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1 Annals of Oncology 18: , 2007 doi: /annonc/mdl458 Published online 21 December 2006 Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/ thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hämato-Onkologie OSHO-53 phase II study M. Montemurro 1, T. Kiefer 1, F. Schüler 1, H. K. Al-Ali 2, H.-H. Wolf 3, R. Herbst 4, A. Haas 5, K. Helke 6, A. Theilig 7, C. Lotze 1, C. Hirt 1, D. Niederwieser 2, M. Schwenke 1,8, W. H. Krüger 1 &G.Dölken 1 * For the Ostdeutsche Studiengruppe Hämatologie und Onkologie 1 Department of Internal Medicine C, Hematology and Oncology, Stem Cell Transplantation, Ernst-Moritz-Arndt-University, Greifswald, Germany; 2 Division of Hematology and Oncology, University of Leipzig, Leipzig; 3 Department of Internal Medicine IV, Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle/Saale; 4 Department of Hematology-Oncology-Bone Marrow Transplantation, Chemnitz Hospital, Chemnitz; 5 Department of Internal Medicine, Hematology and Oncology, Hospital Ernst-von-Bergmann, Potsdam; 6 Department of Radiotherapy, Ernst-Moritz-Arndt-University, Greifswald; 7 Department of Neurology, Ernst-Moritz-Arndt-University, Greifswald; 8 Department of Internal Medicine, BFA-Hospital Ückeritz, Ückeritz, Germany Received 13 May 2006; revised 18 October 2006; accepted 25 October 2006 Background: We investigated the efficacy and safety of tandem high-dose methotrexate (HD-MTX) induction followed by high-dose busulfan/thiotepa (HD-BuTT) with autologous peripheral blood stem-cell transplantation (apbsct) and response-adapted whole-brain radiation therapy (WBRT) in patients with newly diagnosed primary central nervous system lymphoma. Patients and methods: Twenty-three patients were treated with HD-MTX on days 1 and 10. In case of at least a partial remission (PR), HD-BuTT followed by apbsct was given. Patients without response to induction or without complete remission (CR) after HD-BuTT received WBRT. Results: Sixteen patients received HD-MTX and HD-BuTT achieving a CR/PR rate of 69%/13%. CR/PR rates for all patients (n = 23) were 70%/13%. There were three deaths during therapy. With longer follow-up three neurotoxic deaths occurred in irradiated patients (n = 9), while no persistent neurotoxicity was seen after HD-BuTT without subsequent WBRT. At a median follow-up of 15 months (range 1 69) median event-free survival (EFS) and overall survival (OS) for all patients were 17 and 20 months (Kaplan Meier), after HD-BuTT 27 months and not reached, respectively. Estimated 2-year EFS and OS were 45% and 48% for all patients versus 56% and 61% for the HD-BuTT group, respectively. Conclusion: MTX induction followed by HD-BuTT is an effective and very short time-on-treatment regimen. Median survival for patients treated with high-dose chemotherapy is not reached yet. The induction regimen needs optimisation. In this study WBRT was associated with a high incidence of severe neurotoxicity. Key words: autologous stem-cell transplantation, CNS lymphoma, high-dose chemotherapy, methotrexate, neurotoxicity, PCNSL original article *Correspondence to: Prof. Dr G. Dölken, Ernst-Moritz-Arndt-Universität Greifswald, Klinik und Poliklinik für Innere Medizin C, Hämatologie und Onkologie Transplantationszentrum, Sauerbruchstraße, Greifswald. Tel: ; Fax ; michael.montemurro@chuv.ch These authors contributed equally to the paper. introduction Primary central nervous system lymphoma (PCNSL) is a rare disease of increasing incidence mainly affecting the elderly [1]. Most PCNSL are classified as diffuse large B-cell lymphomas (DLBCL), supposedly derived from antigen-selected germinal ª 2006 European Society for Medical Oncology

