- About this Journal
- Abstracting and Indexing
- Aims and Scope
- Article Processing Charges
- Articles in Press
- Author Guidelines
- Bibliographic Information
- Citations to this Journal
- Contact Information
- Editorial Board
- Editorial Workflow
- Free eTOC Alerts
- Publication Ethics
- Submit a Manuscript
- Table of Contents
Volume 2013 (2013), Article ID 214304, 4 pages
Does Time between Imaging Diagnosis and Initiation of Radiotherapy Impact Survival after Whole-Brain Radiotherapy for Brain Metastases?
1Department of Oncology and Palliative Medicine, Nordland Hospital, 8092 Bodø, Norway
2Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway
3Department of Oncology, University Hospital of Northern Norway, 9037 Tromsø, Norway
Received 26 February 2013; Accepted 29 March 2013
Academic Editors: R.-J. Bensadoun, J. Bentel, and B. Comin-Anduix
Copyright © 2013 Carsten Nieder et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Aims. To evaluate whether reduced waiting time influences survival of patients treated with whole-brain radiotherapy (WBRT) for brain metastases. Materials and Methods. Retrospective intention-to-treat study including 110 patients treated with primary WBRT (typically 10 fractions of 3 Gy; no other treatment between diagnosis and WBRT). Uni- and multivariate tests were performed. Results. Median delay between imaging diagnosis and WBRT was 12 days (range 0–66 days). WBRT started within 1 week in 36%, during the second week in 28%, and during the third week in 18% of patients. No significant correlation between waiting time and survival was evident, except for one subgroup of patients. Those without extracranial metastases (potentially more threatened by worse intracranial disease control) survived for a median of 2.5 months from WBRT if waiting time was 2 weeks or longer as compared to 5.6 months if waiting time was shorter than 2 weeks (). The same correlation was seen if survival was computed from imaging diagnosis. Conclusion. If departmental resources are not sufficient to provide immediate WBRT within 2 weeks to all patients, those without extracranial metastases should be prioritised. This study did not address the impact of waiting time on quality of life or symptom palliation.
On an international scale, access to palliative radiotherapy varies with geographic region, health care system, and sociodemographic factors [1, 2]. The presence of waiting lists might cause distress, unnecessary symptom burden, and under certain circumstances compromised outcomes, at least if long waiting time is unavoidable. Regarding treatment of brain metastases, a considerable number of patients continue to receive palliative whole-brain radiotherapy (WBRT) [3, 4]. Administration of 10 fractions of 3 Gy over 2 weeks or 5 fractions of 4 Gy over one week is commonly used fractionation regimens in many countries . Given that median survival of patients managed with best supportive care is limited (in the order of 4–6 weeks [6, 7]), one might assume that delays in starting WBRT should be minimised, if such treatment is indicated and the preferred therapeutic option. Clinical data on the impact of variable waiting times between imaging diagnosis of brain metastases and initiation of WBRT on survival after radiotherapy are scarce . Therefore, we evaluated survival of a contemporary cohort of patients treated with WBRT.
2. Patients and Methods
We analysed patients from a previously described multi-institutional brain metastases database, which is maintained and updated by the first author [7, 9]. The patients were treated at Nordland Hospital (Bodø) and University Hospital of Northern Norway (Tromsø). For this retrospective intention-to-treat study, all patients treated with primary WBRT (prescribed dose 10 fractions of 3 Gy or 5 fractions of 4 Gy; no previous surgery or radiosurgery; no radiation boost) between 2005 and 2012 were selected (). All patients who failed to complete WBRT are included in the analysis. The choice of WBRT dose was made by the treating physician taking into account the life expectancy of individual patients. WBRT commenced without preceding systemic therapy after imaging diagnosis of brain metastases. The patient characteristics are shown in Table 1. For comparison of dichotomous variables the Chi-Square Test and Fisher’s Exact Test, where applicable, were employed and for continuous variables the Mann-Whitney Test (always 2-sided). Actuarial survival was calculated with the Kaplan-Meier method and compared between different groups with the log-rank test. Thirteen patients (12%) were alive at date of the last followup (November 01, 2012) and thus censored. Their median followup was 5 months (range 1–59 months). The prognostic impact of baseline parameters and waiting time was first tested in univariate analyses (log-rank test). For multivariate analysis of survival Cox regression analysis was used. Waiting time was entered as continuous or categorical variable with different cutoff values. A value <0.05 was considered statistically significant.
Of all 110 patients included in the study 36 (33%) started WBRT within one week from imaging diagnosis of brain metastases. Another 28% (31 patients) started during the second week and 18% (20 patients) during the third week. Median delay was 12 days (range 0–66 days). Median survival was 3.0 months from imaging diagnosis and 2.5 months from the first dose of WBRT. As shown in Table 2, no significant correlation between waiting time and survival was evident. The small group of 16 patients (15%) with waiting time >28 days had median survival comparable to patients with waiting time ≤28 days (2.5 months from WBRT, , and 4.2 months from imaging diagnosis, ). Given that most but not all baseline characteristics were balanced between the two groups with waiting time <12 days versus ≥12 days (as shown in Table 1 significant differences regarding primary tumour type were seen), a series of multivariate Cox regression analyses was performed. Waiting time was entered as categorical variable (stratified by median or 4 strata, i.e., <1 week, 1-2 weeks, 2-3 weeks, or more) or as continuous variable. Primary tumour type and prognostic scores (recursive partitioning analysis (RPA) classification  and diagnosis-specific graded prognostic assessment (DS-GPA) score ) were entered as covariates. No significant correlation between waiting time and survival from WBRT or imaging diagnosis was identified (details not shown).
