Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments.

Bessell EM, Lopez-Guillermo A, Villa S, Verger E, Nomdedeu B, Petit J, Byrne P, Montserrat E, Graus F.  J Clin Oncol 2002 Jan 1;20(1):231-6

Department of Clinical Oncology, Nottingham City Hospital, Nottingham, United Kingdom.

PURPOSE: To assess the effect of a reduced dose of radiotherapy (RT) in patients with primary CNS lymphoma (PCNSL) responding to the cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) regimen. PATIENTS AND METHODS: Patients received one cycle of CHOD and two of BVAM. In the first trial, all 31 patients received 45-Gy whole-brain RT (CHOD/BVAM I). In the second, with 26 patients, RT dose was reduced to 30.6 Gy if there was a complete response (CR) after chemotherapy (CHOD/BVAM II). RESULTS: Age, performance status, and chemotherapy received were similar in both protocols. CR rate at the end of all treatment was 68% for CHOD/BVAM I and 77% and for CHOD/BVAM II. Treatment modality was the only predictor of relapse, with 3-year relapse risks of 29% and 70% for CHOD/BVAM I and II, respectively. This was specifically important in the 25 patients less than 60 years old (3-year relapse risk, 25% v 83%; P =.01). The 5-year overall survival (OS) was 36%. Age (< 60 v > or = 60 years) was the only predictor for OS in the multivariate analysis (relative risk, 2.1; 95% confidence interval, 1.4 to 2.8). RT dose was the only predictor of OS in patients younger than 60 years old who achieved CR at the end of all treatment (3-year OS, 92% v 60% for patients receiving 45 or 30.6 Gy, respectively; P =.04). CONCLUSION: Reduction of the RT dose from 45 Gy to 30.6 Gy in patients younger than 60 years old with PCNSL who achieved CR resulted in an increased risk of relapse and lower OS.
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Late neurotoxicity is a major problem in PCNSL patients who survive for longer than 1 year.Cognitive impairment, urinary incontinence, and gait disorders are progressive and dramatically reduce the quality of life of patients who may be cured of the PCNSL. This complication is related to age (it occurs in up to 83% of patients older than 60 years), to RT dose, and to chemotherapy if chemotherapy is given after RT. To decrease the incidence of this complication, chemotherapy alone has been used in a few studies, with cranial RT deferred until relapse of PCNSL. Whether avoiding RT after initial chemotherapy would have a negative impact on survival of patients with PCNSL is unknown and a matter of controversy.

Our results indicate that a reduction in the RT dose to the whole brain from 45 Gy to 30.6 Gy in PCNSL patients younger than 60 years achieving CR after the CHOD/BVAM regimen is associated with a higher risk of relapse and a poorer outcome in terms of survival. This association was not been observed in patients aged 60 years and older, but the number of patients evaluated in this age group was small (16 patients). Therefore, the possibility of finding different results in a larger sample cannot be completely ruled out.

The 5-year OS of PCNSL patients receiving the CHOD/BVAM protocol was 36%, with a median survival time of 40 months. These figures are similar to those obtained with other combined treatments that include methotrexate at doses of 1.5 g/m² or higher.The addition of other drugs to methotrexate in combined protocols with RT has not as yet shown better results than the use of methotrexate as monotherapy. However, the rationale for using multidrug regimens is to achieve long-lasting remissions that are unlikely to be obtained by methotrexate alone (based on the experience with treating systemic lymphoma) and to avoid the use of subsequent RT. The present results suggest that the multidrug regimen CHOD/BVAM is probably more effective when combined with RT. This finding has also been observed in localized, high-grade, systemic lymphomas, where chemotherapy with cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) followed by RT may be superior to CHOP alone.

A novel approach in the management of PCNSL is to use chemotherapy alone upfront and reserve RT for those patients with residual disease or who relapse after treatment.This strategy has also been used in patients with CNS germ cell tumors.The study showed that CNS germ cell tumors that relapsed after chemotherapy could be successfully salvaged with RT and that 50% of the patients could be effectively treated without RT. The experience with chemotherapy as exclusive treatment in patients with PCNSL is limited to a few series with a relative short follow-up. The frequency of relapse after the initial treatment ranged from 38% to 63%, and a substantial number of patients received cranial RT for relapse.In the largest series, 31 patients were initially treated with methotrexate alone, but at the end of the study, 17 (55%) had received RT either because CR was not achieved or the tumor relapsed.

In our study, patients younger than 60 years old who achieved CR with the CHOD/BVAM I treatment had a 5-year probability of survival of above 60%, and no patient treated with 45 Gy to the whole brain, even with a boost to 55 Gy, developed dementia after a median follow-up of 59 months. Only one of 18 patients younger than 60 years old showed mild late neurotoxicity. These data, along with our finding that the RT dose reduction caused an increased risk of relapse, suggest that the CHOD/BVAM regimen alone, and probably any other methotrexate-based chemotherapy regimen, will not offer the best results if RT is withheld. Therefore, one should be extremely cautious when designing randomized trials comparing chemotherapy regimens with and without RT in PCNSL patients younger than 60 years old.

