Evidence Tables

Citation: Aoyama,H.; Tago,M.; Kato,N.; Toyoda,T.; Kenjyo,M.; Hirota,S.; Shioura,H.; Inomata,T.; Kunieda,E.; Hayakawa,K.; Nakagawa,K.; Kobashi,G.; Shirato,H. (2007). Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. International Journal of Radiation Oncology Biology Physics, 68, 1388-95. Design: Multi-centre RCT Country: Japan

Aim: To assess how stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT) compared to SRS alone affect the neurocognitive function of patients with 1-4 brain metastases. Inclusion criteria Patients with - Karnofsky score > 69, and - 1-4 brain metastases that were identified using enhanced MRI and that each measured < 3cm. Exclusion criteria Population • N = 132 randomised to receive WBRT+SRS (n= 65) or SRS alone (n = 67) for brain metastases. • Only patients for whom baseline MMSE (Mini-Mental State Examination) scores were available were analysed (n = 110). • The control group (n = 59, 46 males, 13 females) and the intervention group (n = 51, 36 males, 15 females) did not statistically differ on the following characteristics: Age at diagnosis, gender, Karnofsky performance status, number of brain metastases, brain edema, total volume of brain metastases, primary tumour site (which was lung in 39/50 in the control group and 32/51 in the intervention group), primary tumour status, and status of extracranial metastases (stable/active). Interventions Control group: SRS alone: The SRS dose was prescribed to the tumour margin. Metastases with a maximal diameter of ≤ 2 cm were treated with 22-25 Gy, and those ≥ 2 cm were treated with 18-20 Gy. Intervention group: WBRT + SRS: WBRT: 30 Gy in 10 fractions within 2-2.5 weeks followed by SRS, which was similar to the control group, but with an SRS dose reduction of 30%. Outcomes Primary outcome: MMSE score. • The MMSE was administered before or during brain treatment, 1-3 months after treatment, and, if possible, every 3 months thereafter. A statistically meaningful change was considered to be a change of 3 points (maximum score = 30), a normal score was defined as > 25 Other measures: - Number of brain metastases as assessed by contrast-enhanced MRI, - total volume of brain metastases, - degree of brain edema on T2-weighted MRI (0 = no edema, 1 = edema limited to < one half of one hemisphere, 2 = edema > one half of one hemisphere), - leukoencephalopathy (assessed by MRI according to the criterion in the National Cancer Institute Common Toxicity Criteria, version 2.0) - tumour progression (scored when the tumour had increased in size by 25% or more according to the measurement of the perpendicular diameters). Results MMSE: Baseline (n = 110, 71 of whom had lung cancer): Control group (n = 59, mean = 27.1, standard deviation (SD) = 2.9) not statistically significantly different from the intervention group (n = 51, mean = 26.7, SD = 3.3), p = .86. • When analyses were conducted on the whole sample on the basis of different patient characteristics, it emerged that MMSE scores did not differ between men and women (p = .33), between patients with 1 or 2-4 brain metastases (p = .29), between patients whose primary tumour site was lung or not-lung (p = .86) or between patients with stable or active extracranial disease p = .96); • the MMSE scores were however lower in patients ≥ 65 years at diagnosis (n = 54, mean = 25.9, SD = 3.7) compared to people below 65 years at diagnosis (n = 56, mean = 27.9, SD = 2), and in patients with a Karnofsky performance status of 70-80 (n = 45, mean = 25.5, SD = 3.8) compared to 90-100 (n = 65, mean = 27.9, SD = 1.9), and in patients with a total volume of brain metastases ≥ 3 cm3 (n = 58, mean = 26.1, SD = 3.7) compared to < 3 cm3 (n = 52, mean = 27.8, SD = 1.9).

MMSE: Post-treatment: N = 92, median number of follow-ups = 2.5 times, range 1-17; median follow-up period = 5.3 months, average = 11 months, range = .7 - 58.7 months. • MMSE improvement: The 53 patients (from both groups) whose baseline MMSE = 28-30 were excluded as an improvement of 3 or more points would not be detectable. The control group (n = 22, mean = 25.3, SD = 2.1) was not statistically significantly different from the intervention group (n = 17, mean = 24.9, SD = 3.3), p = .65. An improvement

of 3 or more MMSE points was observed in 11/20 in the control group and 9/17 in the intervention group, and these proportions were not significantly different (p = .85). The improvement was observed at the mean of 3.6 (SD = 2.8) months in the control group and 6 (SD = 5.9) months in the intervention group (p = .24). The MMSE score of 3 patients deteriorated 3 or more points without improvement and 16 patients experienced change of less than 3 points in their MMSE scores.

• MMSE deterioration: This analysis includes patients with baseline MMSE of 27 or more (n = 65) and those whose baseline score was 26 or less, but who improved to a score of 27 or more after the initial brain treatment (n = 17). As the MMSE score of some patients improved after the initial brain treatment, the best MMSE score minus the deteriorated MMSE score was used for the MMSE change measure in this analysis. The patients who did not experience a 3-point deterioration in MMSE score did not differ between the control and intervention groups (p = .73). Deterioration of MMSE score occurred in 12/46 patients in the control group and in 14/36 patients in the intervention group and these proportions did not differ significantly, p = .21. The median time until deterioration was 6.6 (range 1.6 – 12.9) months in the control group and 12 (range 1.8 – 31.1) months in the intervention group and these differed marginally between the groups (p = .05). This deterioration was presumably attributed to brain tumour recurrence in 11 and 3 patients in the control and intervention groups, respectively (p = .0001), and either clinically or radiologically attributed to a toxic radiation event in 0 and 5 patients in the control and intervention groups, respectively. The cause for this deterioration was unclear in the remaining 7 patients. An additional follow-up MMSE was available for 10/26 patients. Of those 10 an improvement of 3 or more MMSE points was observed in 2 patients in the control group and 5 patients in the intervention group (of those 7 patients 1 underwent brain salvage therapy with SRS and 1 with SRS and 5 received close observation or best supportive care (incl., steroids). In patients free of MMSE deterioration when the first event of a decrease was not counted if the MMSE showed significant recovery with additional follow-up the 12-, 24-, and 36-month actuarial free rate of a second event in the 3-point decrease was 59.3 (95% CI 37.5-81.1)%, 51.9 (95% CI 28.6-75.2)%, and 51.2 (95% CI 28.6-75.2)% in the control group and 76.1 (95% CI 58.7-93.5)%, 68.5 (95% CI 47.3-89.7)%, and 14.7 (95% CI 0-39)% in the intervention group, respectively. These differences were not statistically significant, p = .79. The average duration until deterioration was 7.6 (median = 7.4, range 1.6-12.9) months in the control group and 16.5 (median = 15.8, range 1.8-34.5) months in the intervention group, and this difference was marginally significant, p = .05. In patients free of MMSE deterioration to ≤ 26 (an event of a decrease to ≤ 26 was counted as an event unless the MMSE score recovered to ≥ 27 with additional follow-up) the 12-, 24-, and 36-month actuarial MMSE preservation rate (≥ 27) was 53.3 (95% CI 32.9-73.7)%, 42.6 (95% CI 17.9- 67.3)%, and 42.6 (95% CI 17.9-67.3)% in the control group and 78.8 (95% CI 61.6-96)%, 78.8 (95% CI 61.6-96)%, and 22.5 (95% CI 0-49.4)% in the intervention group, respectively. These differences were not statistically significant, p = .46.

• Leukoencephalopathy: Abnormality seen in 7 patients all in the intervention group (grade 1: N = 2; grade 2: N = 4; grade 3: N = 1). 4/7 (split over all 3 grades) experienced a decrease in MMSE scores of 3 or more points. General comments In addition to the fact that only 64.5% of the patients analysed in this study had BM from lung cancer, the results of this RCT is compromised by a number of methodological limitations that collectively serve to downgrade the validity of the findings. Although the randomisation procedure appears to be adequate with patients stratified according to number of brain metastases (1 vs 2-4), extent of extracranial disease (active vs stable), and primary tumour site (lung vs other), it is unclear whether allocation concealment and any level of blinding were employed. Although treatment blinding might be practically challenging, blinding of the researcher during outcome assessments should have been employed as far as possible. It is also of concern that for 11/110 patients the MMSE baseline measures were obtained after initialization of the treatment that is hypothesized to affect MMSE scores. A further concern is that fact that the SRS treatment doses differed between the control and intervention group by 30%. This difference makes it difficult to disentangle the unique contributions of WBRT and SRS, respectively, to MMSE performance changes. The authors themselves point out that a potential confounding variable is the use of corticosteroids in the study patients which was not monitored or co-varied for in the analyses and which conceivably exerts its own influence on MMSE performance. Finally, the overall number of patients was low and this issue is of course more marked in the different sub-analyses that were undertaken, especially when keeping in mind that not all the patients had primary lung tumours. References of Included Studies (For systematic reviews): N/A

Citation: Cao,K.J.; Huang,H.Y.; Tu,M.C.; Pan,G.Y. (2005). Long-term results of prophylactic cranial irradiation for limited- stage small-cell lung cancer in complete remission. Chinese Medical Journal, 118, 1258-62. Design: RCT Country: China

Aim: To evaluate the effects of prophylactic cranial irradiation (PCI) on survival and brain metastases (BM) for patients with limited stage small cell lung cancer (SCLC) in complete remission. Inclusion criteria Patients with: - Histologically/cytologically proven limited stage SCLC in complete remission after initial treatment (NOTE: Limited disease = cancer limited to one hemithorax, the mediastinum and the ipsilateral supraclavicular nodes), - aged ≤ 65 years, - Karnofsky performance score ≥ 70, Exclusion criteria Population Control group: N = 25, 23 males, average age = 55.63 (±7.29) years. Doses in primary tumour = 50.06 (±5.31) Gy. Number of chemotherapy cycles = 6.8 (±1.44).

PCI group: N = 26, 24 males, average age = 54.69 (±7.56) years. Doses in primary tumour = 52.38 (±6.57) Gy. Number of chemotherapy cycles = 7.38 (±1.4).

