Treatment/Prognosis

Question 1

What is the MS time for RTOG RPA classes I, II, and III?

Answer 1

MS according to the RTOG brain met RPA:

Class I: 7.2 mos

Class II: 4.2 mos

Class III: 2.3 mos

Question 2

What is the Sperduto Index?

Answer 2

The Sperduto Index is a graded prognostic assessment based on age, KPS, # of brain mets, and the presence or absence of extracranial mets developed from an analysis of 1,960 pts in the RTOG database. Criteria is based on a point system:

0 points: age >60 yrs, KPS <70, >3 brain mets, presence of extracranial mets

0.5 points: age 50–59 yrs, KPS 70–80, 2 CNS mets

1 point: age <50 yrs, KPS 90–100, 1 CNS met, no extracranial mets

The sum of points predicts MS in mos:

0–1 point: 2.6 mos

1.5–2.5 points: 3.8 mos

3 points: 6.9 mos

3.5–4 points: 11 mos

(Sperduto P et al., IJROBP 2007)

Question 3

What is the Diagnosis Specific Graded Prognostic Assessment (DS-GPA)?

Answer 3

The DS-GPA is a graded prognostic assessment developed from a retrospective database of 4,259 eligible pts from 11 institutions with determination of significant prognostic factors based on the primary histology. (Sperduto P et al., IJROBP 2010)

Question 4

What are the significant prognostic factors of DS-GPA?

Answer 4

The significant prognostic factors vary by Dx:

Non-small cell lung cancer (NSCLC)/small cell lung

cancer: age, KPS, presence of extracranial mets and number of brain mets

Renal cell/melanoma: KPS and the number of brain mets

Breast/GI: KPS

Question 5

In pts with untreated brain mets, what is the MS?

Answer 5

MS of untreated brain mets is 1 mo.

Question 6

What Tx may be used for brain mets?

Answer 6

Brain met Tx: steroids, Sg, fractionated RT (WBRT), and SRS

Question 7

In pts with brain mets treated with steroids alone, what is the MS?

Answer 7

MS in pts with brain mets treated with steroids alone is 2 mos.

Question 8

What randomized data investigated pt survival or QOL with the addition of WBRT to best supportive care?

Answer 8

The completed MRC Quartz trial was a randomized, noninferiority phase III trial investigating the role of optimal supportive care (OSC) + WBRT (4 Gy × 5 fx) vs. OSC alone in pts with inoperable brain mets from NSCLC. The primary outcome measure was quality-adjusted life yrs (QALY). The trial did not show a difference in QALY with the addition of WBRT to OSC—though conclusions related to the specific population examined in the trial. (Mulvenna P et al., Lancet 2016)

Question 9

What are some criticisms of the QUARTZ trial?

Answer 9

Potential bias toward enrollment of pts with poor PS (40% with KPS <70), and perceived shorter life expectancy, as MS was ∼2 mos compared to historical WBRT trials of ∼4 months. Additionally, the WBRT dose/fractionation scheme is not routinely used in pts with perceived longer life expectancy, also suggesting there may have been a bias toward pts with shorter life expectancy/poor PS.

Question 10

Why are steroids used for brain mets and how are they typically prescribed?

Answer 10

In pts with symptomatic brain mets, steroids reduce leakage from tumor vessels, therefore decreasing edema and mass effect. Steroid dose for newly diagnosed brain mets: 4 mg dexamethasone q6hrs; may give initial loading dose of 10 mg. Other dosing regimens, such as dexamethasone 8 mg BID, are occasionally used to simplify dose scheduling. Moving the last dose to early afternoon or evening can sometimes help mitigate the insomnia side effect.

Question 11

What pharmacologic Tx should always accompany steroid Tx?

Answer 11

When prescribing steroids, also provide GI prophylaxis with a proton-pump inhibitor or H2 blocker.

Question 12

Should anticonvulsants be used prophylactically?

