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Results of Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue in 22 Patients With Refractory or Recurrent Primary CNS Lymphoma or Intraocular Lymphoma

From the Service d’Hématologie, Hôpital de Meaux, Meaux; Service d’Hématologie, Hôpital de Versailles, Versailles; Services de Neuro-Oncologie, d’Ophtalmologie, de Neuro-Radiologie, and d’Hématologie and Centre de Transfusion, Hôpital Pitié-Salpêtrière, Paris; Département de Biostatistique et d’Informatique Médicale, Hôpital Saint-Louis, Paris; Service d’Hématologie, Hôpital Necker Paris, Paris; Service d’Hématologie, Hôpital de Colmar, Colmar; and Service d’Hématologie, Institut Gustave Roussy, Villejuif, France.

Address reprint requests to Carole Soussain, MD, Service d’ Hématologie, CHG Meaux, 6-8 rue Saint-Fiacre, BP 218, 77104 Meaux Cedex, France; email: c-soussain{at}ch-meaux.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess the feasibility and efficacy of intensive chemotherapy with hematopoietic stem-cell rescue (IC + HCR) in patients with refractory or recurrent primary CNS lymphoma (PCNSL) or intraocular lymphoma (IOL).

PATIENTS AND METHODS: IC consisted of thiotepa 250 mg/m²/d days -9 through -7, busulfan 10 mg/kg (total dose) days -6 through -4, and cyclophosphamide 60 mg/kg/d days -3 and -2. Intravenous clonazepam 2 mg/d was given prophylactically from the day before initiation of busulfan therapy to the day after completion of busulfan therapy. Patients with refractory or recurrent PCNSL underwent IC + HCR only if they were chemosensitive to two cycles of salvage treatment with cytarabine (2 g/m²/d days 2 through 5 and 50 mg/m²/d days 1 through 5 in a 12-hour infusion) and etoposide (VP-16; 200 mg/m²/d days 2 through 5) (CYVE). Patients with IOL refractory to high-dose methotrexate (MTX) and cytarabine entered the IC + HCR program directly.

RESULTS: Twenty-two patients (10 with relapses, 12 with refractory disease) were enrolled. Twenty patients entered the IC + HCR program: twelve entered after CYVE treatment, seven entered directly, and one had previously been retreated with high-dose MTX. Before IC, eight patients were in complete remission (CR), four were in partial remission (PR), one had stable disease, and seven had refractory disease. After IC + HCR, 16 patients entered CR, two remained in PR, one had stable disease, and one had disease progression. Fourteen patients remained alive (median follow-up time, 41.5 months). The overall probability of survival at 3 years was 63.7%. After IC, that probability was 60% and the 3-year probability of event-free survival was 53%. Seven patients had neurologic adverse events during the entire procedure.

CONCLUSION: IC + HCR proved feasible and effective in patients with refractory or recurrent PCNSL or IOL. The entire procedure seemed to be most toxic in patients 60 years. A prospective multicenter study is ongoing.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE ADDITION OF methotrexate (MTX)-based chemotherapy to radiation therapy has improved the prognosis of patients with primary CNS lymphoma (PCNSL) (and without AIDS),^1-4 but a significant proportion of patients are still not cured. According to published results, the disease of 20% to 30% of patients is primarily refractory to such treatment, and between 11% and 60% of patients who enter complete remission (CR) subsequently relapse.^1,4,5 The few available data show that less than 50% of patients enter second CR^1,2,5,6 and that only a small proportion of patients with recurrent or refractory PCNSL remain alive and disease-free; the median survival time is approximately 6 to 10 months when these patients are retreated with conventional second-line chemotherapy or radiotherapy.^1,5,6 Intensive chemotherapy followed by hematopoietic stem-cell rescue (IC + HCR) is now the standard treatment for patients with relapses of chemosensitive, aggressive, systemic non-Hodgkin’s lymphoma (NHL) without CNS involvement.⁷ The place of high-dose chemotherapy in treating CNS recurrence of NHL was reviewed by van Besien et al⁸: 20% to 40% of adults with a history of CNS involvement by NHL, and few patients with active CNS disease, were cured with high-dose chemotherapy, and no particular regimen proved superior to the others. Only one case of high-dose chemotherapy for PCNSL recurrence has been reported⁹; the patient was alive, in CR, 6 years after transplantation. In a phase II study, we obtained encouraging results with IC + HCR in patients with refractory intraocular lymphoma (IOL), including patients with concomitant initial CNS infiltration. All of the patients entered CR, and no CNS progression was observed after IC.¹⁰