In order to explore the hypothesis that specific subgroups of patients could be more vulnerable to detrimental effects of longer waiting time, more detailed analyses were performed. Irrespective of cutoff chosen, Karnofsky performance status (KPS) and age did not turn out to be relevant. However, extracranial disease extent might be important. In patients with extracranial metastases, survival depends on both intra- and extracranial disease control and is typically shorter than in patients without extracranial metastases (3.0 versus 4.2 months in the present study). In patients with brain metastases only, intracranial disease control is more important, and delayed WBRT could threaten survival. Twenty-one patients in this study did not harbour extracranial metastases. Median survival was 2.5 months from WBRT with waiting time ≥2 weeks and 5.6 months with shorter waiting time (). Comparable results were seen for survival from imaging diagnosis (3.8 versus 5.9 months, ).
The risk of being unable to complete the prescribed course of WBRT was similar across all groups (9% each for interval <12 days versus ≥12 days, 9% for start within one week, 11% for start during the second week, 5% for start during the third week, 10% for start after more than 3 weeks, and for both statistical approaches).
Survival from imaging diagnosis was significantly longer in patients with breast cancer (median 13.9 months) and small cell lung cancer (median 5.3 months) than those with other primary diagnoses. Both RPA classification and DS-GPA score also predicted survival. Median was 29.9 months in RPA class I, 4.2 months in class II, and 2.1 months in class III (). Median was not reached for DS-GPA class I, 4.4 months for class II, 3.7 months for class III, and 2.3 months for class IV (). In the multivariate analyses mentioned above only RPA and primary tumour type remained statistically significant.
Few if any patients with brain metastases would be willing to participate in a randomised trial examining the impact of different waiting times on outcomes after WBRT. In the absence of such trials, the present retrospective intention-to-treat analysis provides interesting results. As shown in Table 2, the data do not suggest that moderately delayed WBRT compromises survival for the majority of patients. Whether or not other endpoints such as neurological function status, steroid dependency or patient reported quality of life might be compromised is currently unknown and cannot be examined retrospectively. Given that extended waiting times are unlikely to provide any medical advantage, efforts should be undertaken to minimise delay between diagnosis and WBRT. Our data suggest that it might be justified to prioritise patients without extracranial metastases in cases where departmental waiting lists cannot be avoided, with the reason being that untreated brain metastases might shorten survival in patients who are not immediately threatened by progression in extracranial sites. However, it must be acknowledged that other parameters might also be important. Such parameters might include neurological function, symptom burden, mass effect, or intracranial tumour volume. Due to a lack of recording in our database we were unable to include any of them. Regarding further potential shortcomings of this study, one should be aware of its retrospective nature and the limited patient numbers.
The major reason for variable waiting times in the present patient population was limited capacity at the treating institutions, but the magnitude of this problem was not constant over time and impacted patients quite randomly. For each given year, seasonal variations, machine maintenance, and breakdown episodes occurred. Occasionally, delayed WBRT was caused by unexpected intercurrent comorbid conditions or patient request. Even during time periods with heavy workload and longer waiting lists, doctors could influence to some degree whether a given patient started WBRT rapidly because a certain number of emergency slots existed. If doctors are effective at distinguishing between more and less aggressive disease states, the impact of waiting time on outcomes might be diminished. These considerations might also explain why some studies on delay of postoperative radiotherapy for glioblastoma described a correlation between longer waiting time and decreased survival while others did not . A combined analysis suggested that moderate wait periods (up to 4–6 weeks) are safe , but these data are difficult to compare with ours (unresected brain metastases).
In a previous study by Lutterbach et al. waiting time was examined only for patients who underwent biopsy or resection before WBRT . Median delay was 13 days, but time from initial imaging diagnosis was not reported. Impact on survival was not analysed either. In a recent randomised trial of WBRT with or without motexafin gadolinium, the median time from brain metastasis diagnosis to randomisation was 15 days . Median interval to neurologic progression was 10 months (delay 2 weeks or less) versus 8.8 months (delay 2–4 weeks) in the WBRT arm alone. Neither significance of this difference nor survival outcomes for different magnitudes of delay were reported. We were unable to identify more reports focussing on impact of waiting time. Danjoux et al. reported that initiation of a rapid response radiotherapy program was effective in reducing waiting time for palliative radiotherapy . Impact of waiting time on survival was not analysed in detail. Whether or not waiting time compromises outcome might depend on primary tumour type, its biological behaviour, and related differences in growth rate or doubling time. In patients with nonsmall cell lung cancer waiting for stereotactic radiotherapy, only 23% of tumours did not show volume increase during waiting times >25 days . In squamous cell head and neck cancer, 62% of cases had measurable increase in tumour volume before radiotherapy, median 46% (median interval between imaging studies 28 days) . Other tumours might grow less rapidly. However, for individual patients prediction is often difficult if not impossible. Indirectly, longitudinal studies such as those in lung and head and neck cancer, provide arguments against waiting times in excess of 2-3 weeks. Regarding brain metastases, there is a need to perform further analyses, for example, based on published randomised studies that included prospective documentation of endpoints other than survival and larger groups of patients.
