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© 2003 American Society for Clinical Oncology Chemotherapy Alone as Initial Treatment for Primary CNS Lymphoma in Patients Older Than 60 Years: A Multicenter Phase II Study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group
From the Fédération Neurologique Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris; Service de Neurologie, CHU Nancy; Service de Neurochirurgie, CHU La Timone, Marseille; Institut Bergonié, Bordeaux; Centre Antoine Lacassagne, Nice, France; Department of Neurology, Universität Klinik Regensburg, Germany; Service de Neurologie, Hôpital Erasme; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium. Address reprint requests to: K. Hoang-Xuan, MD, Fédération Neurologique Mazarin, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l’hôpital, 75651 Paris Cedex 13, France; email: khe.hoang-xuan{at}psl.ap-hop-paris.fr.
Purpose: To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma. Patients and Methods: Fifty patients with a median age of 72 years and a median Karnofsky performance score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years. Results: Twenty four patients (48%) achieved an objective response (compete response [CR], 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval [CI], 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively. Conclusion: In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.
THE INCIDENCE of primary CNS lymphoma (PCNSL) has strikingly increased over the last two decades both in the immunocompromised and in the immunocompetent population.1,2 The addition of high-dose methotrexate (MTX > 1 g/m2) to cranial radiotherapy (RT) has substantially improved the median survival time of patients and represents the current standard treatment for PCNSL in the immunocompetent population.3–6 Unfortunately, combined treatment exposes the patients to delayed neurotoxicity that may occur as early as 6 to 12 months after treatment. Patients older than 60 years are particularly susceptible to delayed neurotoxicity because 50% to 80% of them develop progressive leukoencephalopathy, which leads to severe cognitive dysfunction and ataxia, with devastating consequences on their quality of life.6,7 Moreover, RT alone has been of limited value for the elderly in terms of survival.8 These findings prompted us to evaluate prospectively the activity and the tolerance of chemotherapy used alone as initial treatment in elderly patients. Agents known to penetrate the blood-brain barrier and to be active against lymphoma (high-dose MTX, procarbazine, lomustine, and methylprednisolone), in addition to intrathecal chemotherapy (MTX and cytarabine) to enhance therapeutic leptomeningeal coverage, were selected.
Eligibility Patients were registered at the European Organization for Research and Treatment of Cancer Data Center (Brussels, Belgium). Patients were considered eligible if the diagnosis of PCNSL was histologically confirmed (by brain biopsy, CSF cytology, or vitrectomy), if age was  60 years, and if Karnofsky performance score (KPS) was 40. Positive human immunodeficiency virus type I serology, lymphoma outside the CNS at the pretreatment systemic work-up (including at least a chest x-ray, abdominal computed tomography [CT] scan, and bone marrow biopsy), corticotherapy for more than 3 weeks, prior history of organ transplantation, systemic lymphoma or other malignancy, prior chemotherapy, and serious uncontrolled infection were exclusion criteria. All patients were required to give informed consent, and the protocol was approved by the ethics committees of each institution.
Protocol Treatment
Follow-Up and Assessment Evaluation during the study and the follow-up period included: a clinical evaluation, KPS, Mini-Mental State Examination (MMSE), cranial CT and MRI without and with contrast, ophthalmologic examination with slit lamp, and CSF examination obtained at the time of administration of each intrathecal chemotherapy. These evaluations were performed every 6 weeks (before each cycle of chemotherapy), during the follow-up period, every 3 months thereafter until progression. Response to treatment was based on the following criteria: CR referred to the absence of any contrast enhancement on the CT or MRI of the brain. PR referred to at least a 50% reduction in the product of the perpendicular diameters of the contrast-enhanced area with no new lesion. PD referred to an increase of 25% or more in the product of the contrast-enhanced area or the appearance of new lesions in the CNS, eye, or leptomeningeal space. Stable disease corresponded to all other situations. Criteria for clinical improvement or worsening were defined as a change in KPS of 20 points or more. Criteria for improvement or worsening of cognitive function (MMSE) were defined as a change of the MMSE score of 4 points or more. Acute toxicity was graded according the National Cancer Institute of Canada criteria.
Statistical Analysis
Patient Characteristics Fifty-five newly diagnosed patients with PCNSL, from 12 European institutions and five different countries (France, Germany, the Netherlands, Belgium, and Italy), were entered into this phase II study between January 1997 and April 1999. Five patients were ineligible because of the use of a corticosteroid for more than 3 weeks before the start of the protocol treatment. The main clinical features at diagnosis are summarized in Table 2  .
Treatment Completion The median number of cycles administered was three (range, one to six). Thirty-four patients (68%) completed the induction chemotherapy (first cycle) and continued to receive the maintenance treatment. Twenty patients (40%) completed the full protocol treatment (six cycles). The reasons for discontinuation of chemotherapy were PD (including PD-related death) in 19 patients (38%), toxicity in four patients (8%), patient refusal in two patients (4%), loss to follow-up during treatment in two patients (4%), and intercurrent death in three patients (6%).
