Radiation Oncology/Palliation/Brain Metastases/Randomized

Brain Metastases: Randomized Evidence In progress of being cross-linked from the Brain Metastases chapter Steroids +/- WBRT ECOG -- prednisone +/- whole brain RT Randomized. 48 patients. Brain metastases (by radioisotope brain scan, EEG, echo, angiogram, of CSF studies), and histologically proven cancer. Extracranial disease status not considered. Arm 1) Prednisone 40 mg QD x 4 weeks, then 30 mg QD until disease progression vs. Arm 2) Prednisone 40 mg QD + whole brain RT 4000 r in 22–29 days. At the end, further randomized to +/- prednisone 30 mg daily. Clinical criteria used since imaging unreliable 1971 5541678 -- "The management of metastases to the brain by irradiation and corticosteroids." (Horton J, Am J Roentgenol Radium Ther Nucl Med. 1971 Feb;111(2):334-6.) Outcome: Clinical "remission" prednisone 63% vs. prednisone + RT 61%; duration of remission 5 weeks vs. 11 weeks (wide range); median OS 10 weeks vs 14 weeks Toxicity: Alopecia Conclusion: Combination of radiation and prednisone offers only a slight advantage over prednisone alone Surgery +/- WBRT Patchell study #2, 1998 (1989–97) - 9809728 — "Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial." Patchell RA. JAMA. 1998 Nov 4;280(17):1485-9. 95 pts. Randomized. Solitary brain met. Pts with complete resection (verified by MRI) randomized to postoperative whole brain RT or observation. Dose was 50.4 Gy over 5.5 weeks. Allowed to have other sites of metastases, but KPS >= 70%. Median f/u 43-48 wks. Postop RT was associated with less recurrence anywhere in the brain (18% vs 70%), at the site of resection (10% vs 46%), as well as other areas in the brain (14% vs 37%). Decreased neurologic death (6 of 43 pts, 14%; vs 17 of 39, 44%). No difference in overall survival (unlike Patchell #1) or length of time patient remained independent. Criticism: non-standard whole brain RT dose WBRT +/- Surgery Canada Multi-Institutional (1989–1993) -- WBRT 30/10 vs. Surgery + WBRT 30/10 Randomized. 84 patients. Single brain metastasis, KPS >50, no lymphoma/SCLC. Dexamethasone per institutional policy. Arm 1) WBRT 30/10 vs. Arm 2) Surgery + WBRT 30/10. Treatment within 3 weeks of CT scan. 1996 8839553 — "A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis." (Mintz AH, Cancer. 1996 Oct 1;78(7):1470-6.) Outcome: Median OS WBRT 6 months vs. surgery + WBRT 6 months (NS). No difference in QoL Conclusion: No benefit from adding surgery to whole brain RT Comment: Worse baseline KPS than Kentucky and Netherlands studies. University Hospital Leiden (Netherlands)(1985–90) -- WBRT 40/20 BID vs. Surgery + WBRT 40/20 BID Randomized. 63/66 patients. Single brain metastasis. Arm 1) Pts randomized to resection + WBRT vs WBRT alone. XRT was to whole brain 2Gy BID for 40 Gy over 2 weeks. No MRI. 1993 8498838 — "Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery?" (Vecht CJ, Ann Neurol. 1993 Jun;33(6):583-90.) Outcome: Stable extracranial disease: median OS 7 months vs. 12 months. Progressive extracranial disease: median OS 5 months both groups (NS). Functional independence: Stable extracranial disease: 4 months vs. 9 months. Progressive extracranial disease: 2.5 months both groups (NS). More rapid and longer after surgery + RT 1994 8040016 — "The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age." (Noordijk EM, Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):711-7.) Outcome: median OS WBRT 6 months vs. surgery + WBRT 10 months (SS). Stable extracranial disease (7 months vs 12 months), active extracranial disease (5 months both groups). Age independent predictor (60 years). Majority of deaths due to systemic progression Conclusions: surgery and radiotherapy should be offered over radiotherapy alone. However, for patients with active extracranial disease, radiotherapy alone is sufficient. University of Kentucky / Patchell#1 (1985–1988) -- WBRT 36/12 vs. Surgery + WBRT 36/12 Randomized. 