Annals of Oncology Advance Access originally published online on April 7, 2006
Annals of Oncology 2006 17(7):1141-1145; doi:10.1093/annonc/mdl070
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© 2006 European Society for Medical Oncology
Prospective trial on topotecan salvage therapy in primary CNS lymphoma
1 Department of Haematology, Oncology and Transfusion Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; 2 Department of Radiotherapy and Oncology, Pius-Hospital, Oldenburg; 3 Department of Hematology and Oncology, Klinikum Nord; Nürnberg; 4 Institute for Biostatistics and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Germany
* Correspondence to: Dr L. Fischer, Department of Hematology, Oncology and Transfusion Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. Tel: +49-30-8445-2337; Fax: +49-30-8445-4468; E-mail: lars.fischer{at}charite.de
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Abstract |
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Background: Standard salvage therapy has not been established for recurrent primary central nervous system lymphoma (PCNSL). We report the final results of a prospective study on topotecan chemotherapy in relapsed or refractory PCNSL.
Patients and methods: The study included 27 patients with a median age of 51 years and an ECOG performance status of 2. Fourteen patients were refractory to the last therapy, and 13 relapsed after a median period of 6.0 months. Pretreatment with up to four regimens included chemotherapy in 26 patients and whole brain irradiation in 14. A 30-min daily topotecan infusion of 1.5 mg/m2 for 5 days was repeated every 3 weeks.
Results: The response rate was 33% with five complete (CR) and four partial remissions (PR). The median follow-up was 37.7 months. All complete responders had sustained remissions lasting for 9 to 28 months. The median event-free survival (EFS) was 2.0 months (9.1 months in responders), the overall survival (OAS) was 8.4 months. CTC grade 3–4 leukopenia occurred in 26% and thrombocytopenia in 11% of the patients. Eight of 12 patients alive without cerebral lymphoma 
six months after topotecan exhibited deficits attributable to late neurotoxicity.
Conclusion: Topotecan as monotherapy is active in relapsed and refractory PCNSL with tolerable toxicity.
Key words: PCNSL, salvage therapy, topotecan
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introduction |
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An increasing incidence of PCNSL has been reported among non-immunocompromised individuals [1
]. High-dose methotrexate (HD-MTX) chemotherapy (CHT) is the mainstay of primary treatment and prolongs overall survival to over 30 months as opposed to 12–18 months with whole brain irradiation (WBI) alone [2, 3]. However, up to 35% of the patients are refractory to primary therapy, and 35–60% of the responders will eventually relapse. The prognosis of refractory and relapsed PCNSL is poor if left untreated. There is no standard approach in this setting. Salvage therapy may prolong survival, but less than 50% of the patients who received conventional chemotherapy entered a second remission in the few small series published thus far [4]. Radiotherapy is often applied but involves the risk of additional CNS toxicity, especially in older patients [5].
Topotecan is a semisynthetic camptothecin derivative that selectively inhibits topoisomerase I in the S-phase of the cell cycle. Its mechanism of action differs from that of the antimetabolites MTX and cytarabine most often used in PCNSL therapy. It penetrates the CNS, reaching concentrations in cerebrospinal fluid (CSF) of more than 30% of those in plasma [6, 7]. Topotecan has been successfully used to treat brain metastases of solid tumors [8–10] and has shown activity in non-Hodgkin's lymphomas [11, 12]. Here we present the final results of a multicentre phase II trial on topotecan salvage therapy in non-AIDS PCNSL. Sixteen patients reported here have already been discussed in a previous report; 15 of them had reached the endpoint of disease-free survival [13].
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patients
Inclusion criteria were: relapsed or refractory PCNSL confirmed histologically at initial diagnosis, age
18 years, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 4 due to lymphoma, and adequate bone marrow function (absolute neutrophil count >1.5/nl and platelets >100/nl) as well as renal (creatinine clearance >50 ml/min) and hepatic function (normal bilirubin, aspartate aminotransferase <3 times higher than the normal upper limit). Relapsed PCNSL was diagnosed if new manifestations occurred after complete resolution of contrast-enhancing lesions on MRI or CT scans after previous CHT and/or WBI. Refractory disease was diagnosed if the size of contrast-enhancing lesions had increased or remained unchanged after the last therapy or if new lesions had developed. Exclusion criteria were: immunodeficiency conditions and severe illness unrelated to PCNSL with an ECOG performance status >2 and concurrent or prior treatment of another malignant disease within the last five years. Pregnancy had to be ruled out, and effective contraception was necessary in fecund women. The protocol was approved by the local ethics committee. Written informed consent was obtained from all patients or their legal guardian.
