R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study

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1 Hematological Oncology Hematol Oncol 2008; 26: Published online 17 September 2007 in Wiley InterScience ( Research Article R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study Antonio Rueda 1 *, Pilar Sabin 2, Juli Rifá 3, Marta Llanos 4, José Gómez-Codina 5, Francisco Lobo 6, Ramón García 7, Joaquin Herrero 8, Mariano Provencio 9 and Carlos Jara 10 In representation of the Grupo Oncológico para el Tratamiento y Estudio de los Linfomas (GOTEL) 1 Medical Oncology Service, Hospital Clínico Universitario, Málaga, Spain 2 Medical Oncology Service, Hospital Gregorio Marañón, Madrid, Spain 3 Medical Oncology Service, Hospital Son Dureta, Palma de Mallorca, Spain 4 Medical Oncology Service, Hospital Universitario de Canarias, Tenerife, Spain 5 Medical Oncology Service, Hospital La Fe, Valencia, Spain 6 Medical Oncology Service, Fundación Jiménez Díaz, Madrid, Spain 7 Medical Oncology Service, Complejo Hospitalario, Pontevedra, Spain 8 Medical Oncology Service, Hospital General, Alicante, Spain 9 Medical Oncology Service, Hospital Puerta de Hierro, Madrid, Spain 10 Medical Oncology Service, Hospital Fundación Alcorcon, Madrid, Spain *Correspondence to: Antonio Rueda, Servicio de Oncologíamédica, Hospital Clínico Universitario, Campus de teatinos s/n, Malaga, 29010, Spain. ruedom@yahoo.com Received: 18 February 2007 Revised: 27 July 2007 Accepted: 2 August 2007 Abstract Several studies have shown that adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or reducing the interval between chemotherapy cycles from 3 weeks to 2 weeks improves survival in patients with diffuse large B-cell lymphoma (DLBCL). These studies prompted our group (GOTEL) to evaluate prospectively in a pilot study the feasibility and efficacy of R-CHOP-14 in patients with DLBCL. Patients (<70 years) with stage II bulky or stage III or IV DLBCL and no significant comorbidities were included in the study. Rituximab was administered on day 1 before chemotherapy. R-CHOP was given every 14 days. All patients received filgrastim (5 mg/kg) from days 4 to 10. From May 2002 to August 2004, 80 patients were recruited. Median age was 53 years and 58 patients were <60 years. According to the age-adjusted international prognostic index (aaipi), 13 patients (16%) had low-risk disease, 31 (39%) lowto-intermediate risk, 27 (34%) high-to-intermediate risk and 9 (11%) high-risk disease. Grade 3 4 neutropenia was observed in 15 patients (17.5%) and grade 3 4 infections in 13 patients (16%). After therapy, 58 patients (73%) achieved CR-CRu (95% CI: 55 90%). With a median follow-up of 26 months, progression-free survival (PFS) and overall survival (OS) at 30 months were 72% and 86%, respectively. Administration of R-CHOP-14 is feasible and effective in patients <70 years. Copyright # 2007 John Wiley & Sons, Ltd. Keywords: lymphoma; CHOP; rituximab Introduction The CHOP schedule (cyclophosphamide, doxorubicin, vincristine and prednisolone) administered every 21 days has been the standard chemotherapy for diffuse large B-cell lymphoma (DLBCL) for more than 30 years [1,2]. However, the results obtained with CHOP are far from optimal (less than 40% of patients with advanced stage DLBCL remain free of progression at 5 years [2]), so improving the first-line treatment of DLBCL has been a primordial objective in oncohaematologic investigation in the last 10 years. Two different approaches have improved the results of the classic CHOP schedule. In first place, the addition of rituximab to the CHOP regimen (R-CHOP), administered every 21 days, has improved conclusively the efficacy of DLBCL treatment. This advance has been demonstrated in patients older than 60 years [3,4] and in patients younger than 60 years with good prognostic factors [5]. R-CHOP does not increase toxicity with respect to CHOP [3,5], although there seems to be a tendency towards an increase in infections after finalising treatment in patients older than 60 years [4]. The second path for improvement was to shorten the interval between cycles with the aid of granulocyte growth factor (G-CSF). Two studies made by the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) have demonstrated that administering stan- Copyright ß 2007 John Wiley & Sons, Ltd.

