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Annals of Oncology Advance Access originally published online on August 3, 2006
Annals of Oncology 2006 17(10):1546-1552; doi:10.1093/annonc/mdl153
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© 2006 European Society for Medical Oncology

hematologic malignancies

Sequential high dose chemotherapy as initial treatment for aggressive sub-types of Non-Hodgkin Lymphoma: results of the international randomized phase III trial (MISTRAL)

DC Betticher1,*, G Martinelli2, JA Radford3, M Kaufmann4, MJS Dyer3, U Kaiser4, WE Aulitzky4, J Beck4, A von Rohr1, T Kovascovics1, SB Cogliatti1, S Cina1, R Maibach1, T Cerny1 and DC Linch3

1 SAKK (Swiss Group for Clinical Cancer Research), Bern, Switzerland
2 European Institute of Oncology, Milano, Italy
3 UKCCCR Lymphoma Subcommittee, UK
4 German Lymphoma Study Group, Germany

*Correspondence to: Dr D. Betticher, Clinic of Med. Oncology, Hospital of Fribourg, 1700 Fribourg, Switzerland. E-mail: betticherd{at}hopcantfr.ch


   Abstract
Top
 Abstract
introduction
 patients and treatments
 results
 discussion
 appendix
 Acknowledgements
 References
 
Introduction: Sequential high dose (SHiDo) chemotherapy with stem cell support has been shown to prolong the event-free survival in patients with diffuse large B-cell lymphoma.

Methods: To confirm this result in a multicenter trial, we randomized patients with aggressive NHL, to receive either eight cycles of CHOP or SHiDo. The primary endpoint was overall survival.

Results: 129 evaluable patients were randomized to receive either CHOP or SHiDo: median age, 48 years; 62% male; stage III+IV: 73%; age adjusted International Prognostic Index 1/2/3: 21%/52%/27%. Toxicity grades 3+4 were more pronounced in the SHiDo-arm with 13% versus 3% of patients with fever; 34% versus 13% with infections; 13% versus 2% with esophagitis/dysphagia/gastric ulcer. The remission rates were similar in SHiDo and CHOP arms with 34%/37% complete remissions and 31%/31% partial remissions, respectively. After a median observation time of 48 months, there was no difference in overall survival at 3 years, with 46% for SHiDo and 53% for CHOP (P = 0.48).

Conclusion: In this multicenter trial, early intensification with SHiDo did not confer any survival benefit in previously untreated patients with aggressive NHL and was associated with a higher incidence of grades 3/4 toxicity.

Key words: aggressive lymphoma, autologus bone marrow transplantation, diffuse large cell lymphoma, sequential high dose chemotherapy


   introduction
Top
 Abstract
 introduction
patients and treatments
 results
 discussion
 appendix
 Acknowledgements
 References
 
The cure rate of aggressive non Hodgkin lymphomas (NHL) has been stable over the last 10 years. Until 2003, the standard regimen of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) led to cure in 30 to 60% of patients depending on the number of risk factors present [1]. The addition of the monoclonal antibody, rituximab, to CHOP has been shown to improve the outcome in both the elderly [2, 3] and younger patients [4]. Another approach that has been tested is high-dose therapy and autologous hematopoietic stem cell transplantation as part of initial therapy. Disappointedly, the majority of randomized studies in which high dose therapy and re-infusion was given after CHOP combination or third generation regimens were negative [5–11] or in favor of the standard arm without high dose chemotherapy [12]. A study by GELA, however, after a prolonged follow-up and stratification by the International Prognostic Index score (IPI), showed an improvement of survival in patients with high risk, aggressive lymphomas (IPI 2) [13]. Furthermore, the recently reported study from the GOELAMS demonstrated a longer time to progression and overall survival compared with a CHOP-like regimen, particularly in patients with age adjusted IPI (aaIPI) scores of 1–2 [14].

