Annals of Oncology Advance Access originally published online on December 12, 2006
Annals of Oncology 2007 18(3):541-545; doi:10.1093/annonc/mdl434
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© 2006 European Society for Medical Oncology
hematologic malignancies |
The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma
1 Department of Medical Oncology, Royal Marsden Hospital, London and Sutton
2 Department of Computing, Royal Marsden Hospital, Sutton
3 Department of Histopathology, Royal Marsden Hospital, London
4 Department of Clinical Oncology, Royal Marsden Hospital, Sutton, UK
* Correspondence to: Prof. D. Cunningham, Department of Medical Oncology, Royal Marsden Hospital Sutton, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-207-3528171; Fax: +44-208-6939414; E-mail: david.cunningham{at}rmh.nhs.uk
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: Relapse in the central nervous system (CNS) following initial treatment of diffuse large B-cell lymphoma (DLBCL) is an uncommon but serious complication. This single centre retrospective study investigated the rate of CNS relapse in patients with DLBCL who received standardised intrathecal (IT) chemoprophylaxis.
Patients and methods: A total of 259 patients were newly diagnosed and treated for DLBCL from October 1996 to May 2005 and retrospectively analysed for incidence of CNS relapse. Our institutional policy for patients at risk for CNS relapse was for IT chemoprophylaxis to be administered concurrently with systemic treatment. Defined at-risk patients were those with lymphoma involvement at the following sites: bone marrow, testis, nasal/paranasal sinuses, orbits, bone/vertebrae and peripheral blood.
Results: Of 259 patients with DLBCL, a total of 51 patients (19.7%) received IT chemoprophylaxis. Forty-four patients received single agent IT methotrexate (MTX) 12.5 mg (median 3 doses, range 1–7); 27 patients (53%) received 1–3 doses and 17 patients (33.3%) 4–7 doses of MTX. Seven patients (13.7%) received a combination of IT MTX plus cytarabine. Three patients (1.1%) subsequently developed CNS relapse. One of these patients had IT chemoprophylaxis, the other two did not meet the Royal Marsden Hospital (RMH) criteria for IT chemoprophylaxis. The median time from diagnosis of DLBCL to CNS relapse was 31.8 months (range 27.3–34.1 months).
Conclusion: The CNS relapse rate in this cohort of patients with primary DLBCL was low at 1.1%. This retrospective analysis demonstrates in a homogeneous group of DLBCL patients that a relatively low-intensity IT chemoprophylaxis regimen given according to site-based risk can be associated with a low risk of CNS relapse.
Key words: CNS relapses, diffuse large B-cell lymphoma, DLBCL, intrathecal chemoprophylaxis, methotrexate
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Central nervous system (CNS) relapse in patients with aggressive non-Hodgkin's lymphoma (NHL) is a serious complication with a poor prognosis [1]. The frequency of CNS relapse in aggressive lymphoma is reported to range from 4% to 30% depending on the histology and stage of the lymphoma [2, 3]. CNS relapses have been reported in up to 30% without intravenous (i.v.) and intrathecal (IT) prophylactic chemotherapy in certain subtypes of high-grade lymphoma, such as Burkitt and lymphoblastic lymphoma. For these subtypes part of the standard treatment is CNS prophylaxis using i.v./IT chemotherapy [methotrexate (MTX)] [4].
In the subset of aggressive NHL represented by diffuse large B-cell lymphoma (DLBCL), there is no clear consensus as to which patients benefit from CNS prophylaxis. Without CNS prophylaxis, patients with DLBCL have been reported to have CNS relapse rates between 4% and 27% [5–7]. Multiple retrospective studies have addressed this question and identified potential risk factors for CNS relapse in this lymphoma subgroup. These risk factors include site of lymphoma involvement, such as bone marrow involvement, testis, paranasal sinuses and clinical parameters, such as age, lactate dehydrogenase (LDH) and albumin [3–7].
A recurring difficulty in the interpretation of these studies is the lack of histological homogeneity. Unfortunately, most of the previous studies included lymphomas of non-DLBCL histology as well as DLBCL. In addition, there is no general agreement on the intensity or duration for optimal IT chemoprophylaxis.
This retrospective study was carried out in order to document the CNS relapse rate in a large, histologically homogeneous, single-institution cohort of patients with DLBCL. As part of the Royal Marsden Hospital (RMH) lymphoma guidelines, patients with DLBCL received prophylactic IT chemotherapy if they were at increased risk for CNS relapse according to site-based criteria.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The medical records of all patients diagnosed and treated for DLBCL from October 1996 to May 2005 at the RMH were reviewed. All patients had DLBCL histology which was confirmed by a team of consultant haematopathologists. Patients with transformed follicular lymphoma were excluded, as were patients who were not followed up at the RMH. Patients with a positive human immunodeficiency virus status were excluded from the analysis. CNS involvement was diagnosed by the patients' history, clinical examination, cerebrospinal fluid (CSF) and computed tomography (CT)/magnetic resonance imaging (MRI) examination.
