This retrospective study compares higher-dose whole-brain radiotherapy (hdWBRT) with reduced-dose WBRT (rdWBRT) in terms of clinical efficacy and toxicity profile in patients treated for primary central nervous system lymphoma (PCNSL).
Radiotherapy followed by high-dose methotrexate (HD-MTX)-based chemotherapy was administered to immunocompetent patients with histologically confirmed PCNSL between 2000 and 2016. Response to chemotherapy was taken into account when prescribing the radiation dose to the whole brain and primary tumor bed. The whole brain dose was ≤23.4 Gy for rdWBRT (n = 20) and >23.4 Gy for hdWBRT (n = 68). Patients manifesting cognitive disturbance, memory impairment and dysarthria were considered to have neurotoxicity. A median follow-up was 3.62 years.
The 3-year overall survival (OS) and progression-free survival (PFS) were 70.0% and 48.9% with rdWBRT, and 63.2% and 43.2% with hdWBRT. The 3-year OS and PFS among patients with partial response (n = 45) after chemotherapy were 77.8% and 53.3% with rdWBRT, and 58.3% and 45.8% with hdWBRT (p > 0.05). Among patients with complete response achieved during follow-up, the 3-year freedom from neurotoxicity (FFNT) rate was 94.1% with rdWBRT and 62.4% with hdWBRT. Among patients aged ≥60 years, the 3-year FFNT rate was 87.5% with rdWBRT and 39.1% with hdWBRT (p = 0.49). Neurotoxicity was not observed after rdWBRT in patients aged below 60 years.
rdWBRT with tumor bed boost combined with upfront HD-MTX is less neurotoxic and results in effective survival as higher-dose radiotherapy even in partial response after chemotherapy.
Primary central nervous system lymphoma (PCNSL) is a highly aggressive form of non-Hodgkin’s lymphoma. Optimal treatment for PCNSL is disputed, but high-dose methotrexate (HD-MTX)-based chemotherapy followed by whole-brain radiotherapy (WBRT) remains a standard treatment strategy.
The major drawback of WBRT for PCNSL is the possibility of neurotoxicity [
While these trials omitted WBRT, several attempts were also made to reduce neurotoxicity despite WBRT treatment efficacy as consolidation treatment, by reducing the radiation dose. Morris et al. [
This study was approved by the Institutional Review Board of Seoul National University Hospital before collecting patient information (No. 1904-072-1026). A retrospective review was undertaken using medical records of pathologically confirmed PCNSL patients who underwent upfront HD-MTX-based chemotherapy followed by WBRT from January 2000 to December 2016. Patients with immunocompromised state, previous cancer history, or disease involving extra-central nervous system (CNS) at the time of presentation were excluded. WBRT with dose lower than or equal to 23.4 Gy was defined as reduced-dose WBRT (rdWBRT), and therapy with dose higher than 23.4 Gy was defined as higher-dose WBRT (hdWBRT). The rdWBRT was administered to 20 out of 88 eligible patients. Characteristics of the patients and treatments administered to both groups are summarized in
As specified in eligibility criteria, all patients were treated with HD-MTX-based chemotherapy with median 5 cycles (range, 2 to 6 cycles). Exact chemotherapy regimen was varied depending on the medical oncologist decision and treatment period. Eighty-one patients (92.0%) underwent combination chemotherapy with methotrexate, vincristine, and procarbazine, which was similar to that used in the RTOG 93-10 study [
Radiotherapy started 3 to 6 weeks after HD-MTX chemotherapy. Doses to the whole brain and tumor bed were mainly based on radiological response to upfront chemotherapy. As shown in
A three-dimensional conformal therapy (3D-CRT) based on conventional fractionation of daily 1.8 Gy of 4–6 MV X-rays was administered to 65 patients (73.9%), intensity-modulated radiotherapy (IMRT) was provided to 14 patients (15.9%) since late 2014. One patient underwent WBRT as 3D-CRT then tumor bed boost as IMRT, while 10 patients underwent WBRT as IMRT then tumor bed boost as 3D-CRT. For 3 patients, IMRT was applied to both WBRT and tumor bed boost. Boost to tumor bed was given sequentially, after WBRT was done. The gross tumor volume was delineated based on pre-chemotherapy tumor volume. The clinical target volume margin for tumor bed boost was 0.5 to 1.5 cm, and the planning target volume margin was mostly 0.3 cm. Whole-spine radiotherapy was administered to 5 patients (5.7%) with positive CSF cytology. Range of dose to whole-spine was 19.8 to 36 Gy.
