Prevention of CNS relapse in diffuse large B-cell lymphoma

Transcription

1 Prevention of C relapse in diffuse large B-cell lymphoma Robert Kridel, Pierre-Yves Dietrich C relapse occurs in about 5% of patients during the course of diffuse large B-cell lymphoma and entails a dismal prognosis. This consideration has led to the adoption of C prophylaxis, although known risk factors do not allow for an accurate prediction of C recurrences because they have insufficient sensitivity and specificity. Here, we review the reports of C events in major studies of diffuse large B-cell lymphoma before and after the introduction of rituximab, and probe the evidence that underlies prophylactic strategies such as intrathecal or high-dose intravenous chemotherapy. Now that rituximab is available, C prophylaxis relies on little if any evidence and should not be routinely administered. Nonetheless, several patient subgroups probably have a high risk of systemic and C relapses, and how to manage their treatment is a challenge. These subgroups include patients with testicular lymphoma or those who have more than one extranodal site involved plus at least one additional risk factor. For such patients, we recommend against prophylactic intrathecal chemotherapy because of the rare occurrence of isolated leptomeningeal relapses, the absence of evidence-based efficacy, and the potential harmful side-effects that are associated with this procedure. Because many C events are a result of primary resistance to treatment or accompany systemic relapses, high-dose intravenous methotrexate has been suggested as an alternative approach that needs to be validated in prospective controlled trials. Published Online September 19, 2011 DOI: /S (11) Centre of Oncology, Geneva University Hospital, Geneva, Switzerland (R Kridel MD, Prof P-Y Dietrich MD) Correspondence to: Prof Pierre-Yves Dietrich, Centre of Oncology, Geneva University Hospital, 1211 Geneva 14, Switzerland pierre-yves.dietrich@hcuge.ch Introduction Diffuse large B-cell lymphoma (DLBCL) represents 25 58% of adult non-hodgkin lymphomas, with a crude incidence of three to four cases per every year. 1 It is a potentially curable disease, with 3-year overall survival rates ranging from about 70% in young patients with poor-prognosis and elderly patients 2,3 to more than 90% in young patients with favourable outlooks. 2 C involvement is an uncommon finding at diagnosis when assessed by standard cytology of cerebrospinal fluid (CSF), but is a serious complication in % of patients during the course of the disease. 4 Many C events occur soon after diagnosis (4 7 9 months) and a substantial proportion present during therapy or shortly after completion of treatment, 5 10 which suggests that initial C involvement could have gone undetected in some cases The outcome of patients with C relapse is poor, with median survival times of 2 5 months Thus, the prevention of C recurrence in DLBCL seems desirable. Theoretical strategies include prophylactic cranial irradiation, intrathecal therapy with methotrexate, standard or slow-release cytarabine or corticosteroids, and intravenous administration of drugs with sufficient C penetration to achieve therapeutic concentrations in either the CSF or brain parenchyma, or both. 14,15 When administered alone or in combination, these procedures form an integral part of treatment protocols for acute lymphoblastic leukaemia, and lymphoblastic and Burkitt s lymphomas. Without a preventive approach, C relapse rates are 30 50% in these three diseases, and prophylaxis has unequivocally been shown to reduce the occurrence of C relapse and improve survival rates. 