treatment
Newly diagnosed DLBCL patients at increased risk for CNS relapse were defined as patients with involvement of the following sites: orbit, testis, peripheral blood, bone/vertebrae, nasal/paranasal sinuses and bone marrow. These patients received IT chemoprophylaxis in conjunction with the treatment programme for their systemic disease. In 2001, the RMH policy for IT chemoprophylaxis changed from six cycles IT MTX to three cycles and patients with DLBCL involvement of the bone did not receive any IT chemoprophylaxis from 2003 onwards.
statistical analysis
Survival was calculated using the survival analysis methods of Kaplan and Meier from the date of diagnosis to the date of death from any cause, patients were censored on the date of last follow up. The CNS relapse rate at 3 years from diagnosis and 95% confidence interval (CI) were calculated from a Kaplan–Meier survival curve, dead patients were censored on the date of death, patients with no date of death and no CNS relapse were censored on the date of last follow-up, a CNS relapse was considered an event.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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A total of 259 patients with DLBCL were analysed with a median follow-up of 3.1 years. The median age of patients was 62 years (range 18–93 years); 60% of the patients were male and 40% female. In all patients, stage of disease was defined and in 98.5% of all patients the International Prognostic Index score (IPI) (LDH, age, stage, number of extranodal sites, performance status (ECOG)) was available. Median albumin was 38 g/l (range 18–50g/l) (reference 30–50 g/l), median LDH was 536 U/l (range 79–16 632 U/l) (reference: until February 2005: 180–325U/l; from March 2005: 98–192 U/l) and median performance status was one (range 0–3). Eighty-four patients (32%) had retroperitoneal involvement (Table 1).
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In total, 51 patients (19.7%) of our 259 patients received IT chemoprophylaxis (Table 2). Patients who received IT prophylaxis had following sites of lymphoma involvement: bone marrow, 19 patients (37.0%); bone/vertebrae, seven patients (14.0%); nasal/paranasal sinuses, seven patients (14.0%) and testis, six patients (12.0%). Additional five patients with a high proliferation index of the lymphoma (10.0%), six patients with gastrointestinal involvement (12.0%) and one patient with involvement of the mediastinum (2.0%) received IT chemoprophylaxis. The initial systemic treatment of all 259 patients is described in Table 3. Three patients did not receive any treatment due to rapid progression of disease. The overall survival curve for the entire cohort is depicted in Figure 1.
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Three patients in this cohort (one female and two male) developed CNS relapse (1.1%, 95% CI 0% to 2.5%) following primary treatment of DLBCL. The CNS relapse rate at 3 years was determined to be 2.7% (95% CI 0.88–8.16). Only one patient with CNS relapse had received IT chemoprophylaxis; the other two patients did not have involvement of high-risk sites at initial presentation and therefore did not meet the RMH criteria for IT chemoprophylaxis. The age of the patients was 65, 66 and 85 years. In these patients, advanced stage III/IV disease was seen in two patients and one patient had stage I disease at first presentation. The initial treatment of DLBCL in patients who subsequently developed CNS relapse consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) six and eight cycles. One patient had radiotherapy only as primary treatment.
The median time from first diagnosis of DLBCL to CNS relapse was 31.8 months (range 27.3–34.1 months) (Table 4). Clinically, the patients presented with following symptoms: patient 1: headache, right sixth cranial nerve palsy, weakness of the right hemisphere and marked pyramidal weakness; patient 2: dysphagia and right facial nerve palsy and patient 3: mental changes, memory impairment and incontinence. Patients with CNS relapse received treatment as follows: patient 1: 20 Gy whole brain radiation plus eight doses IT MTX 12.5 mg/cytarabine 50mg every 3–4 days; patient 2: 45 Gy whole brain radiation and patient 3: 20 Gy whole brain radiation. CSF was cytologically positive in two patients and MRI/CT showed CNS disease in one patient. Two patients presented with meningeal involvement whereas one patient had cerebral lymphoma involvement. The time from CNS relapse to death was 3, 1 and 3.2 months.
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All three patients received second-line therapy for systemic relapse before they developed CNS relapse: 2 x PmitCEBO (prednisolone, mitoxantrone, cyclophosphamide, etoposide, bleomycin, vincristine) and 1 x DHAX (dexamethasone, Ara-C, oxaliplatin). One patient received PmitCEBO as third-line treatment.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In this analysis, we have documented a low rate of CNS relapse in a large, homogeneous cohort of DLBCL patients who received relatively low-intensity IT prophylaxis according to site-restricted guidelines. The low observed rate of CNS relapse is significant, as several previously reported series advocate the use of CNS prophylaxis on the basis of IPI, elevated LDH or number of extranodal sites. In addition, some authors have recommended more intensive regimens for CNS prophylaxis [8–11].