2 28 A Rueda et al. dard-dose CHOP every 14 days (CHOP-14) improves overall survival (OS) with respect to CHOP administered every 21 days (CHOP-21), both in patients between 18 and 60 years with good prognostic factors (normal levels of lactate dehydrogenase) [6], and in patients older than 60 years regardless of their prognostic situation [7]. In light of the results discussed, it seems logical to investigate together the two strategies for associating rituximab to the CHOP-14 schedule. Recently, the German group communicated the 3 years results of the RICOVER-60 study [8]. This clinical trial in patients with DLBCL older than 60 years compared the efficacy of R-CHOP-14 versus CHOP-14. The results indicate a significant advantage for the time to failure and OS for patients treated with R-CHOP-14. To date, no randomized study has been communicated in which the efficacy of the R-CHOP-14 schedule was evaluated in patients younger than 60 years. In May 2002, the Oncologic Group for the Treatment and Study of Lymphomas (GOTEL for the Spanish name Grupo Oncológico para el Tratamiento y Estudio de Linfomas) began a prospective (non comparative) pilot study to evaluate the efficacy and toxicity of the R-CHOP-14 schedule in patients younger than 70 years with advanced DLBCL in any prognostic situation. The results of this study are described in this paper. Patients and methods Patients Patients eligible for the study had previously untreated CD-20 positive DLBCL according to the WHO classification [9], age years, stage II bulky, stage III or stage IV disease according to Ann Arbor criteria, and a performance status of 0 3 according to the Eastern Cooperative Oncology Group (ECOG) scale. Patients with all international prognostic index (IPI) scores [10] were included. Bulky disease was defined as a mediastinal mass exceeding one third of the maximum intrathoracic diameter or an enlarged lymph node of more than 10 cm. Patients also were required to have normal renal, liver and cardiac function. Exclusion criteria included lymphoma other than DLBCL, the presence of cardiac or neurologic diseases, central nervous system (CNS) involvement, seropositivity for human immunodeficiency virus and occurrence of a prior neoplasm. Staging procedures included clinical examination, thoracic and abdominal computerized tomography, blood count, bone marrow biopsy and echocardiography, with evaluation of the left ventricular ejection fraction. All patients were re-evaluated after three cycles of chemotherapy and underwent complete restaging at the end of the programme and at intervals of 3 months for the first 2 years of follow-up. Thoracic and abdominal computerized tomography was scheduled every 6 months for the first 3 years and then at the treating physician s discretion. The study complied with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice guidelines. All patients gave written informed consent approved by the Ethics Committee of our Institutions. Treatment The treatment programme consisted in the administration of 6 8 cycles of R-CHOP-14: rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2, doxorubicin 50 mg/m 2, vincristine 1.4 mg/m 2 (maximum 2 mg) and prednisolone 100 mg/day for 5 days. All drugs were administered on day 1 of treatment, leaving an hour between finalization of the infusion of rituximab and the onset of chemotherapy. To maintain the planned dose intensity and interval between cycles, filgrastim was injected subcutaneously (5 mg/kg/ day) to all patient during 7 days (þ4 toþ10) as primary prophylaxis. No antibiotic prophylaxis or prophylaxis for the prevention of recurrences in the CNS was used. A complete blood count was made on day 1 of every cycle. Patients with an absolute neutrophil count of less than 1000/ml or a platelet count of less than /mlnot due to infiltration of the bone marrow suffered a delay of 1 week and received the next cycle on day 21. In the patients that recovered these figures on day 21, we tried to continue treatment every 2 weeks. Treatment was continued every 3 weeks in patients that were not fully recovered on day 21 (these patients were included in all toxicity and efficacy analyses). Rituximab was administered only when the patient was totally recovered to received CHOP chemotherapy. In no case rituximab was administered alone. A total of six cycles of R-CHOP-14 were administered to the patients that achieved complete remission (CR) or unconfirmed complete remission (CRu) after the third cycle of immunochemotherapy and did not have bone marrow involvement at the time of diagnosis. Patients with initial bone marrow involvement or partial remission (PR) after the third cycle received a total of eight cycles. The patients that did not respond were treated at the discretion of each investigator. Complementary radiotherapy (36 Gy) was permitted in case of patients with stage II bulky disease. Radiotherapy was administered to the bulky area