KEY WORDS lymphoma methotrexate central nervous system rapid infusion. J Neurosurg 91: , 1999

Transcription

1 J Neurosurg 91: , 1999 Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas SHOJU HIRAGA, M.D., PH.D., NORIO ARITA, M.D., PH.D., TAKANORI OHNISHI, M.D., PH.D., EIJI KOHMURA, M.D., PH.D., KAZUMI YAMAMOTO, M.D., PH.D., YUZURU OKU, M.D., PH.D., TAKUYU TAKI, M.D., PH.D., MASAHARU SATO, M.D., PH.D., KATSUYUKI AOZASA, M.D., PH.D., AND TOSHIKI YOSHIMINE, M.D., PH.D. Departments of Neurosurgery and Pathology, Osaka University Medical School; Department of Neurosurgery, Osaka Rosai Hospital; Department of Neurosurgery, Kansai Rosai Hospital; and Department of Neurosurgery, Toyonaka Municipal Hospital, Osaka, Japan Object. Twenty-nine nonimmunocompromised patients with primary central nervous system (CNS) lymphoma were treated with high-dose methotrexate (MTX) therapy followed by irradiation. The authors investigated the correlation of infusion schedules with MTX penetration into cerebrospinal fluid (CSF), tumor response, and survival to develop a regimen that would lead to better clinical results. Methods. In this study, 100 mg/kg MTX was administered on either a rapid (3-hour) or regular (6-hour) infusion schedule for two or three cycles. Of 28 assessable patients, a complete or partial response was achieved in 15 (93.8%) of 16 who received rapid and in seven (58.3%) of 12 who received regular infusion therapy (p = 0.034). Rapid infusion significantly increased levels of MTX in the CSF (p 0.001) and resulted in significant tumor volume reduction (p 0.001). The mean tumor volume after the first, second, and third cycle of rapid infusion therapy was reduced to 34%, 14%, and 9%, respectively, of the initial volume, whereas the corresponding values were 54%, 42%, and 37% for regular infusion. The reduction between the second and third cycle was small and not significant for either schedule. Despite the longer median survival time in patients who underwent rapid MTX infusion and irradiation ( 60 compared with 20 months), the difference in survival was not significant (p = 0.147) because of the small number of patients enrolled. The median survival time was 39.3 months for all assessable patients who received highdose MTX and radiation therapy, and the median relapse-free survival time was 35.2 months. Conclusions. Rapid infusion enhanced both MTX penetration into the CSF and tumor response and may improve patient survival. Administration of three or more cycles of therapy should be carefully weighed in terms of cytoreductive benefits. KEY WORDS lymphoma methotrexate central nervous system rapid infusion T HE incidence of primary central nervous system (CNS) lymphoma has recently been increasing among nonimmunocompromised populations 3,13,21, 30,61 as well as in immunocompromised patients who are human immunodeficiency virus positive 5 or who have undergone organ transplantation. 49 Irradiation was the sole effective treatment for primary CNS lymphoma until the early 1980s, but tumor regrowth was quite frequent and the median survival time of these patients ranged from only 10 to 18 months. 6,30,32,37,38,40,53,56,61 High-dose methotrexate (MTX) therapy administered before irradiation has recently been identified as an effective 1,22, 24,26,51 and relatively safe treatment for this type of tumor. However, infusion schedules differ among published studies, and no detailed investigation of the relationship between the infusion schedule and therapeutic effect has been published for patients with primary CNS lymphoma. 1,15,22,24,26,51 Although rapid infusion of MTX has been J. Neurosurg. / Volume 91 / August, 1999 thought to intensify penetration of MTX into cerebrospinal fluid (CSF) and brain tissues, eventually leading to a better antineoplastic effect, 12,51 longer infusion schedules have been adopted in several studies. 50,59 Furthermore, the appropriate number of therapeutic cycles has not been determined. In some studies 24,26 a significant antineoplastic effect has been reported after two to four cycles of high-dose therapy, whereas in others 14,22,51 more than 10 cycles were used. However, late sequelae, including asymptomatic diffuse white matter changes, 36 decline in cognitive function, and development of leukoencephalopathy, have been observed repeatedly in MTX therapy, because this agent is toxic for normal brain tissues. 4,8,19,51,55 Most patients with primary CNS lymphoma are elderly and may be much more vulnerable to MTX than younger patients; 2,18,20 also, combining MTX with radiation therapy increases the incidence of sequelae significantly. 2,14,20,23 Therefore, efforts to avoid excessive exposure to and high 221

