THE PARAMOUNTCY OF LOCAL CONTROL CHANGES THE PARADIGM

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After the 1990 study by Patchell, which established a survival benefit from resection of a single metastatic lesion to the brain beyond that of WBRT alone, the next logical question was whether or not WBRT is necessary after resection at all. In 1998, in a randomized study, the addition of WBRT after complete tumor resection decreased intracranial failure from 70% to 18% (p < 0.001) and decreased local recurrence from 46% to 10% (p < 0.001).³ Although there was improved survival with the use of WBRT, this was not significant, which is an observation worth noting, with the caveat that this study was not powered to assess a survival benefit. Three major directional thrusts emerged as a consequence of this work: First, in several quarters, WBRT became a routine and accepted standard of care after resection to dramatically and convincingly lower intracranial relapse; second, SRS became widespread as a modality for the local control of at-first limited number of brain metastatic lesions but more recently of multiple lesions; third, the role of WBRT in terms of enhancing local control came under intense scrutiny because of concerns regarding its potential for neurotoxicity and a perceived lack of a survival benefit. The bidirectional evolutionary ramifications of the latter trend were to better understand the mechanisms underlying some of these neurotoxicities and efforts to modulate these through the conduct of innovative clinical trials, as well as to become more selective regarding the application of WBRT primarily for patients who had multiple (with a flexible definition of this concept) brain metastases. This selection often has been in the context of a combined approach with systemic therapeutics, a direction that recently has experienced an upsurge because of the emergence of blood-brain barrier–penetrating agents, primarily in malignancies with driver mutations.

THE EMERGENCE OF RADIOSURGERY AS AN EFFECTIVE LOCAL CONTROL THERAPY

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SRS now has become the most widely used focal treatment modality for patients who have brain metastasis. The efficacy of SRS for brain metastases was first reported in multiple retrospective studies. Sanghavi et al⁴ showed in a retrospective, multi-institutional analysis of 502 patients who were stratified by recursive partitioning analysis (RPA) classes I, II, and III that patients treated with WBRT and SRS compared with WBRT alone had a significant increase in median survival times.⁴ The survival times in classes I, II, and III with the combination versus alone were 16.1 versus 7.1 months, 10.3 versus 4.3 months, and 8.7 versus 2.1 months, respectively (p < 0.05).⁴ RTOG 9508 was a randomized, controlled, phase III trial of 333 patients with one to three brain metastases and a Karnofsky performance score (KPS) of 70 or greater who were treated with WBRT and SRS or WBRT alone.⁵ In patients who had a single brain metastasis, treatment with WBRT and SRS compared with only WBRT resulted in a decreased rate of local recurrence at 1 year (18% vs. 29%; p = 0.01) and superior median survival times (6.5 vs. 4.9 months; p = 0.039). In patients who had two or three brain metastases, local control was significantly improved in the combination arm, but there was no difference in survival time between the two groups. There was an additional benefit in outcomes (maintenance or improvement of KPS and corticosteroid use) in patients who received SRS and WBRT compared with WBRT alone.

The role of SRS alone, without WBRT, was evaluated in subsequent studies. Aoyama et al⁶ published a prospective, phase III trial, JROSG 99-1, that randomly assigned 132 patients (mostly with lung cancer) who had a KPS score of 70 or greater and four or fewer metastases to SRS with or without WBRT. The results showed no survival difference (8.0 months for SRS vs. 7.5 months for SRS with WBRT; p = 0.42); however, the trial was not powered to detect a significant difference in overall survival and, relative to longer-term survival, there was a nonsignificant survival trend in favor of the WBRT arm (1-year survival rates of 38.5% in the group treated with WBRT plus SRS vs. 28.4% for SRS alone).⁶ As anticipated, the study demonstrated that local control rates were improved with the addition of WBRT to SRS, with a 1-year failure rate of 23.6% for SRS and WBRT compared with 53.2% for SRS only (p < 0.001). Two additional randomized trials boosted this data set. The EORTC 22952-26001 study randomly assigned 359 patients to either 30 Gy of WBRT or observation after either surgery or SRS that was performed at the individual discretion of the physicians for patients who had one to three brain metastases. After either surgery or SRS, WBRT was associated with improved local and distant brain control (p < 0.001). More robust intracranial control led to less use of salvage therapies and a slightly longer progression-free survival but had no impact on overall survival or survival with functional independence (the primary endpoint of the study). It is important to note that part of the eligibility for the trial required stable systemic disease or asymptomatic primary tumors, thereby attempting to mitigate the dilution effects of extracranial disease progression on the translation of central nervous system (CNS) control to overall survival, but did not mandate this through systematic restaging. Even so, approximately one-third of patients had extracranial progression, which raises the issue of extracranial death as a competing risk.⁷