These results prompted us to assess the feasibility and efficacy of IC + HCR in patients with refractory or recurrent PCNSL or IOL. In this article, we report our results in a series of immunocompetent patients who received IC followed by autologous stem-cell rescue as part of their treatment for recurrent or refractory PCNSL or IOL.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
From March 1992 through March 1995, all consecutive human immunodeficiency virus–negative patients younger than 65 years with refractory IOL treated at Hôpital Pitié-Salpêtrière received IC followed by autologous HCR. All of the patients had previously received high-dose MTX and cytarabine. From May 1995 through August 1998, the same therapeutic procedure was extended to all human immunodeficiency virus–negative patients younger than 65 years with recurrent or refractory PCNSL or IOL who were referred to our center and who had previously received high-dose MTX.

Patients gave oral informed consent in this preliminary study.

Treatment
IC consisted of high-dose thiotepa (250 mg/m²/d days -9 through -7) plus busulfan (total dose 10 mg/kg days -6 through -4) and cyclophosphamide (60 mg/kg/d days -3 and -2). The busulfan dose was reduced to 6 mg/kg in patients 60 years. Clonazepam (2 mg/d intravenously) was given prophylactically from the first day of busulfan therapy to the day after completion of busulfan therapy. Hematopoietic stem cells were infused on day 0.

Patients with refractory or recurrent PCNSL underwent IC + HCR only if they were chemosensitive to two cycles of salvage treatment with high-dose cytarabine (2 g/m²/d days 2 through 5 in a 3-hour infusion; 50 mg/m²/d days 1 through 5 in a 12-hour infusion) and etoposide (VP-16; 200 mg/m²/d days 2 through 5 in a 2-hour infusion) (CYVE).¹¹ Total doses were slightly reduced in patients 60 years (cytarabine 2 g/m²/d days 2 through 4 in a 3-hour infusion; 50 mg/m²/d days 1 through 5 in a 12-hour infusion) and VP-16 (150 mg/m²/d days 2 through 5 in a 2-hour infusion). Peripheral-blood stem cells were harvested after the first course of CYVE and were mobilized with subcutaneous granulocyte colony-stimulating factor 5 µg/kg/d, starting 48 hours after the end of chemotherapy.

Patients with IOL who had already received high-dose MTX and cytarabine as part of their first-line treatment received IC + HCR for refractory disease. Bone marrow was collected in steady-state, and peripheral-blood stem cells were collected after chemotherapy and were mobilized with subcutaneous granulocyte colony-stimulating factor 5 µg/kg/d, starting 48 hours after the end of chemotherapy.

Staging Before Inclusion in the Study
Relapsing patients underwent a staging evaluation that included lumbar puncture, abdominal and thoracic computed tomography (CT), bone marrow biopsy, blood tests (WBC count, biochemical tests, liver tests, and lactate dehydrogenase [LDH] assay), and ophthalmic examination. Eye tests comprised testing of initial visual acuity, testing of ocular pressure, examination of the anterior chamber and entire retina with retinophotography if necessary, fluorescein angiography, testing using a laser cell flare meter, ocular ultrasonography, and angiography with indocyanine green. Histologic studies of the disease relapse were required when stereotaxic biopsy or vitrectomy was feasible. The staging evaluation was not repeated in patients with refractory disease.

Evaluation of Response
Response was assessed using follow-up CT or magnetic resonance imaging according to the criteria of Macdonald et al¹² and, in patients with IOL, by repeated ophthalmic tests. CR was defined as resolution of tumor enhancement, and normalization of the ocular fundi, for at least 4 weeks. Partial remission (PR) was defined as at least a 50% reduction in the size of the CNS mass or a reduction in vitreous infiltration. Stable disease was defined as no objective change in the lesions. Progressive disease was defined as an unequivocal increase in tumor size, or vitreous infiltration, or the appearance of new lesions.

Evaluation of Toxicity
Treatment toxicity was graded according to World Health Organization criteria. Neurologic examinations were performed during each cycle and during follow-up.

Survival
Survival curves were plotted using the Kaplan-Meier method.¹³ Survival time was measured on an intention-to-treat basis from inclusion in the study to last follow-up or death. Survival and event-free survival times after IC were measured from autologous transplantation to last follow-up or death.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patient characteristics are summarized in 1 .

Four patients had increased serum LDH levels.