The median follow-up duration was 3.62 years (range, 0.38 to 19.2 years) in all patients; 3.62 years (range, 1.12 to 7.27 years) for rdWBRT, and 3.60 years (range, 0.38 to 19.2 years) for hdWBRT. Follow-up visit and response evaluation was done every 3 to 4 months for 2 years, every 6 months until 5 years from the end of the therapy, and yearly thereafter. Survival data was retrieved from the national registration system of Korean government.
Radiological response was evaluated after chemotherapy, one month after radiotherapy, and at every subsequent follow-up. Contrast-enhanced magnetic resonance with or without fluid-attenuated inversion recovery (FLAIR), diffusion-, perfusion- or susceptibility-weighted image (SWI) was administered. Response was evaluated according to international response criteria for PCNSL [
Neurotoxicity was evaluated via retrospective analysis of medical records. To exclude disease-related effects, patients who achieved CR within the follow-up period were included in this toxicity analyses. Treatment-related neurotoxicity was defined as occurrence of grade 2 or higher cognitive disruption, memory impairment or dysarthria after completion of radiotherapy. The neurotoxicity was graded by the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0.
The study endpoints were OS, PFS, and freedom from neurotoxicity (FFNT), which were calculated by Kaplan-Meier method. OS and DFS were measured from the date of biopsy or resection for histological diagnosis, for each defined event. The OS event was defined as death of the patient, and the PFS event was defined as disease progression or death. To measure FFNT, time to occurrence of neurotoxicity was calculated from the completion of radiotherapy and censored at the date of last follow-up or the event. The log-rank test was conducted to compare treatment outcomes and toxicity profiles of different treatment groups. Chi-square test were performed to determine differences between categorical values, while Student t-test was used for continuous values. Multivariate Cox proportional hazards model was constructed by including variables considered as potential independent predictors (p < 0.05) based on univariate analysis. Treatment group according to WBRT dose was always included in multivariate analysis, since this factor was mainly evaluated in this study. Univariate and multivariate Cox analyses included variables, such as prognostic and treatment-related factors, which showed differences between treatment groups. All of the statistical analyses were performed using R 3.6.0 (
CR after HD-MTX based chemotherapy was observed in 36 (40.9%) of all patients (n = 88), in 61 (69.3%) patients 1 month after completion of radiotherapy, and in 75 (85.2%) patients during the overall follow-up eventually.
The 3- and 5-year OS rates were 64.8% and 52.9% for all the patients, respectively; 70.0% and 64.2% for rdWBRT, respectively, compared with 63.2% and 50.6% for hdWBRT, respectively. The OS differences between the two treatment groups were not statistically significant (p = 0.77). Univariate Cox analysis revealed age (<60 vs. ≥60 years), involvement of deep structures, dose of methotrexate, number of HD-MTX cycles, administration of postoperative cytarabine, and CR after radiotherapy as potential independent predictors. In multivariate Cox analysis, age (p = 0.0014), involvement of deep structure (p = 0.017), and CR within follow-up period (p = 0.00048) were associated with OS, whereas treatment group by WBRT dose was not.
The 3- and 5-year PFS rates were 46.9% and 32.6% for all the patients, respectively; 48.9% and 15.3% with rdWBRT, respectively, and 46.4% and 35.2% with hdWBRT, respectively. No significant differences in PFS were found between the two groups (p = 0.80). The 5-year PFS for rdWBRT group might appear to be low; however, the 5-year number at risk was 1, so this rate is not representative. Age, involvement of deep structures, and CR within the follow-up period were potential independent predictors in univariate Cox analysis. Age (p = 0.013) and CR within the follow-up period (p = 0.00022) were associated with PFS in multivariate analysis. Treatment group based on WBRT dose was not associated with PFS. The OS and PFS based on WBRT doses in all the patients are presented in
The patterns of failure did not differ by treatment groups. In the hdWBRT group, 35 (51.5%) showed in-brain recurrence, which included 23 (33.8%) cases of recurrence in irradiated tumor bed. CSF failure was detected in 10 (14.7%) cases, and 13 (19.1%) showed distant recurrence. In the rdWBRT group, 11 (55.0%) had in-brain recurrence, and 5 (25.0%) failed in irradiated tumor bed; 3 cases (15.0%) showed CSF failure, and 4 (20.0%) had distant recurrence. There was no significant difference between two groups (p > 0.05)
The effect of WBRT dose on survival of PR patients after chemotherapy was analyzed. Among 45 patients (51.1%) with PR, 9 underwent rdWBRT while 36 underwent hdWBRT. In the rdWBRT group, 3- and 5-year OS rates were 77.8% and 77.8%, respectively, and in the hdWBRT group, the rates were 58.3% and 40.0%, respectively. The OS difference was not significant (p = 0.33). In terms of PFS, 3- and 5-year rates were 53.3% and 20.0%, respectively, in the rdWBRT group, and were 45.8% and 29.6% with hdWBRT. These differences in PFS between the two groups were not significant (p = 0.94). The survival patterns of PR patients based on WBRT dose are shown in
Treatment outcomes according to post-radiation cytarabine were also evaluated. For 27 patients with post-radiation cytarabine, the 3- and 5-year OS rates were 77.8% and 56.0%, respectively; and the 3- and 5-year PFS rates were 59.0% and 30.7%, respectively. In the remaining 61 patients, the 3- and 5-year OS rates were 59.0% and 50.4%, respectively; and the 3- and 5-year PFS rates were 41.8% and 32.7%, respectively. A marginally significant difference was observed in OS (p = 0.083) but not in PFS (p = 0.38) between the two groups.
