. Musch), Bottrop; Kreiskrankenhaus Großburgwedel (C. Schönborn), Burgwedel; St Elisabeth-Stift (R.D. Schopen), Damme; Städtische Kliniken (K.-H. Funke), Delmenhorst; Gemeinschaftspraxis (F.W. Kleinsorge), Detmold; Städtische Kliniken, (B. Theophil), St-Johannes-Hospital (H.-J. Pielken), Dortmund; St Johannes Hospital (M. Westerhausen), Duisburg; Medizinische Einrichtungen der Heinrich-Heine-Universität (K.A. Hartmann), Dominikus-Krankenhaus (V. Cautius), Evangelisches Krankenhaus (H. Neuhaus), Düsseldorf; Hans-Susemihl-Krankenhaus (H. Becker), Emden; St-Antonius-Hospital (R. Fuchs), Eschweiler; Universitätsklinikum (M. Engelhard), Essen; Evangelisches Krankenhaus (C. Tirier), Essen-Werden; Ev-luth Diakonissenanstalt (W. Staemmler), Malteser Krankenhaus St Franziskus-Hospital (J. Benk, H.-J. Brodersen, W. Neugebauer), Flensburg; Ev Diakoniekrankenhaus (U. Brand), Freiburg; Georg-August-Universität (C. Binder, H. Schmidberger), Göttingen; Ernst-Moritz-Arndt-Universitätsklinik (C. Hirt), Greifswald; St Elisabeth Hospital (W.M. Glöckner), Gütersloh; Allgemeines Krankenhaus Altona (F. Hagenmüller, D. Braumann), Allgemeines Krankenhaus St Georg (H.-P. Heilmann), Hamburg; St Marien-Hospital (R. Jany, P. Rohde), St Barbara-Klinik Heessen (W. Frontzek), Hamm; Henriettenstiftung (C. Grotjahn), Medizinische Hochschule (D. Peest), Hannover; Lungenklinik (B. Wahlers), Hemer; Kreiskrankenhaus (H. Behr, I. Czichowski-Vieweger), Herford; Gemeinschaftspraxis (V. Bendel), Hildesheim; Universitätskliniken des Saarlandes (R. Schmitz, C. Rübe), Homburg/Saar; St Ansgar Krankenhaus (E. Wilhelms), Höxter; Gem ökumenische Krankenhausgesellschaft (M. Niemöller, D. Schenk), Ibbenbüren; Städtisches Klinikum (M. Haag), Karlsruhe; Städtisches Klinikum (E.U. Steinhauer), Kurhessisches Diakonissenhaus (H.-J. Bröker), Kassel; Städtisches Krankenhaus (C. Pott), Christian-Albrechts-Universität (F. Gieseler, J. Schultze, B. Kremer), Kiel; Gemeinschaftspraxis (J. Heymanns), Koblenz; Universitätsklinik (M. Reiser), Evangelisches Krankenhaus Kalk (C. Pohl), St Elisabeth-Krankenhaus (J. Schönemann), Köln; Städtische Krankenanstalten (K. Becker, U. Skutta), Krankenhaus Maria-Hilf (U. Peters), Krefeld; Klinikum Lippe-Lemgo (H. Middeke, M. Schütz), Lemgo; Medizinische Universität (K. Weber, T. Feyerabend), Lübeck; Städtisches Klinikum (R. Jakobs, Th. Schnabel), Ludwigshafen; Johannes Gutenberg Universität (M. Thelen), Mainz; Klinikum der Philipps-Universität (I. Uebelacker, R. Engenhart-Cabillic), Marburg; Klinikum (H. Bodenstein), Radioonkologische Praxis (A. Junker), Minden; Krankenhaus Maria-Hilf (D. Kohl; I. Stapels), Mönchengladbach; Evangelisches Krankenhaus (J. Freise, D. Völzke), St Marien-Hospital (M. Schweickert), Mühlheim a. d. Ruhr; Universitätsklinik (P. Koch, G. Reinartz, J. Brockmann), St Franziskus-Hospital (H.A. Schmidt-Wilcke), Münster; Herz-Jesu-Krankenhaus (W. Wiegelmann), Münster-Hiltrup; Städtisches Krankenhaus (H. Appenrodt), Nettetal; Lukaskrankenhaus (W.D. Maier), Neuss; DRK-Krankenhaus (L. Heuser), Neuwied; Albert-Schweitzer-Krankenhaus (M. Wirth), Gemeinschaftspraxis (S. Detken), Northeim; Kreiskrankenhaus (W. Ebert), Nürtingen; Pius-Hospital (A. Temmesfeld, H. Klasen), Internistische Fachpraxis (H.-F. Hinrichs), Städtische Kliniken (F. del Valle, L. Müller, M. Schmidt-Lauber), Oldenburg; Paracelsus-Strahlenklinik (W. Wagner), Osnabrück; Paracelsus Krankenhaus Ruit (H. Gnann), Ostfildern; Brüderkrankenhaus St Josef (H. Keller), Paderborn; Knappschaftskrankenhaus (M. Maier), Püttlingen; Knappschafts-Krankenhaus (K.-A. Husemeyer, V. Schachinger), Recklinghausen; Jakobi-Krankenhaus (D. Bauer), Matthias-Spital (M. Lausen), Rheine; Kreiskrankenhaus (H.-H. Krause), Rinteln; Universitätsklinik (M. Freund, T. Libera), Klinikum Südstadt (P. Ketterer), Rostock; Winterbergkliniken (H. Liehr, H. Jacobs), Saarbrücken; Kreiskrankenhaus St Franziskus (K. Krause), Saarburg; Martin Luther Krankenhaus (G. Paetzmann), Internistische Fachpraxis (C. Petersen), Schleswig; St Marien-Krankenhaus (P. Fritz, E. Strunk), Siegen; Marienkrankenhaus (G. Schütte), Soest; St Lukas Klinik (K.H. Beckers), Solingen-Ohligs; Klinik Dr Hancken (A. Scherpe, C. Thiel), Stade; Kreiskrankenhaus (H.-G. Biedermann, M. Gluth-Stender), Traunstein; Krankenhaus der Barmherzigen Brüder (C.B. Kölbel), Mutterhaus der Borromäerinnen (R. Mahlberg, W. Dornoff), Trier; Kreiskrankenhaus (J. Popp), Vietach; Josephs-Hospital (H. Bauer), Warendorf; Kreiskrankenhaus (K. Heunisch), Weißenfels; and Heinrich-Braun-Krankenhaus (G. Schott, J. Stöltzner), Zwickau, Germany.
Supported in part by Hoffmann-LaRoche AG, Grenzach, Germany. We thank M. Engelhard, MD, and C. Tirier, MD (Essen), for their independent case review, R. Bongartz (Münster) for her secretarial assistance, and N. Eaton-Gray (Chagford, United Kingdom) for his help in preparing the manuscript.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 years), performance status (Karnofsky performance status < 100%, ascertained 2 to 4 weeks after surgery), and elevated LDH (