2 centre B cells [2, 3]. Whole-brain radiation therapy (WBRT) with a median survival of months was regarded standard treatment [4] since DeAngelis introduced combined modality treatment (CMT) [5] increasing median survival to months [6 8]. The most effective component of this treatment is high-dose methotrexate (HD-MTX), obviating the need for intrathecal MTX, but its dosage, the optimal number of treatment cycles and cycle length is yet undetermined [9]. The value of combined or sequential addition of other cytostatic drugs and the role of WBRT in achieving and maintaining a response is still under investigation. WBRT fuels an ongoing controversy [10] as it seems to grossly contribute to neurotoxicity affecting up to 90% of the elderly patients [11]. Deferring WBRT until relapse to avoid neurotoxicity was studied and results approached those of combined modality treatment [12, 13]. In further reducing neurotoxicity, HD-MTX monotherapy was investigated and showed response rates up to 100% and estimated median survival of 30 months with low acute and long-term toxicity [14, 15]. But, as recently shown, HD-MTX monotherapy could also compromise results with a low 35% response rate and short relapse-free survival of 13.7 months even for patients in CR after treatment [16], calling for additional measures to increase response and prevent relapses. Deducted from the excellent treatment results in systemic lymphomas such measures could be high-dose chemotherapy (HDC) and autologous transplantation, CNS tailored with blood brain barrierpenetrating lipophilic drugs, e.g. busulfan and thiotepa. Few data only are published for high-dose therapy in PCNSL showing response rates of 100% [17], 82% [18] and median overall survival (OS) up to 91 months [19] in a poor prognosis group of patients. The herein presented multicenter OSHO-53 study (Ostdeutsche Studiengruppe Hämatologie und Onkologie) investigates a time- and dose-intense treatment regimen in patients with PCNSL. The study was designed to obtain a high CR rate and long-term remission by combining two courses of induction HD-MTX with consolidating HD-BuTT, but to avoid the neurotoxic WBRT for patients in CR after chemotherapy. patients and methods eligibility criteria and baseline evaluation Inclusion criteria were histologically confirmed newly diagnosed non- Hodgkin s lymphoma of the CNS, biological age years, minimum Karnofsky score 50% (CNS any), exclusion of infection with hepatitis B virus, hepatitis C virus (HCV), human immunodeficiency virus, previous malignant disease and absence of severe comorbidity; patients with heart, lung, kidney or liver disease had to be excluded. Systemic lymphoma had to be excluded by bone marrow examination, thoracic computed tomography scan and abdominal ultrasound as minimal requirements. Positron emission tomography scans were not done. The following ranges for laboratory parameters were required: creatinine 150% of the upper normal value, creatinine clearance at least 70 ml/min, bilirubin, alanine aminotransferase and aspartate aminotransferase 200% of the upper normal value, haemoglobin level 90 g/l, platelet count /ll and leucocyte count 1500/ll. Inclusion and exclusion criteria were assessed by the responsible physician at the site of treatment. All decisions regarding the treatment were left to the discretion of the treating physician and followed guidelines of the participating centre. The protocol was reviewed and approved by the local institutional review boards. Prior enrolment voluntary, informed and written consent was obtained from all patients. treatment Treatment consisted of a 4-h infusion of HD-MTX (8 g/m 2 ) on days 1 and 10 followed by leukapheresis. Patients >60 years received 6 g/m 2 MTX. Leucovorin rescue started 24 h after administration of MTX. All patients received filgrastim starting on day 4 or 14. Initial response assessment was scheduled for day 20. Patients in stable or progressive disease (PD) after induction of HD-MTX received WBRT. Patients in complete or partial remission (CR/PR) continued with HD-BuTT starting from day 20 to 28. Busulfan was given orally in four daily doses at a dose of 4 mg/kg body weight (BW) per day from day ÿ8toÿ5, thiotepa 5 mg/kg BW on days ÿ4 to ÿ3. Stem-cell transplantation was on day 0, followed by stimulation of haematopoiesis with filgrastim. Patients with a complete remission received no further treatment. Patients without complete remission underwent WBRT (Figure 1). Irradiation was delivered in a helmet field technique with the caudal border between C2 and C3 in fractions of 