Long-term Remission of Primary Central Nervous System Lymphoma by Intensified Methotrexate Chemotherapy

High-dose (1–3.5g/m²) methotrexate (MTX) followed by whole-brain radiation therapy (WBRT) has consistently improved length of survival in primary central nervous system lymphoma (PCNSL), but the prognosis remains dismal. To optimize and enhance the dose intensity of MTX, we applied MTX at 8g/m² to 20 patients with PCNSL. In an effort to lower the risk of neurotoxic treatment sequelae, the WBRT dose was reduced to 30Gy in cases of complete remission after MTX therapy. Further, omission of WBRT and administration of stereotactic radiotherapy (SRT) were undertaken in 3 older patients. The overall response rate to the MTX therapy was 83%. The median progression free survival (PFS) was 54 months with a median overall survival (OS) of 57 months. Achieving a complete response after MTX therapy was significantly associated with a longer PFS. Late neurotoxicity was encountered in 4 (50%) of 8 patients who were aged 60 years or older and received WBRT, but in none of 12 patients who were aged less than 60 years or avoided WBRT. All older patients who underwent SRT sustained complete remission without a dementing disease. Intensifying the MTX dosage to 8g/m² appears more promising in comparison to results reported with MTX doses of 1–3.5g/m². In younger patients, the establishment of complete remission by intensified MTX therapy and subsequent WBRT with a relatively lower dose could promise durable tumor remission with an acceptable neurotoxicity. In older patients, WBRT should be avoided to sustain a meaningful survival, and SRT may provide a valid strategy in terms of enhancing local disease control without undue risk.     

Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort

We have retrospectively reviewed toxicities and response of a cohort of primary central nervous system lymphoma (PCNSL) patients treated with high dose parenteral methotrexate (MTX) monotherapy without whole brain radiation. From The Massachusetts General Hospital (MGH) Cancer Registry, active since 1946, we selected all immunocompetent patients with histologic and/or radiographic PCNSL diagnosed between 1980 and 2007. We identified the recipients of MTX with leucovorin rescue as sole therapy. No patient received radiation therapy (XRT). We analyzed this cohort for toxicity, response and patterns of recurrence. The cohort of 121 patients received on average 11 cycles of intravenous MTX at a median dose of 8 g/m². Median interval between cycles was 10 days. After 3 months of therapy, the overall response rate was 85% (58% CR, 27% PR). The overall survival (OS) for the cohort was 7 years and progression-free survival (PFS) was 3.14 years. A trend toward a higher PFS was seen in patients who continued to receive MTX (3.48 years) every three months as compared to patients who ceased MTX after one year (2.86 years). Of 68 patients who achieved initial CR, there were 40 recurrences. Twenty-six of the 40 were re-induced with MTX as above; Sixty-nine percent again achieved CR. Eighty-one treatment-related toxicities occurred in 1316 MTX cycles. These toxicities included MRI white matter changes (N = 8) and lead to MTX cessation in 16 patients. High-dose MTX monotherapy of PCNSL is well-tolerated and provides PFS of >3 years and OS >7 years.     

Combination Chemotherapy with High-dose Methotrexate and Cytarabine with or without Brain Irradiation for Primary Central Nervous System Lymphomas

Due to the limited clinical experience there is no standard treatment of primary CNS-lymphomas (PCNSL). Based on the actual data it seems that high-dose methotrexate (HTMRX) and high-dose cytarabine (ARA-C) qualify as treatments of choice for this disease. The role of radiation therapy is still unclear, due to the high long-term toxicity, especially in elderly patients. We treated 14 HIV negative patients with 4–5 cycles of methotrexate (MTX) at 3500 mg/m² and MTX 15 mg intrathecal weekly or MTX 8000 mg/m² weekly without intrathecal treatment. Younger patients (< 60 y) received 3 weeks after last MTX dose a whole-brain irradiation (45 Gy + 9 Gy boost), older patientsts were not irradiated and continued CT. The following treatment consisted in ARA-C 3000 mg/m² d1 + 2 every 3 weeks for two cycles. All patients received steroids for two months or until the end of radiotherapy. The overall response rate was 100%, 12/14 CR (86%). Two patients died still on treatment but not due to lymphoma (1 pulmonary embolism, 1 herpes encephalitis). Toxicity was very mild with no grade 3–4 non-haematological toxic events and almost 100% grade 3–4 leucopenia without episodes of neutropenic fever. After a median follow up of 39 months the PFS and OS are 65% (9/14) and 78% (11/14) respectively, and compare well with other trial results.     