16,17 In DLBCL, the situation is controversial because no clear evidence exists. Guidelines from the National Comprehensive Cancer Network (NCCN) in the USA 18 and the European Society of Medical Oncology (ESMO) 19 recommend a diagnostic lumbar puncture and C prophylaxis for high-risk patients. The NCCN guidelines suggest four to eight doses of intrathecal methotrexate or cytarabine, or both, for selected patients, whereas the ESMO guidelines do not recommend intrathecal methotrexate as the best possible preventive strategy. Unsurprisingly, treatment practices vary widely as shown by various surveys 20,21 and an analysis of the NCCN lymphoma database, 22 showing that administration of C prophylaxis is a result of personal preferences rather than available evidence. In this Personal View we critically review studies that are often regarded as the basis for current practice to assess whether the use of C prophylaxis should be challenged. Which patients need C prophylaxis? Clinical risk factors Many investigators have analysed potential risk factors for C recurrence in non-hodgkin lymphoma (table 1). The factors that are most consistently associated with an increased risk of C recurrence are raised serum lactate dehydrogenase and the involvement of more than one extranodal site or the testes. A large retrospective series 28 of primary lymphoma of the testis (373 patients) by the International Extranodal Lymphoma Study Group, reported a 15% C relapse rate. Similarly, a 2011 retrospective review 29 of nearly 800 patients treated with (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) suggested that initial implication of bone marrow in DLBCL raises the likelihood of C relapse. Additionally, primary lymphoma of the breast has repeatedly been associated with an increased propensity for C recurrence. 14,30 Epidural, sinonasal, and orbital lymphomas, however, were only inconsistently reported to increase the risk of C relapse Published online September 19, 2011 DOI: /S (11)

2 Number of C relapses/number of patients (%) RR associated with significant risk factors after adjustment for confounding factors Increased LDH Extranodal site >1 Advanced stage IPI or aaipi Anatomical site Haioun et al (2000) 5 * 22/974 (2 3%) NR NR Hollender et al (2002) 23 52/1220 (4 3%) Retroperitoneal lymph nodes: 1 9 Feugier et al (2004) 6 20/399 (5 0%) 3 1 NR Björkholm et al (2007) 8 * 29/444 (6 5%) NR (borderline) Testis: NR (p<0 001) Other Low albumin: 2 5 Age < 60 years: 2 8 Boehme et al (2007) 7 * 37/1693 (2 2%) NR Etoposide: 0 4 Bernstein et al (2009) 10 * 25/899 (2 8%) NR Boehme et al (2009) 9 * 58/1217 (4 8%) 3 4 B-symptoms: 1 9 Shimazu et al (2009) 24 42/403 (10 4%) NR Bone marrow: 2 1 Rituximab: 0 5; age>60 years: 2 5 Villa et al (2009) 25 31/435 (7 1%) 9 7 (stage IV) Kidney: 3 2; testis: 3 0 Yamamoto et al (2010) 26 13/375 (3 5%) NR Tai et al (2011) 27 30/499 (6 0%) Testis: 6 7; kidney: 20 1; breast: 6 14 NR Rituximab: 0 5 ECOG>1: 2 0; non-cr: 2 4 RR=relative risk. LDH=lactate dehydrogenase. IPI=International Prognostic Index. aaipi=age-adjusted International Prognostic Index. =not significant. NR=not reported. CR=complete remission. *Study not exclusively undertaken on patients with diffuse large B-cell lymphoma. Analysis restricted to patients who achieved a CR. Patients with high-grade lymphoma excluding lymphoblastic and Burkitt s lymphoma. Results adjusted for treatment only. Patients with advanced stage or testicular involvement. Table 1: Incidence and risk factors for C relapse in studies of aggressive non-hodgkin lymphoma When considered individually, none of the risk factors has sufficient predictive value, but combinations have been associated with a high risk of C recurrence. For example, patients with raised concentrations of lactate dehydrogenase and more than one extranodal site involved had a 17 4% risk of C recurrence after 1 year in retrospective analyses from the MD Anderson Cancer Center 31 and a 7 9% risk in a report from the German High-Grade Non-Hodgkin Lymphoma Study Group. 7 In the RICOVER-60 study, of 1217 patients (6%) with increased lactate dehydrogenase, the involvement of more than one extranodal site, and B symptoms (fever, night sweats, and weight loss) given CHOP-14 (cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone every 2 weeks) or -14 ( every 2 weeks) had a cumulative risk of C recurrence of 23 8% at 2 years. 9 Findings from such risk factor studies were hoped to accurately identify patients who would ultimately have a C relapse and benefit from prophylaxis. However, identification was not possible, as shown by Hollender and co-workers. 