In a previous study,survival in PCNSL patients aged 60 years and older was not shortened when RT was deferred at relapse after chemotherapy. However, the causes of death were different. Patients treated upfront with combined therapy usually died from complications derived from severe neurotoxicity, whereas those initially treated with chemotherapy alone died from progressive PCNSL. We did not observe any late neurotoxicity in the patients who received the reduced RT dose of 30.6 Gy, but the number of patients is too small and the follow-up is still too short to make any definite conclusion. However, since total RT dose is an important predictor of delayed neurotoxicity, a decrease in the incidence of this complication should be expected if the total RT dose is reduced. If one assumes that RT is not a good salvage treatment for PCNSL patients who relapse after chemotherapy, a sound strategy for these older patients could be to treat those who achieve a CR after chemotherapy with a reduced dose of cranial RT.

Long-term survival in primary CNS lymphoma.

Abrey LE, DeAngelis LM, Yahalom J.     J Clin Oncol 1998 Mar;16(3):859-63

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

PURPOSE: We have previously reported on 31 patients with primary CNS lymphoma (PCNSL) treated between 1986 and 1992 with methotrexate (MTX), cranial radiotherapy (RT), and high-dose cytarabine who remained free of disease longer than historical controls. The median cause-specific survival was 42 months, with a five-year survival of 22.3% compared with 3% to 4% in historical controls treated with RT alone. Age less than 50 years at diagnosis was a significant prognostic factor for survival (P = .01). Median disease-free survival was 40.3 months; 15 patients relapsed, all but one in the CNS. Late treatment-related toxicity was observed in nearly one third of patients and those more than 60 years of age were at substantially higher risk . CONCLUSION: Combined modality therapy for PCNSL has improved survival, but relapse is common and late neurologic toxicity is a significant complication. Although this approach is highly effective for younger patients, efficacious but less neurotoxic regimens need to be developed for older patients.

Primary central nervous system lymphoma 1991-1997: outcome and late adverse effects after combined modality treatment.

Herrlinger U, Schabet M, Brugger W, Kortmann RD, Kanz L, Bamberg M, Dichgans J, Weller M.  Cancer 2001 Jan 1;91(1):130-5

Department of Neurology, University of Tuebingen, Tuebingen, Germany. herrlinger@uni-tuebingen.de

BACKGROUND: This retrospective single-center study assesses the feasibility, therapeutic outcome, and late side effects of combined modality therapy with intravenous methotrexate, whole brain radiotherapy (WBRT), and intravenous cytarabine in patients with primary central nervous system lymphoma (PCNSL). METHODS: All 28 consecutive patients diagnosed with PCNSL between 1991 and 1997 were scheduled to receive combined modality therapy. Seven of 28 patients did not receive combined modality treatment: 6 patients had WBRT alone because of poor physical condition, and 1 patient died before receiving treatment. Of the remaining 21 patients, 5 received the complete regimen, and 16 received a modified regimen with reduced dose intensity. RESULTS: Fourteen of 21 patients (67%) treated with combined modality therapy had a complete response; 1 had a partial response. Median survival was 11 months in all 28 patients, 23 months in all patients with combined modality treatment, and 41 months in patients receiving the complete regimen. Of 15 examinable patients with a follow-up of 8 months or more, 10 developed severely symptomatic and 5 mildly symptomatic or asymptomatic diffuse white matter changes. CONCLUSION: Only a small subgroup of all patients with PCNSL appears to be eligible for receiving all parts of the combined modality regimen. Treatment in these patients leads to a marked prolongation of survival. The risk of late side effects is high even with modified, dose intensity-reduced versions of combined modality treatment

Combined modality therapy for primary CNS lymphoma.

DeAngelis LM, Yahalom J, Thaler HT, Kher U.   J Clin Oncol 1992 Apr;10(4):635-43

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

PURPOSE: Primary CNS lymphoma (PCNSL), formerly rare, is being seen with increased frequency among apparently immunocompetent patients. Conventional treatment has consisted of whole-brain radiotherapy (RT) and corticosteroids, with a median survival of 15 to 18 months and a 3% to 4% 5-year survival. Chemotherapy has been useful in the treatment of recurrent PCNSL. In 1985 we began a treatment protocol using chemotherapy and cranial irradiation for the initial therapy of non-AIDS PCNSL. PATIENTS AND METHODS: Thirty-one patients (group A) completed the combined modality regimen. All had placement of an Ommaya reservoir and received pre-RT systemic methotrexate, 1 g/m2, plus six doses of intra-Ommaya methotrexate at 12 mg per dose. A full course of cranial RT (4,000-cGy whole-brain RT plus a 1,440-cGy boost) was followed by two cycles of high-dose cytarabine (ara-C), with each course consisting of two doses of 3 g/m2 ara-C separated by 24 hours and infused over 3 hours. During this period, 16 additional patients (group R) were treated with RT alone, either because patients refused chemotherapy or RT was initiated before our consultation; all would have been eligible to participate in the protocol. Follow-up extended through April 1, 1991. RESULTS: Group A had a significantly prolonged time to recurrence (median, 41 months) compared with group R (median, 10 months; P = .003). Although median survival was doubled from 21.7 months for group R to 42.5 months for group A, this was not statistically significant because of small sample size. More importantly, group R patients received systemic chemotherapy for recurrent PCNSL, which improved survival. CONCLUSION: The addition of chemotherapy to cranial RT for initial treatment of PCNSL significantly improved disease-free survival and contributed to overall survival; all non-AIDS patients with newly diagnosed PCNSL should be considered for combined modality therapy.