The greatest benefit in event-free survival (EFS) seen with high-dose therapy was in the Italian trial reported by Gianni and colleagues [15]. The unique feature of this regimen is the administration of several non-cross resistant drugs, each at the maximal tolerated dose, mainly as single agents, within the shortest possible interval, in order to reduce the risk of the development of drug-resistant malignant cells. The trial conducted in a single center demonstrated a large improvement in EFS with high-dose therapy compared with the MACOP-B regimen, but no significant improvement in overall survival (OS), perhaps due to the low power of this small study and the cross-over of patients after failure in the MACOP-B arm.

The aim of the randomized phase III trial (Mistral: Multicenter International Studies on the Treatment of Aggressive Lymphomas) reported here was to compare the sequential high-dose (SHiDo) strategy with standard CHOP chemotherapy in a multicenter setting.


   patients and treatments
Top
 Abstract
 introduction
 patients and treatments
results
 discussion
 appendix
 Acknowledgements
 References
 
trial design
The trial was a randomized, multicenter, international phase III trial. Participating centers are listed in the Appendix. Randomization was carried out centrally at the SAKK Coordinating Center in Bern. The trial was initially activated in Switzerland and at the EIO (European Institute of Oncology, Milano, Italy). Through continuous effort to improve accrual rate, several centers joined the trial later (notably, the German High-Grade Non-Hodgkin's Lymphoma Study Group, and the UKCCCR lymphoma sub-committee). The protocol had been accepted by the local ethic's committees.

trial aims
The main aim was to compare efficacy and toxicity of SHiDo chemotherapy and a standard chemotherapy in patients with newly diagnosed aggressive NHL presenting poor prognostic factors. The primary endpoint was OS, and secondary endpoints were EFS, time to treatment failure, response rate and toxicity.

patients
This multicenter trial enrolled patients 18–61 years old with previously untreated, histologically documented aggressive lymphoma (encompassing diffuse large B-cell lymphoma, including cases of primary mediastinal [thymic] large B-cell lymphoma, and anaplastic large cell lymphoma, according to the R.E.A.L. classification). For randomization, the histological diagnosis from the local pathology center was used. Patients had to have at least one risk factor according to the aaIPI [16]: stage III or IV disease, elevated LDH (> upper limit of normal value) and/or ECOG performance status 2, 3, or 4. After inclusion of the first 61 patients, subsequent recruitment was restricted to patients with poor prognosis (aaIPI 2–3), based on results of the GELA group showing an advantage for high dose chemotherapy with stem cell support in this patient population [13]. Other inclusion criteria were adequate organ function as defined by the following criteria: calculated creatinine clearance ≥60 ml/min, serum bilirubin <40 micromol/L (unless due to tumor involvement), AST or ALT ≤2x upper limit of normal range (unless due to tumor involvement), no relevant heart failure (in particular normal left ventricular ejection fraction), no history of active angina pectoris or myocardial infarction within the preceding 6 months, no major ventricular arrhythmia, and the absence of infection with the human immunodeficiency virus or other severe active or chronic infection (including hepatitis B or C). Patients with central nervous system involvement by the malignant lymphoma and psychiatric disorders were excluded. The trial was approved by the ethics committee of each treating center, and all patients signed an informed consent.

treatments
Arm A, CHOP: Chemotherapy cycles (dose and drugs see Fig. 1) were repeated every 3 weeks. Patients received at least two more cycles of the CHOP regimen for a minimum of six and a maximum of eight cycles after documentation of a complete response (CR), unless they failed to respond. If no response (at least partial) was seen after three cycles or no CR after six cycles of chemotherapy, this was considered as a treatment failure and salvage therapy was given (at the discretion of the physician).