1.8 Gy five times per week to a total of 45 Gy. Supportive therapy and antiinfectious prophylaxis followed local standard. Neuroimaging was scheduled after each treatment phase to assess response, on day 21 after stem-cell reinfusion and on day 100 of therapy by magnetic resonance imaging (MRI). Follow-up evaluation was scheduled every 3 months for 2 years, then biannually for another 3 years. An MRI of the head was obtained on each visit. Chest X-ray and abdominal ultrasound were minimal requirements for relapse screening. n=23 n=23 n=20 OP / biopsy d1: 8g/m 2 HD-MTX d10: 8g/m 2 HD-MTX CR PR n=16 CR=3 PR=11 NC=1 PD=1 CR=2 PR=5 d20-28: HD Busulfan/Thiotepa (Bu=16mg/kgBW / TT=10mg/kgBW) autologous PBSCT CR = 11 CR=1 (hep+muc III) WBRT CR PR=1 (hep III) HDC NC=1 (ARF) WBRT SU NC=4 WBRT CR=2 PR=2 TRD=1 TRD=2 PR NC,PD PR=2 PD=1 WBRT 45Gy CR=2 PR=1 Annals of Oncology Figure 1. Treatment outline and patient flow. After diagnosis two doses of HD-MTX were given. Evaluation is scheduled after the second dose of MTX and after HD-BuTT. Patients in CR/PR proceed with HD-BuTT, the other patients receive WBRT. If CR is achieved after HD-BuTT then treatment is finished, otherwise patients undergo WBRT. HD-BuTT is scheduled to start between day 20 and day 28. HD-BUTT: Cumulative doses were given. OP, operation; CR, complete remission; PR, partial remission; HD-MTX, high-dose methotrexate; hep, hepatic toxicity; muc, mucosal toxicity; WBRT, whole-brain radiation therapy; HDC, high-dose chemotherapy; NC, no change; ARF, acute renal failure; SU, status unknown; TRD, treatment-related death; PD, progressive disease; BW, body weight; PBSCT, peripheral blood stem-cell transplantation. 666 Montemurro et al. Volume 18 No. 4 April 2007

3 Annals of Oncology An extended screening for somatic toxicity was performed yearly. Carbamazepin was recommended as anticonvulsant therapy throughout the treatment since October 2001 as some patients had experienced hepatic toxicity while on phenytoin. response evaluation End points of this multicenter phase II study were the rates of remission achieved at each treatment step, survival and toxicity. CR required the complete resolution of contrast enhancing lesions, PR a reduction by more than 50% and progressive disease anenlargement of contrast-enhancing lesions by more than 25%. All other situations were considered no change (NC). Toxicity was graded according to World Health Organisation criteria. All survival data were calculated from the day of first treatment. Any progression, relapse or death due to lymphoma or therapy were considered events in the event-free survival analysis. Patients who died of causes unrelated to PCNSL or its treatment were censored at the date of death (Table 2, second patient). All events within 30 days of administration of chemotherapy were regarded as treatment related regardless of the causality and at any time if causality to treatment was assumed. Analysis was performed on the principle of intention-to-treat, if not otherwise stated. In November 2004, the study was closed as both the planned number of enrolled patients and the prespecified stopping rule for treatment-related deaths were met. Follow-up extends through July results patients characteristic Twenty-three patients, 11 women and 12 men, were enrolled in this study from August 1999 to November 2004 at five participating centres, three university hospitals and two large academic teaching hospitals. Median age was 55 years (range 18 69), median Karnofsky performance score 70% (range ) and median Ferreri score 3 (range 0 5) [20]. No patient had intraocular lymphoma or evidence of systemic lymphoma at the time of enrolment. All patients underwent thoracoabdominal CT scanning for initial staging. Twenty-two patients had histologically confirmed DLBCL, one patient an unclassified T-cell lymphoma. Two patients achieved CR and five patients PR after neurosurgical intervention. The time to diagnosis varied from 0 to 721 days with a median of 45 days. In one case, PCNSL was detected incidentally by MRI carried out for other reasons. Details are given in Tables 1 and 2. treatment results and