2 S. Hiraga, et al. cumulative doses of MTX, both of which are predisposing factors for late sequelae, 4,8,36,55 are crucial for obtaining better clinical results. In this study we therefore investigated the correlation of infusion schedules with MTX concentration in CSF, tumor response, and patient survival. Tumor volume reduction in response to each therapeutic cycle was also evaluated to determine the most suitable number of cycles. Clinical Material and Methods Patient Selection Enrollment for this study started in April 1992 and ended in December Observation of the patients was terminated in February Nonimmunocompromised patients with untreated primary CNS lymphoma admitted to Osaka University Hospital or referred from affiliated institutions during this period were enrolled. A surgical specimen was obtained from every patient and was histologically examined according to the criteria of the Working Formulation for Clinical Usage. 45 Patients with a diffuse large-cell, immunoblastic, small noncleaved cell, or polymorphous lymphoma were eligible for this study, and those with a small lymphocytic, small-cleaved cell or mixed-cell type lymphoma were excluded. Although no limit was set for the Karnofsky Performance Scale 34 (KPS) score or age of the patients, those with a creatinine clearance of less than 70 ml/minute or who had severe urolithic problems were excluded. Cytocentrifugation of CSF was performed before the first drug cycle and after completion of the high-dose MTX therapy. Cytological preparations that exhibited unequivocal evidence of malignancy were considered positive, and atypical or suspicious cases were classified as negative. 27,54 Uveal involvement was routinely checked by means of slitlamp eye examination. Systemic examinations including chest radiography, gallium scintigraphy, and whole-body computerized tomography (CT) scanning were also performed to identify patients with metastasis of nonprimary CNS lymphomas into the CNS and exclude them. Bone marrow biopsy sampling was not mandatory 17,18 and depended on the physician s judgment. High-Dose MTX Therapy A dose of 100 mg/kg MTX was intravenously administered for either 3 or 6 hours after sufficient hydration, alkalinization in urine, and diuresis. The 3-hour protocol was defined as rapid infusion and the 6-hour one as regular infusion. The infusion schedules were randomly assigned among the patients. For both schedules, 15 mg of calcium leucovorin was administered intravenously every 4 hours. This agent was started 24 hours after initiation of MTX therapy to neutralize the toxic effect of the latter and was continued until the MTX concentration in the blood had decreased to harmless levels ( 0.05 M). The duration of each MTX cycle was 2 weeks, and the patients received at least two cycles of the therapy unless the disease progressed. The third cycle was limited to patients who exhibited a significant response after the second cycle and was administered depending on the physician s judgment. Radiation Therapy Whole-brain irradiation was started 14 days after completion of chemotherapy or earlier in cases of tumor progression. The minimum dose was 30 Gy, fractionated into 2 Gy/day administered five times per week. For tumors with uveal involvement, the entire orbit was irradiated and the anterior chamber was blocked after 20 Gy. If the enhanced tumor areas remained after the 30-Gy dosage, an additional 10- to 20-Gy boost was given to those areas as well as to the tumor-invaded regions that were visualized as hypodense areas on CT scanning or prolonged signal regions on T 2 -weighted magnetic resonance (MR) imaging. If the enhanced tumor disappeared after the 30-Gy regimen was completed, administration of the radiation boost depended on the physician s decision. Measurement of MTX Concentration in CSF To obtain data about the differences in MTX concentration in CSF between the infusion schedules, informed consent was obtained from the patients for placement of a lumbar intradural catheter. Samples of CSF were collected at 0, 2, 4, 6, 8, 12, 24, and 48 hours after the start of infusion. The catheter was withdrawn immediately after the last sample had been collected. Assessment of Response to Therapy The MR or CT studies were obtained within 3 days before the first MTX cycle, at the 10th to 13th day of a cycle, and after completion of irradiation. Because primary CNS lymphoma frequently entails multiple lesions and tumor response may vary among them, response to treatment was assessed by measuring changes in the total estimated volume of each contrast-enhanced lesion. 