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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

From the Department of Clinical Oncology, Nottingham City Hospital, and Department of Neurosurgery, Nottingham University Hospital, Nottingham, United Kingdom; Departments of Hematology, Radiation Oncology, and Neurology, Hospital Clínic, Institut de Recerca Biomèdica August Pi i Sunyer, University of Barcelona, Barcelona; and Services of Radiation Oncology and Hematology, Institut Català d’Oncologia, l’Hospitalet, Spain.

Address reprint requests to Francesc Graus, MD, Servei de Neurologia, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain; email: fgraus{at}clinic.ub.es

	ABSTRACT

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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 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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE OPTIMAL TREATMENT for primary CNS lymphoma (PCNSL) is not established. In the last decade, several phase II studies have shown that the 5-year actuarial probability of survival with chemotherapy regimens that include high-dose methotrexate followed by radiotherapy (RT) is approximately 30% to 40%.^1,2 This figure is superior to that of 28% at 2 years obtained with RT alone.³ Nevertheless, the combined effect of methotrexate and RT may lead to severe late neurotoxicity.^4,5 The risk of this complication is particularly high in patients older than 60 years, in whom the risk of relapse is higher. To avoid this complication, some authors have proposed that chemotherapy should be used alone, with cranial RT reserved for those patients who are not in complete remission (CR) after chemotherapy.⁶ The risk of this approach is that it reduces the probability of long-term remission if RT is needed to eradicate microscopic disease that persists after chemotherapy. Therefore, the first step before eliminating the RT from a given regimen should be to analyze the impact of reducing the dose of RT on the risk of relapse and on survival of those patients in CR after chemotherapy. This approach has not been systematically studied in the different combined protocols used for PCNSL. In the present study, we report the effect of reducing the RT dose in PCNSL patients who responded to the previously described cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) regimen.^7,8

	PATIENTS AND METHODS

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Patient Characteristics
Fifty-seven newly diagnosed patients with PCNSL were entered onto two successive phase II trials between 1990 and 1995 (CHOD/BVAM I; 31 patients) and between 1996 and 1999 (CHOD/BVAM II; 26 patients). Both protocols included the same chemotherapy regimen, but in CHOD/BVAM II, the dose of RT was reduced if the patient was in CR after chemotherapy (Table 1). None of the patients had clinical evidence of human immunodeficiency virus type 1 infection, had undergone organ transplantation, or had presented any previous malignancy. Patients older than 70 years were not included in these trials. Thirty-three patients were treated in Nottingham, United Kingdom, 22 patients were treated in Barcelona, Spain, and two patients were treated in Birmingham, United Kingdom. The main initial features of the patients at diagnosis are listed in Table 2. The clinical features, response to therapy, toxicity, and outcome of the 31 patients receiving CHOD/BVAM I have previously been reported.⁸ The staging studies recommended in the protocol were the following: (1) analytic: WBC count, hemoglobin and platelet count, erythrocyte sedimentation rate, basic biochemistry, including renal and liver function tests, and lactate dehydrogenase levels, (2) cytology of CSF (performed in 33 patients), (3) bone marrow aspiration and/or trephine biopsy (performed in 54 patients), and (4) computed tomography or magnetic resonance imaging of the brain, thorax, abdomen and pelvis (performed in all the cases). Slit-lamp examination of the eye was carried out in 22 patients. No patient had evidence of lymphoma outside of the CNS after the above-mentioned maneuvers.

All patients gave informed consent according to the ethics committee guidelines of the participating institutions. Computed tomography or magnetic resonance scans of the brain were repeated after surgery, chemotherapy, and RT. Further scans were performed every 6 months during follow-up evaluations for the first 2 years and annually thereafter. Assessment of response was performed as suggested by Macdonald et al.⁹

Statistical Methods
The median follow-up was 59 months (range, 33 to 110 months) and 17 months (range, 12 to 50 months) for currently alive patients included in the CHOD/BVAM I and II protocols, respectively. The end points of this study were CR achievement, risk of relapse, and overall survival (OS) for patients receiving either the CHOD/BVAM I or CHOD/BVAM II regimen. The risk of relapse was determined from the date of CR to the date of relapse or last visit. OS was determined from the date of diagnosis to the date of last follow-up or death. Categorical data were compared using the Fisher’s exact test, two-sided P value; for ordinal data, nonparametric tests were used. The actuarial survival curves were estimated according to the method of Kaplan and Meier,¹⁰ and the curves were compared using the log-rank test.¹¹ For prognostic purposes, all the main initial features were analyzed (age, performance status, uni- or multifocal involvement, initial radiologic response to corticosteroids, and type of surgery, including the treatment modality [CHOD/BVAM I v II]). The initial characteristics as well as the prognostic factors were analyzed for each treatment. All significant variables in the univariate study, including the treatment, were included in a multivariate analysis performed by the stepwise proportional hazards regression method of Cox.¹²

	RESULTS

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Completion of Therapy and Toxicity
The main characteristics at diagnosis of the 57 patients included in the CHOD/BVAM I (31 cases) and II (26 cases) treatments are detailed in Table 2. No significant differences were found between the two regimens, with the exception of the number of CNS lesions: patients receiving CHOD/BVAM I presented with multiple mass lesions in 29% of cases, whereas those included in CHOD/BVAM II showed multiple lesions in 62% of cases (P = .01).