None of the clinical characteristics listed differed significantly between the groups (all ps ≥ .18). Interventions PCI: Began 11-58 days after complete remission and consisted of 6-10 MV photons from linear accelerators or gamma beam from cobalt units. Whole brain irradiation was administered with the use of 2 lateral opposed fields, the inferior margin including the base of the skull with shielding of the ocular globes. The dose was specified at mid-depth of the central axis for 2 lateral parallel opposed fields. Total does = 25.2-30.6 (28.83 ±1.41) Gy. In 13 – 17 fractions of 1.8-2 Gy during 3 weeks. Outcomes Overall survival and Time of BM. Both calculated from the end of initial treatment (i.e., not from randomisation to PCI). Initial treatment consisted of radiotherapy and chemotherapy for all 51 patients. Results 50/51 patients followed up for > 5 years. 1 PCI patient lost to follow up. Overall survival: 1-, 3-, and 5-year survival rates = 84.6%, 42.3% and 34.6% in the PCI group and 72%, 32% and 24% in the control group, respectively (p = .13). The Kaplan-Meier estimated median survival time = 29 (95% CI 18-40) months in the PCI group and 17 (95% CI 10-24) months in the control group. This difference was not statistically examined using the log rank (or other) test. Cause of death: 16/25 and 18/25 patients in the PCI and control groups, respectively, died within 5 years of the initial treatment due to relapse (p = .91). Time of BM: Incidence was 1/26 (3.8%) and 8/25 (32%) in the PCI and control groups, respectively (p = .02), resulting in a number needed to treat of 4 (rounding up from 3.47). Median time to BM = 20 and 11 months in the PCI and control groups, respectively. This difference does not appear to have been statistically examined and only one 95% confidence interval (5-36 months) has been reported. General comments A number of methodological issues render the results of this RCT (potentially) questionable. It is, for example, not clear which method of randomisation was employed or whether there was allocation concealment. It is therefore not possible to adequately evaluate the potential presence of a patient recruitment and/or selection bias. Furthermore, although it is not obviously clear how complete blinding would be achieved in a study such as the present RCT, blinding of the personnel assessing (some of) the outcomes should have been carried out and this does not appear to have been the case. On the other hand, although there is no mention of intention-to-treat analysis, the data appear to have been analysed according to this principle. Therefore, on the basis of the above evaluation in combination with the low patient numbers in each treatment group, this study cannot be considered high quality evidence.

References of Included Studies (For systematic reviews): N/A

Citation: Chua, D., Krzakowski, M., Chouaid, C., Pallotta, M. G., Martinez, J. I., Gottfried, M., Curran, W., and Throuvalas, N. Whole-brain radiation therapy plus concomitant temozolomide for the treatment of brain metastases from non-small- cell lung cancer: a randomized, open-label phase II study. Clin Lung Cancer 11[3], 176-181. 2010. Design: Multi-centre randomised phase II study Country: International

Aim: To compare the effectiveness of whole brain radiotherapy (WBRT) + temozolomide to the effectiveness of WBRT + placebo in patients with non small cell lung cancer (NSCLC) and brain metastasis (BM). Inclusion criteria Patients with - pathologically confirmed stage IV NSCLC, - ≥ newly diagnosed BM (diagnosed within 30 days of randomisation) - postcraniotomy incomplete resection and those with extracranial metastases in ≤ 2 anatomic sites were eligible - aged ≥ 18 years - previous RT to primary tumour and/or systemic metastatic sites were eligible as long as no previous WBRT or radiosurgery had been received for BM - Karnofsky performance score ≥ 70 - adequate organ function Exclusion criteria Patients with: - known leptomeningeal or meningeal metastases - > 1 previous regimen of cytotoxic chemotherapy for metastatic NSCLC - investigational drugs, chemotherapy, immunotherapy or hormonal therapy within 7 days of randomisation - previous treatment wiuth temozolomide - RT to ≥ 50% of bone marrow - females who were pregnant or nursing and not suing birth control if of childbearing age. Population Temozolomide + WBRT: N = 47, 30 males, median age = 59 (range 38-78) years. median Karnofsky PS = 90 (range 70- 100); extracranial metastases No / Yes: N = 21/26; no previous chemotherapy: N = 38. NSCLC controlled / uncontrolled: 24/23. WBRT control: N = 48, 32 males, median age = 62 (range 43-79) years. median Karnofsky PS = 90 (range 70-100); extracranial metastases No / Yes: N = 20/28; no previous chemotherapy: N = 28. NSCLC controlled / uncontrolled: 25/23.

The two treatment groups did not differ significantly on any of these baseline characteristics except that more temozolomide patients had BMs at presentation and had received previous chemotherapy (both ps < .05) than WBRT control patients. Interventions All patients:WBRT (30 Gy in 10 fractions over 2 weeks) including ≥ 4 mg dexamethasone (or steroid equivalent) during WBRT and for 1 week thereafter + (in the first part of the trial before it was converted from a double-blind phase III trial to an open-label phase II trial) 75 mg/m2 temozolomide/placebo daily for 21 days starting on day 1 of WBRT and then 7– day rest (schedule A). Schedule A was subsequently amended so that the temozolomide patients received 75 mg/m2 temozolomide daily for 28 days followed by a 7-day rest while the placebo (now control) patients received WBRT alone (i.e., no placebo) for 2 weeks followed by a 7-day rest (Schedule B). Systemic treatment was allowed only after completion of treatment + a 7-day rest period. Temozolomide doses were withheld/drawn depended on toxicity and treatment day. Outcomes Overall survival, CNS progression, toxicity Results Treatment delivery:

- 43 temozolomide + WBRT patients and 46 WBRT control patients completed treatment. Survival: Temzolomide + WBRT patients (median = 4.4 months) = WBRT alone patients (median = 5.7 months; p = .59; HR = 1.14; 95% CI .71-1.83). Similar analyses by schedule (A, N = 45; B, N = 50) did not reveal any significant differences in survival either. CNS progression: Temzolomide + WBRT patients (median = 3.1 months) = WBRT alone patients (median = 3.8 months; p = .95; HR = 1.01; 95% CI .64-1.62). Similar analyses by schedule (A, N = 45; B, N = 50) did not reveal any significant differences in survival either. Toxicity: Temozolomide + WBRT patients: Most frequently reported adverse events (all grades): Nausea (36%), vomiting (28%), alopecia (26%), fatigue (17%), anorexia (15%) and constipation (15%), whether or not the analyses were restricted to BM. 1 possible treatment-related death occurred. Incidence of adverse events = 81%. Incidence of grade 3/4 haemotology and blood chemistry findings were infrequent with exception of lymphopenia which was 31%. WBRT control patients: Incidence of adverse events = 65%. Incidence of grade 3/4 haemotology and blood chemistry findings were infrequent with exception of lymphopenia which was 18%. General comments Patients in this trial were randomised with stratification for presence/absence of extracranial metastases and controlled/uncontrolled systemic disease. No further details are provided regarding the randomisation method, and it is therefore unclear whether the randomisation method employed was adequate, whether the patients were centrally randomised and whether allocation concealment was used. Furthermore, no level of blinding was employed, and although the data were analysed according to the intention-to-treat principle and initial power analyses were carried out, the study does not appear to have been powered to detect a survival difference that was less-than-double the median survival time in the control group which suggests that the study may be under-powered. The evidence provided by the current trial can therefore be regarded as low quality evidence. References of Included Studies: N/A

Citation: Dae, H. L. Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first: Result of a randomized pilot study. Cancer 113[1], 143-149. 2008. Design: Randomised pilot study Country: Korea

Aim: To compare the effectiveness of chemotherapy followed by whole brain radiotherapy (WBRT) to the effectiveness of WBRT followed by chemotherapy for the treatment of chemotherapy-naive patients with non small cell lung cancer (NSCLC) and synchronous brain metastasis (BM) who has either no neurologic symptoms or signs or neurologic signs and symptoms controlled by supportive care. Inclusion criteria Patients with - pathologically confirmed NSCLC, - BM for which surgery was not deemed appropriate or indicated either because of the number (ie, ≥ 3) or the location of metastatic lesions (ie, the brain metastases located in the critical area that might cause significant neurological sequel after resection). - BM from which patients had no or minimum neurologic symptoms or signs, which were easily controlled by supportive care only, including the administration of corticosteroids. - aged 18-75 years - Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 - bidimensionally measurable lesion(s) in both intracranial and extracranial site - adequate bone marrow, hepatic, and renal functions - no prior chemotherapy or molecular-targeted therapy.

Exclusion criteria Population Ch+WBRT group: N = 25, 19 males, median age = 60 (range 41-70) years. ECOG PS 0-1/2: N = 25/0; Histology adeno/squamous/large cell/NSCLC NOS: N = 23/0/0/2; BM < 3/≥3: N = 9/16; Extracranial extrathoracic metastasis absent/present: N = 3/22.

WBRT+Ch group: N = 23, 19 males, median age = 62 (range 45-75) years. ECOG PS 0-1/2: N = 22/1; Histology adeno/squamous/large cell/NSCLC NOS: N = 17/4/1/1; BM < 3/≥3: N = 8/15; Extracranial extrathoracic metastasis absent/present: N = 2/21. The two treatment groups did not differ significantly on any of these baseline characteristics. Interventions Group Ch + WBRT: 6 cycles of chemotherapy or until disease progression/unacceptable toxicity/patient withdrawal followed by WBRT which was administered regardless of the development of neurologic symptoms or signs. Group WBRT + Ch: WBRT followed by chemotherapy after a minimum of 2 weeks of rest and only when ANC ≥ 1500/mm3, the platelet count ≥ 100,000/mm3, and all nonhematologic toxicities except alopecia = grade 0-1. Chemotherapy was continued until disease progression/unacceptable toxicity/patient refusal/completion of 6 cycles.

Chemotherapy: Up to 6 3-weekly cycles of gemcitabine 900 mg/m2 and vinorelbine 25 mg/m2 on Days 1 and 8. WBRT: 30 Gy in 10 fractions over 12 days Outcomes Response, survival, QoL, toxicity Results Treatment delivery: Ch+WBRT group: All patients received WBRT after disease progression/completion of chemotherapy with none displaying progressive neurologic symptoms or signs at the start of WBRT. WBRT + MGd group: 4/23 patients did not receive chemotherapy due to PS deterioration or death. 19/23 patients received chemotherapy according to the protocol. . Overall response rate: WBRT + Ch patients (9 PR, 4 SD, 6 PD, 4 NA) = Ch + WBRT patients (extra cranial: 7 PR, 10 SD, 8 PD; intracranial: 7 PR, 11 SD, 7 PD). Non significant Progression-free survival: Ch + WBRT group (3.6 months) = WBRT + Ch group (4.4 months; p = .62) Measured after a median follow-up of 40 months (range 20–59 Survival: Ch + WBRT group (9.1 months) = WBRT + Ch group (9.9 months; p = .61) Measured after a median follow- up of 40 months (range 20–59 Grade 3 or 4 neutropenia: Ch + WBRT group (40%) < WBRT + Ch (79%; p =.014). Other toxicities: The frequencies of other severe toxicities did not differ between the groups except for alopecia and mild headache or dizziness; both were more frequent in the WBRT + Ch group. No further inferential statistics reported QoL (N = 33): Baseline: Ch + WBRT = WBRT + Ch. No further inferential statistical results reported. Salvage Therapy on Progression: 15 Ch + WBRT patients received further salvage chemotherapy after the frontline gemcitabine/vinorelbine therapy and WBRT. 12/19 WBRT + Ch patients who received gemcitabine/vinorelbine therapy as first-line chemotherapy per protocol received further salvage chemotherapy. “none of the patients in either group demonstrated a deterioration in neurologic signs or symptoms during the chemotherapy follow-up period. No patient required any surgical resection or stereotactic radiosurgery during this period.” Page 146 General comments Patients in this open label randomized study were randomised with stratification for ECOG PS, the number of intracranial metastases and the presence of extracranial extrathoracic metastasis. It is unclear which method of randomisation was employed and whether allocation concealment was used, and although all the patients were included in the efficacy and safety analyses, it would appear that the study is under-powered. The evidence provided by the current trial can therefore be regarded as low quality evidence. References of Included Studies: N/A

Citation: Fuentes, R., Bonfill, C.X., & Expósito, H.J. (2006). Surgery versus radiosurgery for patients with a solitary brain metastasis from non-small cell lung cancer. Cochrane Database of Systematic Reviews: Reviews, 1. Design: Cochrane Systematic Review Country: Various

Aim: To assess the effectiveness of surgery compared to radiosurgery, either administered alone or in combination with whole brain radiotherapy, in patients with a solitary brain metastasis from successfully treated non-small cell lung cancer.