44 The enhanced tumor area in each slice was measured using an image scanner and software (National Institutes of Health software, version 1.55; National Institutes of Health, Bethesda, MD). The total enhancement was calculated as the sum of individual enhanced tumor areas multiplied by the distance between two adjacent slices. A complete response was defined as the eradication of all tumor enhancement with no evidence of positive CSF cytological findings or active uveal disease. A partial response was defined as tumor volume reduction of 50% or more, and reduction of less than 50% was considered to represent stable disease. Progressive disease was defined as the appearance of new lesions or an increase of 25% or more in the volume of the preexisting tumor. Except for a complete response, tumor responses were rated regardless of CSF cytological findings or uveal disease. A complete or partial response was judged to be a significant one. The tumor reduction rate for a cycle of high-dose MTX therapy was calculated by dividing the tumor volume after each cycle by the initial volume to evaluate the macroscopic therapeutic effect of the cycle. Effect of Glucocorticoid Medications Because approximately 40% of primary CNS lymphomas are reported to respond to glucocorticoid medications, 17 the effect of such agents administered before the initiation of high-dose MTX therapy was evaluated. The tumor volume on CT or MR studies was measured using 222 J. Neurosurg. / Volume 91 / August, 1999

3 Rapid infusion of methotrexate in primary CNS lymphoma the same method as detailed in the latter section. The tumor volume before glucocorticoid administration and the volume before initiation of high-dose MTX therapy were compared. The glucocorticoid was reduced to the minimum dose to reduce perifocal brain edema or tapered off before initiation of MTX therapy. Statistical Analysis Overall and relapse-free survival times from the date of diagnosis were plotted using the Kaplan Meier productlimit method. 33 The difference in survival curves was examined for each of the potential prognostic factors by using the generalized Wilcoxon test. 25 The Cox proportional hazards model was used to determine which prognostic factors were associated with survival. 16 When a potential prognostic factor was judged to be independent and appropriate for the model, the hazard ratio and significance of the factor were also calculated. For comparison of the two groups, the data were analyzed using univariate analysis. All probability values refer to either a chi-square test or Fisher s exact probability test for tables and, where appropriate, to the Mann Whitney U-test for nonparametric data. The time course curve of MTX concentration in CSF and the tumor volume reduction curve for each therapeutic cycle were tested with Fisher s protected least significant difference test by using repeated-measures analysis of variance (MANO- VA) for infusion schedules. These statistics were analyzed using a personal computer running Stat View 4.51J software (Abacus Concepts, Berkeley, CA). Results Patient Characteristics A total of 29 patients (17 men and 12 women) were enrolled in this study. Their ages ranged from 23 to 77 years with a mean age of 56.2 years. All patients had one or more tumors that were assessable on enhanced T 1 - weighted MR or CT studies obtained before treatment. The lesions were solitary in 16 patients and multiple in 13. Twenty-three tumors were located in deep cerebral structures such as basal ganglia, thalamus, and intraventricular regions, and six tumors were superficial. The tumor volume before high-dose MTX therapy ranged from 4.5 to 79.2 ml, with a mean volume of 26.2 ml. Histological examination of surgical specimens resulted in 25 tumors being classified as non-hodgkin s diffuse large-cell type and the other four as an immunoblastic type. Immunohistochemical studies of 25 of the 29 tumors identified all as being of B-cell lineage. Uveal involvement of the lymphoma cells was evident in one patient. Cytological studies of CSF showed positive results for five of 23 patients examined before the high-dose MTX therapy was initiated (Table 1). Previously identified prognostic factors such as tumor location, pretreatment KPS score, and age 41,43,52 were compared between the infusion groups; however, there were no significant differences in any of these factors. Effect of High-Dose MTX Therapy Of the 29 patients enrolled in this study, one patient in J. Neurosurg. / Volume 91 / August, 1999 TABLE 1 Summary of pretreatment data in 29 patients with primary CNS lymphoma High-Dose MTX Factor Rapid Infusion Regular Infusion Total age (yrs) range mean sex male female initial KPS score (range 30 90) mean histological type large cell immunoblastic tumor location deep superficial tumor multiplicity solitary multiple tumor volume (ml) range mean CSF cytological finding positive negative not determined response to glucocorticoids partial response stable disease unknown* not used * Concurrently administered with MTX. the regular infusion group developed an allergic reaction followed by acute renal failure during the first cycle of the therapy. Because the renal as well as general condition of the individual had severely deteriorated, neuroimaging