Figure 1
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  		Figure 1 The treatment protocol: *CHOP arm: CHOP: Cyclophosphamide 750 mg/m2, IV on day 1, Doxorubicin 50 mg/m2, IV, on day 1, Vincristine 1.4 mg/m2, max. 2 mg, IV, on day 1, Prednisone 100 mg, orally, on days 1–5. **BM: bone marrow. SHiDo arm (SHDC: sequential high dose chemotherapy): Phase 1: Doxorubicin 50 mg/m2, IV, on day 1, Vincristine 1.4 mg/m2, max. 2 mg, IV, on day 1, Prednisone 100 mg, orally, on days 1–5 (after amendment of the protocol as of patient 62, Phase 1 was equal to CHOP regimen, in order to allow start of therapy and randomization afterwards). Phase 2: Cyclophosphamide 7000 mg/m2, IV Phase 3: Vincristine 2 mg, IV, Methotrexate 8000 mg/m2, IV Phase 4: Etoposide 2000 mg/m2, IV Phase 5: Mitoxantrone 60 mg/m2, IV, Melphalan 180 mg/m2, IV Stem cell collection was performed after phase II in case that there was no bone marrow infiltration, otherwise after phase IV. Support with G-CSF was given after cyclophosphamide, etoposide and mitoxantrone/melphalan (5 µg/kg, except before apheresis 10 µg/kg).

 
Arm B, SHiDo: Chemotherapy was administered as previously reported [15]. Briefly, the treatment consisted of five phases administered in sequence (for drugs and dosages see Figure 1). Peripheral stem cell apheresis was performed after phase 2 (in the absence of bone marrow involvement), otherwise after phase 4.

In both arms, radiotherapy was given to patients with bulky disease at treatment start (> 5 cm in any dimension) and/or residual mass after chemotherapy (>1.5 cm) after completion of the chemotherapy (CHOP arm <30 days; high dose arm <100 days). The dose of radiotherapy administered was 30 Gy in 2 Gy fractions.

Intrathecal chemotherapy (cytarabine, methotrexate and hydrocortisone) was administered to patients with testicular disease or involvement of the facial sinuses.

assessment of response and follow-up
Patients were seen and examined regularly and assessed by laboratory analyses, bone marrow punctures (if involved at diagnosis) and CT scans. The procedures used to evaluate responses were the same as those used for staging at diagnosis. Follow-up procedures included a physical examination every three months for the first two years, every six months for the next three years and annually thereafter. Thoracic and abdominal computed tomography was performed every six months during the first three years, and as indicated thereafter.

A CR was defined as complete disappearance (with confirmation after a period of at least 4 weeks) of all palpable and radiologically demonstrable disease, including liver and spleen as well as bone marrow disease judged by iliac bone marrow biopsy. Residual masses were considered uninvolved if they measured less double equals1.5 cm in diameter (less double equals2.5 cm in previous bulk). Patients who did not achieve a CR, but had shown a response to therapy with ≥50% reduction in the sum of the products of the dimensions of the measurable lesions, were considered to have a partial response (PR).

statistical considerations
Originally the trial was planned to test a 15% absolute improvement of OS rate at 2 years from 50% in the standard arm to 65% in the SHiDo arm, using 2-sided logrank test at significance level 5%. A 2:1 randomization in favor of the SHiDo was chosen to make the trial more attractive to investigators. A sample size of 230 patients was required to allow for 20 cases of drop-out and to reach 80% power.

After 2 years the trial protocol was revised in view of the collaboration with the UKCCCR lymphoma sub-committee. The randomization ratio was changed to 1:1. The sample size was raised in order to reach 90% power and to adapt to the expectation of reaching a survival plateau of 40% after 5 years in the CHOP arm. One interim analysis was planned after 100 deaths with the possibility to stop the trial early in case of a significant difference. An alpha-spending strategy according to Lan and de Mets [17] was chosen with an O'Brien and Fleming type spending function [18], with 0.0046 from the planned significance level of 0.05 to be spent for the interim analysis. In addition, discontinuation of the trial was to be considered if the treatment related death rate exceeded 10% in the SHiDo arm.