48 patients. Suspected single brain metastasis. Dexamethasone 4 mg Q6 hours. Arm 1) (biopsy) then WBRT vs. Arm 2) Surgery + WBRT. Surgery within 72 hours of randomization. WBRT within 14 days of surgery; within 48 hours of randomization or biopsy; dose 36/12 1990 2405271 - "A randomized trial of surgery in the treatment of single metastases to the brain." (Patchell RA, N Engl J Med. 1990 Feb 22;322(8):494-500. Outcome: Local recurrence WBRT 52% vs surgery + WBRT 20% (SS); time-to-recurrence 5 months vs >14 months (SS). Distant brain recurrence 13% vs. 20% (NS). QoL (KPS >=70, functionally independent) 2 months vs. 9 months (SS) Survival: Median OS 3 months vs. 9 months (SS), "neurologic death" 6 months vs. 14 months (SS). No difference in "systemic death". Toxicity: operative mortality 4%, operative morbidity 8% Conclusion: Patients with single brain metastasis treated with surgery + RT live longer, have fewer recurrences, and better quality of life than patients treated with RT alone SRS +/- WBRT EORTC 22952-26001 (1996–2007) -- Surgery/SRS +/- WBRT See: Radiosurgery +/- WBRT MD Anderson (2001–2007) -- SRS vs SRS + WBRT Randomized. Stopped early due to significantly worse cognitive outcome in WBRT+SRS arm. 58 of expected 90 patients. RPA I-II (KPS >=70), 1-3 brain mets (57% single). Arm 1) SRS (dose per RTOG 9005; median 19 Gy) vs. Arm 2) SRS first (median 20 Gy) + WBRT 30/12. No concurrent chemo. Primary endpoint neurocognitive function using HVLT-R recall test at 4 months 2009 19801201 -- "Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial." (Chang EL, Lancet Oncol. 2009 Nov;10(11):1037-44. Epub 2009 Oct 2.). Median F/U 9 months Outcome: Significant decline in 4-month recall SRS 24% vs. SRS+WBRT 52% (SS). Functional brain assessment no difference. 1-year LC 67% vs. 100% (SS); 1-year distant brain control 45% vs. 73% (SS). 1-year CNS DFS 27% vs. 73% (SS). Median OS 15 months vs. 6 months (SS). Salvage much more aggressive in SRS only arm Toxicity: SRS 7% Grade 4 Conclusion: Patients treated with SRS + WBRT were at greater risk of memory decline at 4 months JROSG 99–1, Japan (1999–2003) -- SRS vs SRS + WBRT Randomized. Stopped early due to low likelihood of showing a difference. 132 of expected 188 patients. 1-4 mets, size < 3 cm. RPA I-II (85% RPA II). 50% active extracranial disease. 11 centers in Japan. Arm 1) SRS alone (dose if <2 cm 22-25 Gy, if 2–3 cm 18-20 Gy) vs. Arm 2) WBRT 30/10 followed by SRS. SRS dose reduced by 30%. Primary endpoint OS 2006 16757720 — "Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases: A Randomized Controlled Trial." (Aoyama H et al. JAMA 2006;295 2483–2491.) Outcome: Median OS SRS 8.0 months vs. SRS + WBRT 7.5 months (NS); 1-year OS 28% vs. 38% (NS); CNS death 19% vs. 23% (NS). 1-year LC ~75% vs. ~90% (SS); 1-year distant brain control 36% vs. 59% (SS). Decreased need for salvage brain treatment (10 pts vs 29 pts) with WBRT. No difference in neurocognitive measures Conclusion: SRS alone can be a reasonable strategy, with close monitoring and salvage retreatment WBRT +/- SRS RTOG 95-08 (1996–2001) -- WBRT vs WBRT + SRS Randomized. 331 patients, 1-3 brain mets with maximum diameter 4 cm, RPA class 1 (26%) or class 2 (74%), lung 63%. Arm 1) WBRT 37.5/15 vs Arm 2) WBRT + radiosurgery (24-18-15 Gy based on size) 2004 15158627 Full text — "Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial." (Andrews DW, Lancet. 2004 May 22;363(9422):1665-72.) Outcome: Mean OS WBRT 6.5 months vs WBRT+SRS 5.7 months (NS); single metastasis 4.9 months vs 6.5 months (SS) though (NS) on multivariate analysis. Higher 3-month response rate and control at 1 yr (71% vs 82%). No difference in overall time to progression (any intracranial failure) and no difference in neurologic death. Local recurrence 43% more likely with WBRT than WBRT+SRS. Improved KPS (4% vs 13%) and decreased steroid use at 6 months but no difference in mental status. Toxicity: Acute G3+ WBRT 0% vs WBRT+SRS 3%; Late G3+ 3% vs 6% Conclusion: WBRT+SRS improved KPS, no difference in OS. Benefit in OS for single metastasis Pittsburgh -- WBRT vs WBRT + SRS Randomized. Trial stopped early after significant interim benefit in brain control for WBRT+SRS arm. 27 patients, 2-4 brain metastases <2.5 cm, KPS ≥ 70. Arm 1) WBRT 30/12 vs Arm 2) WBRT + SRS 16 Gy. Primary outcome brain control. 1999 10487566 — "Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases." Kondziolka D et al. Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):427-34. Outcome: 1-year local failure WBRT 100% vs WBRT+SRS 8% (SS); time-to-failure 6 months vs 36 months (SS). Median OS WBRT 7.5 months vs WBRT+SRS 11 months (NS). However, patients in WBRT arm who received salvage SRS median OS 11 months (NS to WBRT+SRS), while patients who received only WBRT median OS 7 months (SS to WBRT+SRS) Conclusion: WBRT+SRS significantly improves control of brain disease; WBRT alone does not provide effective and lasting control Whole Brain RT Dose Kogarah, Australia -- 40/20 BID vs 20/4 QD Randomized. 113 patients, brain mets, stable or absent extracranial disease, ECOG <3. Surgical resection 36%. Arm 1) 40/20 BID vs. Arm 2) 20/4. Primary outcome intracranial control and QoL. 2009 19836153 -- "Randomized Comparison of Whole Brain Radiotherapy, 20 Gy in Four Daily Fractions Versus 40 Gy in 20 Twice-Daily Fractions, for Brain Metastases." (Graham PH, Int J Radiat Oncol Biol Phys. 2009 Oct 14. [Epub ahead of print]) Outcome: Median OS 40 Gy 6.1 months vs. 20 Gy 6.6 months (NS). Intracranial progression 44% vs. 64% (SS). Median time-to-CNS-progression 9 months vs 5 months (SS). Salvage RT/surgery 4% vs. 21% (SS). CNS death 32% vs. 52% (SS) Toxicity: Minimal. QoL clinically improved in 20 Gy arm over 40 Gy arm, but (NS). Conclusion: Intracranial control better with 40/20 BID than 20/4 QD; should be considered for better prognosis patients Chemo-RT Topotecan Germany -- WBRT vs. WBRT + topotecan Randomized. Closed early due to slow accrual. 96/320 patients with SCLC or NSCLC, with brain metastases. Arm 1) WBRT 40/20 vs. Arm 2) WBRT 40/20 + topotecan 0.4 mg/m2 2009 19127261 -- "A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer." (Neuhaus T, Br J Cancer. 2009 Jan 27;100(2):291-7. Epub 2009 Jan 6.) Median F/U 2.8 years Outcome: No difference in LR or PFS Conclusion: No significant advantage for concurrent topotecan in patients with lung cancer, but number too small Thalidomide RTOG 0118; 2007 (2002–2004) 18164847 -- "A Phase III Study of Conventional Radiation Therapy Plus Thalidomide versus Conventional Radiation Therapy for Multiple Brain Metastases (RTOG 0118)." (Knisely JP, Int J Radiat Oncol Biol Phys. 2007 Dec 28 [Epub ahead of print]) Randomized. Closed early due to non-superiority. 183 accrued patients from goal of 332 patients. Multiple (>3), large (>4 cm), or midbrain metastases from extracranial disease, PS 0–1. Arm 1) WBRT 37.5/15 vs. Arm 2) WBRT 37.5/15 + thalidomide Outcome: median OS 3.9 months for both arms Toxicity: 48% discontinued thalidomide due to toxicity Conclusion: No survival benefit for thalidomide; significant toxicity Motexafin gadolinium Wisconsin; 2003 12829672 -- "Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases." (Mehta MP, J Clin Oncol. 2003 Jul 1;21(13):2529-36.) Randomized. 401 patients (251 NSCLC). Arm 1) 30 Gy WBRT vs. Arm 2) concurrent MGd 5 mg/kg/d Outcome: no difference in survival (4.9 months vs. 5.2 months, NS) or time-to-neurologic progression (9.5 months vs. 8.3 months, NS). Improvement in neurologic progression in NSCLC patients Conclusion: No benefit, except possibly for NSCLC brain mets Bromodeoxyuridine RTOG 89–05; 1995 (1989–93) - 7673021 — "Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05." Phillips TL et al. Int J Radiat Oncol Biol Phys. 1995 Sep 30;33(2):339-48. Randomized. 72 patients, KPS >=70, primary absent, controlled, or under RT; no other mets. WBRT 37.5/15 +/- bromodeoxyuridine (BrdUrd) Outcome: Median OS RT alone 6.1 months vs. RT + BrdUrd 4.3 months (NS) Conclusion: No benefit for BrdUrd Radioprotectants Methylphenidate (d-MPH) Wake Forest; 2007 17869448 -- "A Phase III, Double-Blind, Placebo-Controlled Prospective Randomized Clinical Trial of d-threo-methylphenidate HCl in Brain Tumor Patients Receiving Radiation Therapy." (Butler JM Jr, Int J Radiat Oncol Biol Phys. 2007 Sep 13; [Epub ahead of print]) Randomized. 68 patients with primary or metastatic brain tumors. Arm 1) prophylactic d-MPH 5 mg BID -> 15 mg BID vs. Arm 2) observation. Outcome measure QOL and cognitive function Outcome: No difference in fatigue, QOL, or cognitive function Conclusion: Prophylactic d-MPH not beneficial in brain tumor patients