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Is Withdrawal of Consolidation Radiotherapy an Evidence-Based Strategy in Primary Central Nervous System Lymphomas?

Department of Radiochemotherapy, San Raffaele H Scientific Institute, Milan, Italy.

To the Editor:

High-dose methotrexate- (HD-MTX) containing chemotherapy followed by radiotherapy (RT) is the most commonly used treatment for patients with primary CNS lymphomas (PCNSL), which is in-line with the widely accepted strategy for limited-stage aggressive lymphomas [1]. However, some authorities have considered this approach as associated with severe neurological impairment, mainly in elderly patients. Consequently, to defer RT until relapse in patients achieving complete remission (CR) after HD-MTX–based chemotherapy has been proposed as the main tactic to minimize the incidence of neurotoxicity, supposedly without compromising survival [2-8]. Both monochemotherapy with HD-MTX and substitution of RT with other drugs are the main therapeutic choices to achieve these goals. Reported experiences with these strategies, which consist exclusively in single-arm phase II trials, resulted in unwarranted and untimely enthusiasm, with the risk that this approach is prematurely introduced in ordinary clinical practice. On these bases, any comparison between immediate or delayed use of RT could be biased by selection flaws and limited statistical power. Only randomized trials that include also cognitive function evaluation will allow us to draw reliable conclusions.

In the meantime, our concern about a potentially negative survival impact of RT withdrawal is based on the following arguments:

• 1) HD-MTX alone followed by RT yielded a CR rate of 82% to 88%, a median progression-free survival of 32 to 40 months, and a median survival of 33 months [9,10]. CR rate after HD-MTX alone, even with remarkably higher doses, was 30% to 65%, with a median progression-free survival of 13 to 17 months [3-5]. Thus, RT contribution, at least in terms of activity, appears evident, while survival data for RT withdrawal are not yet mature.
  
• 2) Experience with replacement of RT with other drugs is still limited. Only results of a single phase II trial are available [7]. Despite a highly demanding chemotherapy regimen, including several drugs as well as intrathecal chemotherapy, overall response rate (71%) was not particularly better than those reported with HD-MTX alone [3-5].
  
• 3) Also when considering only elderly patients (> 60 years), chemo-radiation therapy [11-13] yielded clearly better results with respect to chemotherapy alone [6], with an objective response rate of more than 90% versus 48%, and a median survival of 22 to 32 months versus 14 months, respectively.
  
• 4) In a nonrandomized prospective trial, RT dose reduction from 45 to 30.6 Gy consistently compromised survival in younger patients in CR after primary chemotherapy [14], which suggests a positive survival benefit of consolidation RT. Accordingly, at most, a similar efficacy between RT withdrawal and RT dose reduction should be expected.
  
• 5) Unfortunately, in the three main prospective trials addressing deferred RT [3,4,6], data on feasibility, activity, efficacy, tolerance, and the potentially related neurotoxicity of RT at relapse have not been reported. These data could allow us to better compare the two strategies.
  
• 6) Among basic principles of oncology, it is assumed that treatment would produce a much higher cure rate when tumor volume is at a minimum [15]. Thus, consolidation RT against microscopic residual disease should be preferred to RT against more bulky disease at time of failure, until proven differently.
  

The diffused belief that RT is the main cause of neurotoxicity in PCNSL management deserves further analysis, mostly regarding the following aspects:

• 1) In a recent phase III trial, no difference was observed in neurotoxicity rates between PCNSL patients submitted to polychemotherapy with HD-MTX, carmustine, and procarbazine alone (23%) and patients treated with the same regimen followed by RT (21%) [16]. In other series, the 2-year probability of developing neurotoxicity was 8% to 14% among patients who did not receive RT after achieving CR to HD-MTX in combination with some drugs, like carmustine, cytarabine or vincristine, and intrathecal chemotherapy [6,17,18]. This is the same incidence (6% to 10%) reported for patients receiving HD-MTX as a single agent followed by RT [9,10,19]. All these data confirm the well-established role of these drugs and intrathecal chemotherapy in determining neurotoxicity [20-24]. Furthermore, conversely to RT [25-27], their efficacy has not even been prospectively assessed in PCNSL.
  
• 2) Comparison in terms of neurotoxicity incidence may be biased in favor of patients submitted to chemotherapy alone, because toxicity data refer only to the highly selected subset of complete responders, while the figure for patients treated with combined approach also includes partial responders or nonresponders to chemotherapy. Consistently, when data have been reported separately, neurotoxicity has been observed in 15% of cases in the whole population of irradiated patients and in 3.7% of patients receiving RT after CR to polychemotherapy [13].
  
• 3) Cognitive disorders are age-related and their prevalence, which is nearly 9% in the elderly general population [28], confounds neurotoxicity assessment. Of note, the concept that neurotoxicity occurs more often in elderly than in younger patients has been questioned by some retrospective and prospective studies, which showed similar complication rates in both groups [13,19] and higher rates in young patients [29].
  
• 4) Finally, the use of other drugs to replace consolidation RT resulted in very intensive chemotherapy regimens, which, independently of a potential activity reduction, were associated with an increased risk of severe morbidity and of treatment-related deaths, which raised from 0% to 3% [9,10,29] to 6% to 10% [6,7,17,30].
  

In conclusion, no adequate evidence supports that RT deferral is associated with a clear reduction of the risk of neurotoxicity, without compromising survival in PCNSL patients. The role of consolidation RT in PCNSL patients must be investigated through a randomized phase III trial. Meanwhile, chemotherapy as exclusive treatment, in elderly as well as in younger patients, must be considered an experimental approach and its use must be limited to prospective clinical trials.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

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