The majority of patients completed chemotherapy as planned (23 patients [74%] of CHOD/BVAM I and 21 [81%] of CHOD/BVAM II). One patient in the CHOD/BVAM II study received a single dose of methotrexate due to renal toxicity and the PCNSL progressed during chemotherapy. The major acute toxicity was myelosuppression with World Health Organization/Eastern Cooperative Oncology Group grade 3 or 4 neutropenia documented in almost all patients (82%). Thirty-four patients (60%) experienced at least one episode of neutropenic fever, but only 15 patients had positive blood cultures. The only other toxicities apart from alopecia and bone marrow toxicity were hepatic (grade 2, two patients), renal (grade 2, four patients), and neurologic (grade 2, two patients). No significant differences were found between the two studies. Five patients (16%) died during CHOD/BVAM I chemotherapy due to toxic death in two (pulmonary embolus and bronchopneumonia) and tumor progression in three. Three patients receiving CHOD/BVAM II (12%) died during therapy due to pulmonary emboli (two patients) and sepsis (one patient). Only age showed prognostic importance in predicting early death. The mortality of patients 65 years in the first 4 months from diagnosis was significantly higher than that of younger patients (44% v 9%, P = .02).

Response to Therapy
At the end of chemotherapy, the CR rates were 64% (20 of 31 patients) and 62% (16 of 26 patients) for CHOD/BVAM I and II, respectively (Table 3). Twenty-four patients on the CHOD/BVAM I protocol received 45 Gy to the whole brain, with 14 patients receiving the boost RT to 55 Gy. On the CHOD/BVAM II protocol, 16 patients who were in CR after chemotherapy received 30.6 Gy and six patients received 45 Gy because a CR was not obtained. Overall, the CR rates after completion of all treatment were 68% (21 of 31 patients) and 77% (20 of 26 patients) on protocols I and II, respectively (Table 3).

View larger version (24K): [in this window] [in a new window]   Fig 1. (A) Risk of relapse from CR assessment in 41 patients with PCNSL reaching CR according to the treatment modality (CHOD/BVAM I v II) (P = .02). (B) Risk of relapse from CR in the 25 patients younger than 60 years according to the treatment modality (P = .01).

OS
Thirty-one of 57 patients died during the follow-up period, with a median survival time of 40 months. The 3-year and 5-year actuarial probabilities of OS were 55% (95% CI, 41% to 69%) and 36% (95% CI, 20% to 52%), respectively (Fig 2). Five patients died during chemotherapy without evidence of lymphoma due to pulmonary emboli (three patients), bronchopneumonia (one patient), and sepsis (one patient). Eleven patients died during or shortly after treatment due to disease progression. Eleven patients died from lymphoma after clinical relapse, with a median survival from relapse of 5 months (range, 0 to 21 months). Finally, in four patients, the main cause of death was dementia, with no clinical or radiologic evidence of recurrence (no autopsy was performed).

View larger version (11K): [in this window] [in a new window]   Fig 2. OS of 57 patients with PCNSL.

The prognostic study for OS was also performed in the group of 41 patients who achieved CR after all treatment (21 on the CHOD/BVAM I protocol and 20 on the CHOD/BVAM II protocol). No variable reached a significant predictive value, with only the treatment modality (P = .09) and dose of RT (P = .07) having marginal importance. However, when this analysis was performed in younger patients (< 60 years old), those receiving full-dose RT had a better outcome than the remainder (3-year OS, 92% v 60%; P = .04) (Fig 3).

View larger version (16K): [in this window] [in a new window]   Fig 3. OS of 25 patients reaching CR after chemotherapy according to the RT dose administered (45 Gy v 30.6 Gy) (P = .04).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Late neurotoxicity is a major problem in PCNSL patients who survive for longer than 1 year.^4,5 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.^4,8 To decrease the incidence of this complication, chemotherapy alone has been used in a few studies, with cranial RT deferred until relapse of PCNSL.^6,13-15 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.

There was no patient selection in that all eligible patients were included in these two protocols, but patients included in the CHOD/BVAM II treatment presented more often with multiple, contrast-enhanced lesions. This may be due in part to the routine use of magnetic resonance imaging in the second protocol, which may have resulted in the increase of multiple lesions observed. Nevertheless, this feature showed no predictive value for response to therapy, relapse, and OS in either univariate or multivariate analyses that, in line with previous studies,^3,4,16,17 identified age as an important predictor for survival. Treatment modality was the only factor that predicted for relapse, especially in younger patients. Similarly, the number of patients who completed chemotherapy as planned was not different in the two protocols; therefore, no other variable could explain the differences found between the two treatments except the reduction in the RT dose.

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.^2,4,5,18-20 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.^21,22 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.²³

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.^6,13-15 This strategy has also been used in patients with CNS germ cell tumors.²⁴ 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.²⁴ 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.^2,13-15 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.²⁵

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,⁵ 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.

	NOTES

 
Both E.M.B. and A.L.-G. contributed equally to the study.

	REFERENCES

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Submitted May 31, 2001; accepted August 23, 2001.

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