Clinical Research Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India
* Correspondence to: Dr T. Gupta, Clinical Research Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410208, India. Tel: +91-22-27405057; Fax: +91-22-27412894; E-mail: tejpalgupta{at}rediffmail.com
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Abstract |
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Key words: brain metastases, HRQoL, stereotactic radiosurgery
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Introduction |
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Design |
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Results |
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Level I evidence
The first randomized trial [14] evaluating the role of SRS boost in patients with two to four metastases was stopped at an interim analysis at 60% accrual, due to significant benefit in local control for the radiosurgery arm. Twenty-seven patients were randomized (14 to WBRT alone and 13 to WBRT plus SRS). Both groups were balanced for known prognostic factors. The rate of local failure at 1 year was 100% for WBRT alone compared with only 8% for SRS (P = 0.0005). The median time to local failure as well as any brain failure was less for the radiosurgery arm (P = 0.002). Progression of brain disease did not correlate with the number of metastases detected initially and the presence of active systemic disease outside the brain also did not correlate with brain control. No significant difference in overall survival was noted between the two arms (11 and 7.5 months in the SRS boost and WBRT alone arm, respectively; P = 0.22). Few patients in the WBRT alone arm had delayed radiosurgery at the time of progression and their outcome was similar to patients treated with SRS boost upfront. Health-related quality of life (HRQoL) parameters such as improvement in neurologic functioning or activities of daily living were not recorded.
In a larger three-arm prospective trial [15], Chogule et al. randomized 109 patients with brain metastasis to Gamma-Kinfe (GK) radiosurgery alone (36 patients; 30 Gy to tumor margin), WBRT alone (31 patients; 30 Gy/10#), or both (37 patients; 30 Gy/10# WBRT followed by 20 Gy to tumor margin with GK). Patients were stratified by primary tumor site. Surgical decompression of large, symptomatic lesions was undertaken in 51 patients prior to randomization and these were not evenly distributed in the three arms. The overall median survival was 7, 5 and 9 months for the GK, GK + WBRT, and WBRT arms, respectively. The local control was 87%, 91% and 62% for GK, GK + WBRT, and WBRT alone arms, respectively, suggesting that the two radiosurgery arms were superior. However, the occurrence of new brain lesions was lower (43%, 19% and 23% for GK, GK + WBRT, and WBRT alone, respectively) in the two arms receiving WBRT. Regardless of treatment group, the local control and survival for patients who had surgical resection of brain metastases was 88% and 9 months, compared with 73% and 6 months for those without resection suggesting some benefit of surgery. This survival benefit for surgery was not seen in patients who received GK radiosurgery as part of their treatment.
A larger recently published trial (RTOG 95-08) [16] provides compelling evidence for the use of SRS boost following WBRT in patients with newly diagnosed one to three brain metastases with good performance status. In all, 331 patients were randomized, 167 to WBRT alone and 164 to WBRT plus SRS boost. Once again, the prognostic factors were well balanced in the two arms, with the patients being stratified by number of metastases and status of extracranial disease. RPA class 3 was an exclusion criterion. On an intention-to-treat analysis, SRS boost provided a survival benefit over WBRT alone for patients with single brain metastasis (P = 0.0393); one to three metastases and RPA class 1 (P = 0.0453); largest tumor >2 cm (P = 0.0449); and non-small-cell lung cancer/any squamous carcinoma (P = 0.05). In single brain metastasis, the median survival improved from 4.9 months to 6.5 months with SRS regardless of the RPA class (1 or 2). Conversely, in RPA class 1, there was an improvement in median survival from 9.6 months to 11.6 months with radiosurgery regardless of the number of brain metastases (one to three). More importantly, patients in the radiosurgery arm had significantly better or stable KPS scores at 6 months follow-up than patients in the WBRT alone arm (43% versus 27%, respectively; P = 0.03), and reduced steroid requirements irrespective of the number (one to three) of metastases or the RPA class (1 or 2). All this despite a sizeable number of patients (19%) in the radiosurgery arm not receiving the SRS boost.
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Discussion |
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The Chogule trial [15] was reported in abstract form only and the final results had not been published at the time of writing. Nearly half the patients underwent surgical resection prior to randomization without being stratified for it, confounding the overall outcome. The method of randomization was not stated in the abstract nor was the P value reported for any of the time-to-event analysis. In short, it had all the shortcomings associated with an abstract publication.