23 The investigators reported five independent risk factors for C relapse in 1220 patients with high-grade non-hodgkin lymphoma: more than one extranodal site, aged less than 60 years, low albumin concentration, raised lactate dehydrogenase, and involvement of retroperitoneal lymph nodes. The probability of C relapse was 6 2% or less at 5 years with up to three of these risk factors, whereas it rose to 25 3% when individuals had four of these factors and 32 7% with all five. 23 Only 12 3% of the patients were classified into these high-risk categories and could thus serve as a possible target population for C prophylaxis. The drawback of this strategy was that 22 of 48 patients with C recurrence had fewer than four risk factors at the initial presentation and thus almost half of the patients who ultimately had a C relapse would have been missed. It can be concluded that a combination of risk factors could increase specificity, leading to a better prediction of C relapse, although a substantial proportion of patients who will eventually relapse could be missed. Biological risk factors Because clinical risk factors are not sufficient to identify precisely patients who will ultimately have C relapse, some biological properties of malignant lymphocytes could be predictive factors. Gene-expression profiling divides DLBCL into two main categories: germinalcentre B-cell and activated B-cell (which is associated with a poorer prognosis). 33,34 Although a predominance of the activated B-cell subtype has been linked to the poor outcome of primary C lymphoma, 35,36 this molecular classification has not been correlated with C recurrence in DLBCL. However, cytogenetic analysis by fluorescent in-situ hybridisation has identified a small subset of patients with DLBCL harbouring MYC gene rearrangements; 37,38 these individuals have an aggressive disease course and they might have a high propensity for C involvement Published online September 19, 2011 DOI: /S (11)

3 Number of patients Systemic treatment Strategy of C prophylaxis C relapses (%) p value Tilly et al (2003) CHOP vs ACVBP None with CHOP; four intrathecal methotrexate injections during induction followed by consolidation including two courses of high-dose intravenous methotrexate with ACVBP Boehme et 1693 CHOP-14 vs CHOEP-14, al (2007) 7 CHOP-21, CHOEP-21 Bernstein et al (2009) CHOP vs MACOP-B, PROMACE-CytaBOM, m-bacod Boehme et cycles of CHOP-14 al (2009) 9 vs 6 8 cycles of -14 None for DLBCL (but 4 2% of trial population received intrathecal prophylaxis by choice of investigator) None with CHOP and MACOP-B; 24 Gy whole-brain irradiation (if there was bone-marrow involvement) with PROMACE-CytaBOM; and six intrathecal methotrexate and cytarabine injections (if there was bone-marrow involvement) with m-bacod Four intrathecal methotrexate injections for patients with involvement of the upper neck, head, bone marrow or testes 8 3% with CHOP; and 2 8% with ACVBP 2 1% without C prophylaxis; and 4 2% in group with C prophylaxis 4 4% with CHOP; 1 4% with MACOP-B; 3 0% with PROMACE-CytaBOM; and 2 2% with m-bacod 4 4% in group without intrathecal prophylaxis; and 2 5% in intrathecal group* Studies not exclusively undertaken in patients with DLBCL. CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone. ACVBP=doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone. CHOP-14=CHOP every 14 days. CHOEP-14=cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone every 14 days. CHOP-21=CHOP every 21 days. CHOEP-21=CHOEP every 21 days. DLBCL=diffuse large B-cell lymphoma. =not significant. MACOP-B=methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone, and folinic acid. PROMACE-CytaBOM=prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and folinic acid. m-bacod=methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethosone. -14=rituximab plus CHOP every 14 days. *Both groups consisted of patients with involvement of the upper neck, head, bone marrow, and testes; the group without intrathecal prophylaxis arose because of protocol violations. Table 2: Incidence of C relapses in prospective trials according to prophylactic strategy MYC translocations are often found in lymphomas that have features intermediate to DLBCL and Burkitt s lymphoma. 1 They are also included in the so-called double-hit category, defined mainly by the combination of MYC and BCL2 translocations, in which C involvement was reported in 9 50% of cases. 