treatment
Topotecan, 1.5 mg/m2/d, was administered IV over 30 min on days 1 to 5. Treatment was repeated every three weeks and continued for up to six courses until radiologic progression, clinical deterioration, or CTC grade 3 or 4 non-hematologic toxicity (excluding alopecia). A dose reduction of 25% was made up to two times for CTC grade 4 hematological toxicity. Treatment was delayed for a maximum of two weeks if bone marrow function did not recover to required values. Anti-emetics and anticonvulsants were given at the discretion of the attending physician. Concomitant corticosteroid therapy was permissible.
response and toxicity
The clinical status, including neurologic and toxicity assessment, was documented at baseline and then before every course. Toxicity was graded according to CTC criteria. Cranial MRI/CT was performed at study entry, after the first course, and then at least after every second therapy course. CSF, ocular, and systemic involvement was evaluated according to apparent symptoms or signs. Clinical and radiological examinations were continued every 3 months during the follow-up.
All patients alive with no evidence of lymphoma at least six months after topotecan were assessed for brain atrophy and leukoencephalopathy on MRI/CT scans. In addition, a questionnaire sent to the attending physician was used to assess impaired concentration, memory and orientation, the presence of ataxia and incontinence, the need for help, and fitness for work.
statistical analysis
The study included all patients diagnosed with relapsed or refractory PCNSL who presented at the participating institution during four consecutive years starting in June 2000. The primary endpoint was response, and secondary endpoints were EFS and OAS. An exact 95% CI was calculated for the response rate. A post hoc power analysis revealed that, assuming a response rate of 20%, 27 patients were a sufficient number to prove the superiority of a therapy with a 47% response rate (exact binomial test for proportions, 
= 0.05, two-sided, ß = 0.2). Remission categories were derived from a recently published consensus paper [14], and the best response from the start of therapy until progressive disease (PD) was documented. Estimates of overall and event-free survival were calculated using the Kaplan-Meier method. OAS was measured from the first topotecan treatment to the last follow-up or death. EFS was measured from the start of topotecan to the first documentation of progression and the last follow-up or death from any cause. Reasons for study termination were defined as response in fewer than two patients and grade 4 non-hematologic toxicity or grade 4 hematologic toxicity persisting for more than two weeks in more than one of the first 10 patients.
OAS of refractory and relapsed patients was compared using the log rank test. Risk ratios were determined using the Cox-proportional hazards model. The response and CR rate as well as the pretreatment characteristics were compared between both patient groups using Fisher's exact test.
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patient characteristics
Twenty-seven patients with a median age of 51 years (range 26–77) were included in the study (Table 1). Thirteen patients had relapsed after the last therapy before topotecan with a median time to relapse of 6.0 months (range 1.4–25.3). Fourteen patients were refractory to their last therapy.
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Thirteen patients had experienced one relapse before study treatment, two patients two and three relapses respectively, and 10 patients were refractory to all previous therapies.
The median number of previous therapies did not differ between relapsed and refractory patients. However, in relapsed patients pretreatment comprised WBI (10 of 13) more often than in refractory (4 of 14) patients (P = 0.21).
response to therapy
A total of 69 courses of topotecan chemotherapy were administered, with a median of two courses per patient. Nine patients responded to therapy, for an overall response rate of 33% (95% CI: 16.5%–54%) with five complete and four partial remissions. Six patients had stable disease (SD) after one to three courses of topotecan, and 11 patients had progressive disease (PD). Response was not documented in one patient after one course of topotecan, and WBI was started. The response rate did not differ in relapsed (5 of 13) and refractory (4 of 14) patients. However, CR was achieved in four of 13 relapsed patients as compared to one of 14 refractory patients (P = 0.165).
Remission rate was comparable in patients pretreated with WBI (5 of 9) and in radiation-naïve patients (9 of 12; P = 1.0).
The median follow-up time was 37.7 months (range 6.7–57.9). OAS after starting topotecan was 8.4 months (range 1.3–57.9), 9.5 months in responders (Figure 1). The 6-month survival was 52% (33–71%, 95% CI), 12-month survival was 39% (19–59%), and the 24-month survival was 33% (14–52%). Refractory patients had a longer OAS (9.5 months) than relapsed patients (3.4 months) with a risk ratio of 2.0 in favor of refractory patients (P = 0.12).
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The overall median EFS was 2.0 months (range 1.0–28.6) and 9.1 months in responders. Patients with PR to topotecan had a short EFS (1.9–2.7 months) with early progression in two patients, and death of unknown cause and fatal deterioration of pre-existing neurotoxicity in one patient each.