Answer 12

No. In accordance with guidelines from the American Academy of Neurology, pts with newly diagnosed brain tumors should not be started on prophylactic anticonvulsants. (Glantz M et al., Neurology 2000) The 2010 guidelines from the American Association of Neurological Surgeons/Congress of Neurological Surgeons do not recommend routine prophylactic use of anticonvulsants. (Mikkelsen T et al., J Neurooncol 2010)

Question 13

Are there any randomized data on the dose for WBRT?

Answer 13

Yes. The RTOG conducted several RCTs from 1970–1995 of WBRT alone, assessing different fractionation schemes. The 1st 2 trials (RTOG 6901 and 7361) included >1,800 pts randomized to 40 Gy/20, 40 Gy/15, 30 Gy/15, 30 Gy/10, or 20 Gy/5. No significant difference was found in response rates, length of response, or OS. The MS in the 1st study was 4.1 mos and 3.4 mos in the 2nd. (Borgelt B et al., IJROBP 1980)

2 ultrarapid fractionation schemes were also tested on these studies and reported separately; 10 Gy/1 (RTOG 6901) and 12 Gy/2 (RTOG 7361) in 26 and 33 pts, respectively. These schedules were associated with worse toxicity and time to neurologic progression than the standard fractionation. (Borgelt B et al., IJROBP 1981)

2 studies showed no MS advantage to giving a higher total dose. RTOG 7606 randomized 255 pts to 30 Gy/10 vs. 50 Gy/20. MS was 4.1 and 3.9 mos, respectively. (Kurtz J et al., IJROBP 1981) RTOG 9104 randomized 429 pts to 30 Gy/10 vs. 54.4/1.6 Gy bid. MS was 4.5 mos in both arms. (Murray K et al., IJROBP 1997)

Question 14

What dose and fractionation schemes are considered standard for WBRT?

Answer 14

The most commonly utilized WBRT dose is 30 Gy/10. Pts with a good KPS and longer life expectancy may be treated to 37.5 Gy/15, 40 Gy/20, or 50 Gy/20. An alternative is 20 Gy/5 fx, particularly for pts with short prognosis

Question 15

What % of brain met pts have Sx improvement with WBRT?

Answer 15

WBRT improves Sx from brain mets in ∼60% of cases.

Question 16

What is the rate of CR to WBRT for brain mets?

Answer 16

∼25% of pts have a CR to WBRT for brain mets.

Question 17

What data support Sg + RT rather than Bx + RT for brain mets?

Answer 17

The 1st Patchell study for brain mets randomized 48 pts with 1 brain met and KPS ≥70 to Sg + WBRT vs. Bx + WBRT. WBRT in both arms was 36 Gy in 3 Gy/fx. Pts treated with Sg had a longer MS (40 wks vs. 15 wks, p <0.01), longer functional independence (38 wks vs. 8 wks), and ↓LR (20% vs. 52%, p <0.02). (Patchell R et al., NEJM 1990)

Question 18

Did the Netherlands trial of WBRT +/- Sg support or refute the Patchell study?

Answer 18

The Noordijk study supported the findings of the 1st Patchell study. It randomized 63 pts to WBRT alone or Sg + WBRT. WBRT was 40 Gy in 2 Gy bid fx. Pts treated with Sg had improved MS (10 mos vs. 6 mos, p = 0.04) and longer functional independence (7.5 mos vs. 3.5 mos, p = 0.06). (Noordijk E et al., IJROBP 1994)

Question 19

Does adj WBRT after surgical resection of a brain met improve OS?

Answer 19

No. Postop WBRT following resection of a brain met does not improve survival. In the 2nd Patchell study for brain mets, 95 pts following surgical resection of a single met were randomized to no further Tx or WBRT (50.4 Gy in 1.8 Gy/fx). WBRT decreased LR (10% vs. 46%), decreased the rate of any brain failure (18% vs. 70%), and decreased the rate of neurologic death (14% vs. 44%) but did not significantly change MS (48 wks vs. 43 wks). (Patchell R et al., JAMA 1998)

Question 20

Why did the investigators choose a nonstandard WBRT dose in Patchell II?