37 MYC rearrangements might put patients at a sufficiently high risk to justify C prophylaxis, but larger studies are clearly warranted in these patient populations. The expression of adhesion molecules, chemokines, and their receptors, which are all implicated in the homing of specific populations of lymphocytes to their target sites, probably underlies the tropism of some lymphomas eg, extranodal marginal zone lymphoma to mucosae or cutaneous T-cell lymphoma to the skin. Chemokine receptor expression also plays a part in the metastatic process of solid tumours 39 and has been implicated in lymphoma dissemination. 40 Furthermore, the peculiar confinement of primary C lymphoma to the brain, generally without systemic dissemination even in advanced disease, has been linked to the expression of some chemokines (eg, CXCL13) and chemokine receptors (eg, CXCR5), 41,42 although functional data that support these notions are scarce. And whether the expression pattern of certain adhesion molecules, chemokines, and chemokine receptors contributes to C relapse is unknown. Chemotherapies Several retrospective studies have reported outcomes after C prophylaxis, but they were limited by potential selection biases. 24,27,43 45 No prospective study has been designed to specifically address the issue of prophylaxis, but some information can be obtained from landmark randomised trials in which some treatment groups received C prophylaxis (table 2). Pre-rituximab era In 1986, the Southwest Oncology Group began a randomised phase 3 trial 47 to compare CHOP with more intensive regimens (m-bacod [methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone], ProMACE-CytaBOM [prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue], and MACOP-B [methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin]), which used moderate doses of intravenous methotrexate (<1 g/m²) or cytarabine. Patients with initial bone marrow involvement received intrathecal prophylaxis, with six doses of methotrexate and cytarabine in the m-bacod group or whole-brain irradiation in the ProMACE-CytaBOM group, if clearance of the bone marrow after chemotherapy was achieved. A 20-year follow-up of C events in this trial population 10 showed that the cumulative incidence of C relapse was 2 8%, with no significant difference between treatment groups. Additionally, C prophylaxis was not associated with a significant reduction in C relapse. However, in the 1980s and 1990s, the French Groupe d Etude des Lymphomes de l Adulte (GELA) did several Published online September 19, 2011 DOI: /S (11)

4 Number of patients Treatment group C relapses (%) p value Feugier et al (2004) CHOP vs 4 6% with CHOP; and 5 4% with Boehme et al (2009) 9 * 1217 CHOP vs 5 9 % with CHOP; and 3 6% with Shimazu et al (2009) Regimen based on CHOP vs rituximab plus regimen based on CHOP 13 3% with regimen based on CHOP; and 8 4% with rituximab plus regimen based on CHOP Villa et al (2009) CHOP vs 9 7% with CHOP; and 6 4% with Schmitz et al (2010) 54 * 2196 CHOP or CHOEP vs or R-CHOEP, MegaCHOEP R-MegaCHOEP Data not yet published Yamamoto et al (2010) CHOP vs 2 9% with CHOP; and 3 9% with Tai et al (2011) CHOP vs 5 1% with CHOP; and 6 0% with (univariate), 0 03 (multivariate) 0 09 (univariate), 0 03 (multivariate) Data not yet published CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone. = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. =not significant. CHOEP=cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone. R-CHOEP=rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone. MegaCHOEP=high-dose CHOP plus etoposide. R-MegaCHOEP=high-dose plus etoposide. *Study not exclusively undertaken in patients with diffuse large B-cell lymphoma. In this abstract, the investigators reported a significant risk reduction for R-CHOEP versus CHOEP (relative risk [RR] 0 3, p=0 03) but not for R-MegaCHOEP versus MegaCHOEP (RR 0 8, p=0 54). Table 3: Comparison of C relapses with or without rituximab trials to investigate the role of intensive ACVBP chemotherapy (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), which included intrathecal methotrexate during the induction phase and high-dose methotrexate (3 g/m²) treatment during consolidation. The encouraging response, promising overall survival rates, and low C relapse rate (2 2%) recorded in two consecutive protocols (LNH87 and LNH93) 5 prompted a randomised comparison of the ACVBP regimen with standard CHOP in patients with aggressive non-hodgkin lymphoma at risk of poor outcome. 