using tridimensional, conformal techniques. Evaluation criteria and statistical analysis Toxicity was evaluated on day 1 of every cycle by interview, physical examination and complete blood cell count. Haematologic and extra-haematologic toxicities were scored according to WHO criteria [11]. Severe adverse events were defined by the occurrence of documented infection and/or by organ or system toxicity requiring hospitalization. The relative dose intensity (RDI) for each drug of the CHOP combination was calculated according to Hryniuk [12]. The procedures for evaluation of the response were the same as those used for staging at diagnosis. PET scanning was not routinely used to assess response. The response to R-CHOP-14 was evaluated on an intention-to-treat basis and classified according to the proposed International Workshop criteria [13] as complete (CR), unconfirmed

3 R-CHOP-14 in patients with DLBCL 29 complete (CRu), partial (PR) and no response or progressive disease (NR/PRO). Survival analysis was carried out on the whole series and according to the age-adjusted IPI score. Outcome measures included progression-free and OS. Progression-free survival (PFS) was calculated from the date of beginning chemotherapy to the date of progression or relapse or to the date of the last control. OS was calculated from the date of beginning chemotherapy to the date of death from any cause or to the date of the last control. Numerical variables are summarized as the median and range; categorical variables are reported as counts and relative frequencies. Overall and PFS rates were calculated according to the Kaplan Meier method [14] and differences between survival curves were evaluated using the log-rank test [15]. Results Patient characteristics The characteristics of the 80 patients included in this study from May 2002 to August 2004 are shown in Table 1. The median age was 53 years (range, 18 70) and most patients were younger than 60 years (72%). Patients of all the prognostic categories of the age-adjusted international prognostic index (aaipi) [10] were included, moderateto-low risk (39%) or moderate-to-high risk (34%) groups being the most frequent. Compliance with treatment A median of seven cycles was administered. A total of 28 patients (35%) received six cycles and 35 patients (44%) received eight cycles of chemotherapy. Only seven patients (9%) received fewer than six cycles of R-CHOP-14, due either to early progressive disease (two patients) or to toxicity (five patients). Ten patients (12%) who should have received eight cycles refused the last cycle and only received seven. The median RDI of adriamycin and cyclophosphamide was 90% (range, %) if all patients are included. However, since seven patients did not receive the minimum of six cycles and 10 patients that should have received eight cycles only received seven, the RDI was calculated only for the first six cycles of treatment after excluding the two patients that withdrew from treatment due to disease progression. The median RDI of adriamycin and cyclophosphamide was 94%. The administration of complementary radiotherapy for patients with stage II and bulky disease was included as optional in the protocol. Of the 36 patients with stage II bulky disease, 23 (65%) received complementary radiotherapy on the bulky areas (36 40 Gy). Toxicity The appearance of grade 3 4 toxicity was not very frequent (Table 2), so treatment was well tolerated by most patients. Although no significant incidence of severe mucositis (5%) Table 1. Patient characteristics Characteristic Value Age (years) Median 53 Range Sex, n (%) Male 47 (59) Female 33 (41) Stage, n (%) II bulky 36 (45) III 16 (20) IV 28 (35) B symptoms, n (%) Yes 34 (43) No 46 (57) Bone marrow involvement, n (%) Yes 15 (19) No 65 (81) LDH, n (%) Normal 36 (45) High 44 (55) Extranodal sites, n (%) 0 31 (39) 1 25 (31) 2 19 (24) 3 5 (6) Bulky disease, n (%) Yes 51 (64) No 29 (36) ECOG PS, n (%) 0 38 (47) 1 23 (29) 2 14 (18) 3 5 (6) Age-adjusted IPI, n (%) Low 13 (16) Low intermediate 31 (39) High intermediate 27 (34) High 9 (11) was appreciated, the presence of grade 2 mucositis (the day that the next cycle of treatment had to be administered) in 15% of patients made it necessary to delay the cycle for 7 days according to the established protocol. Fifteen patients (19%) required hospital admission for toxicity (13 of them after the first of second chemotherapy cycle): five grade 3 4 infections (1 septic shock and 4 pneumonias), 8 febrile neutropenia, 1 gastric perforation and 1 pulmonary embolism. Gram-negative bacterial pathogens were isolated in two patients with pneumonia and in the patient with septic shock. In the other patients with infectious complications the causal pathogens were not detected. No cases of pneumocystis carinii infections were observed during the period of treatment. Only the patient that developed septic shock died as a consequence of treatment toxicity.