Inclusion criteria RCTs and controlled trials comparing surgery (with or without whole brain irradiation) with all types of radiosurgery (with or without whole brain irradiation) in patients above 18 years old with histologically proven non small cell lung cancer whose primary tumour was in complete remission at the time of solitary brain metastasis diagnosis and who had a contrast enhanced CT or MRI scan as part of their initial evaluation for solitary brain metastases resulting from non-small cell lung cancer. Studies meeting these criteria and also employing equal chemotherapy treatment regimens between the study groups were also considered eligible. Exclusion criteria Other study designs Studies including patients with multiple brain metastases or patients with synchronous or uncontrolled primary lung tumour and a single brain metastasis. Studies where the diagnosis was made without the use of CT or MRI exams. Population See Results section. Interventions Megavoltage stereotactic radiotherapy, with or without relocatable frame, using single or multiple fractions and Leksell gamma knife radiosurgery, including studies with additional whole brain irradiation.

Any kind of tumour excision surgery, including studies where patients were treated with additional whole brain irradiation.

Studies where the chemotherapy regimens differed between the study groups were excluded. Outcomes 1) Overall survival from diagnosis of solitary brain metastasis, 2) Disease-free survival from diagnosis of a solitary brain metastasis 3) Overall survival from first diagnosis of non small cell lung cancer, and 4) Survival free of brain relapse 5) Treatment related toxicity of radiosurgery and complications of surgery 6) Quality of life Results A comprehensive literature search of The Cochrane Central Register of Controlled Trials (2004, issue 2), MEDLINE (1966- prersent), EMBASE (1974-present) CINAHL (1982-present) and the Cochrane Lung Cancer Specialised Register revealed no eligible studies for inclusion in this review. General comments The authors reason that including studies of other designs than RCT and controlled trials would have resulted in misleading findings and conclude that an appropriate randomized trial needs to be carried out in order to determine which technique is superior for patients with solitary brain metastasis from non small cell lung cancer. References of Included Studies (For systematic reviews):

Citation: Gerosa,M.; Nicolato,A.; Foroni,R.; Tomazzoli,L.; Bricolo,A. (2005). Analysis of long-term outcomes and prognostic factors in patients with non-small cell lung cancer brain metastases treated by gamma knife radiosurgery. Journal of Neurosurgery, 102 (suppl), 75-80. Design: Retrospective observational study Country: Italy

Aim: To evaluate the longterm outcomes and the association between survival and potential prognostic factors in patients who have received gamma knife radiosurgery (GKS) for brain metastases (BM) from non-small cell lung cancer (NSCLC). Inclusion criteria NSCLC patients treated with GKS for brain metastases between 1993 and 2003 with

- Karnofsky performance score ≥ 60, - estimated life expectancy ≥ 4 months, - no rapidly evolving intracranial mass effect, - 3 or fewer lesions with max overall volume of 20 ml, - targets well-defined on the neuroimages and - attending follow-up appointments for min 4 months. Exclusion criteria Population 504 patients (321 males) with a mean age = 61.5 (range 25-84) years. Mean follow-up = 16 months (range 4-13 months). 31% had solitary lesions, 29% had single lesions and 40% had multiple lesions. Interventions Prognostic factors evaluated: - age, - KPS, - gender, - oncotype of primary tumour, - stage of primary tumour, - number of BM, - whole brain radiotherapy (WBRT), - recurrence of BM, - mean tumour volume, - edge GKS dose, - maximum GKS dose. These variables were used to form Recursive Partitioning Analysis classes which were used in the analyses. Outcomes Survival Results 1-year local tumour control was 94% (consisting of substantial tumour disappearance (16%), shrinkage (60%), and stable imaging (18%)). Recurrence rate = 9%, mean time to recurrence = 45 weeks. 1-year actuarial progression-free survival = 95%. Mean palliation index = 53 weeks, Functional independence index = 50 weeks Cause of death: Ascertainhed in 253/328 patients of which systemic progression accounted for 61.8% and neurological progression accounted for 17.7% (= 6.3% local and 11.4% distal) Median overall survival = 14.5 months. - Survival was prolonged in the patients with solitary BM compared to patients with single or multiple BM (p < .01). The difference in survival between patients with multiple and single BM was not significant. - Survival was prolonged in the patients with RPA 1 compared to RPA 2 and 3 (p < .0001). - Survival was prolonged in patients with adenocarcinoma compared to other histological types (p < .001). - Total targeted tumour volume and the edge dose were not found to be significant prognostic factors. General comments The authors conclude that “Analysis of long-term outcomes seems to confirm that GKS is a primary therapeutic option in NSCLC brain metastases. The RPA classification is the dominant prognostic factor concerning the outcome of treatment.” (p. 79).

The number of participants in this study is likely to mean that the study is adequately powered for the analyses calculated on all the participants. However, the statistical reporting is lacking and makes it difficult to evaluate the results in detail. In addition, the retrospective nature of this study means that this evidence cannot be considered of high quality. References of Included Studies (For systematic reviews): N/A

Citation: Guerrieri,M.; Wong,K.; Ryan,G.; Millward,M.; Quong,G.; Ball,D.L. (2004). A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung. Lung cancer, 46, 107-11. Design: Two-centre RCT Country: Australia

Aim: To assess the effectiveness of carboplatin chemotherapy in addition to whole brain irradiation compared to whole brain irradiation alone in terms of response and survival in patients with brain metastases from non-small cell lung cancer (NSCLC). Inclusion criteria Patients with - histologically or cytologically proven NSCLC, and - ≥ 1 brain metastases according to CT or MRI scans, and - either inoperable CNS disease or who had refused surgery, and - WHO performance status between 0-2, and - neutrophil count ≥ 1.5 x 109 / L, and - platelet count ≥ 100 x 109 / L, and - urinary creatinine clearance ≥ 50 mL / min, and - have provided written informed consent. Exclusion criteria Prior chemotherapy or brain irradiation. Population Planned accrual = 300 patients over 4 years, but trial was terminated early due to yearly accrual of ≤15 patients. This satisfied the early stopping rule specified in the trial protocol. 43 patients randomised (1 patient excluded from analyses as this patient should not have been included in study due to low creatine clearance) into two groups of 21:

Control group: 15 males and 6 females with median age of 60 years (range: 42-77). 2 patients had squamous cell carcinoma, 8 had adenocarcinoma, 8 had large cell, and 3 had other histological type. 5 patients had single and 16 patients had multiple brain metastases. 3, 14 and 4 patients had WHO performance status of 0, 1, and 2, respectively, and 13, 7 and 1 patients had neurological functional status of 1, 2 and 3, respectively.

Intervention group: 15 males and 6 females with median age of 63 years (range: 39-78). 9 patients had squamous cell carcinoma, 8 had adenocarcinoma, 3 had large cell, and 1 had other histological type. 6 patients had single and 15 patients had multiple brain metastases. 3, 7 and 11 patients had WHO performance status of 0, 1, and 2, respectively, and 8, 8 and 3 patients had neurological functional status of 1, 2 and 3, respectively.

The authors state that “The randomised treatment arms were well-balanced with respect to age, sex and number of brain metastases, but patients on the combined [=intervention] modality arm had somewhat better performance status, neurological function status and fewer CNS signs and symptoms.” No statistics were presented to support this statement. Interventions Control group: Whole brain radiotherapy: Opposed 6MW lateral beams. Mid-plane dose of 20 Gy in 5 fractions over 1 week.

Intervention group: As control group in addition to intravenous infusion of 70 mg / m2 carboplatin per day 30-60 min before every radiotherapy dose.

Steroids, but no other systemic treatments, were administered at the discretion of the investigator based on clinical symptoms. Outcomes - survival,

- objective response rate (assessed 6 weeks after commencing treatment with a CT or MRI scan according to the WHO criteria), - symptom control (assessed by the presence/absence of neurological symptoms/signs, performance status according to the WHO grade, neurological function status and steroid dose), - time to symptomatic neurological progression, - gastrointestinal and haematological toxicity. Results All analyses used intention-to-treat analyses Survival: • Median survival in the control (WBRT) and intervention groups (WBRT+C) were 4.4 (95% CI: 2.0-5.1 months) and 3.7 months (95% CI: 2.7-5.8 months), respectively, and these were not significantly different (p = .64). • The estimated survival for all patients was 3.7 months (95% CI: 3.0-4.8 months), with a 12% (95% CI: 5 – 26%) 12 month survival.

Objective response: • 10 and 5 patients in the control and intervention groups, respectively, were not assessed for this outcome mainly due to death before assessment. • 1 patient in the intervention group had a complete response. • The objective complete and partial response rate was 10% (95% CI: 1- 30%) and 29% (95% CI: 11- 52%) in the evaluable patients in the control and intervention groups, respectively, which was not significantly different (p = .24).

Symptom control: • 9 and 3 patients in the control and intervention groups, respectively, were not assessed for this outcome and the authors did not conduct any statistical comparisons between the groups due to this imbalance. • Descriptively, symptom control compared to pre-treatment improved in 8 and 6 patients, did not change in 1 and 5 patients and increased in 2 and 7 patients in the control and intervention groups, respectively. • Descriptively, WHO performance status compared to pre-treatment improved in 2 and 1 patients, did not change in 6 and 5 patients and worsened in 3 and 12 patients in the control and intervention groups, respectively, and, descriptively, neurological function status compared to pre-treatment improved in 2 and 2 patients, did not change in 7 and 8 patients and increased in 2 and 8 patients in the control and intervention groups, respectively.

Toxicity: The authors report that there were no differences between the groups on this outcome, but provide no statistics to support this claim.