Diagnosis of Recurrences
Diagnosis of recurrences was based on cytologic study of CSF in four patients (patient nos. 2, 3, 18, and 22) and the vitreous in one patient (patient no. 21). In four patients with PCNSL (patient nos. 1, 8, 12, and 19), the lesion was not accessible for stereotactic biopsy, and relapse was diagnosed on the basis of clinical findings and cerebral imaging (CT or magnetic resonance imaging). One patient (patient no. 9), who was blind in one eye, refused vitrectomy of the other eye, and the diagnosis of IOL recurrence was based on characteristic ophthalmologic findings.

Salvage Treatment
Seven patients with refractory IOL entered the IC + HCR program directly. One patient (patient no. 2) with recurrence in CSF was retreated with high-dose MTX-based chemotherapy. Fourteen patients received the CYVE regimen, at full doses in 10 cases and at reduced doses in four cases (patients 60 years). This treatment was second-line chemotherapy for 12 patients, third-line chemotherapy for one patient, and fourth-line chemotherapy for one patient; one patient had received two cycles of the combination of cyclophosphamide, vincristine, prednisone, doxorubicin, and MTX (COPADM¹¹) as second-line treatment, and the remaining patient had received three previous lines of chemotherapy including lomustine, procarbazine, vincristine, cytarabine, and MTX. Two patients died after one cycle of CYVE, one from massive pulmonary embolism while in PR (patient no. 20) and one suddenly from unexplained causes while in CR (patient no. 19). Seven patients entered CR, three patients entered PR, one patient had systemic progression of the lymphoma with complete cerebral remission, and one patient had stable ocular disease.

Status Before IC + HCR
At the time of IC, eight patients were in CR, four were in PR (including one in complete CNS remission but with only a partial systemic response), one was considered to have stable disease, and seven had refractory IOL.

Status After IC + HCR
After IC + HCR, 16 of the 20 patients who entered the IC + HCR program were in CR. These included the eight patients in CR before IC, six patients with refractory IOL, and two patients with conversions of partial responses. Two of the 16 patients relapsed in the eye 3 and 5 months after IC, respectively. Two patients achieved only PR after IC + HCT, one patient continued to have stable intraocular disease, and one patient had systemic progression while still in complete CNS remission.

Toxicity of IC + HCT
After IC + HCR, all patients had grade 4 neutropenia, for a median of 11 days (range, 6 to 16 days), and all patients also had grade 4 thrombocytopenia, for a median of 10 days (range, 1 to 214 days). Nineteen patients had infectious complications, most of which were of moderate severity (four patients had grade 1 complications, 11 had grade 2, three had grade 3, and one had grade 4 complications). One patient developed veno-occlusive disease, with a favorable outcome. One patient died 41 days after IC + HCR, from bleeding due to severe thrombocytopenia.

Survival
During the entire procedure, eight patients died, two after the CYVE regimen. Six patients (patient nos. 1, 4, 8, 10, 11, and 17) died after IC + HCR, three while in CR (patient nos. 4, 8, and 11). The causes of death were bleeding (at 1.5 months, during PR [patient no. 1]), systemic lymphomatous progression (at 3 months [patient no. 17]), neurologic toxicity (at 4 and 22 months [patient nos. 11 and 8, respectively]), a second unrelated tumor (at 33 months, with ocular disease [patient no. 10]), and unknown (at 22 months [patient no. 4]).

The cutoff date for this analysis was October 1999. Median follow-up time from entry onto the study was 41.5 months. Fourteen patients were alive 12 to 70 months after IC + HCT. Twelve patients were in continuous CR. Six of these patients had entered onto the study with progressive disease, and three of the seven patients who entered onto the study with a relapse had a longer second CR than a first CR (data not shown). At the time of analysis, one patient had stable disease and one patient was undergoing treatment for progressive intraocular disease. No cases of CNS progression occurred.

The probability of overall survival at 3 years was 63.7% ( Fig 1). The 3-year probability of survival after IC was 60% ( Fig 2), and the 3-year probability of event-free survival was 53% ( Fig 3).

View larger version (8K): [in this window] [in a new window]   Fig 1. Overall survival of the patient population (n = 22).

View larger version (8K): [in this window] [in a new window]   Fig 2. Overall survival of the 20 patients who received IC + HCR.

View larger version (9K): [in this window] [in a new window]   Fig 3. Event-free survival after IC + HCR.