The RTOG 95-08 [16], although more robust and better designed, also had confounding factors. Patients who had undergone surgical resection of brain metastasis were eligible for randomization if they had residual disease or a distal lesion. However, they were not stratified for the same. The MRI datasets were available for evaluation in only 40% of the patient population, precluding any definitive imaging-based conclusions. The local control was better in the SRS boost arm, but the overall intracranial control and the neurological death rate was not very different from the WBRT alone arm, implying that neurological progression may not be avoidable with SRS. The KPS was better and steroid dependence less in the SRS boost arm, but there was no difference in the mental status as assessed by the mini-mental state examination (MMSE). Perhaps a better HRQoL tool such as European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ C-30) with the Brain Cancer Module (BCM-20) may have been more applicable in this setting. However, there are practical difficulties in administering such complex questionnaires to sick patients where the completion rates are expected to be low.
Is it value judgement?
In a systematic review and meta-analysis on the radiotherapeutic management of brain metastases, Tsao et al. [17] concluded that the three published randomized controlled trials [14
16
] examining the use of WBRT and SRS boost versus WBRT alone failed to demonstrate any survival benefit for patients with multiple metastases. Purists could argue that in the absence of a survival benefit in patients with two or three metastases, SRS investigations should be considered and its advisability in terms of its real impact on the patient preferences, health economic considerations and local logistics of the treating institution should be re-examined. However, HRQoL assessment is even more relevant in determining treatment benefit when survival advantage is limited and other aspects of the patient's life are more important. Hence, patients with limited life expectancy such as with brain metastases could gain substantially from new treatments based on robust HRQoL outcomes, which would help the patient as well as the clinician in decision-making.
Is this the last word?
There is no head-to-head comparison of radiosurgery with neurosurgery in resectable single metastasis. Retrospective series and prospective single-arm studies of SRS for single brain metastasis have shown local control and survival outcomes comparable to surgical resection. A large multi-institutional retrospective study [18] analyzed 122 patients with resectable single brain metastasis treated by SRS and WBRT. The local tumor control was 86% and median overall survival was 56 weeks, which was comparable to the surgery and WBRT arm of a previous randomized trial [8
] conducted in a similar cohort of patients. More recently, a study compared the outcome of patients with solitary brain metastasis who were treated with either radiosurgery (n = 23) or neurosurgery (n = 74) at the same institution [19
]. Patients were included for analysis if tumor size and site would have allowed either type of treatment. There were no significant differences in the 1-year survival between the two groups (56% and 52%, respectively). Radiosurgery as a minimally invasive technique that avoids open brain exposure and neuro-anesthesia, allows faster recovery, is more cost-effective [20
] and could be a potential alternative to open craniotomy [11
]. With the advent of better imaging sciences, SRS could have the added advantage of more complete treatment of the entire tumor bed than is afforded by the surgeon's intraoperative assessment of gross tumor resection. Nevertheless, in certain clinical situations it may be preferable to offer neurosurgical resection over SRS. It would be naïve not to attempt surgical decompression in a patient with a solitary resectable brain metastasis with significant mass effect. Surgery is also more effective in relieving mass effect in cystic and/or hemorrhagic brain metastasis. It could also establish unequivocal tissue diagnosis and guide adjuvant therapy in patients with radiologically documented brain metastases and negative systemic evaluation. But in patients with resectable single metastasis with minimal or no mass effect, it may be worthwhile to attempt such a comparison in a randomized controlled setting to better define the role of SRS in that subset. For patients with two to three metastases, selection for SRS should take into account established prognostic indices such as RPA [5
] class, as well as the Score Index for Radiosurgery in Brain Metastases (SIR-BM) [21
].
Future direction
Upfront SRS alone in patients with single brain metastasis, keeping WBRT and/or a repeat radiosurgery reserved for a second CNS relapse, could also be considered in appropriately selected patients [22]. There is an ongoing debate on the role of WBRT after radiosurgery. Some investigators advocate the omission of WBRT as initial treatment for patients with newly diagnosed brain metastases, whereas others argue in favor of adjuvant WBRT.