As previously stated, a total of 75 patients eventually achieved CR within the follow-up period, and these patients were included in neurotoxicity analyses. The 3-year FFNT rate was 69.7%. At the time of diagnosis, 45 patients were younger than age 60 years whereas 30 patients were not. The 3-year FFNT rate was 77.3% in the young (<60 years) and 55.6% in the older patients (p = 0.081).
Among patients included in neurotoxicity analyses, 18 patients were included in the rdWBRT group, and 57 were in the hdWBRT group. The 3-year FFNT rate was 94.1% for rdWBRT group and 62.4% for hdWBRT group (p = 0.33). Univariate Cox analysis revealed that age, sex, multifocal involvement, involvement of deep structures, and methotrexate dose were potential independent predictors, but only age (hazard ratio=1.05; 95% confidence interval, 1.00–1.11; p = 0.038) showed significant association in multivariate analysis.
Among the young (<60 years), the 3-year FFNT rate was 100% for rdWBRT group and 72.1% in the hdWBRT group (p = 0.14). No neurotoxicity was reported within the follow-up period in younger patients who underwent rdWBRT. Among the old (≥60 years), the 3-year FFNT rate was 87.5% in the rdWBRT group and 39.1% in the hdWBRT group (p = 0.49).
The present retrospective study revealed that reduced radiation dose administered to the whole brain and the primary tumor bed after upfront MTX-based chemotherapy resulted in OS and PFS rates similar to hdWBRT, and less neurotoxicity especially in patients younger than age 60 years. As there are no differences in treatment outcomes between rdWBRT and hdWBRT, radiotherapy with dose reduction is safe and feasible.
Our previous report demonstrated that HD-MTX-based chemotherapy followed by low-dose WBRT with tumor bed boost was an effective strategy for treatment of PCNSL [
There was another attempt to reduce the dose of WBRT ended in failure. Bessell et al. [
Nevertheless, there is already a tendency toward dose reduction in WBRT. As stated before, Koh et al. [
The present study showed the possibility of rdWBRT with tumor bed boost in patients who achieved PR after chemotherapy without increasing the risk of relapse, as there was no difference in treatment outcomes based on WBRT dose. Similar to this study, other studies investigating WBRT dose reduction in patients who achieved non-CR after chemotherapy. Park et al. [
Nevertheless, several aspects of dose reduction strategy involving WBRT remain to be addressed in the absence of consensus regarding the exact limit of low-dose WBRT associated with safety and efficacy [
Neuronal damage of hippocampus due to radiation is known to be related to CNS toxicity [
As previously stated, elderly patients (≥60 years) are vulnerable to neurotoxicity induced by WBRT. A few clinicians insist that although G-PCNSL-SG-1 trial failed to demonstrate the non-inferiority of completely omitting radiotherapy, it also showed a low clinical benefit of radiotherapy [
Although the rates were lower than in elderly patients, reports suggest modest incidence of delayed neurotoxicity in young (<60 years) patients exposed to WBRT [
One of the major limitations of this study is the retrospective nature of neurocognitive function assessment, as this study relies solely on review of medical records. Unreported or undetected treatment-related neurotoxicity might lead to overestimation of FFNT rate in this study. Also, due to the constant progression in treatment strategy of PCNSL, applied treatments were changed during the study period. In addition, concerns of potential bias existed due to unbalanced treatment between different groups based on WBRT dose. Despite these limitations, this study is still informative considering the relative rarity of the disease, the decent number of patients evaluated, and relatively consistent radiotherapy over the study period.