Randomization was stratified by center, number of IPI risk factors (1/2 versus 3), and absence versus presence of bone marrow infiltration and bulky disease.

Survival time was calculated as the interval between date of randomization and either death or last follow-up. EFS was determined by time to first progression, relapse or death. Time to treatment failure was defined as the interval from randomization to discontinuation of the trial treatment for any reason, relapse, progressive disease, or death, whichever occurred first. Time to event endpoints were estimated according to the Kaplan-Meier method. Cox's proportional hazards regression was used for multivariate analyses of OS.

Incidence of grade 3/4 toxicity was compared between treatment arms using chi-squared or Fisher's exact test.


   results
Top
 Abstract
 introduction
 patients and treatments
 results
discussion
 appendix
 Acknowledgements
 References
 
patient characteristics
The trial was closed in 2003 after a planned interim analysis. Based on a review of preliminary efficacy and safety results and power calculations, an independent advisory board consisting of two clinicians and one biostatistician not involved in the trial recommended to stop the trial early due to absence of the potential to detect a relevant difference in OS between treatment arms, the high incidence of severe toxicity with SHiDo, and the development of new treatment strategies in this patient population.

Between April 1997 and November 2003, 136 patients were randomized into the trial. Four patients were found ineligible and were not treated because of concomitant AML (1), HIV positivity (1), renal failure (1), or change of diagnosis (1). One patient refused treatment. No documentation was available for two patients. Among the 129 evaluable patients (median age, 48 years, range, 18–61 years), 59 were randomized to CHOP chemotherapy (arm A) and 70 to SHiDo chemotherapy (arm B). Their main pre-treatment characteristics were comparable (Table 1). The distribution of aaIPI showed a slight imbalance (P = 0.06), which was due to the inclusion of patients with one risk factor and the 2:1 randomization applied up to patient 61. In the CHOP arm, 12% of the patients were classified as low intermediate, 56% as high intermediate, and 32% as high risk; in the SHiDo arm, 29% as low intermediate, 49% as high intermediate, and 23% as high risk.


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  		Table 1 Baseline characteristics of the patients (n = 129)

 
The majority of patients had diffuse large B-cell lymphomas (94 of 129; 73%). Thirteen patients had a primary mediastinal large B-cell lymphoma (10%) and 22 patients anaplastic large cell lymphoma (17%).

feasibility of the treatment
Forty-six patients (78%) received the planned cycles according to protocol in the CHOP arm, and 44 patients (63%) in SHiDo arm.

CHOP arm.
The median number of cycles administered was eight (range 1–8). Eight patients (14%) received six cycles and 34 patients (58%) received eight cycles. The main reason not to receive the minimum number of CHOP cycles according to protocol was refusal in one patient with a complete remission after 5 cycles, and progressive disease in 12 patients (20%). Reasons due to toxicity were rare (four patients, 7%). Two patients died from toxicity after the first cycle (one from sepsis with multi-organ failure, one from cytokine release syndrome). Median dose intensity for CHOP was 98% of the planned intensity for cyclophosphamide, doxorubicin and prednisone, and 87% for vincristine.

SHiDo arm.
Forty-four patients received the five phases of SHiDo. The reasons for stopping therapy were revised diagnosis (three patients, 4%), lack of response (two patients, 3%), progressive disease (12 patients, 17%), toxicity (four patients, 6%), refusal (one patient, 1%), death (four patients, 6%, including three toxic deaths). Toxic deaths were due to cardio-circulatory shock shortly after cyclophosphamide administration (phase 2) in one patient, and bowel perforation including peritonitis after CHOP (phase 1) in two patients.