The preliminary report of a phase II trial [23] of SRS alone for one to three newly diagnosed brain metastases from relatively radioresistant tumors showed that median survival with SRS alone was comparable to published surgical and concurrent SRS + WBRT series and better than WBRT alone. In the 32 eligible patients, the median survival was 8.3 months at a median follow-up of 25 months. The 3 and 6 months in-field failure rate was 28% and 45%, respectively. In contrast, the failure rate outside the radiosurgery volume was 4% and 17% at 3 and 6 months, respectively. Grade 3 or greater acute CNS toxicity was seen in <10% of patients. Another multi-institutional trial [24
] compared radiosurgery with radiosurgery and WBRT randomized patients with one to four brain metastases to SRS alone (61 patients) or SRS plus WBRT (59 patients). In an interim analysis with a median follow-up duration of 6 months, the acturial 1-year survival was 26% in the SRS alone arm versus 39% in the SRS + WBRT arm (P = 0.58). However, the 6-month freedom from new brain metastases was significantly better with the addition of WBRT (49% in SRS alone versus 82% in SRS + WBRT; P = 0.003) as was the local control (70% versus 88%, respectively; P = 0.019). The American College of Surgical Oncology (ACOSOG) is currently randomizing patients with one to three newly diagnosed brain metastases to receive SRS alone or SRS plus WBRT with survival, local control, HRQOL, cognitive functioning and functional independence as end points [25
]. Another randomized phase III trial currently in progress (EORTC protocol 22952-26001) is investigating the effects of WBRT versus the omission of WBRT after focal therapy (surgery or radiosurgery) in patients with one to three brain metastases, good performance status and controlled systemic cancer. A follow-up trial on the RTOG 95-08 is exploring the use of promising enhancers of radiation by randomizing patients with non-small-cell lung cancer and one to three brain metastases to one of the three arms: (1) WBRT + SRS boost, (2) WBRT + SRS boost + temozolomide or (3) WBRT + SRS boost + gefitinib (an epidermal growth factor receptor tyrosine kinase inhibitor, a potent radiosensitizer).
The neuro-oncology community needs to clearly define selection criteria for the use of SRS in brain metastases based on measurable improvement in functional capacity, HRQoL and survival. In recent times evidence-based algorithms have been proposed for the use of radiosurgery for patients with newly diagnosed brain metastases or recurrent brain metastases either alone or in conjunction with WBRT [26, 27
]. However, the timing of radiosurgery is yet to be defined optimally [28
]. Whether SRS should be used as boost with WBRT, at the time of relapse after WBRT, or alone, reserving WBRT for progressive brain disease still remains unanswered and is prone to personal and institutional bias.
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Conclusions |
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Received for publication March 27, 2005. Revision received June 21, 2005. Accepted for publication June 27, 2005.
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References |
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2. Clouston PD, DeAngelis LM, Posner JB. The spectrum of neurological disease in patients with systemic cancer. Ann Neurol 1992; 31: 268273.[CrossRef][ISI][Medline]
3. Delattre JY, Krol G, Thaler HT et al. Distribution of brain metastases. Arch Neurol 1988; 45: 741744.[Abstract]
4. Sperduto PW. A review of stereotactic radiosurgery in the management of brain metastases. Technol Cancer Res Treat 2003; 2: 105110.[ISI][Medline]
5. Gaspar L, Scott C, Rotman M et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745751.[CrossRef][ISI][Medline]
6. Borgelt B, Gelber R, Kramer S et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980; 6: 19.[ISI][Medline]
7. Cairncross JG, Kim JH, Posner JB. Radiation therapy for brain metastases. Ann Neurol 1980; 7: 529541.[CrossRef][ISI][Medline]
8. Patchell RA, Tibbs PA, Walsh JW et al. A randomized trial of surgery in the treatment of single brain metastases to the brain. N Engl J Med 1990; 322: 494500.[Abstract]
9. Noordijk EM, Vecht CJ, Haaxme-Reiche H et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994; 29: 711717.[ISI][Medline]
10. Patchell RA. The management of brain metastases. Cancer Treat Rev 2003; 29: 533540.[CrossRef][ISI][Medline]
11. Boyd TS, Mehta MP. Stereotactic radiosurgery for brain metastases. Oncology 1999; 13: 13971409.[Medline]
12. Leskell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 1983; 46: 797803.[Abstract]
13. Sanghavi SN, Miranpuri SS, Chapell R et al. Radiosurgery for patients with brain metastasis: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys 2001; 51: 426434.[CrossRef][ISI][Medline]
14. Kondziolka D, Patel A, Lunsford D et al. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999; 45: 427434.[ISI][Medline]
15. Chogule PB, Burton-Willaims M, Saris S et al. Randomized treatment of brain metastasis with gamma knife radiosurgery, whole brain radiotherapy, or both. Int J Radiat Oncol Biol Phys 2000; 48: 114 (Abstr).