With topotecan alone, five patients achieved long-term remission lasting for 7.5, 10.5, 15.8, 24.1+ and 28.6 months. After topotecan, sixteen patients received up to five further therapy regimens, including WBI in nine patients and high-dose chemotherapy with autologous stem cell transplantation in two.
toxicity
Toxicity was mainly hematologic with grade 4 leukopenia in three patients and grade 3 in four, grade 3 neutropenia and infection in three patients, grade 4 thrombocytopenia in one and grade 3 in two patients, as well as grade 3 anemia in one patient. Non-hematologic toxicity was usually mild. One patient with prolonged corticosteroid therapy and diabetes developed aspergillus pneumonia (grade 3) that responded to antifungal treatment. One patient developed grade 2 peripheral polyneuropathy. Grade 3 herpes stomatitis and grade 3 paralytic ileus due to grade 4 hypokalemia occurred in one patient each.
Radiological signs of neurotoxicity were detected in 11 of 12 patients alive at least 6 months after topotecan with no evidence of lymphoma. Clinical symptoms indicative of late neurotoxicity were reported in eight patients (Table 2). Seven patients required care to varying degrees, but two of them had residual defects caused by lymphoma (arm paresis in patient no. 4 and hemiparesis in patient no. 5). Overall, three patients died from late neurotoxicity without evidence of lymphoma progression.
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Here we report on a prospective trial assessing topotecan in relapsed or refractory PCNSL. Previous studies have already demonstrated activity of temozolomide alone or in combination with rituximab, PCV – (procarbazine, lomustine, vincristine) or VIA (etoposide, ifosfamide, cytarabine) – regimens and intra-arterial carboplatin (plus IV cyclophosphamide and etoposide) after blood brain barrier disruption with remission rates of 26–53% and a 1-year survival of 30–40% [15
–19]. After high-dose chemotherapy with thiotepa, busulfan and cyclophosphamide and autologous hematopoietic stem cell transplantation a response rate of 81% and a 1-year survival of >75% were reported. However, a substantial toxicity was observed [20]. The response rate of 33% and a 1-year survival of 39% in our study are comparable to the results obtained with other standard-dose chemotherapy regimens.
ECOG performance status and age proved most important risk factors in newly diagnosed PCNSL [21]. The percentage of patients with a reduced ECOG performance status 2 in this study did not differ from that in studies published by others, and the median age of 51 years was relatively low in our collective. However, the time to relapse, which has been reported to affect survival in relapsed PCNSL [4], was only 6 months in our study. Furthermore, our study population was heavily pretreated ( three different regimens in 22% of patients).
More than 50% of our patients were refractory to last therapy. Topotecan proved to be active in both relapsed and refractory patients, although a trend towards higher CR rates was seen in relapsed PCNSL. Interestingly, the OAS was non-significantly longer in refractory than in relapsed patients. This might be partly due to the fact that in the majority of previously refractory patients WBI could be applied after topotecan failure, whereas this was not possible in most relapsed patients already submitted to irradiation.
The toxicity of topotecan was almost exclusively hematologic. This issue should be addressed by considering possible risk factors (e.g., age, prior therapy) and making dose reductions, if indicated [22].
Late neurotoxicity contributes significantly to morbidity and mortality in PCNSL patients [3, 5, 23]. Neuropsychological test batteries developed for dementia are time-consuming and thus difficult to conduct in the setting of a multicenter trial. This study roughly estimated signs and symptoms compatible with late neurotoxicity, concentrating on the ability to cope with everyday life. The majority of patients exhibited deficits and radiographic changes attributable to late neurotoxicity. However, the neurotoxic effects probably resulted from WBI and other treatment before and after topotecan, since topotecan has not been reported to cause increased neurotoxicity [8–10, 24].
Difficulty in distinguishing the influence of corticosteroids from the activity of chemotherapy is a problem inherent to salvage therapy in PCNSL. In our study, responses were only documented if the corticosteroid dose was stable or decreasing. All complete responders were off corticosteroids at some point during chemotherapy. The occurrence of long-lasting remissions points to a true activity of topotecan in this setting.
The results of our study confirm that topotecan salvage therapy can induce long-term remissions in PCNSL with an acceptable toxicity. It may be possible to achieve further improvement of therapy results by combining topotecan with other drugs in both salvage and primary therapy.
Received for publication December 10, 2005. Revision received February 24, 2006. Accepted for publication March 1, 2006.
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