NcXHF

MEHTA AND AHLUWALIA
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 benefıt 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 signifıcantly
underpowered to demonstrate a survival
advantage. In fact, as early as 1998, Pirzkall et al 23 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 signifıcantly) different at 15.4 vs 8.3 months
(p 0.08) in favor of WBRT. 23 More recently, Wang et al 24
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 al 22
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-specifıc Graded Prognostic Assessment
(ds-GPA), a prognostic stratifıcation 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 benefıcial 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
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 al 8 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 signifıcantly
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 preclin-
e102
2015 ASCO EDUCATIONAL BOOK | asco.org/edbook