Strong correlation between imaging response and survival among patients with primary central nervous system lymphoma: a secondary analysis of RTOG studies 83-15 and 88-06

Abstract

Purpose: Primary central nervous system lymphoma (PCNSL) is the brain tumor with the most rapidly increasing incidence, yet little is known about its radiographic response to cranial irradiation. If traditionally used doses of radiotherapy (∼60 Gy) are associated with low rates of complete response and poor survival, then an argument can be made to consider dose escalation of radiotherapy. Alternatively, if poor survival rates are associated with high rates of complete response, there would be no reason to subject patients to higher radiation doses with increased risks of treatment-related morbidity. The purpose of this analysis is to provide a detailed review of response following cranial irradiation. Based on these findings, recommendations are offered for future protocol design. Methods and Materials: Patients were treated on either RTOG 83-15 (whole brain irradiation to 40 Gy followed by a 20 Gy boost to the tumor plus 2-cm margin) or RTOG 88-06 (induction cyclophosphamide, doxorubicin, vincristine, dexamethasone [CHOD] followed by whole brain irradiation to 41.4 Gy and an 18 Gy tumor boost). Imaging surveillance (CT, MR) was required following surgery, prior to the initiation of RT and following completion of RT. Complete response referred to the absence of enhancement on follow-up scans in comparison to the pretherapy study. A tumor size reduction of at least 50% in the product of the largest cross-sectional diameter and its largest perpendicular diameter was scored as a partial response. Results: Seventy-nine patients had scans available for central review. Complete response was achieved in 83% and 85% of patients treated on RTOG 83-15 and 88-06, respectively. The rates of partial response (14%, 11%) and radiographic progression (3%, 4%) also were comparable between the studies. For survival analyses, data were aggregated from the two studies. The 4-year survival rates were 24% for complete responders versus 11% for other patients ( p = 0.0006). In multivariate analysis, only complete radiographic response ( p < 0.0007), and high Karnofsky performance status (KPS ≥ 70) ( p < 0.005) were independently associated with increased rates of 4-year survival. Conclusion: A high rate of complete radiographic response was observed following moderate doses of cranial irradiation (alone or in combination with CHOD chemotherapy). Although complete responders had a statistically significant survival advantage at 4 years when compared with partial responders and nonresponders, the majority of patients who achieved complete response were dead of disease by 4 years following treatment. Based on this analysis of the RTOG database, there is no rationale for radiation dose escalation as a therapeutic strategy to combat PCNSL. Consequently, the radiotherapy component of the current RTOG Phase II trial (RTOG 93-10) now includes relatively low total doses of hyperfractionated irradiation for patients without residual disease (36 Gy/1.2 Gy, twice a day) as well as a more aggressive chemotherapy regimen.