Response
Survival
Acute Toxicity Acute side effects are listed in Table 3 . Data were missing for two patients: one patient received the first cycle, but the treatment form was not disclosed. Therefore, this patient was excluded from toxicity analysis to avoid underestimation of the toxicity rate. The other patient died on the third day of chemotherapy as a result of PD. The chemotherapy toxicity was generally acceptable. Myelosuppression was the most frequent side effect of the treatment and occurred mainly during the induction cycle. National Cancer Institute of Canada grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in nine patients (19%), four patients (8%), and four patients (8%), respectively. Other grade 3 and 4 toxicities included hepatitis in eight patients (16%), renal dysfunction in two patients (4%), stomatitis in three patients (6%), spondylitis in one patient (2%), Pneumocystis carinii in one patient (1%), and corticosteroid-related diabetes mellitus in one patient (2%). One patient died from a pulmonary embolism during the first cycle. No other potentially toxic death was reported. Toxicity required a reduction by more than 30% of the theoretical dose of MTX, lomustine, and procarbazine in 13 (26%), nine (18%), and eight (16%) patients, respectively.
Delayed Toxicity MMSE and KPS changes were analyzed after chemotherapy from baseline until relapse or death unrelated to PCNSL. Most of the patients improved or preserved their cognitive functions and their performance status until progression, reflecting both response to treatment and late consequences of therapy. Thirty-eight patients were available for the MMSE analysis, three patients (8%) deteriorated (MMSE decrease of 7, 17, and 20 points, respectively), 18 patients (47%) remained stable, and 17 patients (45%) improved (median improvement, 9 points; range, 4 to 20 points). Fifty patients were available for the KPS follow-up; six patients deteriorated (12%; median decrease, 40; range, 30 to 50), 26 patients (52%) remained stable, and 18 patients (36%) improved (median improvement, 30; range, 30 to 60). In the long-term responders in remission 2 years after initiation of chemotherapy, cognitive function or performance status decline related to delayed neurotoxicity was observed in one of 14 patients (7%).
This study is the first prospective phase II trial evaluating chemotherapy alone in older patients with PCNSL. Older patients are an important subgroup that accounts for approximately half the cases of PCNSL. In our population with combined established poor prognostic factors9 (median age, 72 years; median KPS, 50), the median survival time was 14.3 months, which indicates that MTX-based chemotherapy alone is at least as effective as RT alone and probably more effective, whereas it reduced the risk of RT- or chemoradiotherapy-induced neurotoxicity.
Prospective PCNSL studies that evaluated radiotherapy alone or chemoradiotherapy and include specific results in elderly patients are scarce and are summarized in Table 4
A recent trial, which associated high-dose MTX (1.5 g/m2) with multiple other agents (carmustine, cytarabine, vincristine, cyclophosphamide, doxorubicin, and dexamethasone) followed by WBRT (45 Gy with a boost of 10 Gy on the tumor bed), reported a median survival duration of 23 months in the elderly-patient subgroup. Although this study included only patients younger than 70 years, the neurotoxicity was also high. (A dementia rate of 62% was observed.) 6 Another recent trial of the Radiation Therapy Oncology Group study group, which delivered a preradiotherapy chemotherapy consisting of high-dose MTX (2.5 g/m2) associated with procarbazine and vincristine, followed by WBRT (45 or 36 Gy hyperfractionated) and high-dose cytarabine, reported a similar median survival time of 21.8 months in patients older than 60 years.13 A 19% rate of delayed leukoencephalopathy was reported. However, the incidence of neurotoxicity was considered by the authors to be probably underappreciated.
