# Radiation Oncology/Palliation/Brain Metastases/WBRT

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Whole Brain Radiation Therapy

## Overview

* 30 Gy in 10 fractions considered standard treatment after RTOG 6901
* Most commonly used for palliation, commonly defined as objective tumor response by CT or decrease in steroid dose
** Princess Margaret Hospital, 2001 - PMID 11578731 — "Radiotherapy for brain metastases: defining palliative response." Bezjak A et al. Radiother Oncol. 2001 Oct;61(1):71-6.
*** Seeks to determine the palliative response using performance status in patients with symptomatic brain mets.
* Median survival 4-7 months
* Routine use of WBRT now debated, since chemotherapy and SRS offer modest benefit with fewer neurological sequelae. Newer measurements of neurological sequelae done with before radiation show that tumor and not radiation possibly more likely to have caused sequelae previously thought to be from radiation (see PCI of small cell lung ca).

## History

Have been doing palliative whole brain radiotherapy for a long time .

## Steroids +/- RT

* 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 PMID 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
* MRC -- dexamethasone +/- whole brain RT
** Randomized. 538 patients. Patients with brain metastases unsuitable for stereotactic radiation therapy or surgery and with "uncertainty in the clinicians’ or patients’ minds about the potential benefit of WBRT" were included. 60% of patients with KPS <80. Arm 1) dexamethasone + WBRT 20/4 vs. Arm 2) dexamethasone alone.
** 2016 PMID 27604504 -- "Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial." (Mulvenna P, Lancet. 2016 Oct 22;388(10055):2004-2014.)
*** Outcome: QALY (quality of life adjusted years) dexamethasone + WBRT 46.4 days vs. dexamethasone 41.7 days (difference of 4.7 days well within the 90% CI). No difference overall quality of life or dexamethasone use.
*** Toxicity: more drowsiness, hair loss, nausea, and dry or itchy scalp in dexamethasone + WBRT arm.
*** Conclusion: WBRT offers no benefit in overall survival, quality of life or decrease of dexamethasone need in this patient group.

## Dose and fractionation studies

* Despite numerous studies testing numerous combinations of dose and fractionation, outcomes remain the same (and poor) as 30/10 established with RTOG 6901
* Representative regimens tried: 10/1, 12/2, 20/5, 30/6, 30/10, 35/15, 18/3 + 18/3 split, 37.5/15, 40/15, 50/20, 50/23, 54/34 BID
* 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 PMID 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
* RTOG 9104, 1997 (1991-1995) - PMID 9336134 — "A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104." Murray KJ et al. Int J Radiat Oncol Biol Phys. 1997 Oct 1;39(3):571-4.
** Compared accelerated hyperfractionation (AH) 54.4 Gy BID (1.6 Gy/fx) vs accelerated fractionation (AF) 30 Gy in 10 fx in pts with unresected brain mets. All had KPS > 70 (RPA class 1 and 2). AH regimen consisted of 32 Gy in 10 days to the whole brain, plus a boost of 22.4 Gy to each tumor.
** Equivalent survival in both arms (median 4.5 mo). For patients with solitary metastases, no difference in survival seen between arms.
* 1996 Royal College of Radiologists (UK), (1990-93) - PMID 8934050 — "Final results of the Royal College of Radiologists' trial comparing two different radiotherapy schedules in the treatment of cerebral metastases." Priestman TJ et al. Clin Oncol (R Coll Radiol). 1996;8(5):308-15.
** 533 pts. 30 Gy in 10 fx vs 12 Gy in 2 fx (in 2 days).
** Median survival 84 days (10 fractions) vs 77 days (2 fractions), with the difference confined to those in the better prognostic group.
* RTOG 8905 1989-1993 PMID 7673021 -- "Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05." (Phillips TL, Int J Radiat Oncol Biol Phys. 1995 Sep 30;33(2):339-48.)
** Randomized. 72 patients treated with RT 37.5/15 or RT 37.5/15 + BrdU x 3 weeks
** Comparable outcome (6.1 months, 4.3 months median survival)
* RTOG 8528 1986-1989
** PMID 8435812 — "Improved survival duration in patients with unresected solitary brain metastasis using accelerated hyperfractionated radiation therapy at total doses of 54.4 gray and greater. Results of Radiation Therapy Oncology Group 85-28." (Epstein BE et al. Cancer. 1993 Feb 15;71(4):1362-7.)
** PMID 8330997 — "Phase I/II trial of accelerated fractionation in brain metastases RTOG 85-28. (Sause WT, Int J Radiat Oncol Biol Phys. 1993 Jul 15;26(4):653-7.)
** Phase I/II dose escalation, accelerated hyperfractionated XRT for unresected solitary brain met. Dose was 32 Gy BID (1.6 Gy/fx) plus an escalating-dose boost for a total of 48-70.4 Gy. Controlled primary tumors.
** Significantly increased survival doses >54 Gy
** NOTE: these results were not validated in the randomized trial RTOG 91-04
* 1993 Institut Gustave-Roussy (France) 1993 - PMID 7681997 — "Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases." Haie-Meder C et al. Radiother Oncol. 1993 Feb;26(2):111-6.
** 216 pts. 18 Gy in 3 fx (in 3 days), 6 Gy/fx, vs. same regimen plus a 2nd course one month later which was either the same regimen again or 25 Gy/10 fractions (total 36 Gy-43 Gy).
** No difference in survival.
* RTOG 7916 1979-1983 - PMID 1993631 — "A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916)." Komarnickly LT et al. Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):53-8.
** 859 pts. Randomized between 2 fractionation schedules (30 Gy/10 fx vs 30 Gy/6 fx over 3 weeks) and with or without misonidazole.
** No difference in survival for any arm. Brain failure cause of death in 1/3 of pts.
* Royal Marsden Hospital (UK), 1990 - PMID 2116386 — "The influence of extent and local management on the outcome of radiotherapy for brain metastases." Hoskin PJ et al. Int J Radiat Oncol Biol Phys. 1990 Jul;19(1):111-5.
** Retrospective. Of a total of 164 pts receiving whole brain RT (35 Gy in 15 fx), 50 pts in addition received boosts of 15 Gy/8 fx. No difference in overall survival or neurologic death.
* RTOG 7606 1976-1979 PMID 6171553 -- "The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group." (Kurtz JM, Int J Radiat Oncol Biol Phys. 1981 Jul;7(7):891-5.)
** Randomized. 255 patients, favorable prognosis from prior trials (controlled primary tumor & no extracranial mets), treated with 30/10 or 50/20
** Comparable outcomes (4.5, 4.2 months median survival)
* RTOG 6901 & 7361; Ultra-rapid 1971-1976 PMID 6174490 — "Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group." (Borgelt B, Int J Radiat Oncol Biol Phys. 1981 Dec;7(12):1633-8.)
** 59 patients from the 2 trials treated with either 10/1 or 12/2
** Comparable outcomes (3.7, 3.2 months median survival); worse than in prior trials (4 weeks vs. 10 weeks)
* RTOG 6901 & 7361
** This pair of trials is often considered together. Randomized to 5 different dose schemes.
** RTOG 6901 (1971-1973) - 910 pts. 30/10, 30/15, 40/15, 40/20
** RTOG 7361 (1973-1976) - 902 pts. 20/5, 30/10, 40/15
** PMID 6154024 — "The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group." (Borgelt B et al. Int J Radiat Oncol Biol Phys. 1980 Jan;6(1):1-9.)
*** 6901: (30/10, 30/15, 40/15, 40/20) - MS 21, 18, 18, 16 wks or 4.8, 4.1, 4.1, 3.6 months
*** 7361: (20/5, 30/10, 40/15) - MS 15, 15, 18, wks or 3.4, 3.4, 3.6 months
*** Comparable outcomes. Shorter schedules (30/10 or 20/5) as effective for palation as longer schedules. Established 30/10 as standard treatment.
** PMID 6169424 -- "Equivalence of radiation schedules for the palliative treatment of brain metastases in patients with favorable prognosis." (Gelber RD, Cancer. 1981 Oct 15;48(8):1749-53.)
*** Subset of favorable prognosis pts, n=561 (breast cancer w/o soft tissue mets, lung ca with primary absent or no extracerebral mets, or other with no extracerebral mets).
*** Favorable pts MS 28 weeks vs 11 weeks. Median time to neurologic progression or death: 21 wks (breast), 13 wks (lung), 15 wks (other). Number without neurol. progression at last f/u: 41%, 46%, 33%. No significant benefit seen for higher dose in this subset.
*** No evidence of superior palliation with higher doses in favorable subset of pts