Long-Term Evaluation of Combination Treatment of Single Agent HD-MTX Chemotherapy up to Three Cycles and Moderate Dose Whole Brain Irradiation for Primary CNS Lymphoma

High-dose methotrexate (HD-MTX)-based chemotherapy in combination with whole brain radiotherapy (WBRT) has been a common therapy for primary central nervous system lymphoma (PCNSL). The aim of this study was to evaluate the survival benefit of a minimized cycle of HD-MTX monotherapy prior to WBRT. A maximum of three cycles of HD-MTX was combined with a WBRT dose of 30?Gy and an additional localized boost was administered where remnant was observed. A total of 54 patients with newly diagnosed PCNSL were enrolled in this study. The objective response rate for HD-MTX was 80% and the median overall survival was 58.4 months. Responders to HD-MTX demonstrated better survival than patients with resistance. The concentration of MTX in serum and cerebrospinal fluid was not related the chemotherapeutic response. This study demonstrated the efficacy of HD-MTX prior to WBRT and indicated that three cycles of HD-MTX monotherapy may be sufficient in combination with radiotherapy.     

Clinical Outcomes of RTOG 9310 Protocol for Primary Central Nervous System Lymphoma: Single-Center Experience with 87 Patients

The Radiation Therapy Oncology Group (RTOG) 9310 protocol clinical trial established high-dose methotrexate (HDMTX) as the standard for primary central nervous system lymphoma (PCNSL). We aimed to investigate the RTOG 9310 protocol’s PCNSL outcomes by examining progression-free survival (PFS) and overall survival (OS) rates and determining the influential factors. Between 2007 and 2020, 87 patients were histopathologically diagnosed with PCNSL and treated with the RTOG 9310 protocol. All received HDMTX 2.5 g/m² and vincristine 1.4 mg/m²/day for 1 day during weeks 1, 3, 5, 7, and 9, and procarbazine 100 mg/m²/day for 1 day during weeks 1, 5, and 9. Dexamethasone was administered on a standard tapering schedule from the first week to the sixth week. Whole brain radiotherapy (WBRT), consisting of 45 Gy for patients with less than a complete response to the chemotherapy or 36 Gy for complete responders, was started 1 week after the last dose of chemotherapy was administered. Within three weeks of the completion of WBRT, patients received two courses of cytarabine, which were separated by 3–4 weeks. Clinical, radiological, and histopathological characteristics were retrospectively reviewed. All patients completed five HDMTX cycles and a mean follow-up of 60.2 (range, 6–150) months. Twenty-eight (32.2%) patients experienced recurrence during follow-up. The mean time to recurrence was 21.8 months, while the mean PFS was 104.3 (95% confidence interval (CI), 90.6–118.0) months. Eleven (12.6%) patients died; the mean OS was 132.1 (95% CI, 122.2–141.9) months. The 3- and 5-year survival rates were 92.0% and 87.4%, respectively. One patient experienced acute renal failure, while the remainder tolerated any cytotoxic side effects. On multivariate analysis, the Eastern Cooperative Oncology Group performance score ≤ 2; the International Extranodal Lymphoma Study Group low-risk status; XBP-1, p53, and c-Myc negativity; homogenous enhancement; gross total resection, independently correlated with long PFS and OS. The RTOG 9310 protocol is effective for PCNSL and features good outcomes.     