studies with contrast enhancement were not performed until the patient had recovered from the toxic event. The tumor showed the same volume on the contrast-enhanced MR image obtained 47 days after the event as was on at the pretreatment image. This patient was therefore excluded from the follow-up evaluation, leaving 28 patients judged as assessable. Of these, 16 were treated with the rapid infusion and 12 with regular infusion. Fifteen (93.8%) of the 16 patients treated with rapid infusion achieved a significant response: complete response in three patients, partial response in 12, and progressive disease in one. A significant response was achieved for seven (58.3%) of the 12 patients treated with regular infusion therapy: partial response in seven, stable disease in four, and progressive disease in one. There was thus a significant difference in the tumor response between these two groups (Fisher s exact test, p = 0.034). The overall 223

4 S. Hiraga, et al. TABLE 2 Summary of therapeutic data in 28 patients with assessable primary CNS lymphoma High-Dose MTX Rapid Regular Infusion Infusion Factor (16 patients) (12 patients) Total FIG. 1. Graph showing the ratio of treatment cycles to initial tumor volume plotted as the mean SEM for each therapeutic cycle. Tumor volume reduction was significantly greater in the rapid infusion group (MANOVA, p 0.001). The tumor volume was significantly reduced between pretreatment and any cycle in either group (Mann Whitney U-test, p 0.001) and between the first and the second cycles in the rapid infusion group (Mann Whitney U-test, p 0.05). response of primary CNS lymphoma to high-dose MTX therapy consisted of three complete responses, 19 partial responses, four stable diseases, and two progressive diseases, and a significant response was achieved in 22 (78.6%) of 28 (Table 2). In two of the four patients with stable disease in the regular infusion group, the tumor regressed significantly during the first two cycles but started to progress after the third, although the increased tumor volume remained less than 25% of the initial tumor volume. The tumor did not respond to MTX at all in one patient with progressive disease in the rapid infusion group, and another patient in the regular infusion group exhibited a new lesion after the third cycle, although the primary lesion showed a partial response. The malignant cells in CSF disappeared after completion of high-dose MTX therapy in the five patients with positive results on CSF cytological studies. The uveal involvement of lymphoma cells in one patient remained unchanged after high-dose MTX therapy alone, although the CNS lesion disappeared completely. This patient was judged to have achieved a partial response for high-dose MTX therapy; the ocular lesion disappeared completely after radiation therapy. The tumor volume reduction for each cycle of highdose MTX therapy was measured in 27 of the 28 assessable patients. In these patients, the initial tumor volume therapeutic cycle of drug mean cycle 1* 1 2 cycles cycles tumor response complete response 3 3 partial response stable disease 4 4 progressive disease significant response 15 of 16 7 of of 28 tumor radiation dose mean Gy Gy Gy tumor response to drug + irradiation complete response partial response significant response 16 of of of 28 final KPS score range mean late toxicity to drug + irradiation: diffuse change on neuroimaging tumor relapse primary site remote neuraxis remote neuraxis + uvea meningeal non-cns * Patient with progressive disease after one cycle. Ratio of the number of patients with complete response or partial response divided by the total number of patients. p = standard error of the mean (SEM) was ml for 16 patients treated with rapid infusion and ml for 11 patients given regular infusion. The initial tumor volumes were not significantly different between the two groups (Mann Whitney U-test, p = 0.693). The mean tumor volume was reduced to 33.5% of the initial volume after the first, 13.8% after the second, and 9.4% after the third cycle of rapid infusion therapy, whereas the corresponding values were 54.3%, 41.9%, and 36.5% for regular infusion. Tumor reduction during the three cycles was thus significantly greater in the rapid infusion group (MANOVA, p 0.001). The differences in tumor reduction at the first cycle and during the first two cycles were also significant for both groups (MANOVA, p = and p 0.001, respectively). The reduction was also significant between pretreatment and after any of the cycles (Mann Whitney U-test, p 0.001) in either group and between the first and second cycle in the rapid infusion group (Mann Whitney U-test, p 0.05). However, the 224 J. Neurosurg. / Volume 91 / August, 1999