Adherence to the protocol was very good with an actual dose intensity over the phases 2–5 of 98% (Table 2). The median time from the administration of cyclophosphamide (phase 2) to the administration of melphalan (phase 5) was 75 days (range, 48–134 days), and the median duration of the overall treatment (from the administration of cyclophosphamide to the final hospital discharge) was 13 weeks (range 9–21 weeks). The median number of days to stem cell apheresis after administration of cyclophosphamide (phase 2) or etoposide (phase 4) was 14 days (range 9–22 days). The median hospital stay for transplantation was 20 days (range 4–60). After phase 5 (including stem cell rescue), the neutrophil recovery to >0.5 x 109/l was seen 11 days (median, range: 8–30) after re-infusion of stem cells.


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  		Table 2 Dose intensity in the SHiDo arm

 
radiotherapy.
Thirty-four patients (16 SHiDo, 18 CHOP) received radiotherapy, in 31 of 34 cases for bulky disease. The median total dose was 30.6 Gy (range 20–50 Gy). In one patient, radiotherapy was terminated after two fractions due to rapid tumor progression.

toxicity
Hematological and non-hematological toxicities are listed in Table 3. Three percent of patients in the CHOP arm and 4% of patients in the SHiDo arm died due to toxic side effects of the therapy.


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  		Table 3 Grade 3/4 non-hematological and hematological toxicities (according to ‘NCI expanded common toxicity criteria’, maximum grade over all cycles)

 
CHOP arm.
CHOP cycles were tolerated as expected from previous trials with the most frequent adverse events being myelotoxicity, infections, and nausea/vomiting (>10% of patients) (Table 3). The median number of days between CHOP cycles was 21 days (range 14–35 days).

SHiDo arm.
Overall toxicity was more pronounced in this arm, particularly after phase 2 (high dose cyclophosphamide, myelotoxicity) and 5 (melphalan and mitoxantrone followed by stem cell rescue, stomatitis and myelotoxicity). 166 red blood cell units and 346 platelet units (pooled donor) were given to 36 patients in phases 1 to 4. A median number of two (range 0–30) red blood cell units and six (0–36) platelet units were necessary in phase 5. Six patients received no transfusions in phase 5.

response to treatment
At the end of therapy, the overall response rates in the CHOP and SHiDo arms were 68% and 66%, respectively. The CR rate was not higher after SHiDo (SHiDo 34%; CHOP 37%). For the subset of patients completing all allocated treatment, CR was seen in 46% after CHOP and 52% after SHiDo.

CHOP arm.
After three cycles of CHOP, 71% had PR and 8% CR. The proportion of patients with CR increased to 25% after six cycles. Nineteen % of patients had progressive disease after six cycles of CHOP.

SHiDo arm.
70% of patients had a response after phase 2 (4% CR and 66% PR), 69% after phase 4 (13% CR, 56% PR). More than half of all patients (52%), who received the five phases of the high dose therapy, obtained a CR. 17% of patients had progressive disease (including one early death) before phase 5 was started and went off protocol treatment.

survival
After a median follow-up time of 48 months in surviving patients, 67 deaths were registered. At three years, there were 39 deaths (46% OS, 95% CI 34–58%) in the SHiDo arm and 28 deaths (53% OS, 95% CI 39–67%) in the CHOP arm (P = 0.48). The reason for deaths was very similar in both arms: 82% of deaths were due to lymphoma independently of the therapy given.

There was no difference in EFS at 3 years: 33% versus 39% in the CHOP and SHiDo arms, respectively (P = 0.67). OS and EFS are shown in Figure 2. The two treatment arms had very similar curves, with no trend for a difference. Median time to treatment failure was 10.7 months following CHOP and 7.4 following SHiDo (P = 0.64).


Figure 2
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  		Figure 2 (A) Overall survival and (B) event-free survival.