46 In the 635 eligible patients, 501 (79%) had DLBCL histology. Patients in the intensive group had better 5-year overall survival rates (46% vs 38%, p=0 036) and had fewer C relapses (2 8% vs 8 3%, p=0 002) than did those receiving standard CHOP. The researchers concluded that C prophylaxis should be mandatory in poor-risk patients although the favourable results for C recurrence might be explained by better systemic control in the ACVBP group. The German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) did several trials from 1990 to 2000 that aimed to improve outcomes in comparison to standard CHOP treatment every 3 weeks. Strategies included cycle-length reduction from 3 to 2 weeks, 51,52 the addition of etoposide, 51,52 and high-dose chemotherapy with autologous stem-cell transplantation. 53 Two-thirds of the patients had DLBCL. 7 The overall incidence of C recurrence was low (2 2%), although only 71 of 1693 patients (4%) received C prophylaxis. 7 Intrathecal chemotherapy was was not associated with a decreased incidence of C relapse, even after adjustment for raised lactate dehydrogenase and extranodal disease. Etoposide did have a protective effect (relative risk [RR] 0 4, p=0 017), whereas cycle-length reduction did not (p=0 903). Overall, the results of the studies reported before the introduction of rituximab did not show lower C recurrence rates after intrathecal chemotherapy, but did point towards a protective effect of systemic control. Rituximab era After the introduction of rituximab, investigators in the RICOVER-60 study 32 randomised 1222 elderly patients (aged years) into four treatment groups (six or eight cycles of CHOP-14, with or without rituximab). DLBCL was the most common lymphoma subtype (82%) and the overall C relapse rate was 5% (58 patients). 9 C prophylaxis with four doses of intrathecal methotrexate (15 mg) was mandatory for patients with bone-marrow or testes infiltration, or lymphoma manifestation in the head or neck. Of 210 patients with these characteristics, only 120 (57%) received intrathecal methotrexate; whereas the physicians did not consider C prophylaxis necessary for 90 patients (43%). This high number of protocol violations allowed the investigators to study C relapse rates in both groups and estimate the effect of prophylactic intrathecal methotrexate in a high-risk population. Of the individuals given intrathecal prophylaxis, 3% had a C event compared with 4% of patients without prophylaxis. This difference was not statistically significant and, although a protective effect of intrathecal methotrexate was suggested in the CHOP groups, no difference was recorded in the groups. The DSHNHL presented a large retrospective analysis of 2797 patients (60 years and younger) with aggressive 4 Published online September 19, 2011 DOI: /S (11)

5 lymphoma, including 2196 patients with B-cell lymphoma, at the 2010 meeting of the American Society of Hematology. 54 The investigators concluded that intrathecal methotrexate, high-dose etoposide (as used in the MegaCHOEP trials 55,56 ), or the standard etoposide dose did not reduce the risk of C relapse in younger patients with lymphoma, although admittedly the percentage of DLBCL patients was not reported in the abstract presented. As a result of the poor efficacy of intrathecal chemotherapy and the favourable results of the French ACBVP regimen before the introduction of rituximab, some institutions adopted high-dose intravenous methotrexate as a prophylactic strategy to achieve a more consistent distribution throughout the C than could be achieved with intrathecal chemotherapy. After rituximab became available, a retrospective report 57 showed that only two of 65 high-risk patients given intravenous methotrexate in combination with subsequently presented with C recurrence at a median follow-up of 33 months. However, this strategy needs to be validated in a larger cohort, or ideally in a prospective controlled trial. Does systemic rituximab prevent C recurrences? The addition of rituximab to CHOP has substantially improved outcomes in patients with DLBCL, with few additional toxic effects. 