Chang et al⁸ performed a phase III study in patients who had one to three brain metastases that compared the approach of combination of SRS and WBRT versus SRS alone (MDACC NCT00460395).⁸ The primary endpoint of this study was neurocognitive function, as measured by the Hopkins Verbal Learning Test-Revised (HVLT-R).⁸ The trial was stopped early after 58 patients were accrued because of a high probability that the SRS-plus-WBRT arm would show a significant decline in learning and memory function (total recall) at 4 months compared with SRS alone. Similar to the previous two studies, there were more CNS recurrences in the group treated with SRS alone; 73% of patients in the SRS-and-WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p = 0.0003). In this trial, the WBRT arm was associated with inferior survival, an issue that has become rather controversial but is most likely explained by maldistribution of patients on this small trial relative to the extent of extracranial disease, a factor that would categorically drive mortality.

EXPANDING THE HORIZONS OF STEREOTACTIC RADIOSURGERY

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Although SRS typically is offered for patients with four or fewer brain metastases, it is increasingly utilized for patients with five or more lesions. A retrospective study showed that the median overall survival in patients with five or more brain metastases was 7.5 months after treatment with SRS.⁹ Interestingly, the number of brain metastases was not a significant predictor of survival, but higher intracranial burden (higher volume of brain metastases within the brain) predicted for poorer outcomes.¹⁰ In a prospective, observational study for one to 10 brain metastases performed in 23 hospitals in Japan, no difference in overall survival was demonstrated in patients who had two to four brain metastases versus five or more brain metastases when treated with SRS alone.¹¹ The median overall survival after SRS was 13.9 months in patients who had a single brain metastasis, 10.8 months in patients who had two to four brain metastases, and 10.8 months in patients who had five to 10 brain metastases. This suggests that SRS may be a reasonable approach in selected patients with up to 10 brain metastases, further broadening the horizon of use of SRS in these patients. This also supports the hypothesis that the volume, and not the number, of metastases may be the driver in determining the outcomes in brain metastases.¹² An ongoing prospective trial, NAGKC 12-01, is comparing the neurocognitive outcomes and survival in patients with five or more brain metastases treated either with SRS or WBRT (NCT01731704); this trial will further define the role of SRS in this patient population.

Another active area of interest is utilization of SRS in lieu of WBRT to prevent local recurrence after resection. Resection bed SRS targeting is more complex because of uncertainties about the interpretation of postoperative MRI. Soltys et al¹³ showed a 1-year local control rate of 94% with the addition of a 2-mm margin around the defined tumor bed versus 78% when there was no margin.¹³ The median overall survival time was 17 months, and 72% of patients were able to avoid WBRT, although intracranial relapse and salvage with other therapies (such as SRS) was required in a substantial proportion of patients. Concerns with this approach include the possibility of leptomeningeal spread secondary to the resection, especially for patients who have breast cancer and those who have posterior fossa disease.¹⁴ The North Central Cancer Treatment Group (NCCTG) study N107C is an ongoing intergroup study of patients who have one to four brain metastases that compares WBRT versus SRS after resection (NCT01372774).