Answer 20

The dose and fractionation schedule were chosen to achieve 90% microscopic Dz control probability.

Question 21

What are the indications for surgical resection?

Answer 21

Single lesion amenable to resection, controlled or absent extracranial Dz, KPS >70, age <60 yo, life expectancy >2 mos, need for immediate relief of neurologic Sx secondary to mass effect, need to establish a tissue Dx.

Question 22

Are there any current randomized studies that support the role of adj WBRT?

Answer 22

Yes. EORTC 22952 enrolled 359 pts with 1–3 brain mets s/p Sg or SRS randomized to no further Tx vs. WBRT (30 Gy in 3 Gy/fx). Adj WBRT reduced the 2-yr relapse rate both at initial sites (Sg: 59% to 27%; SRS: 31% to 19%) and new sites (Sg: 42% to 23%; SRS: 48% to 33%) with decreased rates of death secondary to intracranial progression (44% vs. 28%) without improvement in the duration of functional independence or OS. Pts randomized to observation were more likely to require salvage therapy (51% vs. 16%). (Kocher M et al., JCO 2010)

Question 23

What is the rationale for SRS in the Tx of brain mets?

Answer 23

Spherical/pseudospherical target, generally noninfiltrative lesions (<3–4 cm) located along the gray–white junction (noneloquent regions), ability to deliver a higher dose than can be achieved with WBRT alone (improved LC), Tx of unresectable lesions; also, reduced risk of neurocognitive decline depending on location of lesion(s).

Question 24

What was the 1st RCT study of WBRT +/- an SRS boost?

Answer 24

The 1st RCT of WBRT +/– an SRS boost was conducted at the University of Pittsburgh. 27 pts with KPS ≥70 and 2–4 mets ≤2.5 cm that were at least 5 mm from the chiasm were randomized to WBRT (30 Gy/12 fx) +/– a 16-Gy boost. The trial closed early b/c of significant difference in brain control. The SRS arm had a longer time to LF (36 mos vs. 6 mos, p = 0.0005) and longer time to any brain failure (34 mos vs. 5 mos, p = 0.002) but no difference in OS (11 mos vs. 7.5 mos, p = 0.11). (Kondziolka D et al., IJROBP 1999)

Question 25

According to RTOG 9508, which pts had a survival advantage with the addition of an SRS boost to WBRT?

Answer 25

RTOG 9508 randomized 331 pts with 1–3 brain mets to WBRT + SRS boost vs. WBRT alone. WBRT on both arms was 37.5 Gy in 2.5 Gy/fx. The SRS boost dose was dependent on size in accordance with RTOG 9005. On univariate analysis, the addition of SRS improved the MS for pts with a single brain met (6.5 mos vs. 4.9 mos, p = 0.39). On subgroup MVA, RPA class I pts had improved survival with the SRS boost, as did pts with a lung cancer primary. (Andrews D et al., Lancet 2004)

Question 26

What is the main determinant in selecting the Rx dose for SRS Tx of a brain mets?

Answer 26

The SRS Rx dose for a brain met is determined by size in accordance with the results of RTOG 9005, a dose escalation study: 24 Gy if <2-cm diameter, 18 Gy if 2–3 cm, and 15 Gy if 3–4 cm. (Shaw H et al., IJROBP 1996)

Question 27

In the RTOG SRS dose escalation study, did pts rcv WBRT?

Answer 27

Yes. In RTOG 9005, an SRS dose escalation study, 64% of pts had recurrent brain mets (median prior dose of fractionated RT 30 Gy) while 36% of pts had recurrent primary brain tumors (median initial dose of 60 Gy).

Question 28

What retrospective data support the omission of upfront WBRT in pts treated with SRS for brain mets?