5 Rapid infusion of methotrexate in primary CNS lymphoma reduction was negligible between the first and second cycle in the regular infusion group and between the second and third cycle in both groups (Fig. 1). Tumor Response to Radiation Treatment All assessable patients underwent radiation therapy; the radiation dose to the tumor is shown in Table 2. Although five of the six patients with stable or progressive disease after MTX therapy received 50-Gy dosages to the tumor, there was no difference in the radiation dose between the infusion groups. Of 16 patients treated with rapid infusion, 14 of the 15 who demonstrated a significant response to the MTX therapy achieved a complete response. The one remaining patient and another with progressive disease after MTX therapy achieved a partial response with a 50- Gy dosage of radiation. Of the 12 patients treated with regular infusion, three of the five with stable or progressive disease after the MTX therapy did not achieve a complete response but only a partial response with 50-Gy dosages of radiation, whereas all seven patients with a partial response to MTX achieved a complete response after adjuvant radiation treatment. Improvement of KPS Score The patients initial KPS score ranged from 30 to 90, with a mean of After completion of the high-dose MTX and irradiation regimens, KPS scores improved in 25 of the 28 assessable patients for an overall mean of The improvement in the KPS score was significant in both groups (Mann Whitney U-test, p for rapid and p = for regular infusion group). There was no significant difference in the initial and final KPS score between the rapid and regular infusion groups (Tables 1 and 2). Concentration of Methotrexate in CSF The concentration of MTX in CSF was measured serially in six assessable patients in each of the rapid and regular infusion groups. The maximum concentration ranged from 7.12 to 19 M (mean 11.8 M) at 4 to 6 hours after initiation of the rapid infusion and from 3.83 to 8.31 M (mean 5.71 M) at 6 to 8 hours after initiation of the regular infusion. The time course curve of MTX concentration in CSF was significantly elevated for the rapid compared with the regular infusion group (MANOVA, p 0.001). The total area under the curve of MTX concentration in CSF, plotted as a function of time, was also significantly larger for the rapid infusion group (Mann Whitney U-test, p = 0.025). The mean of the total area under the curve standard deviation was M/hour for the rapid and M hour for the regular infusion group. The concentration of MTX was also significantly higher at 2, 4, 6, and 8 hours after the start of infusion in the rapid infusion group but did not show any difference from the regular infusion group at 12, 24, and 48 hours. The MTX remained above the minimum therapeutic concentration (1 M) 31 in the CSF of all patients until 12 hours after the start of infusion and after 24 hours of infusion in five of the six patients in each group (Fig. 2). J. Neurosurg. / Volume 91 / August, 1999 FIG. 2. Graph showing time course changes in MTX concentration in CSF plotted as the mean SEM for infusion groups (MANOVA, p 0.001). The concentration was significantly different at 2, 4, 6, and 12 hours (Mann Whitney U-test; *p 0.05; **p 0.01). Toxicity and Late Sequelae A total of 73 cycles of the therapy was administered in the 29 patients. As mentioned, one patient who developed acute renal failure was treated with direct hemoperfusion and hemodialysis. Although this patient experienced successive complications classified as World Health Organization Grade 5, including melena, thrombocytopenia, granulocytopenia, and subacute transient encephalopathy, the individual had recovered and survived for 18 months with no evidence of disease before the tumor relapsed. In addition, eight patients in the rapid and six in the regular infusion group experienced toxic events such as granulocytopenia, thrombocytopenia, nausea, diarrhea, and hepatic damage classified as World Health Organization Grades 1 to 3. These events were transient, and postponement of the next therapeutic cycle was not required for any of the patients. These toxic events, except for acute renal failure, were thus considered acceptable, and there was no difference in their incidence between the rapid and regular infusion groups. Neuroimaging studies with contrast enhancement were repeated in all patients at least twice per year and more often in the patients who developed new neurological signs or symptoms after the initial treatment. Five of the 28 assessable patients, three from the rapid and two from the regular infusion group, showed progressive and diffuse changes in the white matter on CT or MR studies 12 to 44 months after the initial diagnosis, and these changes were judged to represent late sequelae of the treatment (Table 2). All these patients were more than 60 years of age, and four of them experienced tumor relapse in the degenerated region, one each at 17, 35, 50, and 53 months after diagnosis. One patient developed a gradual decline in cognitive function and KPS status 12 months after diagnosis and died with no evidence of tumor 6 months after development of the sequelae. 225

