Japanese Journal of Clinical Oncology 33:443-449 (2003)
© 2003 Foundation for Promotion of Cancer Research
Comparable Outcomes of Radiation Therapy without High-dose Methotrexate for Patients with Primary Central Nervous System Lymphoma
1 Department of Radiation Oncology, Gunma University School of Medicine, Maebashi, 2 Department of Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 3 Department of Radiology, Tokyo Women’s Medical University, Tokyo, 4 Department of Neurosurgery, Gunma University School of Medicine, Maebashi, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The previous trials of radiotherapy conducted for primary central nervous system lymphoma (PCNSL) have not been successful. Therefore, we have investigated the clinical outcomes and the role of radiation therapy in the treatment of PCNSL.
Methods: Thirty-three consecutive patients with PCNSL treated with cranial radiotherapy (30–40 Gy whole brain plus 10–20 Gy boost) without administration of high-dose methotrexate were retrospectively analyzed. Nine patients received whole spinal irradiation (WSI) as an additional therapy. The median age of patients was 58 years (range: 28–78 years), and 70% showed a poor performance status (PS).
Results: The median survival time (MST) was 13 months, and the 5-year overall survival rate was 35%. The initial response and the number of tumors were significant prognostic factors, and WSI tended toward significance in a multivariate analysis. Four of five patients, who received prophylactic WSI, were 4-year survivors without a tumor relapse and none of them had tumor involvement in the vertebral canal. One patient developed radiation-induced brain necrosis, however, WSI did not seem to affect the late complications.
Conclusions: We consider it important to reduce severe acute and late complications in patients qualified for receiving an aggressive therapy, and to explore the possible tolerable and curative treatment methods that can be used in order to improve the prognosis for PCNSL. Further modifications, including the application of WSI seem to be necessary in the management of PCNSL.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Primary central nervous system lymphoma (PCNSL) of the brain is a rare malignant tumor (1), but its incidence has been increasing because of the recent remarkable advances in diagnostic imaging techniques, and an increase in the number of patients with immunodeficiency due to acquired immunodeficiency syndrome (AIDS), and organ transplantation (2–6). Nevertheless, the clinical outcome of the disease has been unsatisfactory compared with that of malignant lymphoma in other primary sites, where median survival is <2 years after radiotherapy alone (7,8). Although the Radiation Therapy Oncology Group (RTOG) performed a combined chemotherapy clinical trail that included cyclophosphamide, adriamycin, vincristin, dexamethasone, intrathecal (IT) methotrexate (MTX), with radiation therapy for patients with PCNSL, no significant improvement in prognosis was observed (9). The prolongation of survival time has recently been achieved by a combination of whole brain irradiation (WBI) and chemotherapy with a high dose of MTX or procarbazine, cyclohexychlorothylnitrosourea, and vincristine (PCV). However, aggressive chemotherapy is not always appropriate in a majority of cases because of the impaired physical condition of such patients (10–13). The treatment modality is yet to be established and this issue still remains controversial.
Although primary treatment comprising WBI with a total dose of 40Gy and boost irradiation with a total dose of 10 to 20 Gy are generally delivered and complete response is achieved in most patients, intracranial relapse is frequently observed (7–9). Since intrathecal involvement often develops and a local relapse occurs as characteristics of this disease, additional therapy, for example, chemotherapy and/or whole spinal irradiation (WSI), seems to be required. However, the efficacy of WSI remains unclear with regard to the indication criteria and toxicity, and aggressive chemotherapy is now preferred over WSI as an additional therapy.
