Background We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. Patients and methods From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. Results Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. Conclusions Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of lif

Al-Ali, H. K.

Busemann, C.

Dölken, G.

Helke, K.

Herbst, R.

Hirt, C.

Kessler, C.

Kiefer, T.

Kirsch, M.

Krüger, W. H.

Maschmeyer, G.

Montemurro, M.

Niederwieser, D.

Schroeder, H.

Schüler, F.

Späth, C.

Vogelgesang, S.

Wolf, H.-H

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Annals of Oncology 23: 1809–1812, 2012doi:10.1093/annonc/mdr553Published online 24 November 2011Long-term follow-up of high-dose chemotherapy withautologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosedprimary CNS lymphoma: results of the multicenterOstdeutsche Studiengruppe Hämatologie undOnkologie OSHO-53 phase II studyT. Kiefer1*, C. Hirt1, C. Späth1, F. Schüler2,3, H. K. Al-Ali2, H.-H. Wolf4, R. Herbst5,G. Maschmeyer6, K. Helke7, C. Kessler8, D. Niederwieser2, C. Busemann1, H. Schroeder9,S. Vogelgesang10, M. Kirsch11, M. Montemurro12, W. H. Krüger1 & G. Dölken1 for the OstdeutscheStudiengruppe Hämatologie und Onkologie1Department of Internal Medicine C, Haematology and Oncology, Stem Cell Transplantation, Ernst Moritz Arndt University, Greifswald; 2Division of Haematology andOncology, University of Leipzig, Leipzig; 3Department of Haematology and Oncology, DRK-Krankenhaus Luckenwalde, Luckenwalde; 4Department of Internal MedicineIV, Haematology and Oncology, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale; 5Department of Haematology and Oncology/Bone Marrow Transplantation,Chemnitz Hospital, Chemnitz; 6Department of Haematology, Oncology and Palliative Care, Hospital Ernst von Bergmann, Potsdam; 7Departments of Radiotherapy;8Neurology; 9Neurosurgery; 10Neuropathology; 11Diagnostic Radiology and Neuroradiology, Ernst Moritz Arndt University, Greifswald, Germany; 12ComprehensiveCancer Center, University Hospital Lausanne (Centre Hospitalier Universitaire Vaudois), Lausanne, SwitzerlandReceived 5 October 2011; accepted 11 October 2011Background: We previously reported the results of a phase II study for patients with newly diagnosed primary centralnervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results.Patients and methods: From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partialremission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to inductionor without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-lifequestionnaire (QLQ)-C30 were carried out.Results: Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alivewith a severe neurologic deﬁcit. In seven of eight patients treated with HD-BuTT, health condition and quality of life areexcellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of themhave a Karnofsky score of 90%–100%.Conclusions: Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, nolong-term neurotoxicity has been observed and all patients have an excellent quality of life.Key words: autologous stem-cell transplantation, long-term follow-up, methotrexate, neurotoxicity, primary CNSlymphomaintroductionPrimary central nervous system lymphoma (pCNSL) is a raremalignant non-Hodgkin’s lymphoma of B-cell origin. Whole-brain radiotherapy (WBRT) as the sole treatment modality isassociated with an overall response rate of up to 90% but a veryhigh relapse rate and a median overall survival (OS) of 1 year.In addition, WBRT is associated with an increased likelihoodof treatment-related toxicity, especially in patients >60 years[1]. To improve these results, WBRT has been combined withhigh-dose methotrexate (HD-MTX), the most effectivechemotherapeutic agent for pCNSL. Combination ofmethotrexate (MTX) and WBRT increased the 2-year survival*Correspondence to: Dr T. Kiefer, Department of Internal Medicine C, Haematology andOncology, Stem Cell Transplantation, Palliative Care, Ernst Moritz Arndt University,Sauerbruchstrasse, 17475 Greifswald, Germany. Tel: +49-3834-866698; Fax: +49-3834-866713; E-mail: kiefer@uni-greifswald.deAnnals of Oncology original articles© The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.from 43% to 73% [2]; however, the combination of MTX andWBRT is associated with a high risk of delayed neurotoxicity,primarily in elderly patients [3]. To avoid neurological deﬁcits,we initiated a phase II study [Ostdeutsche StudiengruppeHämatologie und Onkologie (OSHO)-53 study] for patientswith newly diagnosed pCNSL to be treated with high-dosebusulfan/thiotepa (HD-BuTT) followed by autologousperipheral blood stem-cell transplantation (aPBSCT) andresponse-adapted WBRT after induction therapy with HD-MTX. The results of this study were published in 2006 [4].Here, we give a long-term follow-up after >10 years after studyinitiation.patients and methodsTwenty-three immunocompetent patients with histological diagnosis ofpCNSL received HD-MTX. Patients that achieved a complete remission(CR) or partial remission received HD-BuTT with aPBSCT. Patients in CRafter high-dose chemotherapy received no further treatment, all others weretreated with whole-brain irradiation. Patient characteristics and the detailsof the study protocol have been reported [4]. All living patients have beencontacted now to evaluate OS and Mini-Mental State Examination(MMSE) to assess a possible cognitive deﬁciency. Maximum score for nomental restriction is 30 points. A quality-of-life questionnaire (QLQ)-C30was used to assess quality of life. Twenty-eight points indicate the bestpossible quality of life. The number of points is inversely correlated withthe quality of life.resultsIn our initial publication in 2006, we showed the results after afollow-up range of 1–69 months [4]. Median follow-up now is26 months (range 1.4–141). Eight of the 23 patients enrolled inthis study are still alive, while 15 patients died. Causes of deathwere multiorgan failure (two patients), neurological toxicity(three patients after WBRT), pneumonia (three patients; 3, 10,and 47 months after diagnosis), pulmonary embolism (twopatients; 3 and 26 months after start of therapy) (Table 1).Fatal relapses occurred in ﬁve patients. All relapses emergedlater than 12 months from diagnosis (12, 19, 19, 38, and 58months). One testicular relapse occurred 4 months afteraPBSCT. The patient received chemotherapy (R-CHOP) and isalive and in CR, 115 months after diagnosis of pCNSL. Oneadditional relapse occurred 103 months after therapy; rescueTable 1. Patient characteristics including the results of quality-of-life measurementAge/sex HD-BuTT WBRT Neurotoxicity LFU/status/CoD MMSE QLQ-C30Remarks67/male + − − 47 months/CR, dead/pneumonia – –58/male + + + 27 months/CR, dead/neurotoxicity – –48/female − + + 19 months/PD, dead/relapse – –68/female + − + 12 months/SU, dead/relapse – –56/male − − − Day 26 after MTX/NC, dead/PE – –63/male + + + 6 months/PR, dead/neurotoxicity – –66/male − + + 20 months/CR, dead/neurotoxicity – –61/female + − − 3 months/CR, dead/pneumonia – –63/female − + + 19 months/CR, dead/relapse – –55/male − + − 3 months/SU, dead/cardiac/PE – –18/female + − + 10 months/CR, dead/pneumonia – –52/male + − − 1 month/SU, dead/septic MOF – –51/female + − − Day 6/SU, dead/septic MOF – –52/male − + − 58 months/CR, dead, relapse – –53/female + + + 38 months/CR, dead, relapse – –42/female + − − 141 months/CR, alive n.e. n.e. Gall-bladder carcinoma51/female + − − 123 months/relapse → CR, alive 24 33/28 CR after relapse, follow-up 5months48/male + − − 123 months/CR, alive 30 35/2840/male + − − 118 months/CR, alive 29 28/2860/male + − − 4 months after HDC testicular relapse, salvagetherapy/115 months/CR, alive28 40/2856/male + − − 79 months/CR, alive 27 40/2854/female − + + 88 months/CR, alive 20 60/28 Severe neurological deﬁcit69/female + − + 93 months/CR, neurological deﬁcit, alive 17a 41a/28 Lost to follow-up, last follow-upNovember 2009aData from November 2009.CoD, cause of death; CR, complete remission; HD-BuTT, high-dose busulfan/thiotepa; HDC, high-dose chemotherapy; LFU, length/status of last follow-up;MMSE, Mini-Mental State Examination; MOF, multiorgan failure including ventilation; MTX, methotrexate; NC, no change; n.e., not evaluable;neurotoxicity, clinically relevant neurotoxicity; PD, progressive disease; PE, pulmonary embolism; PR, partial remission; QLQ, quality-of-life questionnaire;SU, remission status unknown; WBRT, whole-brain radiotherapy.original articles Annals of Oncology | Kiefer et al. Volume 23 | No. 7 | July 2012therapy (carmustine/thiotepa followed by aPBSCT) has led to aCR lasting now for 5 months. In another patient, a carcinomaof the gall-bladder was