Prognostic factors: The only significant prognostic factor found to affect overall survival was WHO performance status with estimated mean survivals of 7.6, 3.7, and 3.0 months for WHO 0, 1 and 2, respectively (p = .019 for trend), and this factor remained the only significant prognostic factor after controlling for the effects of treatment. General comments The authors conclude that due to poor accrual and the generally low survival rates of this population no firm conclusions about the potential benefits of concomitant carboplatin chemotherapy to whole brain radiation can be drawn on the basis of this study. Methodologically, the study is also potentially compromised by the apparent absence of allocation concealment and any level of blinding, the latter of which should at least have been implemented, if at all practically possible, during the assessment of the outcomes. More descriptive detail of patient recruitment, randomisation and outcome assessment is required in order to adequately assess the potential level and direction of bias in this report. References of Included Studies (For systematic reviews): N/A

Citation: Kepka,L.; Cieslak,E.; Bujko,K.; Fijuth,J.; Wierzchowski,M. (2005). Results of the whole-brain radiotherapy for patients with brain metastases from lung cancer: the RTOG RPA intra-classes analysis. Acta Oncologica, 44, 389-98. Design: Retrospective observational study Country: Poland

Aim: To evaluate the association between survival and potential prognostic factors in patients with brain metastases

(BM) from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) who have received whole brain radiotherapy (WBRT). Inclusion criteria NSCLC and SCLC patients treated with WBRT for brain metastases between 1986 and 1997. BM had been confirmed by CT or MRI, and the patients had received dexamethasone during WBRT, and had no prior radiotherapy to the brain. Exclusion criteria Population 322 patients (232 men/90 women) with a median age = 59 (range 31-79) years. 241/322 were below 65 years old and 81/322 were aged 65 or above. 66/322 had a Karnofsky performance status (KPS) below 70, and 256 had a KPS of 70 or above. 124/322 had single BM, 190/322 had multiple BM, and 8/322 had unknown number of BM. 229/322 had no extracranial metastases whereas 83/322 had, and it was unknown whether 10/322 had extracranial metastases. The BM were synchronous in 147/322 patients whereas they were metachronous in 175/322. 44/322 had and 278/322 had not received previous surgery for BM. 132/322 had SCLC and 190/322 had NSCLC of whom 67(/190) had squamous carcinoma, 76 had adenocarcinoma, 3 had large cell carcinoma and 44 had unspecified NSCLC. The primary tumour was controlled in 88/322 and not controlled in 222/322 patients, and tumour control was unknown in 12/322.30/322 had and 292/322 had not received surgery as part of the treatment of the primary cancer.41/322 patients had a recursive partioning analysis (RPA) class of 1, 215/322 had an RPA class of 2, and 66/322 had an RPA class of 3 (RPA 1 = KPS ≥ 70, age < 65 years, no extracranial metastases, and a controlled primary tumor; RPA 3 = KPS <70; RPA 2 = all others).

WBRT: 33% patients received a total dose of 20 Gy (5 X 4 Gy, 5 days a week). 57% of patients received a total dose of 30 Gy (10 X 3 Gy, 5 days a week), and 10% of patients received a total dose of 40 Gy (10 X 4 Gy, 5 days a week, in 2 courses of 20 Gy with 1-2 month interval between courses) Interventions Prognostic factors evaluated: - age (< 65 vs ≥ 65 and as a continuous variable), - sex, - KPS (< 70 vs ≥ 70), - control of primary tumour, - histology (NSCLC vs SCLC), - number of BM (single vs multiple), - extracranial metastases, - interval from primary diagnosis to development of BM (synchronous vs metachronous), - RPA class (1, 2, 3) Outcomes Survival Results Median survival: All patients: 4 months; RPA 1, 2 and 3 had median survivals of 5.2, 4 and 2.5 months, respectively (p = .003).

All patients: Multivariate analysis (included all significant factors in the univariate analysis). - The following prognostic factors were significantly associated with survival: Presence of extracranial metastases (relative risk (RR) = 1.32; 95% confidence interval (CI) 1.16–1.49; p = .00002), KPS (RR = .63 [for ≥ 70]; 95% confidence interval (CI) .47–.82; p = .003), RPA class (RR = 1.27 [per class]; 95% confidence interval (CI) 1.02– 1.59; p = .03) and control of primary tumour (RR = .98 [for controlled]; 95% CI .97–.99; p = .02). PLEASE NOTE, the authors state that these factors were significant when tested independently without providing additional detail. – And this makes the analysis appear more univariate than multivariate, in effect, and should therefore be interpreted with caution.

Patients split by histology: - NSCLC: Multivariate analyses: The following prognostic factors were found to be significantly associated with survival: Having no extracranial metastases (RR = 1.35; 95% CI 1.23–1.62; p = .001) and having metachronous BM (RR = .68 [for metachronous]; 95% CI .59–.92; p = .01).

- SCLC: Multivariate analyses (RPA class not included due to low N): The following prognostic factors were found to be significantly associated with survival: Having single BM (RR = 1.82; 95% CI 1.55–2.83; p = .007), having no extracranial metastases (RR = 1.28; 95% CI 1.06-1.56, p = .01) and KPS ≥ 70 (RR = .55 [for ≥ 70]; 95% CI .35–.87; p = .01).

Patients split by RPA class: - RPA 1: Multivariate analyses: Having had previous surgery for BM was significantly associated with survival (RR = 1.99 [for no surgery]; 95% CI 1.03-3.82, p = .04). - RPA 2: Multivariate analyses: Having had previous surgery for BM (RR = 1.76 [for no surgery]; 95% CI 1.07-2.93, p = .04), having no extracranial metastases (RR = 1.27 [for extracranial metastases]; 95% CI 1.09-1.48, p = .003), being female (RR = .62 [for female]; 95% CI .46-.81, p = .003), and having a high total dose of Gy (RR = .97 [by 10 Gy]; 95% CI .95-.99, p = .002) were significantly associated with survival. - RPA 3: Multivariate analyses: Having no extracranial metastases (RR = 1.4 [for extracranial metastases]; 95% CI 1.07-1.82, p = .01) and having a high total dose of Gy (RR = .96 [by 10 Gy]; 95% CI .73-.99, p = .02) were significantly associated with survival. General comments The number of participants in this study is likely to mean that the study is adequately powered for the analyses calculated on all the participants. However, the low number of participants in some of the cells of the subgroup analyses and the retrospective nature of this study mean that this evidence cannot be considered of high quality. References of Included Studies (For systematic reviews): N/A

Citation: Kim,D.Y.; Lee,K.W.; Yun,T.; Kim,D.W.; Kim,T.Y.; Heo,D.S.; Bang,Y.J.; Kim,N.K. (2005). Efficacy of platinum-based chemotherapy after cranial radiation in patients with brain metastasis from non-small cell lung cancer. Oncology Reports, 14, 207-11. Design: Retrospective observational study Country: Korea

Aim: To assess the efficacy of systemic platinum-based chemotherapy after cranial radiation compared to cranial radiation alone in patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). Inclusion criteria Patients diagnosed with NSCLC with synchronous BM who had undergone radiotherapy (RT) for the BM. BM was on the basis of neurologic signs and symptoms and not neuroimaging. Exclusion criteria Patients - who did not received RT for BM, - with a diagnosis of combined leptomeningeal carcinomatoses using neuroimaging or lumbar spinal puncture - with an ECOG performance status of 3 or 4, - who had been treated by surgical resection or RT for thoracic lesion and had received open surgical removal of BM, - where the primary site of BM may not have been lung. Population N = 63 (this is out of a possible 82 eligible patients – unclear why not all 82 patients were included) These patients were split into 2 groups:

Cranial RT alone and best supportive care: N = 32, 21 males, median (mean?) age = 57.7 years (range 38-78). Adenocarcinoma (n = 19), squamous cell carcinoma (n = 6), non-small cell (n = 7). Number of BM: 1 (n = 10), 2 (n = 2), > 2 (n = 20). Extracranial metastasis: absent (n = 10), present (n = 22). Pathological TNM stage (excluding BM): I (n = 2), II (n = 3), IIIa (n = 1), IIIb (n = 4), IV (n = 22). ECOG performance status: 1 (N = 18), 2 (n = 14). Type of brain RT: whole brain RT (N = 23), gamma-knife (n = 9). Neurologic response of RT: Improved (n = 24), stable (n = 3), aggravated (n = 4), not evaluable (n = 1). 18/32 patients did not receive systemic chemotherapy as it was not judged to be likely to confer any survival benefit, 7/32 patients refused chemotherapy, 4 patients experienced aggravation of performance status before initialisation of chemotherapy and 3 patients were lost to follow up after being recommended chemotherapy.

Cranial RT + chemotherapy: N = 31, 22 males, median (mean?) age = 54.2 years (range 40-70). Adenocarcinoma (n = 19), squamous cell carcinoma (n = 5), non-small cell (n = 7). Number of BM: 1 (n = 12), 2 (n = 2), > 2 (n = 17). Extracranial metastasis: absent (n = 16), present (n = 16). Pathological TNM stage (excluding BM): I (n = 1), II (n = 2), IIIa (n = 2), IIIb (n = 10), IV (n = 16). ECOG performance status: 1 (N = 21), 2 (n = 10). Type of brain RT: whole brain RT (N = 27), gamma-knife (n = 4), both (n = 1). Neurologic response of RT: Improved (n = 27), stable (n = 3), aggravated (n = 1). Median interval from initiation of cranial RT to firstline chemotherapy = 4.3 (range 0-7.6) weeks.

The above clinical characteristics did not statistically significantly differ between the groups which also did not differ in terms of neurologic signs and symptoms. Interventions Cranial RT: Whole brain RT or stereotactic RT determed on the basis of number, size and location of BM. Radiation treatments were customised for each patient. Radiation dosage of whole brain RT ranged 30-40 Gy. Corticosteroid administration was tailored to the individual patient. Chemotherapy: Platinum-based combination chemotherapy according to the choice of the treating oncologist and adjusted in line with clinical characteristics of the patients (e.g., if the platelet count < 100 000/mm3). Chemotherapy was continued for at least 6 cycles in the absence of disease progression and severe toxicity. 3 more cycles were added if the extracranial response was better than stable disease and no neurological aggravation occurred after 6 cycles or further systemic chemotherapy was postponed until the disease progressed. Systemic chemotherapy was discontinued when the performance status worsened to 3 or 4. Outcomes Chemotherapy-related toxicity and response Survival (measured from time of initiation of cranial RT). Results Chemotherapy response: - Firstline chemotherapy:The most common firstline regimen was a paclitaxel/platinum combination (38.7%) followed by gemcitabine/cisplatin (25.8%), vinorelbine/cisplatin (25.8%) and docetaxel (9.7%). ‘Progression of extracranial lesion’ was the main cause of failure of firstline chemotherapy (58.1%) followed by ‘aggravation of neurologic status’ (19.4%) and ‘aggravation of both’ (9.7% / n = 3). - -Second line chemotherapy: N = 17. Reasons for failure were ‘progression of the extracranial lesion’ (41.7%), ‘aggravation of neurologic status’ (17.6%), and ‘simultaneous aggravation of both’ (4%). Chemotherapy-related toxicity: 4 cycles of grade 3-4 leukopenia and 1 cycle of grade 4 serum transaminase elevation were observed (according to WHO criteria) in 120 cycles of firstline chemotherapy. 2 cycles of grade 3-4 leukopenia were observed in 58 cycles of second line chemotherapy. No treatment-related mortality occurred. Survival: Median oveall suvival = 19 (range 4.9-93) weeks and 58.1 (range 7.4-177.4) weeks in the cranial RT only group and chemotherapy group, respectively (p < .001). General comments