6 S. Hiraga, et al. TABLE 3 Factors affecting survival in 28 assessable patients with primary CNS lymphoma* Factor Contrasted Elements MST (mos) p Value Hazard Ratio univariate analysis survival MTX schedule regular (12) vs. rapid (16) 20.0 vs age (yrs) 60 (13) vs. 60 (15) 14.7 vs KPS score 50 (8) vs. 50 (20) 10.8 vs sex male (16) vs. female (12) 39.3 vs tumor location deep (22) vs. superficial (6) 23.2 vs tumor size (ml) 10 (7) vs. 10 (22) 39.7 vs tumor multiplicity multiple (13) vs. solitary (15) 17.9 vs CSF cytological findings positive (5) vs. negative (17) 10.8 vs relapse-free survival MTX schedule regular (12) vs. rapid (16) 25.0 vs multivariate analysis (28 patients) survival KPS score 50 vs age (yrs) 60 vs MTX schedule regular vs. rapid * Numbers in parentheses indicate the number of patients being compared. Abbreviation: MST = median survival time. Effect of Glucocorticoid Medications Five (20%) of 25 patients who received glucocorticoids prior to high-dose MTX therapy achieved a partial response (Table 1). One of these patients was misdiagnosed as having multiple sclerosis, and the other four initially refused further treatment. These patients were referred for FIG. 3. Graphs showing overall (A) and relapse-free (B) survival of the MTX-treated patients plotted using the Kaplan Meier product-limit method for each therapeutic group. high-dose MTX therapy for treatment of progressive disease following the initial response that lasted for 35 to 137 days. The response to glucocorticoids was not different between the rapid and regular infusion groups (Fisher s exact test, p = 0.545). Survival and Multivariate Analysis of the Patients Clinical follow-up examinations after diagnosis in the 28 assessable patients ranged from 3 to 68.2 months with a mean of 26 months for all patients and 31 months for survivors. Twelve patients suffered a relapse 4 to 53 months after the initial diagnosis (Table 2), and 10 of these died of the relapsed tumor. Among 16 without tumor relapse, two patients died: one died of gradual neurological deterioration and another of adrenal crisis. Thus, 16 patients survived and 12 died during the study period. Although the patients who underwent rapid infusion of MTX showed a longer overall median survival time ( 60 months for the rapid and 20 months for the regular infusion group), the overall survival time was not significantly different for the groups, probably because of the small numbers involved (p = 0.147). The median relapse-free survival time was 50 months for patients who underwent rapid infusion and 25 months for those who received regular infusion, but there was no significant difference (p = 0.194) in the relapse-free survival (Table 3 and Fig. 3). The median survival time of all assessable patients treated with high-dose MTX therapy and radiation was 39.3 months, and their median relapse-free survival time was 35.2 months (Fig. 4). Univariate analysis of all 28 patients treated with highdose MTX therapy revealed that age and initial KPS scores were significant prognostic factors, but tumor multiplicity, location, size, results of CSF cytological studies, and patient gender did not significantly affect survival times (Table 3). Using multivariate analysis of the 28 MTX-treated patients, we demonstrated that the KPS score was a significant prognostic factor. Although the infusion schedule 226 J. Neurosurg. / Volume 91 / August, 1999

7 Rapid infusion of methotrexate in primary CNS lymphoma was not significant, it was nevertheless a relevant factor for the proportional model, and the hazard ratio of regular to rapid infusion was (Table 3). J. Neurosurg. / Volume 91 / August, 1999 FIG. 4. Graphs showing overall (A) and relapse-free (B) survival of all MTX-treated patients plotted using the Kaplan Meier product-limit method. Discussion Prolongation of median survival time for more than 40 months has been reported in three studies in which MTXbased chemotherapy was used. 7,18,44 Combination modalities, including intrathecally administered MTX and highdose MTX given intravenously followed by high-dose cytarabin and radiotherapy, prolonged the median survival time to 42.5 months; 18 intraarterial infusion of MTX with blood-brain barrier modification and intravenously administered procarbazine, cyclophosphamide, and dexamethasone prolonged it to 44.5 months; 44 and a chemotherapy regimen known as C5R consisting of high-dose MTX and cytarabin, cyclophosphamide, doxorubicin, vincristine, and intrathecally administered MTX increased the median survival time to more than 60 months for patients aged younger than 60 years of age. 7 However, the first regimen