detected and she is still receivingchemotherapy. The remaining six patients are in CR. The OSand time to treatment failure, deﬁned as relapse or death dueto pCNSL or treatment-related causes of all patients, are shownin Figure 1. The results from the questionnaires (MMSE andQLQ-C30) are shown in Table 1. Except for one femalepatient, all patients who did not receive WBRT revealedexcellent results upon examination, i.e. between 24 and 30points in the MMSE (median 28 points) and between 33 and40 points (median 35 points) in the QLQ-C30 with norestriction reported in their daily life due to neurologicaldeﬁcits. A 69-year-old female patient with neurological deﬁcitsdespite no irradiation is the oldest patient in this trial andactually lost to follow-up. In November 2009, we were able tocarry out the tests and she showed MMSE only of 17 pointsbut 41 points in QLQ-C30. She needed no help to dress up,was able to wash herself, and could independently go for awalk. She was living with her daughter and both were quitesatisﬁed. The patient who got WBRT reached only 20 points inthe MMSE. Most of the day, she was sitting in a chair due tosevere neurological deﬁcit. She needed help to dress up, wasnot able to wash herself, and was visited two times a day by anurse. QLQ-C30 of this patient shows 60 points, whichdocuments restricted quality of life, but the patient told us tobe satisﬁed with her health and quality of life. Upon univariateanalysis, we found a correlation of the length of the intervalbetween initial diagnosis and initiation of HD-MTX therapywith outcome. If the period exceeded 20 days, there was asigniﬁcantly worse OS (log-rank test, chi-square test, P = 0.046)(Figure 2). No signiﬁcant impact of age (>/< 60 years), gender,initial Karnofsky score (>/< 70%), initial lactate dehydrogenaselevel of serum, and time between the ﬁrst and the second HD-MTX cycle was seen.discussionIn this article, we report a long-term follow-up of patients withpCNSL having been treated in the OSHO-53 study. When westarted this study in 1999, the main question we wanted toanswer was whether patients with pCNSL receiving two cyclesof HD-MTX followed by HD-BuTT with aPBSCT have asurvival rate comparable with studies using chemotherapy plusWBRT regularly. In order to achieve a high tumoricidalimpact, we have chosen a dose-dense protocol including twocycles of HD-MTX and HD-BuTT with aPBSCT within 28days. As shown by univariate analysis (Figure 2), it isimportant to treat patients with pCNSL as soon as possibleafter diagnosis. We hoped to show that by omitting WBRT,less neurotoxicity can be observed and a better quality of lifelater on can be achieved. Analyzing our data 10 years afterinitiating the study, we see an OS of 35%, which is not inferiorto other studies using a combination of chemotherapy andWBRT. Blay et al. [3] shows a 5-year survival of 19%,Poortmans et al. [5] 58% OS after 3 years, and DeAngelis et al.[6] 30% after 5 years. In addition, Thiel et al. [7] reportedrecently no signiﬁcant difference in OS when WBRT wasomitted from ﬁrst-line chemotherapy in patients with newlydiagnosed pCNSL. In this study, a HD-MTX-basedchemotherapy was used without aPBSCT. In order toinvestigate the long-term neurotoxicity in our study protocol,we analyzed the MMSE and QLQ-C30. The patient that wastreated with WBRT because of a lack of response to HD-MTXshows severe neurological deﬁcits. Her daily activity ismarkedly reduced as described above. Results from MMSE andQLQ-C30 show very bad results. Of the remaining sevenpatients that were treated with HD-BuTT, questionnaires couldonly be completed by ﬁve patients. The patient with therecently diagnosed gall-bladder carcinoma denied toparticipate. Another patient has moved to an unknown place,but in November 2009, she ﬁlled out the questionnaires with abad MMSE but a good QLQ-C30 result.As described in other studies, late relapses are notuncommon [5, 8, 9]. We saw the latest relapse after >100months, which underlines the importance of regular and long-lasting follow-up, since a promising salvage therapy is available[10–14].One systemic relapse in the testis occurred and could besuccessfully managed with R-CHOP chemoimmunotherapy.In summary, the results of this study show that HD-MTXwith HD-BuTT followed by aPBSCT results in long-termdisease control in about one-third