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Originally published as JCO Early Release 10.1200/JCO.2003.03.108 on November 3 2003 © 2003 American Society for Clinical Oncology High-Dose Methotrexate-Based Chemotherapy Followed by Consolidating Radiotherapy in Non–AIDS-Related Primary Central Nervous System Lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962
From the Dr Bernard Verbeeten Institute, Tilburg; University Hospital Groningen, Groningen; Daniel den Hoed Kliniek, Rotterdam; Universitair Medisch Centrum, Utrecht; Atrium Medisch Center, Heerlen; University Medical Center, Leiden, the Netherlands; Rigshospitalet, Copenhagen, Denmark; Institut Bergonie, Bordeaux, France; University Hospital Gasthuisberg, Leuven; and the European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium. Address reprint requests to Philip M.P. Poortmans, MD, Dr Bernard Verbeeten Instituut, PO Box 90120, 5000 LA Tilburg, the Netherlands; e-mail: poortmans.ph{at}bvi.nl.
Purpose: To confirm the feasibility and estimate the efficacy of methotrexate (MTX), teniposide, carmustine, and methylprednisolone (MBVP) chemotherapy combined with radiotherapy (RT) for patients with non–AIDS-related primary CNS lymphoma (PCNSL) treated in a multicenter setting. Patients and Methods: Treatment consisted of two cycles of MBVP (MTX 3 g/m2 days 1 and 15, teniposide 100 mg/m2 days 2 and 3, carmustine 100 mg/m2 day 4, methylprednisolone 60 mg/m2 days 1 to 5, and two intrathecal injections of MTX 15 mg, cytarabine 40 mg, and hydrocortisone 25 mg) followed by 40 Gy of RT. Primary end points were response and safety of this regimen. Results: Twelve centers included 52 patients who were all analyzed on an intent-to-treat basis. Median follow-up of all patients was 27 months. One patient progressed and died before treatment, and five patients died during treatment. Four patients received RT after one cycle of chemotherapy, and 42 patients completed the entire treatment. Hematologic grade 3 and 4 toxicity was seen in 78% of patients for leukocytes and 24% of patients for platelets. The overall response rate of all 52 patients was 81%. Two patients who did not fulfill the criteria of objective response survived more than 1 year; one of them is still alive without disease. Eighteen patients died; 11 deaths were a result of tumor, five were probably treatment-related, one was caused by late leukoencephalopathy, and one was a result of intercurrent disease. Median estimated overall survival was 46 months. Conclusion: MBVP followed by RT for PCNSL has a high response rate. However, the 10% toxic death rate during treatment in a multicenter setting underlines the need for highly specialized care.
PRIMARY CNS lymphoma (PCNSL) is a rare tumor, accounting for approximately 1% of all intracranial neoplasms and for approximately 1% to 2% of all non-Hodgkin’s lymphomas.1,2 By definition, PCNSL is not accompanied by localizations outside the CNS.3–5 PCNSL is most often a diffuse B-cell lymphoma and develops mainly in supratentorial sites, including the periventricular white matter, corpus callosum, basal ganglia, and thalamus. Up to 50% of patients present with multifocal cerebral disease. Meningeal seeding is known to occur in one third (10% to 72%) of all PCNSL patients, but this might be an underestimation.6 Rarely, patients without obvious brain parenchymal tumors present with only leptomeningeal involvement, spinal cord lymphoma, or ocular disease.7–9 The prognosis of nonselected patients with PCNSL is comparable to that of glioblastoma multiforme patients, with a 5-year survival rate after conventional chemotherapy and radiotherapy (RT) usually at less than 10%.10 Unfavorable prognostic factors for survival are age greater than 60 years, WHO performance status greater than 2, poor neurologic function, elevated serum lactate dehydrogenase, extensive tumor spread, CSF protein level greater than 0.6 g/L, corticosteroid dependence, and absence of chemotherapy administration.11–15 Corticosteroids and RT up to a dose of 60 Gy showed activity but could not prevent relapse in the majority of patients.14,16,17 A dose reduction from 45 to 30 Gy after high-dose (HD) methotrexate (MTX)-containing chemotherapy led to significantly worse results in two successive phase II trials.18 Given the excellent