The authors conclude: “We suggest that the presence of inoperable BM should not alter the treatment approach to patients with metastatic NSCLC; disseminated disease requires systemic treatment and this can be provided by chemotherapy. Further randomized studies are warranted to compare radiation alone with sequential radiochemotherapy for NSCLC with BM to confirm the benefit of chemotherapy in this situation.” (p. 211)

The results of this study must however be tempered by the fact that the patient numbers are very low in both groups and further by the different chemotherapy regimens used within the chemotherapy group which makes it difficult to draw any firm conclusions regarding specific chemotherapy regimens. An additional limitation of this study concerns its retrospective design, and collectively, these factors mean that the evidence provided by this study is not of high quality. References of Included Studies (For systematic reviews): N/A

Citation: Lee,D.H.; Han,J.Y.; Kim,H.T.; Yoon,S.J.; Pyo,H.R.; Cho,K.H.; Shin,S.H.; Yoo,H.; Lee,S.H.; Lee,J.S. (2008). Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first : result of a randomized pilot study. Cancer, 113,

143-49. Design: Single-centre pilot RCT Country: Korea

Aim: To compare the feasibility of primary chemotherapy in terms of efficacy, survival, toxicity, and quality of life (QoL) with whole brain radiotherapy (WBRT) given first in chemotherapy-naïve patients with non-small cell lung cancer (NSCLC) and synchronous brain metastases (BM) that are either asymptomatic or controlled by supportive care. Inclusion criteria Patients with: - Pathologically confirmed NSCLC, - clinically silent BM not appropriate for surgery either due to number (> 2) or location (Note ‘clinically silent’ = lesions from which patients had no or minimum neurologic signs or symptoms, that were easily controlled by supportive care only (incl corticosteroids)). - aged 18 - 75 years, - ECOG performance status of 0-2, - bidimensionally measurable lesions in both intra- and extracranial site, - white blood cell count ≥ 4000/mm3, - absolute neutrophil count (ANC) ≥ 1500/mm3, - platelet count ≥ 100 000/mm3, - haemoglobin counts ≥ 10mg/dL, - alanione aminotransferase or aspartate aminotransferase ≤ 2.5 times the upper limit of normal, - serum bilirubin ≤ 1.2 mg/dL, - serum creatinine ≤ 1.5 mg/dL, and - no prior chemotherapy or molecular-targeted therapy. Exclusion criteria Population Stratification according to performance status (0-1 vs 2), number of BM (1-2 vs > 2) and presence/absence of extrathoracic metastasis. Chemotherapy + WBRT: N = 25, 19 males, median age = 60 (range 41-70) years. Performance status: 0-1 (n = 25), 2 (n = 0). Histology: adenocarcinoma (n = 23), NSCLC-not otherwise specified (n = 2). Number of BM: 0-2 (n = 9), > 2 (n = 16). Extracranial, extrathoracic metastasis: absent (n = 3), present (n = 22). 15 received further salvage chemotherapy after the frontline chemotherapy therapy + WBRT. Regimens used in the salvage second-line therapy included irinotecan plus cisplatin (n = 6), paclitaxel plus cisplatin (n = 2), docetaxel plus capecitabine (n = 2), docetaxel plus cisplatin (n = 1),single-agent docetaxel (n = 2), and gefitinib (n = 2).

WBRT + chemotherapy: N = 23, 19 males, median age = 62 (range 45-75) years. Performance status: 0-1 (n = 22), 2 (n = 1). Histology: adenocarcinoma (n = 17), squamous cell carcinoma (n = 4), large cell carcinoma (n = 1), NSCLC-not otherwise specified (n = 1). Number of BM: 0-2 (n = 8), > 2 (n = 15). Extracranial, extrathoracic metastasis: absent (n = 2), present (n = 21). 4/23 patients did not receive chemotherapy due to early death (n = 2) or deterioration in performance status (n = 2). 12 patients received further salvage chemotherapy. Regimens used in salvage second-line setting included irinotecan plus cisplatin (n = 4), paclitaxel plus cisplatin (n = 1), docetaxel plus cisplatin (n = 2), docetaxel plus capecitabine (n = 1), and gefitinib (n = 4).

None of the clinical characteristics listed differed significantly between the groups (all ps > .1). Interventions Chemotherapy consisted of 900 mg/m2 gemcitabine and 25 mg/ m2 vinorelbine given on days 1 and 8 and repeated every 3 weeks. WBRT consisted of 30 Gy administered over 12 days in 10 fractions Chemotherapy + WBRT: Chemotherapy administered in up to 6 cycles or until disease progression, unacceptable toxicity or patient withdrawal and then followed by WBRT which was administered regardless of the development of neurologic signs or symptoms. WBRT + chemotherapy: WBRT administered first followed by chemotherapy which was commenced after at least 2 weeks of rest after completion of WBRT and only when ANC ≥ 1500/mm3 and platelet count ≥ 100 000/mm3, and all nonhematologic toxicities except alopecia had recovered to grade 0 or 1. Chemotherapy was continued until disease

progression, unacceptable toxicity or patient withdrawal, or for a maximum of 6 cycles.

Outcomes Response rates Progression-free survival = interval between the start of chemotherapy and disease progression/death Overall survival = interval between randomisation and death Toxic effects Quality of life: Measured by the EORTC’s QLQ-C30 and L13. Results Median follow up = 40 months (range 20 – 59) Overall response rates: The 2 groups did not differ in overall response rates (no statistics reported). Disease-free survival: Medians = 3.6 and 4.4 months in the chemotherapy-first and WBRT-first groups, respectively (p = .62). Overall survival: Medians = 9.1 and 9.9 months in the chemotherapy-first and WBRT-first groups, respectively (p = .61). Toxic effects: Grade 3-4 neutopenia occurred in 40% and 79% of patients in the chemotherapy-first and WBRT-first groups, respectively (p = .014). The frequency of mild headache, dizziness and alopecia were also reported to be higher in the WBRT-first group compared to the chemotherapy-first group, although no statistics are reported. Quality of life (QoL): This variable was assessed in 33 patients starting from patient number 16th for unexplained reasons. The QoL section also presents no statistics to clarify statements such as “as chemotherapy proceeded, cognitive function in the primary chemotherapy arm became impaired, whereas that in the WBRT-first arm improved slightly from the most impaired score immediately after WBRT” (p 146). No data on this variable should therefore be considered from this study. General comments A number of methodological issues render the results of this RCT unconvincing or, at least, potentially questionable. It is, for example, not clear which method of randomisation was employed or whether there was allocation concealment. It is therefore not possible to adequately evaluate the potential presence of a patient recruitment and/or selection bias. With regards to blinding, it is not obviously clear how complete blinding would be achieved in a study such as the present RCT, however blinding of the personnel assessing the outcomes should have been carried out and this does not appear to have been the case. On the other hand, although there is no mention of intention-to-treat analysis, the data appear to have been analysed according to this principle.

Therefore, on the basis of the above evaluation in combination with the low patient numbers in each treatment group, this study cannot be considered high quality evidence. References of Included Studies (for systematic reviews): N/A

Citation: Le, Péchoux C., Dunant, A., Senan, S., Wolfson, A., Quoix, E., Faivre-Finn, C., Ciuleanu, T., Arriagada, R., Jones, R., Wanders, R., Lerouge, D., Laplanche, A., and Prophylactic Cranial Irradiation (PCI) Collaborative Group. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. The Lancet Oncology 10[5], 467-474. 2009. Design: Multi-centre RCT Country: International

Aim: To compare a standard dose prophylactic cranial irradiation (PCI; consisting of 25 Gy in 10 daily fractions of 2.5 Gy) to a high dose PCI (consisting of 36 Gy delivered either in 18 daily fractions of 2 Gy or in 24 fractions over 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h) in patients with limited disease (LD) small cell lung cancer (SCLC) in complete remission after chemotherapy and thoracic radiotherapy (RT). Inclusion criteria Patients with - histologically proven limited-stage SCLC in complete remission after initial treatment - no evidence of brain or leptomeningeal metastases either on brain CT scans or MRI - a baseline quality of life assessment and baseline clinical neurological assessment

- age ≤ 70 years (except for patients randomised through the Radiation Therapy Oncology Group (RTOG), where no age limit was applied) - WHO performance status ≤ 2. Exclusion criteria Patients with a past history of cerebrovascular disease, cancer (except in-situ uterine cervix carcinoma or skin carcinoma), or epilepsy requiring continuous treatment. Population Standard dose (SD) group: N = 360, 234 males, median age = 60 (range 38-83) years. Receipt of platinum-containing regimen: N = 323; median interval between start of induction treatment and randomisation = 142 (range 39-379) days; PCI delivered: N = 355; Delay between randomisation and start of PCI > 15 days: N = 61; Median time between start of induction treatment and start of PCI = 151 (range 40-383) days; Median time between end of induction chemotherapy and start of PCI = 46 (range 0-318) days; chemotherapy after PCI: N = 32; Thoracic irradiation: N = 341. High dose (HD) group: N = 360, 226 males, median age = 60 (range 34-78) years. Receipt of platinum-containing regimen: N = 333; median interval between start of induction treatment and randomisation = 147 (range 0-363) days; PCI delivered: N = 356; Delay between randomisation and start of PCI > 15 days: N = 58; Median time between start of induction treatment and start of PCI = 154 (range 1-367) days; Median time between end of induction chemotherapy and start of PCI = 42 (range 3-271) days; chemotherapy after PCI: N = 31; Thoracic irradiation: N = 344.

None of the clinical characteristics listed differed significantly between the groups (no statistics reported). Interventions SD group: PCI consisting of 25 Gy in 10 daily fractions of 2.5 Gy excluding weekends HD group: PCI consisting of 36 Gy administered either - in 18 daily fractions of 2 Gy (group HD-conventional) excluding weekends, or - in 24 fractions of 1.5 Gy given twice daily for 12 days with a minimum interval of 6 h (group HD-accelerated) excluding weekends. Within RTOG, there was a second randomisation in the HD-group to either group HD-conventional or group accelerated.