of the patients. Most ofFigure 1. Overall survival (OS) and time to treatment failure (TTF) of all23 patients who had been enrolled in the study. Treatment failure wasdeﬁned as relapse or death due to primary central nervous systemlymphoma or treatment-related reasons.Figure 2. Overall survival depending on the time interval between initialdiagnosis and start of therapy with high-dose methotrexate. Log-rank test,P = 0.046, standard error of the mean, SEM.Annals of Oncology original articlesVolume 23 | No. 7 | July 2012 doi:10.1093/annonc/mdr553 | them show no compromising cognitive functions and have anexcellent quality of life. These long-term results supportongoing treatment efforts aiming to increase the tumor-eradicating potential of primary therapy, to minimize earlymortality, and to avoid neurotoxicity due to WBRT. Addingrituximab, cytarabine, and thiotepa to HD-MTX, the ongoingrandomized trial NCT01011920, initiated by A. Ferreri, willhelp to establish a more effective therapy strategy before high-dose chemotherapy and aPBSCT.disclosureThe authors declare no conﬂict of interest.references1. Nelson DF, Martz KL, Bonner H et al. Non-Hodgkin’s lymphoma of the brain: canhigh dose, large volume radiation therapy improve survival? Report on aprospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. IntJ Radiat Oncol Biol Phys 1992; 23: 9–17.2. Ferreri AJ, Abrey LE, Blay JY et al. Summary statement on primary central nervoussystem lymphomas from the Eighth International Conference on MalignantLymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 2003; 21:2407–2414.3. Blay JY, Conroy T, Chevreau C et al. High-dose methotrexate for the treatment ofprimary cerebral lymphomas: analysis of survival and late neurologic toxicity in aretrospective series. J Clin Oncol 1998; 16: 864–871.4. Montemurro M, Kiefer T, Schuler F et al. Primary central nervous systemlymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa,autologous stem-cell transplantation and response-adapted whole-brainradiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study. Ann Oncol 2007; 18: 665–671.5. Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H et al. High-dosemethotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization forResearch and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J ClinOncol 2003; 21: 4483–4488.6. DeAngelis LM, Seiferheld W, Schold SC et al. Combination chemotherapy andradiotherapy for primary central nervous system lymphoma: Radiation TherapyOncology Group Study 93-10. J Clin Oncol 2002; 20: 4643–4648.7. Thiel E, Korfel A, Martus P et al. High-dose methotrexate with or without wholebrain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3,randomised, non-inferiority trial. Lancet Oncol 2010; 11: 1036–1047.8. Omuro A, Taillandier L, Chinot O et al. Primary CNS lymphoma in patients youngerthan 60: can whole-brain radiotherapy be deferred?. J Neurooncol 2010; 104(1):323–330.9. Illerhaus G, Marks R, Muller F et al. High-dose methotrexate combined withprocarbazine and CCNU for primary CNS lymphoma in the elderly: results of aprospective pilot and phase II study. Ann Oncol 2009; 20: 319–325.10. Enting RH, Demopoulos A, DeAngelis LM et al. Salvage therapy for primary CNSlymphoma with a combination of rituximab and temozolomide. Neurology 2004;63: 901–903.11. Herrlinger U, Brugger W, Bamberg M et al. PCV salvage chemotherapy forrecurrent primary CNS lymphoma. Neurology 2000; 54: 1707–1708.12. Nguyen PL, Chakravarti A, Finkelstein DM et al. Results of whole-brain radiationas salvage of methotrexate failure for immunocompetent patients with primaryCNS lymphoma. J Clin Oncol 2005; 23: 1507–1513.13. Reni M, Mason W, Zaja F et al. Salvage chemotherapy with temozolomide inprimary CNS lymphomas: preliminary results of a phase II trial. Eur J Cancer2004; 40: 1682–1688.14. Voloschin AD, Betensky R, Wen PY et al. Topotecan as salvage therapy forrelapsed or refractory primary central nervous system lymphoma. J Neurooncol2008; 86: 211–215.original articles Annals of Oncology | Kiefer et al. Volume 23 | No. 7 | July 2012

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hämatologie und Onkologie OSHO-53 phase II study

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hämatologie und Onkologie OSHO-53 phase II study

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