sensitivity of lymphoma to chemotherapy, the disappointing overall results of RT alone on PCNSL have led to the investigation of chemotherapy regimens for this disease.19–21 The blood-brain barrier prevents hydrophilic compounds, including most chemotherapeutic agents, from entering the cerebral tissue. This may account for the poor results of cyclophosphamide, doxorubicin, vincristine, and prednisone–based regimens in PCNSL.22–24 With HD cytarabine (ARA-C) and MTX, therapeutic drug concentrations are attained in both the brain and the CSF. Several retrospective and phase II prospective studies incorporating HD MTX with or without HD ARA-C, followed by consolidating RT, have shown an improvement in median survival to around 3 years.25–28 At the time of the design of this study, there was no consensus for a standard chemotherapy schedule, although many studies supported the use of an intravenous HD MTX–based chemotherapy regimen followed by consolidating whole-brain RT. We based our treatment schedule on the extensive and favorable experience of the French Groupe Ouest Est D’Étrude des Leucémics et Autres Maladies du Sang (GOELAMS) group.29 They included more than 150 patients in a prospective phase II trial in which PCNSL patients were treated with three cycles of MTX, teniposide, carmustine, and methylprednisolone (MBVP), followed by RT at a dose of 40 Gy and, if possible, by a boost of 10 Gy to the primary tumor region. We wanted to confirm the feasibility and the results of this MBVP schedule combined with RT for patients with PCNSL up to 65 years of age in an international multi-institutional trial. Because, in the French trial, the third MBVP cycle did not increase the overall response rate but only contributed to toxicity, we limited the regimen in our trial to two cycles. Moreover, in view of the lack of evidence that higher RT doses improved outcome and because up to half of the long-term survivors developed delayed neurocognitive disturbances in the GOELAMS experience, we limited the RT dose to 40 Gy with the option to limit the fields to only the tumor volume after 30 Gy. Primary end points were the response rate and safety of this chemotherapy regimen. Secondary end points were duration of response, progression-free survival, overall survival, improvement of cognitive functions, and quality of life. Analysis of the latter two end points will be reported separately.
Patient Selection All patients were prospectively registered onto a phase II trial of the European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group. This was performed centrally using the minimization technique at the EORTC Data Center through the phone or Internet before the start of treatment. Inclusion criteria of the patients were age 16 to 65 years, a Karnofsky performance score of 40 to 100, a neurologic function status of 0 to 3, histologically or cytologically proven non-Hodgkin’s lymphoma of the CNS, including the leptomeninges and the spinal cord, and at least one measurable lesion for response evaluation. The upper age for inclusion in our study was limited to 65 years because of the reported increased risk of delayed neurologic toxicity with age. During the first 2 years of accrual, the upper age limit was 60 years to avoid competition with an EORTC study on PCNSL in elderly patients. Exclusion criteria were as follows: congenital or acquired immunodeficiency, including patients with previous organ transplantation, concurrent treatment with immunosuppressive drugs, and AIDS-related PCNSL; disease confined to the eye without another localization in the CNS; the presence or history of systemic lymphoma; any prior malignancy with the exception of adequately treated nonmelanoma skin cancer and carcinoma-in-situ of the cervix uteri; a serious impairment of cardiac, renal, or liver function; pregnancy; any severe uncontrolled infection; prior chemotherapy, with the exception of corticosteroids, for a maximum period of 6 weeks before and after diagnosis or surgery; and Burkitt’s lymphomas or low-grade T-cell lymphomas. As part of the general Quality Assurance Measures of the EORTC Lymphoma Group, central pathology review was performed. The protocol was approved by the ethics committees of all participating institutions, and all patients signed an informed consent.