toxicity All patients received the first cycle of MTX induction after a median time from biopsy of 19 days (range 0 57). HD-MTX induced response in 16 patients. One bedridden patient with deep vein thrombosis died 26 days after second MTX due to pulmonary embolism and right heart failure. Six patients were excluded from HD-BuTT [renal failure = 1, liver toxicity = 1, no change (NC) = 4] and received WBRT. Sixteen patients received HD-BuTT, including two cases of protocol violation [NC = 1, progressive disease (PD) = 1 after HD-MTX]. A complete remission was seen in 11 of these patients (69%). These patients did not receive any further protocol/study treatment. Two patients died during HD-BuTT of infectious causes 6 and 36 days after autologous stem-cell transplantation. A median of CD34 + cells/kg BW (range 2 9) were given with leucocyte recovery >1000/ll on day 8 (median, range 7 12) and thrombocyte recovery of >50,000/ll on day 11 (median, range Table 1. Patient characteristics Characteristic Value No. of patients Gender Male 12 Female 11 Age (years) Median 55 Range >60 years 7 KPS (%) Median 70 Range >70% 11 LDH Elevation 15 % of UNV median 161 % of UNV range DBSI 14 CSF protein concentration Elevation 11 Normal 4 Not determined 8 Multilocular PCNSL 12 Neurosurgical technique Stereotactical biopsy 14 Resection 9 KPS (%) patients alive Median Neurotoxicity after treatment Affected patients 9 WBRT, no relapse 6 WBRT and relapse 2 Neurotoxic death 3 KPS, Karnofsky performance score; LDH, lactate dehydrogenase; UNV, upper normal value; DBSI, deep brain structures involvement; CSF, cerebrospinal fluid; PCNSL, primary CNS lymphoma; WBRT, whole-brain radiotherapy. 8 15). Two patients in PR and one patient with progressive disease after HD-BuTT received response-adapted WBRT leading to an additional two complete and one partial responses, respectively. A total of nine patients were irradiated (NC after HD-MTX = 4, due to MTX toxicity = 2, post-hd-butt = 3) (See Figure 1 for flow of patients and Table 3). Treatmentassociated toxicity was seen in 16 patients (Table 2) but changed the treatment course in three patients only (Figure 1). Three irradiated patients died of neurotoxicity at 6, 10 and 27 months. response rates and survival data Overall CR/PR rates were 70%/13% (n = 23) herein included the patients with early WBRT carried out because of MTX-related toxicity (n = 2) or because of NC or PD after HDMTX (n =4) and patients with WBRT after HDC (n = 3). At a median follow-up of 15 months, the median OS and EFS were 20 and 17 months for all patients, for patients treated with HD-BuTT not reached and 27 months, respectively. Two-year OS and EFS were 48% and 45% for all patients, 61% and 48% for the HD-BuTT group, respectively (Figure 2). Volume 18 No. 4 April 2007 doi: /annonc/mdl

4 668 Montemurro et al. Volume 18 No. 4 April 2007 Table 2. Patient data Age/sex KPS (%) F-score DP MTX/Tox HD-BuTT/Tox WBRT Neuro-Tox Relapse progress LFU/status/CoD KPS (%) Remarks 42/f CR CR/hep III CR No 69 months/cr, alive 100 RPA 67/m 80 4 PR PR/hep III, hem III CR/muc III, colitis III No 47 months/cr, dead/ pneumonia 42 months: gastric cancer, no autopsy 51/f 80 3 NC PR/hep III CR No 52 months/cr, alive 100 RPA 48/m CR CR/hep III CR No 49 months 04/05: testicular relapse, ongoing R-CHOP 52 months/cerebral CR, alive 100 RPA 58/m 60 4 NC PR PR CR Yes 27 months/cr, dead/ No autopsy neurotoxicity 40/m 80 4 NC PD CR/convulsion, No 47 months/cr, alive 100 RPA, post MTX:PD/HDC infect IV, vent 4d 60/m 60 4 NC PR/myocardial. infarction CR No 6 months: syst relapse, 8 R-CHOP,CR 40 months/cr, alive 70 Incomplete hemiparesis, aphasia 53/f 70 na PR PR/DVT PR CR Yes 35 months/cr, alive 60 56/m 40 3 NC PR/septic shock, hemorrhage shock CR No 9 months/cr, alive 80 Retroperit.haematoma/persistent lesion of plexus lumbosacralis 48/f 70 na NC NC CR Yes 17 months: cerebral relapse, no therapy 19 months/pd, dead No autopsy 68/f 90 2 PR PR CR/Extrapyr. symptoms Yes 9 months: cerebral relapse, WBRT 12 months/su, dead No autopsy 56/m 90 2 NC NC, DVT, PE, No Day 26 post-mtx/nc, Autopsy RHF, death dead/pe 63/m 70 4 NC NC PD/mucositis