## Adjuvant WBRT

WBRT after Surgical Resection:
* See: Surgery +/- WBRT
WBRT after SRS:
* See: Radiosurgery +/- WBRT

## Chemo-RT
### Temozolomide

* Lanzhou, China; 2010 PMID 19881333 -- "Concomitant or adjuvant temozolomide with whole-brain irradiation for brain metastases: a meta-analysis." (Liu R, Anticancer Drugs. 2010 Jan;21(1):120-8.)
** Meta-analysis. 4 trials, 280 patients. Whole brain RT vs WBRT + temozolomide
** Outcome: WBRT+TMZ superior in objective response, partial response, stable disease, and progressive disease
** Toxicity: WBRT+TMZ worse for Grade 3 GI toxicity and myelosuppression
** Conclusion: Combination may moderately improve response rate but increase toxicity

### Thalidomide

* RTOG 0118 (2002-2004)
** 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
** 2007 PMID 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])
*** Outcome: median OS 3.9 months for both arms
*** Toxicity: 48% discontinued thalidomide due to toxicity
*** Conclusion: No survival benefit for thalidomide; significant toxicity
** 2007 PMID 18164829 -- "Prospective Evaluation of Quality of Life and Neurocognitive Effects in Patients with Multiple Brain Metastases Receiving Whole-Brain Radiotherapy with or without Thalidomide on Radiation Therapy Oncology Group (RTOG) Trial 0118." (Corn BW, Int J Radiat Oncol Biol Phys. 2007 Dec 28 [Epub ahead of print])
*** QoL outcomes with Spitzer Quality of Life Index (SQLI) and Mini-Mental Status Exam (MMSE)
*** Outcome: Baseline SQLI predicted survival; slow steady neurocognitive decline in both arms but SQLI remained stable
*** Conclusion: QoL and neuropsychologica testing can be prospectively evaluated

### Motexafin gadolinium

* Wisconsin; 2003 PMID 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 5mg/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

### 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 PMID 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
* Cologne; 2007 (Germany)(1999-2001) PMID 17379446 -- "A phase I/II trial of topotecan and radiation therapy for brain metastases in patients with solid tumors." (Hedde JP, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):839-44.)
** Phase I/II. 75 patients. WBRT 40/20 + topotecan 0.2 mg/m2/d to 0.5 mg/m2/d within 2 hours of RT
** Outcome: Response rate 72%; OS 4.2 months and 7.5 months among responders
** Toxicity: MTD topotecan 0.4 mg/m2/d; Grade 3-4 toxicity 20%
** Conclusion: Recommend a Phase III trial

### Bromodeoxyuridine

* RTOG 89-05; 1995 (1989-93) - PMID 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