of combination modalities resulted in a high incidence of leukoencephalopathy in patients older than 50 years of age, 2 and in the second, complications developed in 21% of the 471 treatments and the therapy had to be continued for 1 year. Patients undergoing the third therapy, C5R, exhibited a high incidence of severe toxicity, and it could be completed in only 18 (72%) of the 25 patients who were enrolled. Moreover, the median survival time of the patients older than 60 years of age was less than 1 year. By contrast, high-dose MTX therapy followed by radiotherapy is simple and can be used for older patients, 24,26 not only in cancer centers but also in smaller hospitals, even though its efficacy (median survival time 33 months) 26 was reportedly not superior to that of the other intensive therapies. Hence, we chose to research this therapy in an attempt to improve its clinical efficacy. At an MTX dose level of 100 mg/kg, which was approximately equivalent to the 3.5 g/m 2 used in previous studies, 24,26 22 (78.6%) of our 28 assessable patients responded to the therapy. The median survival time of all patients treated with MTX therapy and radiotherapy was 39.3 months, and the median relapse-free survival time was 35.2 months. These results were similar to but slightly better than those achieved in previous studies. 24,26 Prolongation of survival was significant (p = 0.001) compared with the survival of the previous 20 consecutive patients (median survival time 9.2 months). These patients had similar characteristics but had been treated with radiotherapy alone or combined with non-mtx based chemotherapy between January 1981 and March 1992 in our hospital and affiliated institutions (unpublished data). However, there was a significant difference in tumor response between the rapid and regular infusion groups. The median survival time and median relapse-free survival time were significantly longer and survival tended to be prolonged in the rapid infusion group. Thus, it can be concluded that rapid infusion is superior to regular infusion. The time course curve of MTX concentration in CSF was significantly elevated and the total area under the curve was significantly larger for the rapid infusion compared with the regular infusion group. These findings indicate that the higher exposure to MTX resulting from the rapid infusion correlated with an intensified tumor response. Rapid infusion has been shown, both theoretically and practically, to enhance the tumor response to the same dose as that used for slower infusion. 12,51 Recently, Miyauchi, et al., 42 reported on the use of bolus administration plus a continuous or gradually increased infusion of MTX to maintain higher levels of the drug in the blood and thus to obtain better tumor response for soft-tissue sarcomas. Because MTX penetration into the CSF is linked to this agent s concentration in the blood, such schedules may be more useful for achieving subsequent therapeutic improvement with the same dose of MTX. For either schedule, the MTX concentration in the CSF was higher than that previously reported for young leukemia patients with normal blood-brain barriers, the latter concentrations ranging from 0.59 to 2.05 M with a 3- or 4-hour infusion of 100 mg/kg of MTX. 11,19 The higher concentration of MTX in the CSF in our patients may be accounted for by the impaired efficiency of the barrier at the tumor site 48 and higher penetration into unaffected brain tissues in older patients. 11 However, prolonged exposure of the CNS to higher levels of MTX as well as patient age, the cumulative amount of MTX, and existence of intracranial lesions are known risk factors for subclinical injury of brain tissues and late sequelae caused by MTX and radiation therapy. 2,8,14,18,20 Because we can infer from these data that the maximally feasible reduction in the number of therapeutic cycles is highly desirable to reduce such sequelae, we investigated the antineoplastic effect of MTX for each cycle. 227

8 S. Hiraga, et al. Analysis of tumor volume changes revealed that the effect of the third cycle of therapy was modest and that there was no significant difference in the tumor volume between the second and the third cycle regardless of the infusion schedule, as seen in Fig. 2. The tumor started to progress in two patients and a new lesion appeared in another, even though their tumors had previously exhibited a partial response following regular MTX infusion. These findings indicate a diminished antineoplastic effect for the third cycle. Although the microscopically confirmed cytoreductive effect may be consistent throughout any number of cycles, our data indicate that two cycles of the therapy is effective but that careful investigation is needed before using a third or subsequent cycle. The diminished macroscopically observed cytoreductive effect of the third cycle may partly reflect a reduction in the capillary permeability of the treated primary CNS lymphoma itself. The capillary permeability in untreated primary CNS lymphomas was reported to be 10 to 40 times higher than that of the normal brain. 