In conclusion, rdWBRT with tumor bed boost combined with upfront HD-MTX is less neurotoxic and results in effective survival as higher-dose radiotherapy even in PR after chemotherapy. Treatment with rdWBRT (≤23.4 Gy) combined with HD-MTX showed no statistically significant difference compared with hdWBRT in terms of OS and PFS. Also, patients aged younger than 60 years and exposed to rdWBRT did not show neurotoxicity in present study, which indicates that these group of patients might benefit from rdWBRT.
No potential conflict of interest relevant to this article was reported.
Histogram representing treatment groups over different time periods.
Overall survival (A) and progression-free survival (B) of patients, based on dosage of whole-brain radiotherapy.
Overall survival (A) and progression-free survival (B) of patients who achieved partial response, by dose of whole-brain radiotherapy.
Freedom from neurotoxicity rates, by age.
Freedom from neurotoxicity by dose of whole-brain radiotherapy, patients with age older than or equal to 60 years (A) and younger than 60 years (B).
Patients’ characteristics
Characteristic | Reduced-dose WBRT | Standard-dose WBRT | p-value |
---|---|---|---|
Age at diagnosis (yr) | 58.7 (46.2–75.2) | 56.1 (23.4–75.1) | 0.599 |
<60 | 11 (55.0) | 44 (64.7) | |
≥60 | 9 (45.0) | 24 (35.3) | |
Sex | 0.852 | ||
Male | 12 (60.0) | 37 (54.4) | |
Female | 8 (40.0) | 31 (45.6) | |
ECOG performance status | 0.683 | ||
0–1 | 14 (70.0) | 42 (61.8) | |
2–4 | 6 (30.0) | 26 (38.2) | |
Pathology | 0.399 | ||
Diffuse large B-cell lymphoma | 17 (85.0) | 64 (94.1) | |
Other B-cell lymphoma | 1 (5.0) | 1 (1.5) | |
T-cell lymphoma | 2 (10.0) | 3 (4.4) | |
Eye involvement | 0.134 | ||
Yes | 3 (15.0) | 2 (2.9) | |
No | 17 (85.0) | 66 (97.1) | |
CSF involvement | 0.703 | ||
Yes | 3 (15.0) | 6 (8.8) | |
No | 17 (85.0) | 62 (91.2) | |
Operation | 0.190 | ||
Stereotactic biopsy | 20 (100) | 58 (85.3) | |
Gross total resection | 0 (0.0) | 7 (10.3) | |
Subtotal resection | 0 (0.0) | 3 (4.4) | |
Number of lesions | 1.000 | ||
Single | 5 (25.0) | 19 (27.9) | |
Multiple | 15 (75.0) | 49 (72.1) | |
Deep structure involvement |
0.864 | ||
Yes | 14 (70.0) | 44 (64.7) | |
No | 6 (30.0) | 24 (35.3) | |
LDH elevation | 0.640 |
||
Yes | 6 (30.0) | 27 (39.7) | |
No | 13 (65.0) | 39 (57.4) | |
Not reported | 1 (5.0) | 2 (2.9) | |
Rituximab usage | 0.003 | ||
Yes | 10 (50.0) | 10 (14.7) | |
No | 10 (50.0) | 58 (85.3) | |
Post-radiation cytarabine | 0.003 | ||
Yes | 12 (60.0) | 15 (22.1) | |
No | 8 (40.0) | 53 (77.9) |
Values are presented as median (range) or number (%).
WBRT, whole-brain radiotherapy; ECOG, Eastern Cooperative Oncology Group; CFS, cerebrospinal fluid; LDH, lactate dehydrogenase.
Deep structure was defined as basal ganglia, corpus callosum, brainstem, and cerebellum.
Calculated only for reported numbers.
Radiation dosage in different treatment groups based on response to chemotherapy
Response after chemotherapy | WBRT dose (Gy) | Total dose (Gy) |
---|---|---|
Standard-dose group (>23.4 Gy) | ||
CR (n = 27) | 27.0 (25.2–30.6) | 45.0 (36.0–54.0) |
PR (n = 36) | 30.6 (25.2–36.0) | 50.4 (45.0–55.8) |
SD/PD (n = 5) | 30.6 (27.0–36.0) | 50.4 (45.0–54.0) |
Reduced-dose group (≤23.4 Gy) | ||
CR (n = 9) | 19.8 (18.0–23.4) | 36.0 (36.0–50.4) |
PR (n = 9) | 21.6 (18.0–23.4) | 45.0 (45.0–50.4) |
SD/PD (n = 2) | 20.7 (18.0–23.4) | 42.3 (39.6–45.0) |
Values are presented as median (range).
WBRT, whole-brain radiotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.