Therefore, in order to improve the prognosis and to establish an appropriate therapy, we investigated the clinical outcome and prognostic factors, and retrospectively reassessed the efficacy of radiation therapy for PCNSL in this study. Consecutive patients treated in our institution were enrolled to avoid any bias against the method of treatment.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
From 1981 to 1999, 33 non-immunocompromised patients with PCNSL received radiation therapy with or without chemotherapy at the Department of Radiology and Radiation Oncology, Gunma University School of Medicine. Twenty-nine patients were histologically diagnosed as having PCNSL. Tumor specimens were obtained by biopsy from 17 patients among them and by partial resection from 12 patients. The remaining four patients were diagnosed by cerebrospinal fluid (CSF) cytology. The patients’ conditions were followed up periodically for a minimum of 36 months or until death, and the median follow-up period was 62 months (range: 36–122 months). The patient characteristics are summarized in Table 1. Of the 33 patients, 23 were males and 10 were females. The median age of the patients was 58 years (range: 28–78 years) at the start of the treatment. Nine patients (27%) had dissemination of lymphoma cells into the vertebral canal that was detected by CSF analysis at the initial presentation. Surgical removal was performed for the purpose of histopathological examination and reduction of tumor volume in three patients. Twenty-three patients (70%) were in poor physical condition with a WHO performance status (PS) of 3–4. The histopathological diagnoses according to the Working Formulation (14) are shown in Table 2. The most dominant histological subtype was a diffuse large cell type, which is similar to that of other reports (15,16).
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Treatment Technique
Our radiotherapy treatment policy for PCNSL involved performing a combination therapy of WBI with a dose of 30–40 Gy and an additional boost with a dose of 10–20 Gy, and a total dose of 50 Gy through opposite lateral fields using a 10 MV photon beam. In three cases of remaining tumors, after administering a planning dose, a total dose of 60 Gy was delivered for the target with more shrunken fields. Since the enhanced mass lesion had not completely disappeared in case of one patient, the patient was administered an additional 20 Gy boost by a stereotactic technique with eight portals four weeks after radical irradiation with a total dose of 60 Gy. On the other hand, treatment irradiation was discontinued for a 28-year-old man who was receiving an irradiation dose of 34 Gy due to the deterioration of his general condition. Further, because four patients underwent total removal before radiation therapy (RT), only WBI with a total dose of 40 Gy was delivered. Therefore, in this series, the total doses ranged from 34 to 80 Gy, with a median dose of 50 Gy as the initial treatment. Fractionation involved a 2 Gy tumor dose daily: five fractions per week. WSI was administered to four patients with a dissemination of lymphoma cells into the CSF and was administered prophylactically for five patients without CSF involvement. After 17 or 18 fractions from the initiation of WBI, WSI was performed at a total dose of 30 Gy using a 10 MV photon beam with a posterior field, and a fraction dose was used at a tumor dose of 1.5 Gy. Systemic chemotherapy (MEPP: mitoxantrone, 5 mg/m2, day 1; etoposide, 100 mg/m2, day 1–3; carboplatin, 300 mg/m2, day 1; prednisolone; 60 mg/body, day1–5) was administered to eight patients before radiotherapy. For patients with CSF infiltration (n = 9), WSI (n = 4) and/or intrathecal injection of MTX (n = 4), were administered, with the exception of three patients who had a very poor clinical condition during the treatment. A combination therapy of WSI and chemotherapy was performed for two patients. Systemic chemotherapy was administered for eight recurrent tumors, and re-irradiation was also performed using fields localized to the tumors for two patients with intracranial recurrence.
Statistics
Survival time was calculated from the date of the start of irradiation to death or to the last follow-up, according to the Kaplan–Meier method (17). The survival curves were compared by the log-rank test. A multivariate analysis for overall survival was performed using Cox’s proportional hazard model. The parameters evaluated were as follows: gender, age, PS, CSF involvement, tumor size, number of tumors, initial response to treatment, total dose, WSI, chemotherapy, and surgical removal. Differences were considered significant if P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Response and Relapse
All tumors except one had distinctly reduced, but the initial effects of tumors were judged as partial response (PR) when delineations of enhanced lesions remained, even though they were very small lesions. Of the 33 patients, 22 (67%) achieved a complete response (CR) and 10 (30%) achieved a PR, and one patient had no response to the treatment. The overall objective response rate (CR + PR) on completion of the radiation therapy was 97%. Twenty-four patients had a relapse and one patient died of heart failure at 71 months after completion of treatment. Another patient, who received prophylactic WSI, died of cardio-vascular disease at 21 months after radiotherapy, without tumor relapse. A relapse in the intracranial region (within the radiation field for the whole brain) was observed in 16 patients (67%) and the involvement in the CSF was observed in eight patients (33%). However, none of the five patients who received WSI as a prophylactic therapy had recurrent tumors in the vertebral canal.