 
From the patients who reached a CR after completion of therapy in the CHOP arm (22) and in the SHiDo arm (24), 42% and 64% respectively were relapse free at 3 years after start of therapy (P = 0.24).

relapses and rescue treatment
Five patients who had treatment failure in the CHOP arm crossed over to sequential high dose treatment. Three of these patients reached a CR immediately (1) or some time later (2) after high dose chemotherapy, whereas two died within a short time.

subgroup analyses
A multivariate analysis investigating effects of treatment, aaIPI (3 versus 1/2), age (45+ versus younger), bulky disease and bone marrow involvement on OS was performed. Patients with high risk disease (aaIPI = 3) showed a shortened OS (hazard ratio 4.1, P < 0.0001). Bone marrow involvement also seemed to confer a higher death risk (hazard ratio 2.875, P = 0.0002). The survival analyses by patient characteristics shown in Table 1 did not allow identification of a subgroup who might have had a benefit from SHiDo. However, the limited sample size results in a lack of power for the evaluation of interactions between the treatment and prognostic factors. Among the 96 patients who achieved an early response after phase 2 or cycle 3, 41 died and overall survival was non-significantly lower in the SHiDo arm (hazard ratio 1.17, P = 0.63). Qualitatively, the same results hold true for those 90 patients who were in response after phase 4 of the SHiDo or six cycles of CHOP.


   discussion
Top
 Abstract
 introduction
 patients and treatments
 results
 discussion
appendix
 Acknowledgements
 References
 
This international, multicenter randomized trial in patients with previously untreated high risk aggressive lymphomas show that toxicity is more pronounced in the sequential high dose arm (SHiDo) without any indication of a better outcome (response rate, time to treatment failure, event-free survival or overall survival). These results do not reproduce those of Gianni and colleagues from Milan [15]. Although the number of patients in our trial is small (n = 129), the size is comparable with the Milan trial (n = 98). In their study, SHiDo therapy (as given in the present trial) was associated with a higher rate of complete responses (96% versus 70%, P = 0.001), seven year freedom from relapse (84% versus 49%, P < 0.001) and event-free survival (76% versus 49%, P = 0.004) when compared with the MACOP-B regimen. Overall survival at seven years, however, did not reach statistical significance (81% versus 55%, P = 0.09) and as in the present trial, there was a higher incidence of toxicity after SHiDo therapy.

Trials in multicenter setting may suffer from worse compliance and decreased quality compared with a single center investigation. However, we have no indication that the high dose arm was not given as planned in the protocol: in fact the median dose intensity of the cytotoxic drugs in all phases of SHiDo was close to 100%. An analysis of patients stratified between different centers did not identify any location associated with a worse outcome. Based on these results we conclude that sequential high dose chemotherapy should not be recommended as the standard approach for previously untreated patients with aggressive lymphomas.

Originally, the value of high-dose chemotherapy with autologous hematopoietic stem cell support in aggressive NHL has been evaluated in patients with first or subsequent relapse or patients who were refractory to first line therapy. These patients obviously have a very poor prognosis, since only few will attain long term remissions after standard chemotherapy. A randomized phase III trial resulted in a significant improvement of complete remission rate, event-free survival rate, and overall survival rate after high-dose chemotherapy with autologous stem cell support, compared with conventional chemotherapy, in patients with high grade and intermediate grade NHL in chemosensitive relapse [19]. These beneficial results of high dose chemotherapy in patients with relapsed or refractory aggressive NHL were further supported by a number of non-randomized phase II studies in which a variety of cytotoxic drug regimens has been tested [20–22].

The next logical step was to test this concept as a first line therapy in untreated patients with aggressive NHL. Our results with high dose therapy and autologous stem cell reinfusion are in only partial agreement with the findings of other recently reported randomized trials [5–10, 12–14, 23]. Their designs, however, differ markedly with respect to patient eligibility, time to randomization, and nature of treatment in the control arms. In some trials patients were randomized only if they reached a response after several cycles of chemotherapy [6, 7, 13]. The adherence to the protocol is, however, low in the majority of the trials. It varies between 61% and 85% of patients assigned to the high dose arm, who really received the planned therapy. The best compliance (85% of patients) was seen in the trial reported by Milpied et al. [14], in which patients had a benefit from the high dose treatment. Nevertheless, a meta-analysis assessing 14 randomized trials (involving 2018 patients) with autologous stem cell support in the first line treatment of aggressive lymphoma has been recently presented [24]. Despite higher complete response rate there was no evidence that high dose chemotherapy improves overall or event-free survival.