4 30 A Rueda et al. Table 2. Grade 3 4 toxicity Toxicity Frequency, n (%) Vomiting Grade 3 2 (2.5) Grade 4 2 (2.5) Mucositis Grade 3 4 (5) Neurotoxicity Grade 3 4 (5) Liver Grade 4 1 (1) Kidney Grade 3 1 (1) Infections Grade 3 4 (5) Grade 4 9 (11) Anaemia Grade 3 5 (6) Grade 4 2 (2.5) Thrombocytopenia Grade 3 3 (4) Grade 4 1 (1) Neutropenia Grade 3 6 (7.5) Grade 4 9 (11) Rituximab infusional toxicity Hypotension (grade 3) 1 (1) Anaphylaxis (grade 4) 1 (1) Bronchospasm (grade 3) 1 (1) Figure 1. Actuarial progression-free survival group presented two or three factors of the aaipi (moderate-to-high and high risk according to aaipi). The PFS at 30 months was 72% for the entire series. For the 44 patients (55%) that belonged to the group of good prognosis, the PFS at 30 months was 84%; while it was 62% for the 36 patients (45%) that belonged to the poor prognosis group ( p ¼ 0.02) (Figure 1). The actuarial OS at 30 months was 86%. The patients with a good prognosis had a 30-month survival of 91% versus 81% for the patients with a poor prognosis ( p ¼ 0.23) (Figure 2). In the group of 58 patients younger than 60 years, PFS and OS at 30-month were 78% and 86%, respectively. The figures were very similar for the 25 patients in CR after the third cycle (PFS and OS at 30-month 76% and 92%). We also analysed the effect of complementary radiotherapy in patients with stage II bulky disease. PFS at 30 months was 84% for the 13 patients who did not received radiotherapy and 88% for the 23 patients who did it. Efficacy Of the 80 patients included, 79 were considered valuable for response (one patient died of septic shock before the response evaluation). After the third cycle of chemotherapy 25 (31%) CRs and 50 (62.5%) partial responses were achieved. At the finalization of chemotherapy, 44 (55%) CR, 14 (18%) CRu and 17 (22%) partial responses were observed; 4 patients (5%) had progressive disease. A total of 20 (25%) patients presented disease progression during or after treatment with R-CHOP-14. Aside from the four patients with progression during treatment, another 16 relapsed or progressed after chemotherapy (one patient relapsed in the CNS). Eleven deaths were observed until the moment of the current analysis. Nine deaths were due to disease progression, one due to toxicity and one patient that achieved CR died from a cause unrelated to the disease or treatment. The median follow-up for all the patients was 26 months (range 1 46 months). Patients were grouped for the analysis of survival and PFS depending on their prognostic characteristics according to the aaipi [10]. Patients in the good prognosis group presented no factor or only one factor of poor prognosis (low and moderate-to-low risk according to the aaipi). Patients in the poor prognosis Discussion Recently, Pfreundschuh et al. [8] reported the superiority in event-free survival of the R-CHOP-14 schedule compared to CHOP-14 for the treatment of 1222 patients older than 60 years with DLBCL. In this randomized study, 81% of the patients treated with R-CHOP-14 attained CR/CRu and achieved an event-free survival at 3 years of 66%. The differences in OS were also significant (78% vs. 68% at 3 years, p ¼ 0.018). For the German group the results after Figure 2. Actuarial overall survival

5 R-CHOP-14 in patients with DLBCL 31 six cycles of R-CHOP-14 in this largest randomized trial are the best reported for elderly patients with CD20 þ DLBCL and considered that 6xR-CHOP-14 should be a reference standard in future trials for elderly patients with DLBCL. For the moment, experience with R-CHOP-14 in patients younger than 60 years is very limited. Only two published prospective studies have evaluated the feasibility of this schedule of treatment in patients with DLBCL [16,17]. The first study included 26 patients older than 60 years [16,17] and the second included 50 patients age years, 36 of which were younger than 60 years [17]. The present study is the largest prospective experience reporting on R-CHOP-14 treatment of patients with DLBCL, including patients younger than 60 years. The results obtained for the 80 patients (CR-CRu rate 76%, PFS 72% at 30 months and OS 86% at 30 months) and for the 58 patients younger than 60 years (PFS 78% and OS 86% at 30 months) are very promising for a population in which almost half of the patients have a poor prognosis. The results obtained in the 36 patients (45% of the entire series) of moderate-to-high or high risk according to the aaipi also seem to be good. In this