Survival and Prognostic Factors
Median overall survival time (MST) and the 5-year actual overall survival rate for the 33 patients were 13 months (range: 1–122 months) and 35% (95% confidence interval (CI): 17.9–52.1%), respectively (Fig. 1). Eleven patients were 4-year survivors, and their characteristics are summarized in Table 3. With regard to the survival time, the initial response to the treatment and the number of tumors were significant prognostic factors (P = 0.020 and P = 0.024, respectively). The PS and WSI tended towards statistical significance in the analysis by the log-rank test (P = 0.087 and P = 0.092, respectively) (Table 4). In the multivariate analysis, the initial response and the number of tumors had independent impacts on the survival of patients with PCNSL, and WSI had a tendency of significance (Table 4). Moreover, WSI was a powerful prognostic factor in the case of 24 patients without intrathecal involvement. Four of the five patients treated with WSI were 4-year survivors without recurrent tumors, whereas 14 of the 19 patients without WSI developed recurrence, including three patients with involvement of the vertebral canal, nine patients with intracranial tumors, one patient with pericardial dissemination, and one patient with skin metastasis. The 5-year survival rates of the patients with and without WSI were 80% (95% CI: 46.9–100%) and 31.6% (95% CI: 10.9–52.3%), respectively (Fig. 2), and the difference between the survival curves of the two groups was statistically significant (P = 0.035).
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Complications
The evaluation for acute and late complications related to the treatment was possible for 33 and 11 patients with PCNSL, respectively (Table 5). As acute toxicity, neurological complications were observed in 10 patients, but the addition of WSI and/or chemotherapy did not enhance acute neurological toxicity. However, bone-marrow toxicity increased after combined treatment modality. Acute gastrointestinal and pulmonary complications, in particular, were characteristic of patients for whom WSI was performed, but the medication was successful. With regard to late toxicity, most patients developed memory loss, and brain necrosis was observed in one (9%) of 11 patients who were long-term survivors. However, the patient who received a combination therapy of WBI at a total dose of 50 Gy with WSI as a prophylactic therapy had a tumor relapse at 79 months after the first treatment; and owing to the inoperable condition, re-irradiation at a total dose of 50 Gy was administered with localized irradiation fields. Neurological findings and the physical condition of the patient were transiently improved, but brain necrosis appeared at nine months after re-treatment. Therefore, brain necrosis was caused not by the first but the second irradiation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PCNSL is an aggressive lymphoma with a much higher rate of local relapse than non-Hodgkin’s lymphoma arising from other primary sites. Previous studies demonstrated that the clinical outcome of the disease when treated with radiation therapy alone is inadequate (7,18). Therefore, agents capable of penetrating the blood–brain barrier, including MTX and procarbazine, were administered as an additional chemotherapy combined with radiotherapy. Also, there has been a greater improvement in the median survival time (MST) in case of radiotherapy combined with chemotherapy than with radiation therapy alone (7,12,19–23). However, it is considered that the feasibility and efficacy of the combined treatment modality have not been clear, because recent studies on the management of patients with PCNSL may have been conducted on a select patient population. Moreover, the side-effects of aggressive chemotherapy combined with WBI seem to be more frequent and more severe than radiation therapy alone (20,24–26). Therefore, in order to improve the prognosis and to design an optimized treatment modality we retrospectively re-examined the efficacy of radiation therapy for all patients who were histologically or cytologically diagnosed with PCNSL in our institution from 1981 to 1999. In the current study, 70% of these patients were in very poor physical condition (PS = 3 or 4) and 18 of 33 patients (55%) received only WBI without chemotherapy or WSI. Consequently, the MST of patients in this analysis was 13 months and the 5-year actual overall survival rate was 35%. Although MST in this study was shorter than those in recent studies reported by Herrlinger and Bessell (25,27,28), our results of the 5-year survival rate are similar to theirs. Further, the corresponding rate for patients who received WSI as a prophylactic therapy was 80% and the MST of these patients was over 60 months, but the number of patients in this group was small. Although this treatment modality seems to be successful considering the results of our study, three of the five patients (60%) with prophylactic WSI had a good PS and all the patients were less than 60 years old. Therefore, we would admit that our selection criteria for the treatment method for patients with PCNSL also had a bias, in that, WSI was performed only for patients who could tolerate such an intensive therapy. However, in contrast to most other studies, age had no impact on prognosis in our analysis. Also, no late complication of grade 4–5 including leukoencephalopathy was observed by the inclusion of WSI in this study. Therefore, a re-evaluation of the usefulness of prophylactic WSI may be necessary in the management of PCNSL (29).