An approach to potentially minimize leptomeningeal spread is to perform neoadjuvant SRS before surgery to sterilize the tumor cells before surgical resection. Neoadjuvant SRS in 47 patients, who were undergoing preoperative SRS with a median dose of 14 Gy (range, 11.8 to 18 Gy), was reported by Asher et al.¹⁵ Surgical resection performed after SRS resulted in control in 86% at 1 year, and only 15% of the patients eventually required WBRT. Significantly, no leptomeningeal failures were observed in this study.

There is no level-1 evidence to support use of SRS in lieu of surgery. More than one randomized effort to answer this question has failed because of poor accrual. In a retrospectively matched series of 75 patients treated by surgery and SRS, a median survival time of 7.5 months with SRS versus 16.4 months in the surgical group was reported.¹⁶ However, the dosing regimen for SRS in this study resulted in the use of lower prescriptions to the tumor margin than would be considered standard according to the widely accepted RTOG dosing schema.^5,17 Auchter et al¹⁸ reported a multi-institutional data set of SRS in 122 highly selected patients who had one resectable brain metastases. The median survival was 56 weeks in this retrospective series, which was comparable to the results of most surgical series.¹⁸ Schoggl et al¹⁹ performed a retrospective case-control analysis with 133 patients who were treated with either SRS (67 patients) or surgery (66 patients) along with WBRT. There was no difference in median survival (SRS vs. surgery, 12 vs. 9 months; p = 0.19), but the local control rate was superior with SRS.¹⁹ In a retrospective study that compared surgery and SRS for the treatment of a solitary brain metastasis, no significant difference was found in patient survival. However, the difference in the local tumor control rate was significant (100% after SRS vs. 58% after surgery).²⁰ Muacevic et al²¹ compared surgery and WBRT with SRS in patients who had single brain metastases.²¹ The approaches—of surgery and WBRT, or of SRS—resulted in similar 1-year survival rates (53% vs. 43%; p = 0.19), 1-year local control rates (75% vs. 83%; p = 0.49), and 1-year neurologic death rates (37% vs. 39%; p = 0.8).

THE ABANDONMENT OF WHOLE-BRAIN RADIOTHERAPY

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The randomized studies discussed above demonstrate that postoperative WBRT clearly improves intracranial control of brain metastases, but they also demonstrate that this benefit has not categorically translated into an overall survival benefit. Further, there are concerns regarding the potential for cognitive decline in patients receiving WBRT. More importantly, there are emerging data presented by Sahgal et al²² showing an overall survival advantage of SRS alone over WBRT (10 vs. 8.2 months) for patients age 50 or younger who have one to four brain metastases, on the basis of a meta-analysis of three phase III studies.²² Collectively, these factors, as well as the ability to salvage intracranial relapses with further application of SRS (an opportunity afforded in abundance by withholding WBRT), recently have led to the wholesale abandonment of WBRT, with its use reserved largely for patients who have multiple brain metastases and are not deemed favorable SRS candidates.

This approach requires thoughtful scrutiny. The analysis by Sahgal et al²² was conducted by merging the EORTC 22952-26001, JROSG99-1, and MDACC NCT00460395 data sets. Collectively, these three trials included patients who had one to four brain metastases, who were treated with SRS with or without WBRT, and who had variable entry criteria for each trial and considerable variability in terms of systemic therapies, enrollment eras, SRS dose, follow-up imaging, and re-treatment considerations. Further, the EORTC trial also included patients undergoing resection at physician discretion. A total of 364 patients is available in this collated data set, of whom 51% (185 patients) were treated with SRS alone and only 19% (69 patients) were younger than age 50. The results demonstrate a curious blend of outcomes; for the post hoc–defined subset of these patients younger than age 50, the overall survival was superior with the SRS-alone arm (10 vs. 8.2 months), but the time to distant brain failure was shorter for patients older than age 55 who were treated with SRS alone (4.5 vs. 6.5 months). The time to local failure was superior with the use of WBRT (7.4 vs. 6.6 months). Crucially, it is important to recognize that the recommendation regarding the survival gain in the younger patient category with SRS alone is based on approximately 35 patients per arm and on a post hoc analysis of a cohort in which the pre-enrollment balance regarding the extent of systemic disease could not be assured, because structured pre-SRS staging—a necessary element for assessing overall survival as an endpoint to avoid systemic burden as a confounder—was not performed.