The RMH lymphoma unit's CNS prophylaxis policy for DLBCL is on the basis of a retrospective study showing that patients with lymphoma involvement of the bone marrow, peripheral blood, bone, testis and paranasal sinuses have a higher incidence of CNS relapse [12]. The low rate of CNS relapse in the analysis of our cohort appears to justify this approach, despite analyses from other groups indicating the utility of IPI scores, or other risk assessment scores in predicting patients at high risk for CNS relapse.
A recently published paper summarises the results of a survey which evaluated the current practice of IT chemoprophylaxis for DLBCL in the United Kingdom. Most responders considered involvement of high-risk sites to be the major indication for IT chemoprophylaxis. Ninety-six percent of the responders regarded sites such as paranasal sinuses (88%), testis (85%), orbital (78%), bone marrow (65%) and bone (25%) to be an indication for IT chemoprophylaxis. The most commonly used regimen was 12.5 mg MTX with each cycle of chemotherapy for a total of six courses [13].
Hollender et al. reported CNS relapse rates of 4.3% in 1220 patients with high-grade lymphoma histology. This study included a heterogeneous group of patients with aggressive lymphoma histology [centroblastic (16.1%), immunoblastic (5.2%), high-grade B cell (9.4%), anaplastic large cell (4%), peripheral T cell (4.8%), high-grade unclassified (8.9%); Burkitt and lymphoblastic lymphoma were excluded]. In this retrospective analysis, 12% of patients received prophylactic IT chemoprophylaxis. The CNS relapse rate was 4.3%. This relatively high rate could have been related to the significant proportion of patients who did not receive IT chemoprophylaxis despite having lymphoma involvement at high-risk sites. Seventy out of 336 patients (21%) had lymphoma involvement at high-risk sites such as bone marrow, testicles and skeleton or head and neck sites close to the CNS. Secondly, the inclusion of patients with aggressive non-DLBCL histology in this study may have resulted in a higher CNS relapse rate.
Hollender et al. [5] found that factors other than ‘site of involvement’ were independent risk factors for CNS relapse: age (>60), LDH (>450 m/l), albumin (<35 g/l), retroperitoneal glands and number of extranodal sites (
2). Using these five clinical risk factors the authors developed a model predicting the risk of CNS recurrence. Patients with less than four risk factors were part of a low risk group with an estimated CNS relapse rate of <6.2% at 5 years whereas patients with more than four risk factors had an risk of >25% to develop CNS relapse within 5 years. The authors recommended that CNS prophylaxis should be administered to patients with more than four risk factors.
This study could not detect a higher incidence for CNS relapse in patients with involvement of the testicles, paranasal sinuses or skeleton whereas patients with bone marrow involvement had a significantly higher risk for CNS relapse but only in the univariate analysis [5].
Multiple retrospective and prospective trials have reported additional risk factors for CNS relapse such as, advanced disease (LDH, stage IV disease), B symptoms, age, performance status and IPI [8–11, 14–17]. A pooled analysis of the French Groupe d'Etudes des Lymphomes de l'Adulte (GELA) study group showed in 974 patients with aggressive NHL a CNS relapse rate of 2.2%. Again, heterogeneous histologies were included: diffuse large B cell, non-anaplastic/anaplastic PTCL and large cell NHL, unclassifiable (lymphoblastic and Burkitt lymphoma were excluded) [9]. This analysis was on the basis of two pooled prospective studies where all patients received a standardised systemic treatment (ACVBP: doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) with high-dose i.v. (two courses 3 g/m2 i.v. MTX at a 15-day interval) and IT chemoprophylaxis (15 mg IT MTX d1 and five each cycle of ACVBP) to prevent CNS relapse. Compared with the IT chemoprophylaxis used in our trial [12.5 mg MTX weekly x 3 (53%), 12.5 mg MTX x 6 (33.3%) and 12.5 mg MTX/50 mg Cytarabine (13.7%)], the regimen of i.v. and IT chemoprophylaxis used by the GELA group was more intensive although no major side effects related to this regimen were reported in this study.
Multivariate analysis of the GELA study concluded that IPI was an independent prognostic factor for CNS relapse. CNS relapse rates were 0.6% in the low (IPI 0–1) and low-intermediate IPI-risk group (IPI 2) (68% of the patients) and 4.1% in the high-intermediate (IPI 3) and high IPI-risk group (IPI 4–5) (32% of the patients); P = 0.002. The authors recommended that CNS chemoprophylaxis should be administered to all patients within the high-intermediate and high-risk group (IPI 3–5). Unfortunately, as with the Hollender study, the heterogeneous nature of the cohort limits the applicability of these conclusions to DLBCL patients.
We report a low incidence of CNS relapse in a large single-institution cohort of patients with DLBCL treated with a relatively low-intensity IT prophylaxis according to site-based risk. This implies that the true risk of CNS recurrence for patients with DLBCL may be lower than for heterogeneous populations of aggressive lymphoma and underscores the importance of expert histopathological classification in determining risk of CNS relapse. We conclude that low-intensity IT prophylaxis according to site-based risk may be appropriate for patients with DLBCL.
Received for publication July 20, 2006. Revision received September 26, 2006. Accepted for publication October 23, 2006.
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