Salvage therapy with bendamustine for methotrexate refractory recurrent primary CNS lymphoma: a retrospective case series

There is comparatively limited therapy for recurrent primary central nervous system lymphoma (PCNSL). Salvage therapies include re-challenge with high-dose methotrexate (HD-MTX), whole brain radiotherapy, temozolomide, topotecan and premetrexed. Bendamustine is a novel bifunctional alkylator with established activity in B cell systemic lymphomas but never previously evaluated in PCNSL. The objective of the current study was to assess response and toxicity of bendamustine in recurrent PCNSL following prior salvage therapy in a retrospective case series. Twelve adults [six males; six females: median age 59 years (range 43–74)] with HD-MTX refractory recurrent PCNSL were treated with bendamustine. All patients were treated at second recurrence following failure of prior salvage therapy. A cycle of bendamustine was defined as two consecutive days of treatment (100 mg/m²/day) administered once every 4 weeks (maximum number of cycles 6). Toxicities seen were Grade 2 (24 episodes in 10 patients) and 3 (10 episodes in 5 patients) only and included lymphopenia (8 patients), hyperglycemia (7 patients), fatigue (7 patients) and nausea (4 patients). The median number of cycles of therapy was 3.5 (range 1–6). Radiographic response was progressive disease in 5 (42 %), stable disease in 1 (8 %), partial response in 3 (25 %) and complete response in 3 (25 %). Median progression free survival (PFS) was 3.5 months (range 1–14 months) and 6-month PFS was 33 %. In this small retrospective series of select patients with recurrent PCNSL refractory to HD-MTX, bendamustine appears to have modest single agent activity with manageable toxicity. Confirmation in a larger series of similar patients is required.     

Adjuvant six cycles of high-dose adriamycin,cyclophosphamide, methotrexate, 5-fluorouracil (ACMF) vs. 12 cycles of low-dose acmf with tamoxifen for premenopausal,node-positive breast cancer patients: Results of a prospective randomized study

A prospective randomized study was conducted to compare the adjuvant efficacy of six cycles of high-dose ACMF (Adriamycin, ADM; cyclophosphamide, CPA; methotrexate, MTX; 5-fluorouracil, 5-FU) with that of 12 cycles of low-dose ACMF in premenopausal, node-positive breast cancer patients. The six-cycle ACMF group (93 patients) received, intravenously (iv), 130 mg/m² CPA, 26 mg/m² MTX, and 600 mg/m² 5-FU on days 1 and 8, and 26 mg/m² ADM on day 1 of each cycle. The 12-cycle ACMF group (97 patients) received, iv, 65 mg/m² CPA, 13 mg/m² MTX, and 300 mg/m² 5-FU on days 1 and 8, and 13 mg/m² ADM on day 1 of each cycle. These treatments were repeated every 4 weeks, and all the patients took tamoxifen (30 mg/day) for 2 years. The background factors of the two groups were comparable. There were non-significant trends toward better disease-free and overall survival rates in the high-dose, six-cycle ACMF group. Both treatments were well tolerated, but more patients in the low-dose, 12-cycle group refused to continue to receive chemotherapy. These data suggest that escalating doses of ACMF over a shorter period, even with doses within the conventional range, are superior to low-dose, prolonged therapy. © 1995 Wiley-Liss, Inc.     

Salvage therapy and late neurotoxicity in patients with recurrent primary CNS lymphoma treated with a modified ProMACE-MOPP hybrid regimen

We report the efficacy of salvage therapy with a modified ProMACE-MOPP combined with radiation in patients with primary central nervous system lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristin, and methotrexate (MTX: 500 mg/m²) administered in 21-day cycles. Patients received 20 Gy of whole-brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every four months for two years. Nine patients with CNS relapse were retreated with additional cycles of the ProMACE-MOPP hybrid regimen with a 90% objective response rate. Median complete response (CR) duration was 13.2 months and median survival time (MST) for the nine patients treated after initial relapse was 30 months. One of 17 patients (5.8%) who had less than 20 Gy of whole brain irradiation developed dementia. In contrast, six of seven (85.7%) patients who had more than 30 Gy of whole brain radiotherapy became demented. Maintaining a moderate dose of MTX, while adding chemotherapeutic agents and 20 Gy of whole brain radiation therapy, improved disease control and overall survival and lowered the incidence of delayed neurologic toxicity in patients with PCNSL. Additional treatment with a ProMACE-MOPP hybrid regimen is still effective for relapsed disease.     