Therefore, it is reasonable to hypothesize that, in reality, the survival benefit from WBRT is likely limited primarily to patients who do not experience extracranial disease progression. Unless this question is studied in such an enriched cohort, most other studies would likely remain significantly underpowered to demonstrate a survival advantage. In fact, as early as 1998, Pirzkall et al²³ reported on a 236-patient retrospective cohort and found a trend toward improved longer-term survival in favor of SRS plus WBRT (actuarial 1- and 2-year survival rates: 30% and 14% vs. 19% and 8%). More importantly, for patients without extracranial disease, the median survival was impressively (but not significantly) different at 15.4 vs 8.3 months (p = 0.08) in favor of WBRT.²³ More recently, Wang et al²⁴ retrospectively reviewed a 528-patient database (lung cancer, 257 patients; breast cancer, 102 patients; melanoma, 62 patients; renal cell carcinoma, 40 patients) from Columbia University; patients were treated between 1998 and 2013 with SRS alone (206 patients), with SRS and WBRT (111 patients), with resection followed by SRS (109 patients), or with all three modalities (102 patients). The overall median survival was 16.6 months; for patients who had a single brain metastasis, the median survival times after SRS, SRS plus WBRT, SRS plus resection, and all three modalities were 9.0, 19.1, 25.5, and 25.0 months, respectively. Even for patients who had more than one metastasis, the corresponding median survival times were 8.6, 20.4, 20.7, and 24.5 months, respectively, which demonstrated the survival inferiority of SRS alone as a modality in this cohort. This inferiority associated with the use of SRS alone as a modality was validated in a multivariate analysis.²⁴

The data that call the meta-analysis by Sahgal et al²² most into question, however, come from one of the key sources used within that analysis, JROSG 99-1. At the JASTRO 2014 annual meeting, Aoyama et al (personal communication, March 2015, quoted with permission) presented their own reanalysis of this study, using the now widely accepted disease-specific Graded Prognostic Assessment (ds-GPA), a prognostic stratification tool.²⁵ Because the ds-GPA relies on molecular variables for stratifying patients who have breast cancer, information that was not collected on JROSG 99-1, these patients could not be adequately categorized and were excluded; 88 (of the 132 total enrolled patients) patients who had non–small cell lung cancer were grouped into favorable (ds-GPA of 2.5 to 4; 47 patients) and unfavorable (ds-GPA of 0.5 to 2; 41 patients) categories. The median survival time was 16.7 versus 10.6 months in favor of the WBRT arm over SRS alone (p = 0.03) for the favorable group, but a similar survival improvement was not observed in the unfavorable group (personal communication, March 2015, quoted with permission). This lends credence to the hypothesis that in patients with a high ds-GPA category, improved brain control translates to a survival advantage because these patients do not die as rapidly from extracranial progression. Therefore, the beneficial effects of improved brain control from WBRT actually affect overall survival. This is quite contrary to the current wisdom of reserving WBRT only for the prognostically least-favorable group of patients. This issue, therefore, remains unresolved.

THE ELEPHANT IN THE ROOM: NEUROCOGNITIVE ISSUES

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Diffuse radiographic periventricular white matter changes (leukoencephalopathy) after cranial radiation have been well described and occur at a far higher frequency with WBRT than with SRS.²⁶ The pathogenesis and clinical relevance of this difference, however, is not well established. In contrast, neurocognitive dysfunction after cranial radiation is multifactorial and is typically mild to moderate in most people; however, this remains one of the most distressing side effects of WBRT and often is the rationale for not utilizing it. However, the clinical results with and without WBRT, in the context of SRS, remain mixed. As mentioned previously, Chang et al⁸ demonstrated a decline in HVLT-DR associated with WBRT. Aoyama et al,⁶ in contrast, demonstrated that progressive disease has a greater impact than WBRT in terms of cognitive decline, with patients who receive SRS alone experiencing a faster decline in scores of the mini mental status examination.^6,8 The NCCTG, in concert with NRG Oncology, recently has completed accrual to a phase III trial (N0574) comparing SRS versus SRS followed by WBRT for patients who have one to three brain metastases, with built-in early cognitive change as an endpoint. Results are pending.