The target volume for PCI was the whole brain, extended to the lower border of the second cervical vertebra. PCI started within 15 days of randomisation. Chemotherapy or any anti-tumour agent administered during PCI was not permitted because of the risk of additional neurological toxicity. Outcomes Incidence of brain metastases at 2 years, overall and disease-free survival at 2 years. Results Treatment delivery: 341/360 SD-group patients received the prescribed dose of 25 Gy; 3/360 SD-group patients received a lower dose, and 11/360 SD-group patients received a higher dose (26–36 Gy). 335/360 HD-group patients received the prescribed dose of 36 Gy, 6/360 HD-group patients received less than 25 Gy, 2/360 HD-group patients received 25 Gy, and 13/360 HD-group patients patients received 26-35 Gy. N = 79 in group HD-accelerated and N = 277 in group HD- conventional. Development of BM: 82/360 in SD-group and 63/360 in the HD-group developed BM (HR = .8, 95% CI .57-1.11, p = .18). 2-year incidence rates of BM = 29% (95% CI 24–35) in the SD-group and 23% (95% CI 18–29) in the HD-group. Adjusted (Gray’s test) HR = .76 (95% .54–1.05, p= .10) of the cumulative incidence curves. HR = .48 (95% CI .29–.81, p = .005) favouring the HD-group when brain metastasis is considered as an isolated first site of failure, and the corresponding 2-year incidence rates = 12% in the SD-group and 6% in the HD-group. Overall survival: 2-year overall survival = 42% (95% CI 37–48%) in the SD-group and 37% (95% CI 32–42%) in the HD- group (HR = 1.2, 95% CI 1–1.44, p = .05). Relapse and disease-free survival: 2-year incidence of relapse = 40% (95% CI 34–46%) in the SD-group and 48% (95% CI 42–54%) in the HD-group (HR = 1.33, 95% CI 1.05–1.69, p = .02). HR = 1.33 (95% CI.98–1.79, p = .06) and the corresponding 2-year relapse rates = 20% in the SD-group and 26% in the HD-group when chest relapses were considered as an isolated first site of failure. The 2-year incidence of extracranial metastases = 40% (95% CI 35–47%) in the SD-group and 42% (95% CI 37–48) in the HD-group (HR = 1.21, .95–1.54, p = .13). 2-year disease-free survival = 33% (95% CI 28–38) in the SD-group and 29% (95% CI 25–34) in the HD-group (HR 1.16, 95% CI .97–1.37; p = .1).

Toxic effects:

Acute events: Headache: N = 85 SD-group patients and N = 99 HD-group patients in the 36 Gy group (ns); Fatigue: N = 106 SD-group patients and N = 121 HD-group patients (ns); Insomnia: N = 14 SD-group patients and N = 13 HD-group patients (ns); Nausea or vomiting: N = 80 SD-group patients and N = 101 HD-group patients (ns). 2 HD-group patients interrupted PCI because of acute toxicity. Treatment-related deaths: Four SD-group patients died of systemic treatment toxicity. Serious adverse events: N = 5, all in SD-group patients (one death 2 months after PCI with undocumented neurological deterioration, one generalised seizure 12 months after PCI treated with no sequelae, one transient ischaemic attack 6 months after PCI, one bilateral cataract 29 months after PCI, and one death due to generalised seizure in a patient treated for epilepsy 29 days after PCI. This patient inadvertently received 36 Gy (table 3). Other reported adverse events: N = 2 HD-group patients; Persistent nausea 21 days after PCI and scalp dermatitis 19 days after PCI. General comments This RCT is an adequately powered well-conducted study that employed a number of good RCT design and analysis strategies including allocation concealment, central randomisation (with stratification according to institution, age and interval between the start of induction treatment and the date of randomization) and intention-to-treat analysis. No level of blinding (e.g., of outcome assessors) appears to have been employed. This study can therefore be regarded as moderate-high quality evidence. References of Included Studies: N/A

Citation: Lester, JF., Coles, B, & MacBeth, F. Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small cell lung cancer. Cochrane Database of Systematic Reviews: Reviews. Cochrane Database of Systematic Reviews 2005 Issue 2. [2]. 2005. Chichester (UK), John Wiley & Sons, Ltd. Design: Cochrane systematic review Country: International

Aim: To examine the effectiveness of prophylactic cranial irradiation (PCI) in patients with NSCLC treated with radical intent Inclusion criteria Published and unpublished RCTs comparing external beam megavoltage RT given to the whole brain (PCI) to no PCI in patients with histologically or cytologically confirmed NSCLC treated with radical intent and no radiological evidence of brain metastases (BM) prior to randomisation. Exclusion criteria Population 4 trials which were not combined into a meta-analysis: VALG: N = 281 male patients w/ non-metastatic inoperable NSCLC. Karnofsky > 50; any age allowed; Patients were randomised to either 50Gy/25F/5 weeks or 42Gy/15F/3 weeks of thoracic RT. SWOG: N = 254 patients w/ stage III inoperable NSCLC; Karnofsky > 60, any age allowed; Patients were randomised to 58Gy/29F/6 weeks of chest RT alone or neoadjuvant chemotherapy plus chest RT plus adjuvant chemotherapy. RTOG 84-03: N = 187 patients w/ adenocarcinoma or large cell carcinoma confined to the chest; 161/187 patients received 55-60Gy/30F/6 weeks of primary thoracic RT; 26/187 received 50Gy/25F/5 weeks of post-operative RT following resection of all gross intrathoracic disease; any age and performance status allowed. Umsawasdi 1984: N = 97 patients w/ locally advanced NSCLC (13% had stage I/II, 87% had stage III); any age and any performance status allowed. Interventions VALG: 20Gy/10F/2 weeks PCI v observation. SWOG: 37.5Gy/15F/3 weeks PCI (first 34 patients) or 30Gy/15F/3 weeks (77 patients) v observation. RTOG 84-03: 30Gy/10F/2 weeks PCI v observation. Umsawasdi 1984: 30Gy/10F/2 weeks PCI v observation. Outcomes Incidence of BM, overall survival, disease-free survival, short and long term toxicity, and QoL Results Incidence of BM:

VALG: PCI (6%) < observation (13%; p = .038). Additional analyses suggested that adenocarcinoma was the only specific cell type in which PCI significantly more effectively reduced the incidence of brain metastases (PCI = 0%; Observation = 29%; p = .04). SWOG: PCI (1%) < observation (11%; p = .003). RTOG 84-03: PCI (9%) = observation (19%; p = .1). The same result held in a subgroup analysis on the 26 patients who had surgical resection of gross intrathoracic disease followed by mediastinal RT (PCI = 0%, observation = 25%; p = .06) and also in a subgroup analysis on the 161 patients receiving primary thoracic RT (PCI = 10%, observation = 18%; p = .34). Umsawasdi 1984: PCI (4%) < observation (27%; p = .02). Multivariate analysis suggested that the beneficial effect of PCI was limited to females, patients with a good performance status, weight loss less than 6%, squamous histology and stage III disease, however, the authors note that “ This analysis should be interpreted with caution, as only 97 patients in total were evaluable, and sample sizes may have been too small to reliably detect differences.” (page 5)

Time to BM: VALG: PCI: 34 weeks; observation 29 weeks. SWOG: Not reported RTOG 84-03: The prevalence of BM at 1 and 2 years were 15% and 15% for PCI and 17% and 31% for observation (p = .1). Umsawasdi 1984: PCI (50.5 weeks) > observation (23 weeks; p = .02).

Survival: VALG: PCI (median survival = 35.4 weeks) = observation (median survival = 41.4 weeks, p = .5). SWOG: PCI (median survival = 8 months) < observation (median survival = 11 months, p = .004). RTOG 84-03: PCI (median survival = 8.4 months) = observation (median survival = 8.1 months, p = .36). PCI (1- and 2-year survival = 40% and 13%) = observation (1- and 2-year survival = 44% and 21%, p = .36). Umsawasdi 1984: PCI = observation

Toxicity VALG: Not reported SWOG: No excessive neurological toxicity with PCI (but did not define ‘neurological toxicity’). RTOG 84-03: No late complications of PCI; no acute toxicity other than epilation and skin reactions. Umsawasdi 1984: No late complications of PCI.

QoL: Not carried out in any of the studies. General comments This Cochrane review is of a high quality with a thorough literature search and explicit assessment of the quality of the included studies. The overall quality of the studies included appears to be moderate at best. It is for example unclear whether blinding of outcome assessors was employed in any of the studies. The evidence provided by this Cochrane Review can therefore only be considered of moderate quality. References of Included Studies (for systematic review): RTOG 84-03 {published data only}: Russell AH, Pajak TE, Selim HM, Paradelo JC, Murray K, Bansal P, et al.Prophylactic Cranial Irradiation For Lung Cancer Patients At High Risk For Development Of Cerebral Metastasis: Results Of A Prospective Randomised Trial Conduced By The Radiation Therapy Oncology Group. International Journal of Radiation Oncology Biology and Physics 1991;21:637–43. SWOG {published data only}: Miller TP, Crowley JJ. Mira J, Schwartz JG, Hutchins L, Baker L, et al.A Randomized Trial of chemotherapy and Radiotherapy for Stage III Non-Small Cell Lung Cancer. Cancer Therapeutics 1998; 4:229–36. Umsawasdi 1984 {published data only}: Umsawasdi T, Valdivieso M, Barkley HT, Chen T, Booser D, Chiuten DF, et al.Combined Chemoradiotherapy In Limited-Disease Inoperable Non-Small Cell Lung Cancer. International Journal of Radiation, Oncology, Biology and Physics 1987;14:43–8 AND Umsawasdi T, Valdivieso M, Chen TT, Barkley HT, Booser JD, Chiuten DF, et al.Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. Journal of Neuro-Oncology 1984;2:253–9. VALG {published data only}: Cox JD, Stanley K, Petrovich Z, Paig C, Yesner R. Cranial Irradiation in Cancer of the Lung of All Cell Types. Journal of the American Medical Association 1981;245:469–72.

Citation: Liu, R. F., Wang, X. H., Ma, B., Yang, K. H., Zhang, Q. N., and Tian, J. H. Concomitant or adjuvant temozolomide with whole-brain irradiation for brain metastases: a meta-analysis. Anti-Cancer Drugs 21[1], 120-128. 2010.