Prognostic Factors
The following factors were studied for their prognostic value: status after first-line treatment (relapse v refractory disease), disease type according to site (IOL v intracerebral disease v CSF involvement), performance status (PS) at the time of recurrence or progression (score of 0 or 1 v score of 2 or 3), age (< 60 years v 60 years), LDH level at the time of relapse or progression (normal v above-normal), type of primary chemotherapy (MTX doses, addition of procarbazine or lomustine), prior radiotherapy, neurotoxicity, and duration of first CR (> 15 months v 15 months). In univariate analysis, age 60 years and poor PS (score of 2 to 3) were associated with a poorer prognosis: survival time among patients 60 years of age was 6 months, whereas median survival time among younger patients had not been reached (P = .009, log-rank test). Median survival time had not been reached among patients with a PS of 0 or 1 but was 7 months among patients with a PS of 2 or 3 (P = .0005, log-rank test). Patients with isolated refractory IOL or isolated CSF lymphoma (median survival time not reached) seemed to have longer survival times than did patients with intracerebral tumor at the time of relapse or progression (median survival time, 5.5 months; P = .00005, log-rank test). However, among the eight patients with intracerebral tumor, six had a PS of 2 or 3, five were 60 years of age, and six died from toxicity, either after CYVE (n = 2) or after IC + HCT (n = 4, two from neurotoxicity), but no CNS recurrence was observed in these patients. The other factors studied were not found to be prognostic.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The aim of this study was to assess the feasibility and efficacy of IC followed by autologous stem-cell transplantation in patients with recurrent or refractory PCNSL or IOL. This intensive approach was taken because of the poor prognosis of these patients when retreated with conventional chemotherapy or radiotherapy and because of available experience in recurrent systemic NHLs. Nevertheless, PCNSL and IOL need to be studied separately from systemic lymphoma because of the need for drug passage through the blood-brain and blood-retina barriers in the PCNSL and IOL. These barriers are composed of capillaries with tight junctions covered by astrocytes; when intact, they cannot be crossed by lipid-insoluble, high-molecular-weight compounds. Brain penetration of drugs can be enhanced by inflammatory processes around the tumor, leading to greater neurologic toxicity. The thiotepa-cyclophosphamide-busulfan combination was chosen for IC because of the good CSF and brain diffusion of thiotepa and busulfan.^14,15 The validity of the use of cyclophosphamide is debatable, because this hydrophilic drug theoretically does not cross the intact blood-brain barrier, but data on its CNS penetration are conflicting. Meningeal uptake of the active metabolite is limited, but cyclophosphamide seems to reach therapeutic concentrations in brain tumors.¹⁶ The combination was used as originally described because it proved effective in a phase I-II study involving patients with refractory systemic NHL,¹⁷ because of our encouraging results in IOL,¹⁰ and because the toxicity of this conditioning regimen is known to be acceptable. Moreover, cyclophosphamide remains an effective drug in the treatment of systemic lymphoma and can thus play a role in treating subclinical systemic lymphomatous infiltration, which is found at autopsy in approximately 7% of cases.¹⁸

The CYVE regimen was given as second-line treatment for three reasons: the lack of cross-resistance between cytarabine or VP-16 and MTX (used in the first-line therapy), the good CNS diffusion of high doses of cytarabine and VP-16, and the known efficacy of this regimen in adults and children with Burkitt’s lymphoma and initial CNS disease.^11,19

CYVE, administered as salvage treatment after failure of high-dose MTX-based chemotherapy, yielded 12 objective responses (eight complete responses and four partial responses) among the 14 patients thus treated. These good results call for studies of the CYVE regimen as consolidation after high-dose, MTX-based first-line induction. Consolidation with CYVE instead of cranial radiotherapy might be effective, and the neurologic toxicity of the combined treatment would be avoided if the CYVE regimen were used. The neurologic toxicity observed in our series after IC in previously irradiated patients less than 60 years of age is similar to that described by other authors^9,20 and may be explained by disruption of the blood-brain barrier by irradiation.⁸ Successful treatment with chemotherapy alone has already been reported in young and older patients.^6,21

In our series, patients with intracerebral recurrence or progression had a poorer prognosis than did patients with IOL or CSF disease, but they were also older and had a poorer PS and a high treatment-related mortality rate. However, no CNS progression occurred in these patients after transplantation. The poorer prognosis associated with age 60 years and a PS score of 2 or 3 that we found in our study in univariate analysis was previously found in another study in univariate and multivariate analysis in untreated patients.²²