Today, chemotherapy combined with rituximab has replaced CHOP as the standard treatment for diffuse large B cell lymphoma. Combinations of chemotherapy with other targeted therapies are also showing promise. Further trials are required to define the value of high dose therapy in the context of rituximab containing regimens, but it is unlikely that the impact of high dose therapy strategies will be greater than in the comparison with regimens such as CHOP without rituximab. Patient selection will therefore be even more important in future trials.

In conclusion, the results of this trial show first, that administration of sequential high dose chemotherapy with stem cell support is feasible in a multicenter setting; second, that the incidence of grade 3/4 toxicity associated with this treatment is higher than with CHOP therapy; and third that this increased toxicity is not associated with any benefit in terms of response, event-free survival or overall survival. CHOP (now in combination with rituximab) remains the standard of care for the first line treatment of patients with aggressive subtypes of non-Hodgkin lymphoma.


   appendix
Top
 Abstract
 introduction
 patients and treatments
 results
 discussion
 appendix
Acknowledgements
 References
 
Participating centers, with principal investigator and number of patients recruited (in brackets):

Swiss Group for Clinical Cancer Research (SAKK):

Bern: D. Betticher (13); Lausanne, T. Kovacsovics (9); Ticino: M. Ghielmini (5); Geneva: G. Zulian (4); Aarau: M. Wernli (3); Basel: R. Herrmann (3); Zurich: C. Taverna (2), Baden: A. Streit (1); Zurich/Hirslanden; A. von Rohr (1), Milano: European Institute of Oncology, G. Martinelli (21).

German High-Grade Non-Hodgkin's Lymphoma Study Group:

Stuttgart: M. Kaufmann (11); Mainz: J. Beck (8); Dresden: R. Naumann (5), Marburg: U. Kaiser (5); München: C. von Schilling (4); Halle: H. Schmoll (1), Hamm: B. Schmid (1), Kaiserslautern: G. Hübner (1), Kassel: B. Ritter (1); M. Schulze (1);

Warsaw: J. Walewski (4);

UKCCCR lymphoma sub-committee:

Manchester: J. Radford (12); Leicester: M. Dyer (7); Hull: R. Patmore (4); Wakefield: P. Hillmen (2); Edinburgh: M. Mackie (1), Liverpool: A. Pettitt (1); London: R. Pettengell (1); Northwood: P. Hoskin (1); Oxford: C. Hatton (1); Swindon: N. Blesing (1); Torquay: S. Smith (1)


   Acknowledgements
Top
 Abstract
 introduction
 patients and treatments
 results
 discussion
 appendix
 Acknowledgements
References
 
We thank the members of the Independent Data Monitoring Committee for their expert advice concerning the interpretation of the interim analysis: Volker Diehl (chairman, onco-hematologist), German Hodgkin Study Group, John Sweetenham (onco-hematologist), University of Colorado Health Sciences Center, Denver CO, USA, Pinuccia Valagussa (statistician), Instituto Nazionale Tumori, Milano, Italy. This study was partially supported by Roche Pharma (Schweiz) AG and Amgen Switzerland.

Received for publication February 18, 2006. Revision received May 22, 2006. Accepted for publication May 26, 2006.


   References
Top
 Abstract
 introduction
 patients and treatments
 results
 discussion
 appendix
 Acknowledgements
 References
 
1. Fisher RI, Gaynor ER, Dahlberg S, et al. (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328:1002–1006.[Abstract/Free Full Text]

2. Coiffier B, Lepage E, Briere J, et al. (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242.[Abstract/Free Full Text]

3. Feugier P, Van Hoof A, Sebban C, et al. (2005) Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 23:184117–4126.[Abstract/Free Full Text]

4. Habermann TM, Weller EA, Morrison VA, et al. (2004) Phase III trial of tiruximab-CHOP (R-CHOP) versus CHOP with a second randomization to maintenance rituximab (MR) or observation in patients 60 years of age and older with DLBL. Blood 102:Suppl 1, abstr 6a.