16. Andrews DW, Scott CB, Sperduto PW et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 95-08 randomized trial. Lancet 2004; 363: 16651672.[CrossRef][ISI][Medline]
17. Tsao MN, Lloyd NS, Wong RKS et al. Radiotherapeutic management of brain metastases: A systematic review and meta-analysis. Cancer Treat Rev 2005; in press [available online 20 June 2005].
18. Auchter RM, Lamond JP, Alexander E et al. A multi-institutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996; 35: 2735.[CrossRef][ISI][Medline]
19. O'Neill BP, Iturria NJ, Link MJ et al. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastasis. Int J Radiat Oncol Biol Phys 2003; 55: 11691176.[CrossRef][ISI][Medline]
20. Mehta M, Noyes W, Craig B et al. A cost-effectiveness and cost-utility analysis of radiosurgery verssus resection for single brain metastasis. Int J Radiat Oncol Biol Phys 1997; 39: 445454.[CrossRef][ISI][Medline]
21. Weltman E, Salvajoli JV, Brandt RA et al. Radiosurgery for brain metastases: A score index for predicting prognosis. Int J Radiat Oncol Biol Phys 2000; 46: 11551161.[CrossRef][ISI][Medline]
22. Sneed PK, Such JH, Goetsch SJ et al. A multi-institutional review of radiosurgery alone versus radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 2002; 53: 519526.[CrossRef][ISI][Medline]
23. Manon RR, Oneill A, Mehta M et al. Phase II trial of radiosurgery (RS) for 1 to 3 newly diagnosed brain metastases from renal cell, melanoma, and sarcoma: An Eastern Cooperative Oncology Group study (E6397). J Clin Oncol 2004; 22 (14S): 108s (Abstr 1507).[CrossRef]
24. Aoyama H, Shirato H, Nakagawa K et al. Interim report of the JROSG99-1 multiinstitutional randomized trial, comparing radiosurgery alone vs radiosurgery plus whole brain irradiation for 14 brain metastases. Proc Am Soc Clin Oncol (abstr) J Clin Oncol 2004; 22 (14S): 108s (Abstr 1506).[CrossRef]
25. American College of Surgical Oncology (ACOSOG). Phase III randomized study of radiosurgery with or without whole brain radiotherapy in patients with one to three cerebral metastases (ACOSOG Z0300). Available at http://www.acosog.org/studies/synopses/Z0300_synopsis.pdf.
26. Warnick RE, Darakchiev BJ, Breneman JC. Stereotactic radiosurgery for patients with solid brain metastases: current status. J Neuro-Oncol 2004; 69: 125137.[CrossRef][ISI][Medline]
27. Kaal ECA, Niel CGJH, Vecht CJ. Therapeutic management of brain metastasis. Lancet Neurol 2005; 4: 289298.[CrossRef][ISI][Medline]
28. Tsao MN, Lloyd NS, Wong RKS and the supportive care guidelines group of Cancer Care Ontario's Program in Evidence-based care. Clinical practice guideline on the optimal radiotherapeutic management of brain metastases. BMC Cancer 2005; 5: 34.[CrossRef][Medline]
29. Regine WF, Schmitt FA, Scott CB et al. Feasibility of neurocognitive outcome evaluations in patients with brain metastases in a multi-institutional co-operative group setting: results of Radiation Therapy Oncology Group trial BR0018. Int J Radiat Oncol Biol Phys 2004; 58: 13461352.[CrossRef][ISI][Medline]
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