Mitigation of cognitive dysfunction, therefore, has become an important research direction. The RTOG performed two studies to try to modulate this side effect. In the study RTOG 0614, patients were randomly assigned to receive memantine, an NMDA receptor agonist, versus placebo.²⁷ The patients in the memantine arm had a significantly longer time to cognitive decline (p = 0.02). The median decline on HVLT-R scale was 0 in the memantine arm compared with −2 in the placebo arm (p = 0.059). Fewer patients treated with memantine had a decline in the Controlled Oral Word Association test at 16 weeks (p = 0.004) or in the Trail-Making test part A at 24 weeks (p = 0.014).

Hippocampal neural stem cell injury from irradiation during WBRT may play a role in memory decline, primarily by shifting the stem cell maturation cycle from neurogenesis to gliogenesis, a phenomenon that is well established in preclinical models.^28,29 In a prospective human study, a strong association with increasing hippocampal radiation dose and neurocognitive dysfunction was demonstrated.³⁰ Intensity-modulated radiotherapy can be used to conformally avoid the hippocampal neural stem cell compartment during WBRT (HA-WBRT). This hypothesis was tested in a single-arm phase II study of HA-WBRT for brain metastases that used a prespecified comparison with a historic control of patients treated with WBRT without hippocampal avoidance (RTOG 0933).³¹ The primary endpoint was change in HVLT-DR measured at 4 months. The historic control (without hippocampal avoidance) resulted in a 30% mean relative loss in HVLT-DR from baseline to 4 months. The actual observed mean relative decline in HVLT-DR from baseline to 4 months was, in fact, only 7.0%, which was significantly lower than the historic control of 30% (p = 0.0003). No decline in quality-of-life scores up to 6 months was seen.³¹ These observations now form the basis of two newer phase III trials, NRG CC 001 and CC 002.

CONCLUSION

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The management of brain metastases has evolved over the years from palliation to an era of exciting active research. Local therapies (WBRT, SRS) are important modalities in the management of brain metastases. Areas of active investigation include techniques to preserve neurocognitive function with radiotherapy. The optimal management strategy for these patients involves a multidisciplinary approach that accounts for individual characteristics of both the patient and the tumor. A number of ongoing prospective clinical trials will help further define the role and application of WBRT and SRS in the management of brain metastases.

Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.

Employment: None. Leadership Position: Minesh P. Mehta, Pharmacyclics. Stock or Other Ownership Interests: Minesh P. Mehta, Pharmacyclics. Honoraria: Minesh P. Mehta, Ca Progress, Elekta, Research to Practice, Serono Foundation. Manmeet S. Ahluwalia, Elekta, Sigma-Tau. Consulting or Advisory Role: Minesh P. Mehta, Abbvie, Best Medical Opinion, BMS, Celldex, GLG, MedaCorp, Medical Director Solutions, Novelos, Novocure, Philips Healthcare, Roche/Genentech, Strategic Edge, US Oncology Ask The Expert. Manmeet S. Ahluwalia, Genentech/Roche, Monteris Medical, Novocure. Speakers' Bureau: Manmeet S. Ahluwalia, Sigma-Tau. Research Funding: Minesh P. Mehta, Novelos (Inst), Novocure (Inst). Manmeet S. Ahluwalia, Boehringer Ingelheim, Lilly/ImClone, Novartis, Novocure, Spectrum Pharmaceuticals, TRACON Pharma. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Manmeet S. Ahluwalia, Elekta. Other Relationships: None.