Rituximab,methotrexate, procarbazine,vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study

Primary CNS lymphoma (PCNSL) is chemosensitive to high-dose methotrexate-based chemotherapy. However, responses in the elderly are short-lasting and outcome is poor. Given that radiotherapy and intensive chemotherapy expose elderly to severe toxicities, alternative consolidation approaches need to be evaluated. In this multicenter study, we retrospectively analyzed consecutive patients with newly-diagnosed PCNSL, aged >60, treated with a (R)-MPV-AAA regimen. The regimen consisted of three 28-day cycles of methotrexate (3.5 g/m² D1, D15), procarbazine, vincristine, followed by three 28-day cycles of cytarabine consolidation (3 g/m² D1-2). Addition of rituximab (375 mg/m² D1) was optional. The results were compared with the historical MPV-A regimen. Ninety patients received the (R)-MPV-AAA regimen with (n?=?39) or without (n?=?51) rituximab. Median age was 68 and median KPS 60. 55% of patients achieved a complete response, 8% a partial response and 37% progressed. The median PFS was 10 months, the median OS 28.1 months. Toxicity was mainly hematological, with 54 and 51% of grade III-IV neutropenia and thrombopenia. The response rate was higher in patients receiving rituximab (77 vs. 53%; p?=?0.03), whereas no difference was observed in terms of PFS or OS. When comparing the results to the historical MPV-A, there was no difference in terms of response rate, PFS or OS, but a higher rate of hematotoxicity. This study suggests that extending cytarabine consolidation after methotrexate-based chemotherapy does not improve the MPV-A efficacy but increases toxicity in the elderly. The addition of rituximab may improve the response rate, but its impact on final outcome remains unclear.     

Non-deep-seated primary CNS lymphoma: therapeutic responses and a molecular signature

The survival of patients with primary CNS lymphoma (PCNSL) has been improved by high-dose methotrexate (HD-MTX). Since the combination therapy of HD-MTX and whole-brain radiotherapy (WBRT) carries a significant risk for delayed neurotoxicity, it is important to know the therapeutic potential and prognostic factors for HD-MTX without WBRT. We retrospectively reviewed 46 consecutive patients with PCNSL treated with a HD-MTX (3.5 g/m²) and deferred WBRT. Patients who achieved complete response or partial response after three courses of HD-MTX were cautiously followed-up without additional treatment. Patients who had either stable disease, progressive disease, or disease relapse were offered salvage therapy. The median progression-free survival period was 10 months and the median overall survival period was 52 months, with a 5-year survival rate of 39 %. Nineteen patients (49 % of the evaluable patients) achieved a complete response at the initial response assessment. Involvement of deep structures of the brain (corpus callosum, basal ganglia and brainstem) was significantly associated with the worse progression-free survivals (p = 0.0058) and overall survivals (p = 0.0177). Gene expression profiling analysis by microarray was compared in eight patients between PCNSLs located in the deep structures of the brain and non-deep-seated tumors. The result showed that up-regulation of signal transduction-related genes and down-regulation of catalytic activity-related genes in the non-deep-seated PCNSL compared with the deep-seated tumors. The present study shows that PCNSL located in non-deep structures of the brain responds better to HD-MTX alone than those involved deep-structures.     

Immunochemotherapy with rituximab,methotrexate, procarbazine,and lomustine for primary CNS lymphoma (PCNSL) in the elderly

BackgroundPrimary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system. In this article, we report the results of a pilot trial adding rituximab to the established regimen consisting of methotrexate, procarbazine, and lomustine (R-MCP).Design and methodsPCNSL patients ≥65 years without Karnofsky performance score (KPS) limit were included. R-MCP regimen consisted of rituximab (375 mg/m² i.v. on days -6, 1, 15, and 29), methotrexate (3 g/m² i.v., days 2, 16, and 30) followed by folinic rescue, procarbazine (60 mg/m² orally, days 2–11), and lomustine (110 mg/m² orally, day 2). A maximum of three 43-day cycles were applied. Primary end point was response to treatment obtained by magnetic resonance imaging. Secondary end points were overall survival (OS) and progression-free survival (PFS).ResultsTwenty-eight patients were included (median age 75, median KPS 60%). Best documented response: complete remission in 18 of 28 (64%), partial remission in 5 of 28 (18%), stable disease in 1 of 28 (4%), and progressive disease in 2 of 28 (7%) patients. Response was not assessed in two patients. Two treatment-associated deaths were observed. After a median follow-up of 36 months, the 3-year PFS and OS was 31%.ConclusionR-MCP regimen is well tolerated and active in elderly patients with newly diagnosed PCNSL.     