These results raise the question of whether IC and autologous stem-cell transplantation should be introduced earlier in the course of treatment, to improve the results of first-line treatment and reduce cumulative toxicity. A pilot study has been conducted in this setting²³: four of six patients entered CR after induction chemotherapy and did not have neurologic toxicity after subsequent high-dose chemotherapy. Unfortunately, the small number of patients precludes the drawing of firm conclusions. Another approach to intensive delivery of chemotherapy in PCNSL is to administer intra-arterial chemotherapy with osmotic blood-brain barrier disruption,²⁴ and results need to be compared with other first-line chemotherapy regimens. Because first-line treatment has recently been improved by the introduction of high-dose MTX, the use of intensive treatment and autologous stem-cell transplantation as part of first-line treatment seems premature. In contrast, we now treat eligible patients who have IOL, which is clearly resistant to various conventional chemotherapies, directly with IC and autologous stem-cell transplantation.¹⁰

In conclusion, this phase II study shows that IC + HCR is feasible and effective in patients with refractory or recurrent PCNSL or IOL. However, patients 60 years are poor candidates for this procedure; five of the seven patients 60 years in this study died from treatment complications.

A prospective multicenter study is ongoing; a larger group of patients will be studied. Neurologic toxicity and prognostic factors will be evaluated prospectively.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. DeAngelis LM, Yahalom J, Thaler HT, et al: Combined modality therapy for primary CNS lymphoma. J Clin Oncol 10: 635-643, 1992[Abstract/Free Full Text]

2. DeAngelis LM, Yahalom J, Heinemann MH, et al: Primary CNS lymphoma: Combined treatment with chemotherapy and radiotherapy. Neurology 40: 80-86, 1990[Abstract/Free Full Text]

3. Blay JY, Conroy T, Chevreau C, et al: High-dose methotrexate for the treatment of primary cerebral lymphomas: Analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 16: 864-871, 1998[Abstract]

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[Abstract/Free Full Text]

5. Sarazin M, Ameri A, Monjour A, et al: Primary central nervous system lymphoma: Treatment with chemotherapy and radiotherapy. Eur J Cancer 12: 2003-2007, 1995

6. Freilich RJ, Delattre JY, Monjour A, et al: Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology 46: 435-439, 1996[Abstract/Free Full Text]

7. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared to salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333: 1540-1545, 1995[Abstract/Free Full Text]

8. van Besien K, Forman A, Champlin R: Central nervous system relapse of lymphoid malignancies in adults: The role of high-dose chemotherapy. Ann Oncol 8: 515-524, 1997[Abstract/Free Full Text]

9. Khalfallah S, Stamatoullas A, Fruchart C, et al: Durable remission of a relapsing primary central nervous system lymphoma after autologous bone marrow transplantation. Bone Marrow Transplant 18: 1021-1023, 1996[Medline]

10. Soussain C, Merle-Béral H, Reux I, et al: A single-center study of 11 patients with intraocular lymphoma treated with conventional chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation in 5 cases. Leuk Lymphoma 23: 339-345, 1996[Medline]

11. Patte C, Leverger G, Perel Y, et al: Updated results of the LMB86 protocol of the French Pediatric Oncology Society (SFOP) for B-cell non-Hodgkin’s lymphoma (B-NHL) with CNS involvement (CNS+) and B-ALL. Med Pediatr Oncol 18: 406, 1990 (abstr)

12. Macdonald DR, Cascino TL, Schold SC Jr, et al: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8: 1277-1280, 1990[Abstract]

13. Kaplan FL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 52: 457-481, 1958

14. Wolff SN: High-dose therapy for brain tumors: Rationale, results, and future prospects, in Armitage JO, Antman KH (eds): High-Dose Cancer Therapy: Pharmacology, Hematopoietins, Stem Cells (ed 2). Baltimore, MD, Williams & Wilkins, 1995, pp 879-883

15. Balis FM, Poplack DG: Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hematol Oncol 11: 74-86, 1989[Medline]

16. Talha MRZ, Rogers HJ, Trounce JR: Distribution and pharmacokinetics of cyclophosphamide in the rat. Br J Cancer 41: 140-143, 1980[Medline]

17. Przepiorka D, Nath R, Ippoliti C, et al: A phase I-II study of high-dose thiotepa, busulfan and cyclophosphamide as a preparative regimen for autologous transplantation for malignant lymphoma. Leuk Lymphoma 17: 427-433, 1995[Medline]

18. O’Neil BP, Dinapoli D, Kurtin PJ, et al: Occult systemic non-Hodgkin’s lymphoma (NHL) in patients initially diagnosed as having primary central nervous system lymphoma (PCNSL): How much staging is enough? Proc Am Soc Clin Oncol 14: 151, 1995 (abstr)

