To the best of our knowledge, the present study is the first series ever published on a prospective evaluation of QoL in patients with BM, not including primary brain tumors, treated with VMAT and dose escalation. The efforts at developing new therapeutic strategies in BM should not only focus on increasing survivorship but should also assess their relative impact on QoL. Dose escalation may be potentially neurotoxic and thus negatively affect health-related QoL in these BM patients. As such, we embarked in a careful prospective evaluation of QoL in a pilot VMAT dose escalation protocol. Our data suggests several comments. First, QoL assessment was indeed difficult in this patient cohort, even though a dedicated physician was assigned to do the QoL assessment. The difficulty in assessing QoL or neurocognitive function in patients with BM has been reported by other investigators [5, 14]. Only one patient out of two could be assessed at the 3 months post-VMAT time point, as a result of decreasing performance status and/or cognitive function, administrative issues or patient refusal. Second, the overall QoL of these patients did indeed decrease 3 months after VMAT as reported by other authors (Table 3). In order to avoid any potential bias originating from the death of patients with poor-QoL, the comparison of QoL at the two time points (i.e. baseline and at 3 months) was performed using only data from patients completing questionnaires at both time points . Additionally, performance status did also significantly decrease, but the neurocognitive function, assessed with the MMSE, appeared to be stable in this small cohort. Interestingly, the levels of three EORTC-BN20 domains, namely visual disorder, motor dysfunction and communication deficit, remained stable at this time point, suggesting a possible association between MMSE and these scores, as reported by other authors . Third, except for physical and role functioning (Figure 1), the observed QoL did not substantially decrease during treatment. MMSE significantly increased during treatment, possibly as a result of the therapeutic effect of radiation. Although one third of patients experienced alopecia, the EORTC-BN20 mean score for this item was decreased (Table 2), suggesting that there is not necessarily agreement between patient and physician reports of symptoms or toxicity [20, 21]. Some EORTC-BN20 domains were even improved during VMAT (Table 2), with an observed statistical trend for future uncertainty levels, which may reflect the effectiveness of coping strategies. Finally, lower functional and GHS scores in the EORTC-C30 questionnaire and higher EORTC-BN20 domain's scores were associated with decreased survival suggesting that these scores may be relevant prognosticators for BMs . Although no statistical trend was observed, possibly as a result of small numbers, all Kaplan-Meier curves were parallel to what was expected, i.e. worse QoL was related to decreased survivorship (data not shown). Using traditional method of statistical analysis (i.e. Cox multivariate model) controlled for major clinical prognostic factors, some EORTC-C30 or -BN20 items, such as cognitive function or GHS, have been significantly associated with survival in two prospective trials [22, 23], although these results are controversial [9, 24, 25]. The mechanisms underlying these potential associations are however unclear. QoL scores may reflect the patient's physical and psychological state that may have a positive effect on the overall disease process (i.e. higher QoL score are a proxy for the patient's health status that may have a positive effect on the underlying disease). Alternatively to this true causative relationship, these scores may reveal the early perception and severity of the disease more accurately than conventional prognostic indices (i.e. lower QoL score reflect a worse underlying disease). Of note, several issues, such as the intercorrelation of the QoL parameters or the high variability in survival in patients with identical QoL scores to name a few, have been raised by the use of classical methods of statistical computation . Further research regarding the prognostic value of health-related QoL is justified in the framework of future prospective trials.
We sought to investigate whether a hypofractionated SIB approach for the treatment of patients with 1 - 4 BMs would be a safe alternative to WBRT with or without radiosurgery. The observed toxicity was minimal. Less than one third of patients had alopecia at the end of treatment. These results may be in keeping with recent phase I dose escalation studies reporting the toxicity in patients treated with WBRT and an SIB technique [26, 27]. In the US study, alopecia and skin reaction were reported in 16% and 6% of patients, respectively . The reduction of the observed alopecia rates, when compared to those observed with WBRT, may have an impact on the patient's QoL, as assessed by the EORTC-BN20 questionnaire (Table 4).
The treatment of patients with BM can consist of best supportive care, surgery or radiosurgery with or without WBRT. We have included patients with one BM in our treatment protocol as the modulation of the WBRT by a VMAT approach may produce steeper radiation-dose gradients than plans with conventional WBRT summed with radiosurgery dose deposition . For patients with good- to intermediate-prognosis (i.e. RPA I - II), such as those treated in our protocol, a multi-modality treatment strategy is usually proposed with the aim of preventing intracranial progression, preserving the neurologic function and possibly the overall QoL. In our study, local and distant brain tumor control was achieved in a majority of patients. Unfortunately, systemic extracranial progression was observed in a majority (74.0%) of patients with a consequential impact on survivorship. Interestingly, the estimated 6-months OS was significantly increased (72% vs. 33.5%) when surgery was performed to patients with 1 - 4 BM. These results should be interpreted cautiously, as they may be subject to uncontrolled patient selection into different treatment groups (i.e. better KPS and RPA/GPA scores for patients undergoing surgery). They are however in line with several prospective studies confirming the importance of surgery in selected patients [29, 30]. Although we did not perform a multivariate analysis as the number of events relative to the potential parameters was inappropriate, these data suggest that dose escalation only with a SIB technique may not be the optimal treatment for these good- to intermediate-prognosis patients.
There were several limitations of our study. First, the small sample size of 29 patients limited the statistical power to assess fully the QoL of BM patients treated with VMAT and to detect associations between survival and the EORTC-C30 and -BN20 parameters. Second, the rate of completion of the questionnaires in these severely ill patients, although identical to the compliance rate reported in the literature, was suboptimal. High compliance in questionnaire completion is difficult to achieve in severely ill patients as their condition deteriorates over time. Third, as the number of brain progressions was low, the impact of this event on patient's QoL at the 3 months time point was not assessable. This being said, this study was a prospective study with specific QoL endpoints and the BM patient cohort studied was homogeneous and represented a good- to intermediate-prognosis population for whom the QoL is of paramount importance.
In summary, the delivery of 40 Gy in 10 fractions using a VMAT technique was achieved with no significant toxicity. The majority of patients presented with extracranial progressive disease. Surgery and performance status were significant prognostic factors for survival. Although the QoL did not decrease significantly during treatment, a decrease of several EORTC-C30 and -BN20 parameters was observed at 3 months after VMAT.