High-dose methotrexate for elderly patients with primary CNS lymphoma

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.     

Treatment for primary CNS lymphoma: the next step.

PURPOSE: The use of preradiotherapy (RT) methotrexate (MTX) has improved disease control and survival in patients with primary CNS lymphoma (PCNSL). The reported protocol was designed to optimize and enhance the chemotherapeutic component of treatment. PATIENTS AND METHODS: Fifty-two patients were treated with five cycles of high-dose MTX 3.5 g/m(2), procarbazine 100 mg/m(2)/d, and vincristine 1.4 mg/m(2). Thirty patients received whole-brain RT (45 Gy). Twenty-two older patients deferred RT to diminish the risk of delayed neurotoxicity; these patients are compared with 12 older patients who completed the entire treatment regimen. Most patients (n = 35) received high-dose cytarabine after RT. RESULTS: Objective response rate to the induction chemotherapy regimen was 90%; overall median survival is 60 months. Grade 3 or 4 myelosuppression was seen in 30 patients, primarily in association with cytarabine; grade 3 nephrotoxicity due to MTX was seen in two patients. Older patients had similar median survival with or without the addition of RT: 32 versus 33 months, respectively. However, late neurotoxicity was significantly more common in those older patients who received RT (P: =.00004). Patients younger than 60 years who received the complete treatment regimen have not reached median disease-free or overall survival. CONCLUSION: Increasing the dose of MTX and adding procarbazine and vincristine improved disease control and overall survival in patients with newly diagnosed PCNSL. Younger patients in particular fared extremely well with this treatment regimen. In older patients, deferring whole-brain RT did not compromise overall survival but did reduce treatment-related toxicity.     

A phase II study of Tomudex alternated with methotrexate, 5-fluorouracil, leucovorin in first-line chemotherapy of metastatic colorectal cancer

Purpose: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of tomudex with methotrexate (MTX)/5-fluorouracil (5-FU)/leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer.Patients and methods: Patients with histologically proven metastatic colorectal cancer and at least one bidimensionally measurable lesion, aged 18–70, with performance status 2, normal baseline biological values, and no prior chemotherapy, were selected. Treatment was tomudex 3 mg/m² and, after two weeks, MTX, 200 mg/m² by 30 infusion after hydration with 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m² and leucovorin, orally, 15 mg for six times every 6 hours, beginning 24 hours after MTX. Cycles were repeated every four weeks. Tumor response assessment was performed after three cycles.Results: Thirty-four patients were enrolled in this study, of whom twenty-four had liver metastases, nine local relapse, five lymph node involvement, four lung metastases, and three peritoneal carcinomatosis. Four patients achieved objective responses (one complete and three partial), for an overall response rate of 12% (95% CI: 0%–22%). Twelve patients had stable disease and 18 progressed on therapy. Median survival for all patients was 13 months. Two patients experienced grade 3 WHO neutropenia while hepatotoxicity was reported in 13 patients (6 grade 1, 3 grade 2, 3 grade 3, 1 grade 4), suggesting that this combination could increase hepatic toxicity in comparison to tomudex or MTX/5-FU alone.Conclusions: Our results suggest that this regimen does not warrant further investigation in advanced colorectal cancer patients, at least not with this schedule and doses.     

Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly

Background Treatment for primary CNS lymphoma (PCNSL) in the elderly is associated with lower response rates and higher risks of acute and late delayed toxicity as compared to younger patients. Temozolomide has emerged as a new alternative treatment for PCNSL and constitutes an attractive option for the elderly because of its favorable toxicity profile. In this study we report outcomes of a consecutive series of PCNSL elderly patients initially treated with an innovative regimen combining methotrexate and temozolomide without radiotherapy or intra-thecal chemotherapy. Methods Histologically confirmed newly-diagnosed PCNSL patients older than 60 years were included. An induction chemotherapy was initially given (methotrexate 3 g /m² on days 1, 10, and 20, and temozolomide 100 mg/m² on days 1–5). Patients achieving a partial or complete response proceeded to a maintenance phase (up to 5 monthly cycles of methotrexate 3 g/m² on day 1, and temozolomide 100 mg/m² days 1–5). Non-responders were treated on an individual basis. Results Among the 23 included patients, a complete response was observed in 55%, and disease progressed in the other 45%. Median event-free survival was 8 months, and median overall survival was 35 months. Grades 3 or 4 toxicities included nephrotoxicity in three patients, and hematotoxicity in five; no neurotoxicity has been observed to date. One patient died while on treatment from complications of intestinal obstruction. Conclusion Our efficacy results are comparable to other reported regimens, with the advantages of a favorable toxicity profile, and absence of intra-thecal chemotherapy. Prospective, controlled studies are warranted to confirm such results.     

Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced,aggressive T-cell or NK/T-cell lymphoma

The aim of the study was to determine the maximum tolerated dose (MTD) and safety of the combination of bortezomib and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) as first-line therapy in advanced, aggressive T-cell lymphoma. Patients received increasing doses of bortezomib on days 1 and 8 (weekly schedule, 1.0, 1.3, and 1.6 mg/m²/dose) in addition to 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1.4 mg/m² vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5, every 3 weeks. Six cycles of therapy administered every 21 days were planned. Thirteen patients, who had stage III/IV chemonaive aggressive T-cell lymphoma, received a total of 55 cycles of treatment. One patient experienced hematologic dose-limiting toxicity (grade 4 neutropenia associated with febrile episode) at the 1.0 mg/m²/dose of bortezomib. There was no dose-limiting non-hematologic toxicity. The MTD was not reached at 1.6 mg/m² dose level of bortezomib. The overall complete remission rate in all patients was 61.5% (95% confidence interval = 31.6–86.1). Bortezomib can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced-stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II studies of bortezomib plus CHOP is 1.6 mg/m²/dose of bortezomib on days 1 and 8 every 3 weeks as first-line treatment.     

A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome

Background

The treatment of primary CNS lymphoma (PCNSL) comprises high dose methotrexate (HDMTX) based chemotherapy followed by whole brain radiotherapy (WBRT), the major drawback of which is long term neurotoxicity. We intended to assess the feasibility of response adapted WBRT in PCNSL in the Indian setting.

Methods

We screened 32 patients and enrolled 22 eligible patients with PCNSL from 2015 to 2017 in a prospective phase II trial. The patients underwent five 2-weekly cycles of induction chemotherapy with rituximab, methotrexate, vincristine, procarbazine. Patients with complete response(CR) to induction chemotherapy were given reduced dose WBRT 23.4 Gy/13 fractions/2.5 weeks while those with partial response (PR), stable or progressive disease (SD or PD) were given standard dose WBRT 45 Gy/25 fractions/5 weeks. Thereafter two cycles of consolidation chemotherapy with cytarabine were given. The primary endpoints of the study were assessment of response rate (RR) and progression free survival (PFS). The secondary endpoints of the study were assessment of overall survival (OS), toxicity profile of treatment and serial changes in quality of life and neuropsychological parameters.

Results

Out of 19 patients who completed HDMTX based chemotherapy, 10 (52.63%) patients achieved CR, 8 (42.11%) patients had PR and 1 patient had PD. After a median follow-up period of 11.25 months, the estimated median OS was 19 months. The actuarial rates of PFS and OS were respectively 94.1 and 68.2% at 1 year and 50.2 and 48.5% at 2 years. Three patients in reduced dose WBRT arm had recurrence and two of them died of progressive disease, whereas there was no recurrence or disease related death in standard dose WBRT arm. On univariate analysis of PFS, age?≤?50 years and use of standard dose WBRT (45 Gy) led to significantly improved outcome (p value 0.03 and 0.02 respectively).

