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There has been renewed interest in utilizing WBRT in the treatment of PCNSL, although current regimens are employing reduced, response-based doses as part of therapy, either intercalated with chemotherapy (as in the DeAngelis regimen), or as a consolidation approach per the Italian regimen detailed by Ferreri et al. Based on these findings, there is no standard therapy for newly diagnosed patients with PCNSL; consequently, there is a need to treat patients during clinical trials. Multicenter trials are thus needed to better define adjuvant treatment.
Treating older patients with PCNSL presents unique challenges, which clinicians should be particularly sensitive to. In young patients, treatment is initiated with curative intent, whereas in older patients, treatment is palliative in nature and designed to minimize neurotoxicity. The use of HD-MTX, which is employed in our study, may require that early WBRT-permitting radiotherapy be deferred until PCNSL progression is eliminated altogether in patients with a likely curative response to first-line therapy. Importantly, current regimens of HD-MTX reflect the optimal responses evident in other HD-MTX-only regimens; specifically, this approach accelerates the time to a complete response and improves progression-free survival. These results may define the recommended treatment approach for newly diagnosed PCNSL among patients younger than 60 years old. When treated with this regimen, about one-third of patients relapsed, and salvage therapy often resulted in a durable second remission. With prolonged follow-up, the reported risk of neurotoxicity (26%) may actually be acceptable to some patients and practitioners, while it may be unacceptable to others. However, data obtained from patients treated with chemotherapy alone suggest that deferring WBRT may significantly compromise disease control. In addition, data from Bessell et al. suggest that lowering the dose of WBRT in young patients who achieve a complete response with chemotherapy compromises both progression-free survival and OS. Therefore, it would seem critical to intensify or alter the chemotherapy regimen in an effort to improve its efficacy, especially if decisions are typically made to defer WBRT in young patients.
Among older patients treated with chemotherapy alone, it is important to note that most died of a progressive tumor. In older patients treated with both chemotherapy and WBRT, the most common cause of death is neurotoxicity. The fact that older patients have identical OS rates, irrespective of whether or not they receive WBRT as part of their initial therapy, indicates that the impact of treatment-related neurotoxicity and recurrent PCNSL are roughly equivalent. As a result, it is critical to design more effective and less toxic treatment regimens for older PCNSL patients. This is particularly important because patients over 60 years of age comprise at least half of the PCNSL population.
We established that if treatment initiation incorporates high-dose MTX, it becomes more effective in the management of PCNSL. In addition, the important role played by radiotherapy in the treatment of this malignancy was confirmed: a higher complete response was observed after radiotherapy than after upfront chemotherapy. Our experience suggests that low-dose WBRT with tumor bed boost after HD-MTX-based chemotherapy is an effective strategy for PCNSL management.
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