To our knowledge, only four studies using chemotherapy alone have been reported with specific attention to the elderly. Two of them used high-dose MTX (1 to 3.5 g/m2) in association with other agents, mainly procarbazine and vincristine.14,15 The third study used MTX as single-drug therapy but at a higher dose (8 g/m2).16 The last study delivered intra-arterial MTX (2.5 g/m2) with blood-brain barrier disruption combined with intravenous cyclophosphamide and etoposide.17 Whatever the dose of MTX, tolerance was good, and high response rates with prolonged median survival time, ranging from 16.3 to 36 months, were reported (Table 5
Another issue is the high vulnerability of the elderly to delayed neurotoxicity. In this study, MMSE and KPS were evaluated prospectively and, so far, treatment-related cognitive decline and performance-status decline were observed in 8% and 12% of patients, respectively, whereas most of the patients maintained or improved their cognitive functions and performance status until progression. These results are in agreement with the previous reports using high-dose MTX-based chemotherapy alone in the elderly14–17 (Table 5  ). Thus, Abrey et al,15 who reported the experience of the Memorial Sloan-Kettering Cancer Center (New York, NY) found a 5% rate of delayed neurotoxicity in patients older than 60 years treated with high-dose MTX-based chemotherapy alone, in contrast to a 82% rate of delayed neurotoxicity in patients treated with the same chemotherapy regimen but followed by WBRT; no survival-time difference was observed between the two groups. Nevertheless, our regimen exposed patients to substantial systemic toxicities—mainly myelosuppression, hepatitis and renal dysfunction leading to a dose reduction (in 26%) or discontinuation of chemotherapy (in 8%). Other serious complications were related to treatment-induced immunosuppression (pneumocystosis or spondylitis). However, most of the systemic toxicities were manageable and reversible. Except for a fatal pulmonary embolism, no toxic death was reported during chemotherapy. In summary, our phase II trial in older patients confirms that high-dose MTX-based chemotherapy alone compares favorably to RT alone in terms of survival benefit and compares favorably to combined treatment in terms of delayed neurotoxicity. RT could therefore be reserved for recurrence or refractory disease. Future protocols for the elderly should try to define the optimal chemotherapy regimen more clearly (such as dose and intensity of MTX, and drugs to associate with MTX) to defer RT as much as possible or completely avoid it. However, older patients are also vulnerable to intensive chemotherapy, and this issue should be given special attention in future trials.18
We thank R. DeBock, Antwerpen; J. Thomas, Leuven, Belgium; P. Hupperets, Maastricht; W. Boogerd, Amsterdam, the Netherlands; A. Brandes, Padova, Italy; H. Loiseau, Bordeaux; and V. Leblond, Paris, France, who contributed to the study.
Presented in part at the Fourth Meeting of the European Association of Neuro-Oncology (EANO), Copenhagen, Denmark, June 3–6, 2000.
1. Coté TR, Manns A, Hardy CR, et al: Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. J Natl Cancer Inst 88:675–679, 1996 2. Corn BW, Sue MM, Topham A, et al: Will primary central nervous system lymphoma be the most frequent brain tumor diagnosed in the year 2000? Cancer 79:2409–2413, 1997[CrossRef][Medline]
3. De Angelis LM, Yahalom J, Thaler HT, et al: Combined modality therapy for primary CNS lymphoma. J Clin Oncol 10:635–643, 1992
4. Blay JY, Bouhour D, Carrie C, et al: The C5R protocol: A regimen of high dose chemotherapy and radiotherapy in primary cerebral non Hodgkin’s lymphoma of patients with no known cause of immunosuppression. Blood 86:2922–2929, 1995
5. O’Brien P, Roos D, Pratt G, et al: Phase II multicenter study of brief single-agent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol 18:519–526, 2000 6. Bessel EM, Graus F, Lopez-Guillermo A, et al: CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 50:457–464, 2001[CrossRef][Medline] 7. Abrey LE, De Angelis L, Yahalom J: Long term survival in primary central nervous system lymphoma. J Clin Oncol 16:859–863, 1998[Abstract] 8. Nelson DF, Martz K, Bonner H, et al: Non-Hodgkin’s lymphoma of the brain: Can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG)—RTOG 8315. Int J Radiat Oncol Biol Phys 23:9–17, 1992[Medline] 9. Corry J, Smith JG, Wirth A, et al: Primary central nervous system lymphoma: Age and performance status are more important than treatment modality. Int J Radiat Oncol Biol Phys 41:615–620, 1998[CrossRef][Medline]
10. Schultz C, Scott C, Sherman W, et al: Pre-irradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD) for PCNSL: Initial report of Radiation Therapy Oncology Group (RTOG) protocol 88-06. J Clin Oncol 14:556–564, 1996 11. O’Neill BP, Wang CH, O’Fallon JR, et al: Primary central nervous system non-Hodgkin’s lymphoma: Survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) study 86-72-42. Int J Radiat Oncol Biol Phys 23:559–563, 1999 12. Desablens B, Gardembas M, Haie-Meder C, et al: Primary CNS lymphoma: Long term results of the GOELAMS LCP88 trial with a focus on neurological complications among 152 patients. Ann Oncol 10:14, 1999 (suppl 3, abstr)
13. De Angelis L, Seiferheld W, Schold SC, et al: Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20:4643–4648, 2002
14. Freilich RJ, Monjour A, Delattre JY, et al: Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology 46:435–440, 1996
15. Abrey LE, Yahalom J, De Angelis L: Treatment of primary CNS lymphoma: The next step. J Clin Oncol 18:3144–3150, 2000 16. Siobhan NG, Rosenthal MA, Ashley D, et al: High dose methotrexate for primary CNS lymphoma in the elderly. Neuro-oncol 2:40–44, 2000[Abstract] 17. McAllister LD, Doolittle ND, Guastadisegni PE, et al: Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 46:51–60, 2000[CrossRef][Medline]
18. Soussain C, Suzan F, Hoang-Xuan K, et al: Results of intensive chemotherapy followed by hematopoietic stem cell rescue in 22 patients with refractory or first relapse primary central nervous system lymphoma or intraocular lymphoma. J Clin Oncol 19:742–749, 2001 Submitted November 8, 2002; accepted April 30, 2003.
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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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