Treatment
Trial Design and Response Evaluation Tumor response was evaluated after completing each cycle of chemotherapy, 1 month after completing RT, and then every 3 months for the first year and every 6 months thereafter. In case of neurologic deterioration, evaluation was performed earlier. Evaluation was performed by clinical examination and by radiologic evaluation by computed tomography or magnetic resonance imaging scanning with contrast enhancement. Examination of the CSF was not advised, unless clinical suspicion of recurrent disease was present in the absence of clear radiologic abnormalities. CR was defined as a total disappearance of all enhancing tumor, and PR was defined as a more than 50% reduction in the product of the perpendicular diameters of contrast enhancement without the appearance of new lesions. Patients with progressive disease during treatment, as defined by neurologic deterioration and radiologic progression, received further treatment according to the local policy. Toxicity was scored according to the common toxicity criteria of the National Cancer Institute of Canada. All toxicity events were scored separately, meaning that one patient could have several grade 3 and/or grade 4 complications concomitantly or consecutively. Cognitive functions were quantitatively scored with the Mini Mental State Examination. Quality of life was assessed by the EORTC Quality of Life Questionnaire C30, including the Brain Module. Central pathology review was performed. Overall survival was measured from the date of diagnosis. All patients were observed until death. Survival was computed by an actuarial Kaplan-Meier method, and patients who died were censored at the date of death for follow-up estimate. The objective of this trial was to confirm the feasibility of the studied regimen in terms of response rate scored at 1 month after completing RT. A two-step Simon design was used with the following hypotheses: a response rate of 70% would justify further investigation of this combination (P1 = 0.7), and a response rate of 50% would not justify further investigation of this combination (P0 = 0.5). Thirty-one patients had to be entered onto the first step of the study; if 16 or more responses were observed, another 19 patients needed to be entered. The therapy would be considered worthy of further investigation if at least 30 responders were observed out of 50 eligible patients. At both the interim and the final analyses, all case report forms were reviewed at the EORTC Data Center by the study coordinators and the data manager. Queries were sent to investigators whenever inconsistencies or missing data occurred. In case of uncertain tumor response, radiologic data were reviewed as well.
From October 1997 to February 2002, 12 European centers from four countries included 52 patients; this was two more patients than originally planned because one patient progressed and died before the start of treatment and another patient was not eligible because of a history of doubtful cerebral abnormalities with further diagnosis being impossible, which disappeared after one course of chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus MTX). This analysis is based on all 52 patients for response and on 51 treated patients for toxicity. Median follow-up time of the entire patient group was 27 months. Patient characteristics are listed in Table 2  . Thirty-one patients had unifocal and 21 had multifocal tumor localizations. Two patients had only spinal cord disease. Ocular involvement was found in two patients. The CSF was positive in seven (16%) of 43 examined patients. Because of symptoms of elevated intracranial pressure, a lumbar puncture was not performed in nine patients.
All patients were hospitalized during chemotherapy. RT was performed on an outpatient basis. As expected, grade 3 and 4 hematologic toxicity was seen in a high percentage of patients (78%) for WBC count only. Grade 3 and 4 toxicity was reported in 24% of patients for platelets and in 14% of patients for anemia. Grade 3 and 4 nonhematologic toxicity was limited and included a grade 4 infection in two patients and a grade 3 infection in six patients, neurologic toxicity in six patients, a possible treatment-induced depression in one patient, stomatitis in four patients (one grade 4), genitourinary toxicity in three patients (one grade 4), thromboembolic complications in four patients (one grade 4), liver toxicity in two patients (one grade 4), allergic reactions (including hypotension) in two patients, and skin toxicity in one patient. Unfortunately, five patients died probably because of treatment-related infectious complications; four patients died during the first cycle, and one patient died during the second cycle. Delay of chemotherapy administration and dose reduction according to the protocol occurred in six and 13 patients, respectively, during the first chemotherapy cycle and in 19 and five patients, respectively, during the second cycle. Forty-two of the 46 irradiated patients received a dose of 39 to 40 Gy. One patient each received a modified dose of 30, 34, 45, or 50 Gy as palliative or intensified RT after insufficient tumor response to chemotherapy.