19. Soussain C, Patte C, Ostronoff M, et al: Small noncleaved cell lymphoma and leukemia in adults: A retrospective study of 65 adults treated with the LMB pediatric protocols. Blood 85: 664-674, 1995[Abstract/Free Full Text]

20. van Besien K, Przepiorka D, Mehra R, et al: Impact of preexisting CNS involvement on the outcome of bone marrow transplantation in adult hematologic malignancies. J Clin Oncol 14: 3036-3042, 1996[Abstract]

21. Cohen IA, Vogel R, Matz S, et al: Successful nonneurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB). Cancer 57: 6-11, 1986[Medline]

22. 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[Medline]

23. Marks R, Warnke P, Guttenberg R, et al: Primary CNS lymphoma (PCNSL): High-dose chemotherapy with autologous PBSCT and hyperfractionated radiotherapy within first-line treatment. Ann Oncol 10: 15, 1999 (suppl 3, abstr)

24. Doolittle ND, Miner ME, Hall WA, et al: Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 88: 637-647, 2000[Medline]

Submitted December 28, 1999; accepted September 18, 2000.

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				H. Pels, I. G.H. Schmidt-Wolf, A. Glasmacher, H. Schulz, A. Engert, V. Diehl, A. Zellner, G. Schackert, H. Reichmann, F. Kroschinsky, et al. Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy J. Clin. Oncol., December 15, 2003; 21(24): 4489 - 4495. [Abstract] [Full Text] [PDF]

				L. M. DeAngelis Primary Central Nervous System Lymphoma: A Curable Brain Tumor J. Clin. Oncol., December 15, 2003; 21(24): 4471 - 4473. [Full Text] [PDF]

				L. E. Abrey, C. H. Moskowitz, W. P. Mason, M. Crump, D. Stewart, P. Forsyth, N. Paleologos, D. D. Correa, N. D. Anderson, D. Caron, et al. Intensive Methotrexate and Cytarabine Followed by High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Patients With Newly Diagnosed Primary CNS Lymphoma: An Intent-to-Treat Analysis J. Clin. Oncol., November 15, 2003; 21(22): 4151 - 4156. [Abstract] [Full Text] [PDF]

				K. Hoang-Xuan, L. Taillandier, O. Chinot, P. Soubeyran, U. Bogdhan, J. Hildebrand, M. Frenay, N. De Beule, J.Y. Delattre, and B. Baron 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 J. Clin. Oncol., July 15, 2003; 21(14): 2726 - 2731. [Abstract] [Full Text] [PDF]

				A. J.M. Ferreri, L. E. Abrey, J.-Y. Blay, B. Borisch, J. Hochman, E. A. Neuwelt, J. Yahalom, E. Zucca, F. Cavalli, J. Armitage, et al. Summary Statement on Primary Central Nervous System Lymphomas From the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002 J. Clin. Oncol., June 15, 2003; 21(12): 2407 - 2414. [Abstract] [Full Text] [PDF]

				T. T. Batchelor, G. Kolak, R. Ciordia, C. S. Foster, and J. W. Henson High-Dose Methotrexate for Intraocular Lymphoma Clin. Cancer Res., February 1, 2003; 9(2): 711 - 715. [Abstract] [Full Text] [PDF]

				N. D. Doolittle, L. E. Abrey, N. Ferrari, W. A. Hall, E. R. Laws, R. E. McLendon, L. L. Muldoon, D. Peereboom, D. R. Peterson, C. P. Reynolds, et al. Targeted Delivery in Primary and Metastatic Brain Tumors: Summary Report of the Seventh Annual Meeting of the Blood-Brain Barrier Disruption Consortium Clin. Cancer Res., June 1, 2002; 8(6): 1702 - 1709. [Abstract] [Full Text] [PDF]

				A. J. M. Ferreri, J.-Y. Blay, M. Reni, F. Pasini, A. Gubkin, U. Tirelli, A. Calderoni, E. Zucca, S. Cortelazzo, C. Chassagne, et al. Relevance of intraocular involvement in the management of primary central nervous system lymphomas Ann. Onc., April 1, 2002; 13(4): 531 - 538. [Abstract] [Full Text] [PDF]

				A. Lister, L. E. Abrey, and J. T. Sandlund Central Nervous System Lymphoma Hematology, January 1, 2002; 2002(1): 283 - 296. [Abstract] [Full Text]

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