Conflict of Interest
Conflict of interests does not exist.
- E. Rosenblatt, J. Izewska, Y. Anacak, et al., “Radiotherapy capacity in European countries: an analysis of the Directory of Radiotherapy Centres (DIRAC) database,” The Lancet Oncology, vol. 14, no. 2, pp. e79–e86, 2013.
- M. R. Lavergne, G. M. Johnston, J. Gao, T. J. B. Dummer, and D. E. Rheaume, “Variation in the use of palliative radiotherapy at end of life: examining demographic, clinical, health service, and geographic factors in a population-based study,” Palliative Medicine, vol. 25, no. 2, pp. 101–110, 2011.
- W. Kong, C. R. Jarvis, D. S. Sutton, K. Ding, and W. J. Mackillop, “The use of palliative whole brain radiotherapy in the management of brain metastases,” Clinical Oncology, vol. 24, no. 10, pp. e149–e158, 2012.
- M. N. Tsao, D. Rades, A. Wirth, et al., “International practice survey on the management of brain metastases: third international consensus workshop on palliative radiotherapy and symptom control,” Clinical Oncology, vol. 24, no. 6, pp. e81–e92, 2012.
- D. Rades, S. Kieckebusch, R. Lohynska et al., “Reduction of overall treatment time in patients irradiated for more than three brain metastases,” International Journal of Radiation Oncology, Biology, Physics, vol. 69, no. 5, pp. 1509–1513, 2007.
- R. E. Langley, R. J. Stephens, M. Nankivell, et al., “Interim data from the Medical Research Council QUARTZ trial: does whole brain radiotherapy affect the survival and quality of life of patients with brain metastases from non-small cell lung cancer?” Clinical Oncology, vol. 25, pp. e23–e30, 2013.
- C. Nieder, J. Norum, A. Dalhaug, G. Aandahl, and A. Pawinski, “Radiotherapy versus best supportive care in patients with brain metastases and adverse prognostic factors,” Clinical & Experimental Metastasis, 2013.
- J. Lutterbach, S. Bartelt, F. Momm, G. Becker, H. Frommhold, and C. Ostertag, “Is older age associated with a worse prognosis due to different patterns of care? A long-term study of 1346 patients with glioblastomas or brain metastases,” Cancer, vol. 103, no. 6, pp. 1234–1244, 2005.
- C. Nieder, A. Pawinski, and M. Molls, “Prediction of short survival in patients with brain metastases based on three different scores: a role for ‘triple-negative’ status?” Clinical Oncology, vol. 22, no. 1, pp. 65–69, 2010.
- L. Gaspar, C. Scott, M. Rotman et al., “Recursive Partitioning Analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials,” International Journal of Radiation Oncology, Biology, Physics, vol. 37, no. 4, pp. 745–751, 1997.
- P. W. Sperduto, N. Kased, D. Roberge, et al., “Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases,” Journal of Clinical Oncology, vol. 30, no. 4, pp. 419–425, 2012.
- M. Jackson, S. Bydder, E. Maujean, M. Taylor, and A. Nowak, “Radiotherapy in the management of high-grade gliomas diagnosed in Western Australia: a patterns of care study,” Journal of Medical Imaging and Radiation Oncology, vol. 56, no. 1, pp. 109–115, 2012.
- Y. R. Lawrence, D. T. Blumenthal, D. Matceyevsky, A. A. Kanner, F. Bokstein, and B. W. Corn, “Delayed initiation of radiotherapy for glioblastoma: how important is it to push to the front (or the back) of the line?” Journal of Neuro-Oncology, vol. 105, no. 1, pp. 1–7, 2011.
- M. P. Mehta, W. R. Shapiro, S. C. Phan et al., “Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial,” International Journal of Radiation Oncology, Biology, Physics, vol. 73, no. 4, pp. 1069–1076, 2009.
- C. Danjoux, E. Chow, A. Drossos et al., “An innovative rapid response radiotherapy program to reduce waiting time for palliative radiotherapy,” Supportive Care in Cancer, vol. 14, no. 1, pp. 38–43, 2006.
- T. Murai, Y. Shibamoto, F. Baba, et al., “Progression of non-small cell lung cancer during the interval before stereotactic body radiotherapy,” International Journal of Radiation Oncology, Biology, Physics, vol. 82, no. 1, pp. 463–467, 2012.
- A. R. Jensen, H. M. Nellemann, and J. Overgaard, “Tumor progression in waiting time for radiotherapy in head and neck cancer,” Radiotherapy and Oncology, vol. 84, no. 1, pp. 5–10, 2007.