The response to therapy is summarized in Fig 1
Several authors have published their experience with HD MTX–based chemotherapy, followed by consolidating RT, for treatment of PCNSL. The overall response rate ranged between 65% and 95%, and the 2-year survival rate ranged between 22% and 86%. A 3-year survival rate of 45% and a 5-year survival rate of 30% to 56% have been reported in series with a limited number of patients after a short period of follow-up.25–28 Our results, in a heterogeneous group of 12 centers in four countries, with a tumor response rate of 81% and 2- and 3-year survival rate estimates of 69% and 58%, respectively, compare favorably with previously published results. For correct interpretation of our results, we have to emphasize that patients older than 65 years and in very poor general or neurologic condition were not eligible for participation, thereby excluding the subset of patients with the worst prognosis. Nevertheless, our patient characteristics did not differ substantially from those of most other published series, apart from the rather low median age. Moreover, patients with a Karnofsky performance score as low as 40 and a neurologic function status as high as 3 were accepted in our study, especially if some improvement was obtained with short-term corticosteroid treatment, which increased the hope for a favorable reaction to protocol treatment. Although we slightly modified the original GOELAMS schedule (two instead of three MBVP cycles and RT dose up to a maximum of 40 Gy), this modification did not have a negative impact on the results. The overall response in our series compared with the GOELAMS series was 81% versus 65%, respectively, and 2- and 3-year survival rates were also slightly better in our series (69% v 52% and 58% v 45%, respectively).29 Several authors have suggested that adding HD ARA-C to HD MTX might improve outcome. The results of a Dutch trial, in which ARA-C was given before MTX in each cycle, were not superior to the results of RT alone.30 This might suggest that if ARA-C is given in combination with MTX, the latter should be given first. Others advocate postponing RT until disease progression after chemotherapy alone to avoid treatment-induced late neurotoxicity, especially for older patients.31–33 The acute chemotherapy-induced toxicity was mainly leukocytopenia, which caused death in five patients despite hospitalization. Referral to regional centers with more experience in supportive hematologic care during chemotherapy-induced aplasia might limit the number of serious complications. Early radiologic evaluation of response of the patients proved to be difficult; patients in PR after RT had the same prognosis as patients in CR after RT, and even the two patients who did not fulfill the criteria of CR or PR after RT survived more than 1 year. Residual radiologic abnormalities may have been the result of non–tumor-containing residual fibrotic tissue or nonspecific tissue reaction, rather than a result of viable tumor cells, because later evaluations showed that patients in PR turned out to have CR. This is in agreement with the observation that radiologic abnormalities can disappear slowly over time.34 The low percentage of CR after chemotherapy, 19% and 33% after one and two cycles, respectively, might at least partially be explained by slow regression of tumor. The true response to chemotherapy might be higher if the radiologic evaluation would have been performed later. This was impossible in view of the strict timetable of the combined-modality treatment. Moreover, according to the study design of a phase II trial with response as an end point, we had to perform the final evaluation 1 month after completion of RT, even if examinations later during follow-up showed further improvement or no further change. The spurious low percentage of CR at radiologic evaluation performed soon after chemotherapy might also hamper the conduct of trials evaluating chemotherapy as a single-treatment modality. At this moment, a worldwide platform for the study and treatment of PCNSL is being formed.35 A consensus was reached that intrathecal chemotherapy can be left out if a sufficiently high dose of MTX is given intravenously. Moreover, many investigators are joining forces to optimize the collection of patient information and the performance of clinical trials. This will ensure a more rapid accrual in this rare disease and the conduct of several concomitant trials for different patient subgroups based on age and other prognostic factors. The MBVP regimen followed by consolidating RT, for which we confirmed a high response rate and an acceptable toxicity, can be a valuable treatment schedule to incorporate in those future trials.
The authors indicated no potential conflicts of interest.
We thank the participating patients, the Dutch Cancer Foundation for providing a grant for data management for the Dutch patients, Dr Christiane De Wolf–Peeters for reviewing pathology, and many colleagues for their active contribution to this trial.
Supported in part by a grant from the Dutch Cancer Foundation. Presented in part at the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12–15, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