5. Santini G, Salvagno L, Leoni P, et al. (1998) VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16:2796–2802.[Abstract]

6. Intragumtornchai T, Prayoonwiwat W, Numbenjapon T, et al. (2000) CHOP versus CHOP plus ESHAP and high-dose therapy with autologous peripheral blood progenitor cell transplantation for high-intermediate-risk and high-risk aggressive non-Hodgkin's lymphoma. Clin Lymphoma 1:219–225.[Medline]

7. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. (2001) Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 93:22–30.[Abstract/Free Full Text]

8. Haioun C, Lepage E, Gisselbrecht C, et al. (1994) Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission: a study of 464 patients. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 12:2543–2551.[Abstract/Free Full Text]

9. Kaiser U, Uebelacker I, Abel U, et al. (2002) Randomized study to evaluate the use of high-dose therapy as part of primary treatment for ‘aggressive’ lymphoma. J Clin Oncol 20:4413–4419.[Abstract/Free Full Text]

10. Martelli M, Gherlinzoni F, De Renzo A, et al. (2003) Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 21:1255–1262.[Abstract/Free Full Text]

11. Olivieri A, Santini G, Patti C, et al. (2005) Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG. Ann Oncol 16:1941–1948.[Abstract/Free Full Text]

12. Gisselbrecht C, Lepage E, Molina T, et al. (2002) Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472–2479.[Abstract/Free Full Text]

13. Haioun C, Lepage E, Gisselbrecht C, et al. (2000) Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol—a Groupe d'Etude des Lymphomes de l'Adulte study. J Clin Oncol 18:3025–3030.[Abstract/Free Full Text]

14. Milpied N, Deconinck E, Gaillard F, et al. (2004) Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350:1287–1295.[Abstract/Free Full Text]

15. Gianni AM, Bregni M, Siena S, et al. (1997) High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336:1290–1297.[Abstract/Free Full Text]

16. A predictive model for aggressive non-Hodgkin's lymphoma. (1993) The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994.[Abstract/Free Full Text]

17. Lan KKG and DeMets DL. (1983) Discrete sequential boundaries for clinical trials. Biometrika 70:549–556.

18. O'Brien PC and Fleiming TR. (1979) A multiple testing procedure for clinical trials. Biometrics 35:549–556.[CrossRef][Web of Science][Medline]

19. Philip T, Guglielmi C, Hagenbeek A, et al. (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540–1545.[Abstract/Free Full Text]

20. Bosly A, Coiffier B, Gisselbrecht C, et al. (1992) Bone marrow transplantation prolongs survival after relapse in aggressive-lymphoma patients treated with the LNH-84 regimen. J Clin Oncol 10:1615–1623.[Abstract/Free Full Text]

21. Vose JM, Anderson JR, Kessinger A, et al. (1993) High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11:1846–1851.[Abstract/Free Full Text]

22. Kessinger A, Armitage JO, Smith DM, et al. (1989) High-dose therapy and autologous peripheral blood stem cell transplantation for patients with lymphoma. Blood 74:1260–1265.[Abstract/Free Full Text]

23. Haioun C, Lepage E, Gisselbrecht C, et al. (1997) Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15:1131–1137.[Abstract/Free Full Text]

24. Greb A, Bohlius J, Schwarzer G, et al. (2005) High-dose chemotherapy with autologous stem cell support does not improve outcome in the first-line treatment of aggressive non-Hodgkin's lymphoma—results of a comprehensive meta-analysis. Ann Oncol 16:v55 (Abstr. 68).


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Poor results and patient selection bias
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