48 However, it decreased to normal levels within 5 weeks after initiation of chemotherapy including MTX. 48 This dramatic reduction in capillary permeability restricts MTX delivery into the tumor, resulting in a reduced antineoplastic effect. Although it goes against the general recommendation to reduce the cumulative amount of MTX for the prevention of late sequelae, an increase in the MTX dose for the third or subsequent cycle might be considered for younger patients to obtain a pharmacokinetically consistent effect. 15 We excluded small lymphocytic, small cleaved, and mixed cell type primary CNS lymphomas from this study because, first, in several studies a rather long median survival time of more than 30 months has been reported for these tumors. 28,30,61 Second, chemotherapy is not as effective in these types of non-cns lymphomas as in highergrade ones. 29,39 Third, we postulated at the beginning of this study that if the incidence of late sequelae increased significantly as a result of a combination of high-dose MTX and radiation therapy compared with radiation alone, survival or KPS status of the patients with these tumors would deteriorate as a result of the combination therapy itself. Response to glucocorticoids can be an important factor for the evaluation of clinical outcome. However, five patients in this study who initially showed a partial response to glucocorticoids were treated with MTX therapy because of tumor progression after the initial response. Therefore, prolonged response duration and survival should be considered to be results of the high-dose MTX therapy. Fifteen (52%) of our 29 patients were 60 years of age or older. Five of these 15 patients exhibited late sequelae demonstrated as a progressive and diffuse change in white matter seen on neuroimaging studies, and one of them died with no evidence of tumor. Thus, older patients seemed to be more vulnerable to adverse effects of highdose MTX therapy and radiotherapy. To avoid such sequelae, in three studies 10,14,23 postponement of cranial irradiation until tumor progression occurred was recently reported in older patients who achieved a complete response to chemotherapy including high-dose MTX therapy. The response duration ranged from 8 to 46 months, 10,14 disease-free survival at 20 months was 60%, 23 and during the response period the patients received many cycles of a higher dose (8 g/m 2 ) of MTX therapy or combination chemotherapy that included other agents. Although the response duration is short in patients with a partial response and not always sufficiently long in patients with a complete response, 1 the various strategies discussed here may have some effect on prolongation of meaningful survival in older patients. The addition of some treatment modalities is required for further clinical improvement. However, it is not clear whether a synergistic antineoplastic effect can be achieved in combination chemotherapy and high-dose MTX, whereas a higher incidence of toxicity will surely become evident. 7 A standard regimen for nonprimary CNS lymphomas, CHOP therapy (cyclophosphamide, hydroxydaunomycin/doxorubicin, Oncovin [vincristine], and prednisone) can be combined with high-dose MTX therapy. However, preirradiation CHOP therapy resulted in a short response duration and early multifocal neuraxial relapse. 35,46,57 These results indicate that the therapy, which consisted of blood-brain barrier nonpermeable agents, was ineffective against microscopic lesions that the drugs could not reach and that a sensitive and permeative agent was needed for effective cytoreduction of microscopic as well as macroscopic tumors to prolong response and survival time. A liposoluble analog 60 of doxorubicin, which is a key drug for nonprimary CNS lymphoma, may be a candidate for inclusion in a regimen including high-dose MTX therapy for primary CNS lymphoma. An alternative is a combination with recently developed antiangiogenic drugs such as angiostatin, 47 endostatin, 9 and squaramine. 58 Although these drugs are still being tested in animal experiments or human trials, combining MTX therapy with these agents may hold the promise of longer patient survival by inhibiting both macroscopic tumor growth and the development of microscopic into macroscopic growth. Conclusions Rapid infusion of MTX increased its penetration into CSF and enhanced tumor response and thus may contribute to better patient survival. The median survival time of all MTX-treated patients was 39.3 months and median relapse-free survival time was 35.2 months. 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