It has been assumed that tumors would be easily eliminated by irradiation in malignant lymphoma and the local relapse rate is very low because of the high radiosensitivity of lymphoma cells. However, local relapse is more frequent in PCNSL than in non-Hodgkin’s lymphoma arising from other primary sites. Therefore, in order to improve the prognosis it is important to control the brain tumor and to prevent its metastasis especially to the vertebral canal. The reasons for poor local control are still speculative. One possibility is that an uncommon environment in the brain tissue might affect the local relapse. It is also possible that the immune reactions in the intracranial region might be weak because of the difference between the immune systems of the brain and other organs. Another explanation is that adhesion of malignant cells and re-proliferation of the tumor may occur post-irradiation for the brain as a result of reseeding from micrometastasis in the CSF. In the current study, three of 19 patients, who received WBI without WSI but did not have tumor cell involvement in the CSF at the time of diagnosis, developed dissemination in the vertebral canal. Loeffler et al. suggested a better survival rate with WSI in addition to WBI because MST was 41 months in the WBI plus WSI group but 19 months in WBI alone group (30). Some previous reports have supported these results (1,31). Our study indicates the possibility that prophylactic WSI as well as MTX decrease the probability of a tumor relapse.
In our study the initial response to treatment and the number of tumors were prognostic factors in the management of PCNSL, and WSI tended to be significant as shown by the multivariate analysis. The number of tumors may have a correlation with the intrathecal involvement of the tumors. In fact, six (54%) of the 11 patients with multiple brain tumors had involvement of the CSF, whereas only three (14%) of the 22 patients with a solitary tumor had dissemination in the CSF. Contrary to some reports, the effect of age and PS on survival time was not apparent in our study. This can be attributed to the small number of patients used for the study and unexpected better outcomes for patients with poor physical conditions. It is also possible that the improvement of general condition in terms of excellent and rapid response of lymphoma cells to this treatment coincided with good results even in patients who could not endure systemic chemotherapy.
This single institutional experience with conventional treatment has resulted in a shorter MST than in recent combined modality series, even though the 5-year survival results are comparable (13,28,34). The major reasons for a shorter MST appear to be: older age of the patients (14/33 patients (42%) were over 60 years old); poor performance status (70% had a PS of 3–4); and CSF involvement in 9/33 patients (27%) at the time of diagnosis. The acute toxicity of aggressive combined modality therapy is not well-tolerated by older patients, and it is reported that 62% of the patients aged 60–69 years became demented by cyclophosphamide, doxorubicin, vincristin, and dexamethasone (CHOD) and carmustine (BCNU), vincristine, arabinoside, and MTX (BVAM). Therefore, it is important to reduce the severe acute and late complications in these patients, while concurrently trying to provide a cure. Thus, prospective trials are needed to define the role of craniospinal irradiation of 30 Gy plus a tumor boost of 50 Gy in patients with PCNSL without positive CSF cytology.
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ACKNOWLEDGEMENTS |
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This work was supported by the Japan Society for the Promotion of Science for Young Scientists. The study was also supported in part by Grant-in-Aid for Scientific Research on Priority Areas (12217022, 13218015) and for Scientific Research (13670918) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
The authors thank Dr. Hideyuki Kurihara for his assistance with patient treatments as well as retrospective data analysis.
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FOOTNOTES |
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+ For reprints and all correspondence: Hitoshi Ishikawa, Department of Radiology and Radiation Oncology, Gunma University School of Medicine, 3–39–22 Showa-Machi, Maebashi, Gunma, Japan. E-mail: hisikawa{at}med.gunma-u.ac.jp
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Received April 10, 2003; accepted August 3, 2003
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