32,58 61 Table 3 shows relevant studies comparing C outcomes in patients treated with and without rituximab. In the GELA trial, 6 rituximab did not seem to affect the risk of C recurrence in 399 elderly patients (aged years) with DLBCL randomly assigned to eight cycles of CHOP-21 (CHOP every 3 weeks) or -21 ( every 3 weeks) without C prophylaxis. By contrast, in the larger RICOVER-60 study 32 C events occurred in 22 of 608 patients (4%) given -14 and in 36 of 609 patients (6%) given CHOP The researchers concluded that rituximab significantly lowered the incidence of C disease (p=0 043), probably through improved systemic control. Similarly, results from several DSHNHL trials showed a reduction in C disease for younger patients with aggressive lymphoma, at least when rituximab was given with CHOP or CHOEP. 54 Finally, analyses of data from several purely retrospective studies suggested either no benefit of rituximab 26,27 or a protective effect on C recurrence. 24,25 In conclusion, whether rituximab prevents C disease is unknown, although findings from the DSHNHL suggest that it might be beneficial. 54 Conceptually, improved systemic disease control could prevent C relapses or progressions that originate from uncontrolled lymphoma growth outside the C, as is achieved by the addition of rituximab to chemotherapy. However, rituximab diffuses poorly into the C, 62 and thus might not eradicate subclinical disease in the leptomeninges or the brain parenchyma. This consideration could explain Number of C relapses C relapses occurring in the brain parenchyma (%) Hollender et al (2002) 23 * Tilly et al (2003) 45 * Boehme et al (2007) 7 * Bernstein et al (2009) 10 * Boehme et al (2009) 9 * Shimazu et al (2009) Villa et al (2009) *Study not exclusively carried out on diffuse large B-cell lymphoma patients. Table 4: Distribution of C relapses in the brain the finding that the proportion of isolated C relapses (ie, without systemic lymphoma recurrence) seemed to be higher in the rituximab groups than those not given rituximab of the RICOVER-60 trial 9 and in a retrospective study from British Columbia, Canada. 25 Why is intrathecal chemotherapy unlikely to prevent C relapses? In addition to the benefit provided by rituximab or intensive systemic polychemotherapy, whether a prophylactic treatment delivered directly to the leptomeninges intrathecally can further reduce the C relapse rate is unknown. Unfortunately, intrathecal chemotherapy has several inherent limitations. Ideally, intrathecally administered chemotherapy should homogeneously diffuse into the leptomeninges, reach the brain parenchyma, and stay in these compartments with a sufficient half-life to kill lymphoma cells; however, this situation is far from reality. Most agents administered intrathecally are readily eliminated from CSF by flow excretion. 63 Drugs also undergo detoxification in the choroid plexus, and are exported into the bloodstream. Although methotrexate and standard cytarabine have fairly slow clearance rates from the CSF, they are cell-cycle dependent and repetitive administrations are necessary to achieve therapeutic concentrations during the length of the cell cycle in lymphoma cells. 63 Slow-release cytarabine has a more favourable pharmacokinetic profile, and intrathecal injections every 2 weeks yield higher response rates in the palliative setting compared with standard cytarabine. 64 Furthermore, the lumbar intrathecal route results in a delayed and unpredictable appearance of methotrexate in the ventricular system, as shown by pharmacokinetic and radionuclide CSF flow studies in patients with leptomeningeal metastases. 65,66 This slow release is a concern because the increased sensitivity of ventricular compared with lumbar cytology suggests that neoplastic cells inside the leptomeninges preferentially reside in the cerebral ventricles Finally, early experiments on rhesus monkeys showed that brain tissue concentrations of intrathecally C relapses occurring exclusively in the leptomeninges (%) Published online September 19, 2011 DOI: /S (11)