Design: Meta-analysis Country: China/International

Aim: To compare the efficacy and safety of concomitant or adjuvant tomozolomide (TMZ) + whole brain radiotherapy (WBRT) with the efficacy and safety of WBRT alone in patients with brain metastases (BM). Inclusion criteria Published and unpublished RCTs which compared concomitant or adjuvant TMZ with WBRT versus WBRT alone in patients with histologically proven BMs (single or multiple sites, assessable by contrast-enhanced computed tomographic scan or gadolinium-enhanced magnetic resonance imaging) at the primary site (lung, breast, or melanoma) or from an unknown primary tumour. Exclusion criteria Population 4 RCTs with N = 283, 235/283 patients had lung cancer primary (18 Had breast primary and 30 had unknown primary). N = 142 in group TMZ+WBRT, N = 138 in group WBRT, and N = 3 lost to follow up. Interventions TMZ: Oral administration of 75 or 200 mg/m2/day during the radiation treatment and 150–200mg/m2/day X 5 days every 28 days after WBRT from the first treatment day continuing to disease progression or unacceptable toxicity. WBRT: 30-40 Gy in 10-20 fractions over 2-4 weeks. Outcomes Response, toxicity, median survival and progression-free survival Results Complete response (3 trials, N = 177): 15/90 for the TMZ+WBRT group and 10/87 for the WBRT group; risk ratio = 1.36 (95% CI .7–2.66, p = .37; no significant heterogeneity) Partial response (3 trials, N = 177): 34/90 for the TMZ+WBRT group and 17/87 for the WBRT group; risk ratio = 1.89 (95% CI 1.19–3.02, p = .007; no significant heterogeneity) Overall response (4 trials, N = 280): 74/142 for the TMZ+WBRT group and 41/138 for the WBRT group; risk ratio = 1.72 (95% CI 1.32–2.24, p < .0001; no significant heterogeneity) Stable disease (3 trials, N = 177): 16/90 for the TMZ+WBRT group and 19/87 for the WBRT group; risk ratio = .82 (95% CI .45–1.5, p = .53; significant heterogeneity) Progressive disease (3 trials, N = 177): 4/90 for the TMZ+WBRT group and 15/87 for the WBRT group; risk ratio = .29 (95% CI .1–.78, p = .01; no significant heterogeneity) Nausea & vomiting (3 trials, N = 180): 43/91 for the TMZ+WBRT group and 13/89 for the WBRT group; risk ratio = 3.75 (95% CI 1.04–13.44, p = .04; significant heterogeneity) ≥ grade 3 myelosuppression,and hematological adverse events (2 trials, N = 132): 12/66 for the TMZ+WBRT group and 0/66 for the WBRT group; risk ratio = 13 (95% CI 1.75–96.79, p = .01; no significant heterogeneity) Survival (not meta-analysis): All 4 RCTs reported that the TMZ+WBRT group had numerically longer median survival than the WBRT group (4.5 vs. 3.1 months, 8.6 vs. 7.0 months, 8.6 vs. 4.5 months, and 7.9 vs. 4.3 months). General comments The present study is a well-conducted systematic review with a thorough search for both published and unpublished studies conducted independently by two of the authors. Data extraction was similarly conducted independently by two of the authors. However, all of the included RCTs appear to be of low quality and it is unclear whether the analyses were performed according to the intention to treat principle. In addition, two of the analyses were marked by significant unexplained between-study heterogeneity. The results of these analyses must therefore be interpreted with caution. The evidence provided by this meta-analysis can therefore only be considered of moderate quality. References of Included Studies (for systematic review): - Verger E, Gil M, Yaya R, Vin˜ olas N, Villa` S, Pujol T, et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Oncol Biol Phys 2005; 61:185–191. - Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 2002; 20:3644–3650. - Xie JY, Xiang DB, Wang G, Yang ZZ, Li Y, Yu X, et al. Clinical research of TMZ combined treatment with WBRT in the metastases patients of NSCLC. ChongQin Med 2007; 36:1941–1942.

- Antonadou D, Coliarakis N, Paraskevaidis M, Athanasious H, Sarris G, Synodinou M, et al. A multi-institutional trial comparing survival of patients with brain metastases from lung cancer treated with temozolomide plus radiotherapy versus to radiotherapy alone. Lung Cancer 2003; 41 (Suppl 2): S22–S23.

Citation: Mehta,M.P.; Rodrigus,P.; Terhaard,C.H.; Rao,A.; Suh,J.; Roa,W.; Souhami,L.; Bezjak,A.; Leibenhaut,M.; Komaki,R.; Schultz,C.; Timmerman,R.; Curran,W.; Smith,J.; Phan,S.C.; Miller,R.A.; Renschler,M.F. (2003). Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 21, 2529-36. Design: Multi-centre RCT Country: International

Aim: To evaluate survival, neurologic and neurocognitive function in patients with brain metastases (BM) from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). Inclusion criteria Please note: Only the patients with non small cell lung cancer will be described and only the results directly pertaining to these patients will be reported.

Patients with: - MRI-proven BM from histologically proven solid tumour, - WBRT requirement - Karnofsky performance status ≥ 70, - absolute granulocyte count ≥ 1500/μL - platelets ≥ 50 000/μL, - total bilirubin, ALT and AST < 2 X the upper limit of normal - serum creatinine < 2 mg/dL. Exclusion criteria Patients with: - small cell lung cancer, - lymphoma, - germ cell tumours, - prior partial or complete BM resection, - prior cranial irradiation, - leptomeningeal metastases, - two or more sites of extracranial metastases, except when breast was the primary cancer, - planned chemotherapy during WBRT or the subsequent 14 days, - or if radiosurgery was the initial therapy. Population N = 251 with NSCLC: Adenocarcinoma (43%), large cell (15.2%), squamous cell (16.3%), other (2%), not specified (23.5%). 46.6% had synchronous BM; 61.4% had brain as only site of metastasis. None of the patients had 2 or more extracranial organs with metastatic involvement. The median sum of the indicator lesion volume = 7 mL. Median time from primary cancer diagnosis = 3.8 months, and the mean number of prior chemotherapy cycles = 3.5.

Random assignment to one of 2 groups: WBRT: N = 128 WBRT + MGd: N = 123 Interventions WBRT: 30 Gy given in 10 daily fractions, WBRT + MGd: MGd was injected intravenously at a dose of 5 mg/kg/d, 2 to 5 hours before each fraction of WBRT. Outcomes Survival Time to neurologic progression Time to loss of functional independence Time to neurocognitive progression Neurocognitive function (outcome reported in a separate publication by Meyers et al. (2004) on the same patients)

Results Survival: Median survival = 4.3 and 4.9 months for the WBRT and WBRT+MGd groups, respectively (p = .72). 51.5% and 36.4% died from CNS-causes in the WBRT and WBRT+MGd groups, respectively (p = .037). Time to neurologic progression (as assessed by the investigator(s)) = 3.7 and 5.5 months for the WBRT and WBRT+MGd groups, respectively (hazard ratio (HR) = .68 [for the WBRT+MGd group relative to the WBRT group]; p = .025). Time to neurologic progression (as assessed by the Events Review Committee) = ‘not reached’ and 7.4 months for the WBRT and WBRT+MGd groups, respectively (hazard ratio (HR) = .61 [for the WBRT+MGd group relative to the WBRT group]; p = .048). Time to loss of functional independence (measured by the Barthel Index): The groups did not differ (p = .18). Time to neurocognitive progression: The groups did not differ in terms of progression of fine motor skills: HR = .76, p = .23. Memory and executive function combined: HR = .55 [for the WBRT+MGd group relative to the WBRT group], p = .047; that is, compared to the WBRT group, the hazard for deterioration in memory and executive function for the MGd+WBRT group was approximately half. However, Meyers et al (2004) also report this outcome in the same patients, but with slightly different results: The groups did not differ in terms of progression of fine motor skills: HR = .85, p = .51. Memory and executive function combined: HR = .56 [for the WBRT+MGd group relative to the WBRT group], p = .062; that is, in contrast to Mehta et al. (2003), the hazard ratio is not significant. Neurocognitive function (outcome reported by Meyers et al. (2004) on the same patients): Time to progression (= 4.5 standard deviation change) in recall memory = 18.1 (95% CI 9.73-unknown) months and ‘not reached’ for the WBRT and WBRT+MGd groups, respectively (p = .026). Time to progression in executive function (as measured by the Controlled Oral Word Association task) = 18.1 (95% CI 9.73-unknown) months and ‘not reached’ for the WBRT and WBRT+MGd groups, respectively (p = .056). [Note from reviewer: I am aware that the numbers within this section are identical apart from the p values. This is also the case in the Meyers et al. (2004) paper]. General comments A number of methodological issues challenge the validity of this RCT and necessitates cautious interpretation of the results. Firstly, this RCT is open-label and uses no placebo. This absence of (double-)blinding and placebo-control (and, potentially, allocation concealment) leaves the trial open to the influence of a number of different kinds of biases that all threaten the internal validity of this trial. The use of a blinded Event Review Committee introduces some (third- level)blinding (of outcome assessment) which goes a little way in addressing the likely influence of different kinds of biases. From an analysis perspective, the study does employ intention-to-treat analyses, but fails to provide variability data (such as ranges, standard deviations and confidence intervals) which makes it difficult to evaluate the (precision of the) results in detail. Collectively, all these issues mean that this study cannot be considered high quality evidence. References of Included Studies: Meyers,C.A.; Smith,J.A.; Bezjak,A.; Mehta,M.P.; Liebmann,J.; Illidge,T.; Kunkler,I.; Caudrelier,J.M.; Eisenberg,P.D.; Meerwaldt,J.; Siemers,R.; Carrie,C.; Gaspar,L.E.; Curran,W.; Phan,S.C.; Miller,R.A.; Renschler,M.F. (2004). Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 22, 157-165.

Citation: Mehta, M. P., Shapiro, W. R., Phan, S. C., Gervais, R., Carrie, C., Chabot, P., Patchell, R. A., Glantz, M. J., Recht, L., Langer, C., Sur, R. K., Roa, W. H., Mahe, M. A., Fortin, A., Nieder, C., Meyers, C. A., Smith, J. A., Miller, R. A., and Renschler, M. F. Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. International Journal of Radiation Oncology, Biology, Physics 73[4], 1069-1076. 2009. Design: Multi-centre RCT Country: International

Aim: To compare the effectiveness of motexafin gadolinium (MGd) + whole brain radiotherapy (WBRT) to the effectiveness of WBRT alone for the treatment of brain metastases (BM) from non small-cell lung cancer (NSCLC). Inclusion criteria Patients with - BM from NSCLC - Karnofsky performance status ≥ 70

- absolute granulocyte count ≥ 1,500/mm3 - platelet count ≥ 50,000/mm3 - total bilirubin, alanine aminotransferase, and aspartate aminotransferase < 2 X the upper limit of normal - serum creatinine ≤ 2.0 mg/dL - lactate dehydrogenase ≤ 1.3 X the upper limit of normal.