III PR Yes 6 months/pr, dead/ neurotoxicity T-cell NHL; post-mtx:nc/ HDC, no autopsy 66/m 70 5 NC CR/hep III, laryngitis III CR Yes 20 months/cr, dead/neurotoxicity 1 MTX only, no autopsy 61/f 40 na PR PR/hep III CR/pneumoniaIV, vent4d No 3 months/cr, dead/pneumonia 1 MTX only, no autopsy 63/f 90 na NC NC CR Yes 9 months: syst relapse, 19 months/ No autopsy 1 R-CHOP/CR CR, dead 55/m 70 3 NC NC acute Yes 3 months/su, dead/ 1 MTX only renal failure cardiac/pe 18/f 30 2 NC CR/muc IV, infect III CR/muc IV, infect III Yes 5 months: cerebral relapse, 2 R-DHAP/CR 10 months/cr, dead/ pneumonia Time to diagnosis = 2 years, no autopsy 52/m 90 2 PR PR/muc IV, hep III SU, septic MOF, death Day 36 HDC/SU, dead/septic MOF No autopsy 54/f 80 na NC NC CR Yes 18 months/cr, alive 80 69/f 70 3 NC PR CR No 20 months/cr, alive 70 RPA 51/f 70 na NC PR SU, septic MOF, death Day 6/SU, dead/ No autopsy septic MOF 52/m 90 2 NC NC PR No 11 months/cr, alive Gy WBRT only, followed by 4 HD-AraC KPS, Karnofsky performance score; F-score, prognostic index (Ferreri et al. JCO 2003); DP, diagnostic procedure (operation/biopsy) reported is the best result after the respective intervention or treatment, followed by a description of toxicity (tox); na, not available; CR, complete remission; PR, partial remission; NC, no change; PD, progressive disease; MTX, methotrexate; HD-BuTT, high-dose busulfan/thiotepa; extrapyr., extrapyramidal; WBRT, whole-brain radiation therapy; ÿ, not applicable; Neuro-Tox, clinically relevant neurotoxicity; Relapse/progress, time of relapse or progression after initial treatment, salvage therapy and response to salvage therapy; LFU, length/status last follow-up; CoD, cause of death; hep, hepatic; hem, haematologic; RPA, patient resumed previous daily/professional activities; muc, mucositis; R-CHOP, rituximab-combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone; PD, progressive disease; syst, systemic; DHAP, combination chemotherapy with dexamethasone, high-dose cytosinarabinosid and cisplatin; HDC, high-dose chemotherapy; infect, infection; vent, ventilation (invasive and noninvasive); DVT, deep vein thrombosis; SU, remission status unknown; PE, pulmonary embolism; RHF, right heart failure; MOF, multi organ failure including ventilation; HD-AraC, high-dose cytosinarabinosid. Annals of Oncology

5 Annals of Oncology % Figure 2. Overall survival. Survival was strongly determined by toxicity, response to HD-MTX and treatment with HD-BuTT. Early toxic deaths and fatal neurotoxicity in irradiated patients accounted for the disappointing short-term results while encouraging long-term results were determined by responders to HD-BuTT. The latter group showed no clinical signs of neurotoxicity and resumed their previous daily or professional activities. There were three systemic relapses 6, 9 and 49 months after start of therapy, two successfully treated with rituximab-combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) polychemotherapy, one patient with testicular relapse receiving ongoing treatment with rituximab- CHOP (staging testicular ultrasound was negative). Upon univariate analysis, we found no correlation of LDH, involvement of deep brain structures, multilocular manifestation or Karnofsky performance score with outcome. There were no significant differences between patients >60 years and younger patients (P = 0.42, log-rank test). Patients not receiving HD-BuTT had a dismal prognosis with no patient alive beyond 19 months on Kaplan Meier analysis of OS (Figure 2). discussion no HD-BuTT 24 This multicenter phase II trial investigated the efficacy and safety of tandem HD-MTX induction followed by HD-BuTT and autologous peripheral stem-cell transplantation as primary treatment of PCNSL. On the basis of the promising pilot data of HD-MTX therapy [14, 21, 22] and pharmacokinetic considerations [23], we chose a time-intense tandem 8 g/m 2 HD-MTX as induction therapy. We expected a response rate >80% and therefore most patients to undergo HD-MTX followed by HD-BuTT. HD-BuTT was chosen because of encouraging pilot data [24] with busulfan [25] and thiotepa [26] achieving high cerebrospinal