6 Number of patients C relapses (%) Isolated C progressions or relapses (%) C relapses after CR (%) Isolated C relapses after CR (%) Haioun et al (2000) NR NR 1 6% 1 2% Tilly et al (2003) 45 * % 3 9% NR NR Feugier et al (2004) % NR 1 0% 0 8% Boehme et al (2007) 7 * % 0 9% 1 3% 0 6% Björkholm et al (2007) 8 * % 2 9% 3 2% 1 6% Bernstein et al (2009) 10 * % 1 2% NR NR Boehme et al (2009) 9 * % 2 8% 1 6% 1 0% Shimazu et al (2009) % 6 9% NR NR Villa et al (2009) % 5 1% 3 0% NR CR=complete remission. NR=not reported. *Study not exclusively carried out on patients with diffuse large B-cell lymphoma. Table 5: Isolated C progressions and relapses, and C relapses after CR administered chemotherapy rapidly decreased as distance from the ependymal surface increased. 70 Tissue concentrations of agents such as hydroxyurea, methotrexate, and cytarabine fell to less than 1% of their corresponding concentration at the ependymal surface within a distance of 1 3 cm. This finding potentially represents a major drawback in the prevention of C relapses, because a substantial proportion of events occur in the parenchyma, either in isolation or in combination with leptomeningeal involvement (table 4). Factors that hamper prospective, randomised trials Several barriers preclude the appropriate design of randomised clinical trials that aim to assess the potential efficacy of prophylactic strategies. First, no consensus about the choice of an experimental group has been reached. How should we choose the best drug (methotrexate, liposomal cytarabine, or even rituximab 71 ) and best schedule? Should we begin at treatment initiation or when complete remission is achieved? Second, the question of how to identify patients at risk of C relapse with sufficient sensitivity and specificity is unanswered. Although we might be able to identify patients with DLBCL who have a risk of about 20 25%, such a selection omits a large proportion of patients who will ultimately have C relapses. Third, C recurrences, although universally dramatic because of their devastating effect on quality and quantity of life, are infrequent complications in DLBCL, 4 which means that randomised phase 3 trials are unlikely to be done. Indeed, if a DLBCL patient population with a C relapse rate of 5% is assumed, and if prophylaxis is expected to lower this rate by 30%, a sample size of about 2100 participants per group would be needed for a power of 90% and a significance level of 5%. 72 This large sample size is obviously a serious impediment. Enrolment of higher-risk patients would reduce the required sample size, but would inevitably limit the generalisability of results. Phase 2 trials might be a more realistic study design. 72 Finally, what qualifies as a C event still has to be precisely defined. Such events can occur in patients on first-line therapy and thus indicate primary resistance to treatment. 6,7,9,10 Alternatively, C relapses can accompany a systemic relapse, 5 10 but this scenario is highly unlikely to be prevented by a C-directed prophylactic strategy. Additionally, C recurrences can be isolated events after complete remission (table 5), which probably results from the failure to control a sanctuary site (where residing lymphoma cells are inaccessible for treatment). If we consider isolated C relapses after complete remission as the best definition, the required sample size for a randomised trial would have been greatly underestimated. Discussion We have reviewed C events in large cohorts of patients with DLBCL or related lymphomas (with the exception of Burkitt s, lymphoblastic, and HIV-associated lymphomas). Improved systemic lymphoma control seems to be associated with fewer C recurrences, as suggested by the low incidence of C events when patients are treated with an intensive chemotherapeutic regimen such as ACVBP 5,46 and by the probable reduction in C recurrence achieved by addition of rituximab to CHOP (the present standard of care). 6,9,24 27,54 Nevertheless, no benefit of specific C-directed prophylactic strategies could be identified. A minor benefit of intrathecal chemotherapy in the pre-rituximab era cannot be ignored, as shown by the analysis of C events in the RICOVER-60 trial. 9 In the present rituximab era, universal C prophylaxis is unnecessary, as shown by the experience of the DSHNHL. 9,54 However, a difficult decision has to be made in daily practice about how to treat patients at the highest risk of C recurrence. Should we favour C prophylaxis considering the severity of C relapses? Or, according to the fundamental principle primum non nocere, should we avoid a potentially harmful procedure in the absence of evidence of efficacy? Patients at high risk of systemic and C relapse probably benefit from intensive 6 Published online September 19, 2011 DOI: /S (11)