Answer 28

Sneed et al. compiled a database from 10 U.S. institutions to assess the effect of omitting upfront WBRT in pts treated with SRS for brain mets. 983 pts were analyzed and excluded pts treated with Sg (159 pts) and pts with a >1-mo interval b/t WBRT and SRS (179 pts). Of 569 evaluable pts, 268 had SRS alone and 301 had upfront WBRT + SRS. When adjusted for RPA class, there was no difference in survival. 37% of pts Tx with SRS alone rcvd salvage therapy (median 5.7 mos) vs. 7% of pts Tx with SRS + WBRT (median 8.0 mos). No LC data were provided. (IJROBP 2002)

Question 29

What data argue against omission of WBRT following SRS alone?

Answer 29

Regine et al. retrospectively analyzed 36 pts Tx with planned observation following SRS alone (median dose 20 Gy). With an MS of 9 mos, brain tumor recurrence occurred in 47% (17/16 pts) with 71% symptomatic at the time of recurrence and 59% with a neurologic deficit. (IJROBP 2002)

Question 30

According to randomized data, what is the effect of delaying WBRT after SRS for pts with 1–4 brain mets?

Answer 30

JROSG99–1 showed that the omission of WBRT after SRS for 1–4 brain mets does not affect survival but increases the risk of intracranial relapse (46% with SRS + WBRT vs. 76.4% with SRS alone) and thus increases the need for salvage Tx. (Aoyama H et al., JAMA 2006)

Question 31

What was the 1st randomized trial to assess the effect of delaying WBRT after SRS?

Answer 31

The 1st trial to assess the effect of delaying WBRT after SRS was JROSG99–1. 132 pts with 1–4 mets were randomized to SRS or WBRT + SRS. The SRS dose was based on size (lesions ≤2 cm to 22–25 Gy; lesions >2 cm to 18–20 Gy) and randomization (30% SRS dose reduction for pts on the WBRT arm). The WBRT dose was 30 Gy in 10 fx. (Aoyama H et al., JAMA 2006)

Question 32

What prospective data support the omission of WBRT in pts treated with SRS alone?

Answer 32

Chang EL et al. randomized 58 pts with 1–3 brain mets (57% single) with KPS ≥70 to SRS alone vs. SRS + WBRT (30 Gy in 2.5 Gy/fx). SRS + WBRT resulted in a significant decline in 4-mo recall (24% vs. 52%) and median OS (15 mos vs. 6 mos) as compared to SRS alone. Pts treated with SRS + WBRT experience improved 1-yr LC (100% vs. 67%) and 1-yr distant brain control (73% vs. 44%) with SRS alone pts requiring more frequent salvage therapy. (Lancet 2009)

Question 33

What are some criticisms of the Chang EL et al. trial?

Answer 33

Utilization of a single neurocognitive metric to assess learning and memory (HTLV-R) at a single time point (4 mos post-Tx); decreased survival in the SRS + WBRT group despite 100% 1-yr LC and improved neurologic DFS (73% vs. 27%); incomplete accrual (stopped early due to worse cognitive outcomes in the WBRT + SRS arm).

Question 34

What were the results of the NCCTG (Alliance) N0574 study investigating SRS +/- WBRT?

Answer 34

N0574 reported on 213 pts randomized to SRS alone vs. SRS + WBRT (30 Gy in 2.5 Gy/fx), and also found improved LC at 3 mos with the addition of WBRT to SRS (97% vs. 75.3%). However, they also found no significant difference in OS b/t the 2 groups (10.4 mos with SRS alone vs. 7.4 mos), and additionally demonstrated improved QOL and less cognitive decline in the SRS alone group. This supports the recommendation for initial Tx of 1–3 newly diagnosed brain mets with SRS alone f/b close observation in order to preserve cognitive function. (Brown PD et al., JAMA 2016)

Question 35

Are there any data on SRS dosing with planned WBRT?

Answer 35

Yes. Retrospective data from the University of Kentucky showed that optimal control of brain mets ≤2 cm was achieved with SRS of 20 Gy + WBRT. Pts treated with >20 Gy SRS + WBRT had higher rates of grade 3–4 neurotoxicity. (Shehata M et al., IJROBP 2004)

Question 36

Are there any data comparing Sg + WBRT with SRS alone?