fluid levels. Unexpectedly, in our group the CR rate after HD-MTX induction was 17% only with two toxicity-related drop outs and one treatment-related death. This differs from the 65% CR rate in a single-institution study [14] and the 52% CR rate [15] in a multicenter setting, while a German multicenter study [16] achieved a 30% CR rate only with a similar regimen. Differences 36 Months 48 p= 0.15 HD-BuTT in the number of MTX cycles given, namely two cycles in this study, a median three cycles in the NOA-3 study [16] and a median six cycles to best response in the NABTT-trial [15] might account for differing response rates and underline the problems with cross-study comparisons (NOA, Neuroonkologische Arbeitsgemeinschaft, Germany; NABTT, New Approaches to Brain Tumor Therapy, USA). Sample size bias or chance differences, however, cannot be ruled out. Although there were no obvious differences in eligibility criteria, especially renal function, MTX-infusion or leucovorin rescue [16] we cannot rule out differences in MTX metabolism. First, assessment of renal function is notoriously difficult and subject to great variability [27], but important, as MTXclearance and MTX-area under the curve correlate to rates of response and toxicity [28]. Secondly, drug interactions could increase the level of active MTX and its metabolites not determined by standard assays as shown, e.g. for pantozole [29]. Furthermore, differences in MTX-metabolising methionin synthase could account for differing toxicity [30] and outcome [31]. The treatment-related mortality (TRM) in this study was higher than that reported for HDC of entities other than PCNSL, but usually a Karnofsky index below 70% is an exclusion criterion in such protocols [32, 33]. Even after conventional chemotherapy, patients with PCNSL suffer from higher TRM than patients with peripheral lymphoma. Therefore, the herein reported 13% treatment-related deaths were in line with the previously reported 5% 29% TRM rates [6, 9, 12, 34, 35]. One reason for the high TRM might be the high grade of immobilisation of patients with PCNSL. In particular, the occurrence of pulmonary embolism in two of 23 patients and one fatal pneumonia in this study cohort might have resulted from this feature. Pels et al. [12] described three of 65 patients experiencing deep venous thrombosis, Poortmans et al. [6] thromboembolic complications in four of 52 and Calderoni and Aebi [34] one treatment-related death caused by pulmonary embolism in 14 patients. In this study eight of nine irradiated patients developed clinically relevant neurotoxicity, leading to death in three patients. Resource intense, individualised neuropsychological testing was not performed in this phase II study because we did not expect to generate meaningful data. One patient received only 31 Gy and showed no neurotoxicity at a follow-up of 11 months. The NOA-03 investigators report a 58% neurotoxicity rate in irradiated patients versus 10% in nonirradiated patients [36], confirming our assumption that WBRT should be avoided in first-line therapy of PCNSL and postponed until relapse. This approach of deferred radiotherapy does not compromise the efficacy of WBRT as recently shown [13, 36]. HD-BuTT was a very effective component of our treatment plan that increased CR rates from 17% to 48% (n = 23) and was able to induce a CR in a patient with progressive disease. The CR rate is 69% for the 16 patients treated with HD-BuTT. There were no signs of clinical neurotoxicity after HD-BuTT and therefore five out of seven nonirradiated patients alive at the time of this analysis returned to their previous daily or professional activities. Furthermore, duration of treatment is very short, that being by itself an important aspect of patients quality of life. Another advantage of this treatment strategy is Volume 18 No. 4 April 2007 doi: /annonc/mdl