7 Search strategy and selection criteria We limited our search to the adult population and excluded AIDS-related lymphoma, Burkitt s lymphoma, lymphoblastic lymphoma, and primary C lymphoma trials. We searched PubMed, the Cochrane Library, and the Web of Science databases between April, 1975, and April, 2011, for the terms non-hodgkin lymphoma, diffuse large B-cell lymphoma, central nervous system, leptomeningeal, recurrence, relapse, and event, alone and in combination. The term rituximab was then added to the search. Only articles published in English were included. The results were analysed in a non-systematic manner. regimens that include C prophylaxis, although the best way to achieve such prophylaxis has not been elucidated. For patients who have more than one extranodal site involved and at least one additional risk factor (table 1), and probably those with testicular 28 or breast lymphoma, 30 we would favour high dose intra venous methotrexate ( 3 g/m²). This recommendation is based on limited data, but is indirectly supported by the expected favourable distribution of methotrexate throughout the C 73,74 and the consideration that systemic lymphoma control seems to have a beneficial effect on C recurrence. 7,9,24,25,46,54 Similarly, subsets of patients with lymphomas that are in the WHO 2008 category of lymphomas with intermediate features between DLBCL and Burkitt s lymphoma 1 probably have an increased risk of C relapse and might best be treated with an aggressive approach that includes C prophylaxis. However, risk factors such as epidural or paranasal sinus involvement have not been reported with sufficient consistency to justify C prophylaxis on their own. 14 We recommend against prophylactic intrathecal chemotherapy, because we have no evidence of efficacy, it could theoretically prevent only the rare isolated leptomeningeal relapses, and it produces many toxic effects. Indeed, intrathecal chemotherapy has been associated with rare but serious neurological complications eg, chemical aseptic meningitis, paraplegia, seizures, and encephalopathy which have a debilitating effect on the quality of life of lymphoma survivors. 15,75 Additionally, the systemic diffusion of intrathecally administered cytotoxic agents 63 explains why side-effects such as leucopenia or mucositis are increased by these agents. 76 The extent to which new diagnostic methods help to define the at-risk population remains unknown. Multiparameter flow cytometry is clearly more sensitive than is conventional cytology for the detection of malignant lymphocytes in the CSF, but the clinical significance of only a few lymphoma cells in the CSF is difficult to assess. By definition, patients with only a few lymphoma cells in the CSF would not qualify for prophylaxis but rather for therapeutic measures that maintain cytotoxic concentrations in at least the leptomeningeal compartment, and potentially the brain parenchyma. More than 20% of patients with aggressive lymphoma show leptomeningeal infiltration by flow cytometry in selected series, but whether this technique correctly identifies patients at risk is unclear. Prospective collection of outcome data in patients with occult CSF involvement as identified by flow cytometry at diagnosis will hopefully clarify this issue in the future. Contributors Both authors wrote the report. Conflicts of interest RK has received support from Roche to cover travel and accommodation expenses. P-YD has received support from Celgene and Novartis to cover travel and accommodation expenses, and has been a paid consultant for Novartis, Bayer, and Pfizer. 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