Answer 36

Yes. Retrospective data from Germany comparing RPA class I–II pts with 1–2 brain mets treated either with Sg + WBRT or SRS alone suggests that SRS is as effective. Of 206 pts treated from 1994–2006, 94 pts had SRS alone (18–25 Gy), and 112 pts had resection + WBRT (30 Gy/10 or 40 Gy/20). At 12 mos, there was no difference in OS (∼50% in both groups), LC, or brain control. There was no difference according to the RPA group. (Rades D et al., Cancer 2007)

Question 37

What is the role for stereotactic body radiotherapy (SBRT)?

Answer 37

Large mets (>3 cm) and irregular shaped lesions correlate with inf outcomes and increased toxicity with SRS. Martens B et al. retrospectively analyzed therapeutic results in 75 pts with 108 intracranial mets (48% rcvd primary SBRT while 52% were treated following prior WBRT) with a variety of dose concepts (primary SBRT: 5 Gy × 6–7 fx and 6 Gy × 5 fx; recurrent SBRT 4 Gy × 7–10 fx and 5 Gy × 5–6 fx). A cumulative EQD2 (equivalent dose 2 Gy) of ≥35 Gy resulted in improved LC with acceptable toxicity. (Cancer 2012)

Question 38

Can pts treated with WBRT for brain mets be reirradiated?

Answer 38

Yes. Wong WW et al. reported on a series of 86 pts Tx with reirradiation (median dose 20 Gy) due to progressive brain mets (median initial dose 30 Gy). 70% experienced neurologic improvement (24% complete resolution; 47% partial resolution). (IJROBP 1996)

Question 39

What dose should be used for reirradiation after WBRT for brain mets?

Answer 39

The optimal dose for reirradiation after WBRT is unknown. 20 Gy in 10 fx is often used.

Question 40

How are the fields arranged for WBRT?

Answer 40

WBRT is delivered using opposed lat fields; a post gantry tilt of 3–5 degrees is used to avoid divergence into the eyes; and multileaf collimation or custom blocks are used to ensure adequate coverage of the cribriform plate, temporal lobe, and brainstem while protecting the eyes, nasal cavity, and oral cavity. The inf border is generally set at C1–2.

Question 41

Should Sg be used for recurrent tumors?

Answer 41

Yes. Retrospective data from MDACC have suggested that reoperation for recurrent brain mets can prolong survival and improve QOL. MVA revealed several negative prognostic factors: presence of systemic Dz, KPS <70, short time to recurrence (<4 mos), age ≥40 yrs, and breast and melanoma primaries. (Bindal R et al., J Neurosurg 1995)

Question 42

What is the advantage of tumor bed radiosurgery after brain met resection?

Answer 42

Retrospective data from the University of Sherbrooke in Canada have suggested that SRS to the tumor bed following resection for brain mets achieves LC rates that are comparable to WBRT but does not impact the development of remote brain mets. 40 pts underwent resection → SRS at a median of 4 wks post resection. 73% achieved LC, and 54% developed new brain mets. (Mathieu D et al., Neurosurgery 2008)

Question 43

Are any prospective trials investigating the role of SRS vs. WBRT for resected metastatic brain Dz?

Answer 43

Yes, RTOG 1270 is an RCT open to accrual investigating the role of postop SRS boost to the surgical cavity vs. adj WBRT following surgical resection of intracranial mets. Interim analysis reported at the ASTRO 2016 annual meeting suggest equivalent survival with improved preservation of cognitive function with SRS, however greater long-term control of CNS mets with WBRT. The study is ongoing, and formal publication is awaited.

Question 44

Are professional guidelines available to provide Tx recommendations for pts with newly diagnosed brain mets?

Answer 44

Yes, ASTRO published an evidence-based guideline of Tx recommendations dependent on the goal of Tx (survival, LC, distant brain control, and neurocognitive function) and estimated prognosis. (PRO 2012)

Question 45

What is the recommended interval for surveillance imaging after Tx of brain mets?

Answer 45

MRI is generally recommended every 2–4 mos in pts with good PS and potential for salvage therapy if additional mets are identified.