6 that it does not require a maintenance therapy [15, 16] and therefore is finished after 2 3 months only. The 2-year OS rates of our study were 48% for all and 61% for HD-BuTT patients at a median follow-up of 15 months. For the group of patients who underwent HD-BuTT, median OS was not reached yet. Other groups investigating HDC have reported a median OS of 24 months [17] and 91 months [19], the latter being the longest OS reported yet for PCNSL to our knowledge. Illerhaus et al. [37] recently reported an OS of 64% for all patients, and 81% for the patients who received the planned HD-MTX/HD-AraC/ thiotepa induction followed by HD-camustine-thiotepa/ autologous peripheral blood stem-cell transplantation and consolidating WBRT, at a median follow-up of 37 months. In contrast to the general notion that age is a strong prognostic factor in PCNSL [7, 12, 20], we found no outcome differences between patients >60 years and younger patients (P = 0.42, log-rank test), but this might be a chance finding due to the small number of patients treated. We conclude that primary high-dose therapy for PCNSL is a promising approach with good response rates, without severe neurotoxicity when WBRT avoided, and safely applicable even in the elderly. This and the short duration of therapy have substantially contributed to the patients quality of life. But it has to be pointed out that tandem induction therapy with HD-MTX alone seems to be insufficient and should be improved. Future trials investigating high-dose chemotherapy should include a more powerful induction therapy, but should avoid radiotherapy of the brain [38]. acknowledgements We thank Röth (University Hospital Essen) for critical comments and our colleagues in private oncology practice Aldaoud/Schwarzer (Leipzig) and Grundeis (Chemnitz) for meticulous patient follow-up. This article is dedicated to Frieda Rodemerk. The study has been presented in part at meetings of the Ostdeutsche Studiengruppe Hämatologie und Onkologie and the Deutsche Gesellschaft für Hämatologie und Onkologie. references 1. Olson JE, Janney CA, Rao RD et al. The continuing increase in the incidence of primary central nervous system non-hodgkin lymphoma a surveillance, epidemiology, and end results analysis. Cancer 2002; 95: Montesinos-Rongen M, Kuppers R, Schluter D et al. Primary central nervous system lymphomas are derived from germinal-center B cells and show a preferential usage of the V4-34 gene segment. 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7 Annals of Oncology 27. Manjunath G, Sarnak MJ, Levey AS. Estimating the glomerular filtration rate dos and don ts for assessing kidney function. Postgrad Med 2001; 110: Ferreri AJM, Guerra E, Regazzi M et al. Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas. Br J Cancer 2004; 90: Troger U, Stotzel B, Martens-Lobenhoffer J et al. Severe myalgia from an interaction between treatments with pantoprazole and methotrexate. Br Med J 2002; 324: Linnebank M, Pels H, Kleczar N et al. MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology 2005; 64: Ferreri AJM, Dell Oro S, Capello D et al. Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas. Br J Haematol 2004; 126: Armitage JO. High-dose chemotherapy and autologous hematopoietic stem cell transplantation: the lymphoma experience and its potential relevance to solid tumors. Oncology 2000; 58: Gisselbrecht C. Autologous stem cell transplantation in aggressive non-hodgkin s lymphoma. Hematol Cell Ther 1996; 38: Calderoni A, Aebi S. Combination chemotherapy with high-dose methotrexate and cytarabine with or without brain irradiation for primary central nervous system lymphomas. J Neurooncol 2002; 59: Depil S, Coiteux V, Guillerm G et al. Primary central nervous system lymphoma in immunocompetent adults: poor results mainly associated with high treatment related toxicities. Leuk Lymphoma 2002; 43: Herrlinger U, Kuker W, Uhl M et al. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 2005; 57: Illerhaus G, Marks R, Derigs G et al. Primary CNS lymphoma: results of a multicenter phase ii study including high-dose-chemotherapy with autologous PBSCT and hyperfractionated radiotherapy as first-line-therapy. Ann Oncol 2005; 16: v Herrlinger U, Korfel A, Hebart H et al. Meeting report: primary central nervous system lymphoma: standards of care and future perspectives. Onkologie 2005; 28: Volume 18 No. 4 April 2007 doi: /annonc/mdl