Conclusion

In patients with PCNSL, reduced dose WBRT after CR to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression and early death. Trial Registration No CTRI/2015/10/006268

     

A phase I/II study of high-dose megestrol acetate in the treatment of metastatic breast cancer

Summary Thirty four patients treated with mastectomy and axillary node dissection for potentially curable breast cancer received a seven month combined adjuvant chemotherapy and radiation therapy program. These patients were considered to be at high risk for recurrence because they had either three or more positive axillary lymph nodes or their primary tumor was greater than 5 cm in diameter. The chemotherapy given at 3-week intervals consisted of cyclophosphamide, 600 mg/m², Adriamycin 40mg/m², and methotrexate 40 mg/m² during cycles 1 through 3 and 7 through 9. Radiation therapy was administered during cycles 4 through 6 with concomitant administration of 5-fluorouracil 600 mg/m², vincristine 1.4 mg/m², and prednisone 40 mg/m² for 7 days. Median follow up time from initiation of study is 60 months (range 36–93). Seventeen of 34 patients (50%) remain free of recurrent breast cancer. Distant metastases and local-regional recurrence have occurred in 16 (47%) and 4 (12%) patients, respectively. Significant myelosuppression and infections requiring hospitalization were seen in 4 patients, with 1 treatment-related death. Adriamycincontaining chemotherapy and post-operative radiotherapy can thus be combined in an adjuvant treatment program with acceptable toxicity.     

34例原发性中枢神经系统恶性淋巴瘤临床分析

目的：分析免疫功能正常的中国人原发性中枢神经系统淋巴瘤（PCNSL）的临床资料,探讨PCNSL的临床特征,评价大剂量甲氨蝶呤（HD-MTX）加全脑放疗（WBRT）治疗PCNSL的疗效.方法：回顾性分析34例经病理证实的PCNSL患者的临床资料以及治疗效果,Kaplan-Meier法分析患者生存期.结果：34例PCNSL患者中B细胞淋巴瘤31例（91.2%）,T细胞淋巴瘤3例（8.8%）;所有患者治疗后评价完全缓解率（CR）41.2%,2年生存率60.2%;病理类型和是否接受HD-MTX加放疗是影响PCNSL生存期的主要原因（P＜0.05）.结论：PCNSL以颅内高压为主要表现,B细胞亚型占绝对优势,具有独特的预后因素,HD-MTX联合放疗是PCNSL有效的治疗方法.     

Intravenous Methotrexate as Initial Treatment for Primary Central Nervous System Lymphoma: Response to Therapy and Quality of Life of Patients

In anticipation of a consortium study of methotrexate (MTX) therapy provided to patients with primary central nervous system lymphoma (PCNSL) we have provided intravenous MTX without irradiation therapy to 31 non-immunosuppressed individuals. Twenty (65%) achieved complete response and 11 (35%) partial response to therapy. For the 31 patients the median survival was 30.43 months with an actuarial median follow up time of 30.69 months. The 2+ year survival was 63% for all patients and 90% for complete responders. Of 375 drug cycles, grade 3 leukopenia was identified in 3 cycles, mucositis in 6 cycles and delayed drug clearance in 47 cycles. Recurrences included brain (9/20) and/or spinal fluid (2/20). The median Karnofsky scale improved from 40 (10–80) prior to therapy to 90 after treatment. Eleven patients, in complete response for a median of 22+ months after diagnosis were evaluated using 4 instruments that assess Quality of Life Functional Assessment of Cancer Therapy – Brain (FACT-BR) modified, Symptom Questionnaire, Social Adjustment Scale-Self-Report and Problem Solving Inventory. Their psychosocial adjustment, well-being and stress coping abilities were comparable to the normative groups. Further there was no evidence of any MTX-induced, Magnetic Resonance Imaging (MRI)-detected encephalopathy in these individuals and there was preservation of clinical cognition and memory. We conclude that therapy with MTX, without radiation can be used in PCNSL patients without limitations of age or pretreatment Karnofsky scores. Further rates of response and median survival approach those of therapies using multiple drugs and radiation, but with a less likely risk of dementia.