small group, the PFS at 30 months was 62% and the OS was 81%. These results are difficult to compare with previously published data because the studies that have evaluated biweekly chemotherapy in patients with DLBCL included either only patients older than 60 years [7,8] or patients younger than 60 years with a good prognosis [6]. The comparative LNH93-3 study of the Groupe d Etude des Lymphomes del Adulte (GELA) seems suitable for comparing our results in patients with a poor prognosis [18]. The LNH93-3 study included patients up to 60 years with at least two factors of poor prognosis according to aaipi. In this study, the patients treated with biweekly ACVBP chemotherapy (doxorubicin 75 mg/m 2 on day 1, cyclophosphamide 1200 mg/m 2 on day 1, vindesine 2 mg/m 2 and bleomycin 10 mg on days 1 and 5, prednisone 60 mg/m 2 from days 1 to 5, and intrathecal methotrexate 15 mg on day 2) achieved an event-free survival at 30 months of 55% and OS of 65%, figures lower than those obtained in the present study. For patients in CR after the third cycle of chemotherapy we observed a similar evolution than for the whole group. It can be explained by the high number of patients with initial bulky disease (64%) that usually presented a residual mass after the third cycle of treatment (we did not realized a routine PET scan to evaluate early response). These patients with a residual mass were considered in PR after the third cycle of chemotherapy. The toxicity observed in this study was moderate and similar to that communicated in two other prospective trials that have evaluated the toxicity and efficacy of the R-CHOP-14 schedule. The incidence of grade 3 4 neutropenia was 19% and of grade 3 4 infections, 16%. Recently, Brusamolino et al. [17] reported a rate of severe infections of 20% and a rate of grade 3 4 neutropenia of 53% in a similar series of patients. The difference in the incidence of neutropenia in the two studies can be explained by the blood count made every 2 3 days in the study of Brusamolino et al. [17] The rate of grade 3 4 neutropenia was 19% in the study of Rigacci et al. [16] in which blood counts were made only on day 1 of every cycle. In the experience of Brusamolino et al. [17], the most worrisome adverse event was Pneumocystis carinii pneumonia (PCP) which occurred in 6% of patients, in the absence of routine cotrimoxazole prophylaxis; this is at variance with our report and the study of Rigacci et al. [16], in which no unexpected toxicities were documented. In the Memorial Sloan Ketering Cancer Center experience with R-CHOP-14 supported by filgrastim [19], the infectious risk after RCHOP-14 could effectively be managed by the routine use of anti-pcp prophylaxis and by anti-fungal and antiherpes therapy. An important aspect is the RDI of adriamycin and cyclophosphamide achieved in the present study (90% overall and 94% for the first six cycles of treatment). In the RICOVER-60 study, patients treated with six cycles of R-CHOP-14 received a dose intensity of 99% [20]. However, in the two studies published, the dose intensity for six cycles of R-CHOP-14 was 94% [16] and 95% [17], respectively. These differences can be explained by the different schedules of G-CSF used in each study (Table 3) or by the greater experience of DSHNHL in the use of CHOP-14 for the treatment of DLBCL [6,7]. In the present study, filgrastim 5 mg/kg was used for 7 days based on the results of a large randomized study of the adjuvant treatment of operable breast cancer [21]. In this trial, it was possible to administer cyclophosphamide 600 mg/m 2 and adriamycin 60 mg/m 2 every 2 weeks without dose reductions or delays in 95% of the cycles. In conclusion, the administration of six to eight cycles of R-CHOP-14 is safe and efficacious in patients younger than 70 years. This schedule should be compared to the current standard R-CHOP-21 in all age groups and all prognostic groups. Investigation should continue on improving support treatment of dense dose schedules of immunochemotherapy because it seems unlikely that the optimization of G-CSF administration will improve the Table 3. Different G-CSF schedules to support R-CHOP-14 Study G-CSF Dose Duration mrdi (%) Present Filgrastim 5 mg/kg Days RICOVER-60 [20] Filgrastim 5 mg/kg Days Brusamolino et al. [17] Pegfilgrastim 6 mg Day 3 95 Rigacci et al. [16] Lenograstim 300 mg Days mrdi, median relative dose intensity achieved for cyclophosphamide and/or doxorubicin.

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