Exclusion criteria Patients with liver metastases, ≥ 2 sites of extracranial metastases, leptomeningeal metastases, or patients who had undergone previous resection of a single brain metastasis, previous WBRT, previous stereotactic radiosurgery (SRS) if more than one treatment had been given or more than lesions had been treated, or who had an absence of new lesions after SRS. Population All had advanced lung cancer WBRT group: N = 275, 152 males, median age = 59 (range 37-94) years. Karnofsky performance score 70-80/90-100: N = 124/151; BM single/multiple: N = 46/229; Extracranial metastases none/one other metastatic site/≥ 2 metastatic sites: N = 126/134/15; Previous antineoplastic therapy Yes/No: N = 115/160. WBRT + MGd group: N = 279, 166 males, median age = 59 (range 33-83) years. Karnofsky performance score 70-80/90- 100: N = 129/150; BM single/multiple: N = 58/221; Extracranial metastases none/one other metastatic site/≥ 2 metastatic sites: N = 143/118/18; Previous antineoplastic therapy Yes/No: N = 124/155. Interventions WBRT group: WBRT consisting of 30 Gy in 10 fractions WBRT+MGd group: WBRT as WBRT group with 5 mg/kg/d MGd 2-5 hours before each WBRT fraction Outcomes Interval to neurologic progression or death with evidence of neurologic progression, interval to neurocognitive progression, survival, safety. Results Treatment delivery: WBRT group: 3/275 patients received no WBRT; 263/275 received the full course of WBRT. WBRT + MGd group: 7/279 patients received no MGd; 224/279 received the full course of 10 doses of MGd; 262/279 received the full course of WBRT. 92.4% of the intended MGd doses were administered.

Interval to neurologic progression (on data by blinded outcome assessors): - The median interval to neurologic progression = 10 (95% CI 7.43–13.5) months for the WBRT group and 15.4 (95% CI 10.7–24.2) months for the WBRT + MGd group (p = .122) with a hazard ratio (HR) = .78 (95% CI .58–1.06, p = .11). - Multivariate analysis: Baseline performance status, histologic type, and region were independent predictors of the interval to neurologic progression. Geographic region, and not baseline performance status or histologic type, interacted with the treatment effect (p = .012): In North America (n = 348), the median time to neurologic progression = 8.8 (95% CI 7.33–20.2) months for the WBRT group and 24.2 (95% CI 11.60–not reached) months for the WBRT+MGd group (p = .004, HR = .53). In the United States (n = 185), the median time to neurologic progression = 8.7 (95% CI 5.63– not reached) months for the WBRT group and 24.2 (95% CI 15.37–not reached) months for the WBRT+MGd group (p = .004, HR = .39). The authors explored the potential reasons underlying the regional differences in the effect of treatment by comparing the promptness of treatment between the different regions which were found to differ significantly in terms of time between diagnosis of BM and randomisation (p < .0001); e.g. in North America 59.8% of the patients were randomised within 2 weeks of BM diagnosis, whereas in Europe/Australia only 32% of patients were randomised within 2 weeks of BM diagnosis. Another potential source of the regional differences concerned delay of WBRT by the use of chemotherapy alone as the initial therapy for BM (p < .0001) a practice which was more common in Europe/Australia (17.5%) than in North America (1.7%). When the analyses were confined to patients who had been enrolled within 4 weeks of BM diagnosis from all the regions, treatment with WBRT+MGd was associated with longer time to neurologic progression compared to treatment with WBRT alone (N = 435, p = .038, HR = .69). When 2 sites which were outliers with respect to treatment delay were excluded (N = 44), exploratory analyses showed that WBRT + MGd treatment (median = 15.37 months, 95% CI 10.70–not reached months) was associated with longer time to neurologic progression relative to WBRT treatment alone (median = 8.17 months, 95% CI 7.10–12.37 months; p = .030; HR = .68, 95% CI .50–.93). Interval to neurologic progression (on data by unblinded outcome assessors): - The median interval to neurologic progression = 11.8 (95% CI 7.8–16.2) months for the WBRT group and 13.2 (95% CI, 10.3–18.2) months for the WBRT + MGd group (p = .21).

Interval to neurocognitive progression: HR = .78 (p = .057) (North America only: HR = .73, p = .062). Survival: Median = 5.8 (95% CI 4.6–7) months in the WBRT group and 5.1 (95% CI 4.4–5.8) months in the WBGRT+MGd group (p = .684, HR = 1.02). (North America only: Median survival = 5.2 (95% CI, 4.1–6.7) months in the WBRT group and 4.9 (95% CI, 4.2–5.7) months in the MGd group (p = .938, HR = .97). Salvage SRS or brain metastasis resection procedures (performed if patients had recurrent, persistent, or progressive brain metastases according to the investigators’ standard of care): N = 54 in the WBRT group and N = 25 in the WBRT+MGd group (p < .001). Adverse events: The five most common grade 3 or above adverse events in the WBRT group were: Asthenia (N = 15), muscular weakness (N = 6), nausea & vomiting (N = 5), diarrhoea (N = 2), and liver function abnormalities (N = 2). The five most common grade 3 or above adverse events in the WBRT+MGd group were: Asthenia (N = 19), liver function abnormalities (N = 17), hypertension (N = 11), muscular weakness (N = 9), and pain & paresthesia (N = 9).

General comments Patients in this RCT were randomised according to an urn randomization scheme that balanced allocation by centre, performance status, and age. However, it is unclear whether allocation concealment was employed. The outcomes were assessed by blinded assessors and the analyses were conducted according to the intention-to-treat principle. The study is however likely to be slightly underpowered due to a lower-than-expected event rate. This study can therefore be regarded as moderate quality evidence. References of Included Studies: N/A

Citation: Meyers,C.A.; Smith,J.A.; Bezjak,A.; Mehta,M.P.; Liebmann,J.; Illidge,T.; Kunkler,I.; Caudrelier,J.M.; Eisenberg,P.D.; Meerwaldt,J.; Siemers,R.; Carrie,C.; Gaspar,L.E.; Curran,W.; Phan,S.C.; Miller,R.A.; Renschler,M.F. (2004). Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 22, 157-165. Design: See review of Mehta et al. (2003) Country:

Aim: Inclusion criteria Exclusion criteria Population

Interventions Outcomes Results General comments References of Included Studies:

Citation: Neuhaus,T.; Ko,Y.; Muller,R.P.; Grabenbauer,G.G.; Hedde,J.P.; Schueller,H.; Kocher,M.; Stier,S.; Fietkau,R. (2009). A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer. British Journal of Cancer, 100, 291-297. Design: Multi-centre RCT Country: Germany

Aim: To compare the efficacy of topotecan + whole brain radiotherapy (WBRT) to WBRT alone in patients with brain metastases (BM) from lung cancer. Inclusion criteria Patients with: - histologically proven lung cancer,

- at least one measurable BM, - age 18 – 75 years, - ECOG performance status of 0-2, - neutrophil counts ≥ 1500 μl-1 - leukocyte counts ≥ 3500 μl-1 - platelet counts ≥ 100 000 μl-1 - haemoglobin counts ≥ 9g dl-1 - serum creatinine concentration ≤ 1.5 mg% or creatinine clearance > 60 ml min-1 Exclusion criteria Prior cerebral radiotherapy, and/or surgery of BM (except stereotactic biopsy), solitary intracerebral BM suitable for neurosurgery, meningeosis carcinomatosa, active uncontrolled infection, concomitant or previous malignancies except basal or squamous cell carcinoma or carcinoma in situ or the cervix and history of therapy with and/or known allergy to topoisomerase I inhibitors, pregnant or breast-feeding women.

Population Randomisation appears to be stratified by lung cancer type (small cell, non-small cell) and by extracerebral metastases and number of BM.

Combination therapy: N = 47, 32 males, median age = 58 (range 34-75) years. ECOG performance status: 0 (n = 8), 1 (n = 29), 2 (n = 7), 3 (n = 1), not reported (n = 2). Primary tumour site: NSCLC first line (n = 7), NSCLC recurrence (n = 24), SCLC first line (n = 3), SCLC recurrence (n = 13). > 4 BM (n = 11), Extracerebral metastases (n = 35). Courses of continuation therapy: 1 (n = 1), 2 (n = 1), 3 (n = 6).

WBRT: N = 49, 30 males, median age = 59 (range 42-75) years. ECOG performance status: 0 (n = 2), 1 (n = 22), 2 (n = 19), 3 (n = 2), not reported (n = 4). Primary tumour site: NSCLC first line (n = 8), NSCLC recurrence (n = 24), SCLC first line (n = 2), SCLC recurrence (n = 15). > 4 BM (n = 14), Extracerebral metastases (n = 37). Courses of continuation therapy: 1 (n = 2), 2 (n = 1), 3 (n = 4). Interventions Combination therapy: - Topotecan: 30 min infusion with 0.4 mg m-2 day-1 for 5 days over 4 weeks within 2 hours before WBRT. - WBRT: fraction size of 2 Gy day-1 to a total of 40 Gy. WBRT: - As per the schedule WBRT in the combination therapy group.

Continuation therapy (both groups): Patients with extracerebral cancer metastases could choose to receive three additional cycles of topotecan therapy (1.25 mg m-2 day-1, d1–5, q21d), starting on day 15 after the end of WBRT. If a patient was chemo- or radiochemotherapy-naive before entering the study, the chemotherapeutic regimen preferred by the institution was allowed to be used instead. Continuation therapy was terminated after three cycles or after occurrence of tumour progression of the extracerebral metastases. Outcomes Response rate measures: Complete response = a complete disappearance of all evidence of disease in the brain; partial response = radiological response >50% in all brain metastases. Progression-free survival: Stable disease = responses in tumour lesions <50% or increase in size less than 25%; progressive disease = either the occurrence of new lesions or an increase in size of more than 25%. Overall survival. Results Interim analysis planned after the death of 150 patients, but 34 months of recruitment only resulted in 95 patients in 11 centres. The interim analysis was performed on these patients and did not show any benefit of radiochemotherapy in terms of overall survival. The study was subsequently terminated.

51% of the patients were treated according to the protocol. The main reason for deviation from the protocol was early death (14/47 and 9/49 in the combination therapy and WBRT groups, respectively). Other reasons included tumour progression haematological toxicities, dosage failure, and worsening of general condition. The main reason for early death was tumour progression (7/14 and 6/9 in the combination therapy and WBRT groups, respectively).

Responses of BM were only assessable in 44 patients (25/47 and 24/49 in the combination therapy and WBRT groups, respectively) and were unspecified in a further 2/47 and 3/49 patients in the combination therapy and WBRT groups, respectively.

Overall survival: Combination therapy: Median = 87 (range 3–752) days. WBRT: Median = 95 (range 4–433) days; Hazard Ratio 1.32 (95% CI 0.83–2.1; p = .43).

Progression-free survival: Combination therapy: Median = 71 (range 3–399) days. WBRT: Median = 66 (range 4–228) days; Hazard Ratio 1.28 (95% CI 0.73–2.43; p = .89). General comments A number of methodological issues render the results of this RCT unconvincing or, at least, potentially questionable. It is, for example, not clear which method of randomisation was employed or whether there was allocation concealment. It is therefore not possible to adequately evaluate the potential presence of a patient recruitment and/or selection bias. Furthermore, as dropouts were not considered, selective attrition may have occurred although lack of detail about dropouts makes this difficult to assess. With regards to blinding, it is not obviously clear how complete blinding would be achieved in a study such as the present RCT, however blinding of the personnel assessing the outcomes should have been carried out and this does not appear to have been the case. On the other hand, although there is no mention of intention-to-treat analysis, the data appear to have been analysed according to this principle. It is however a further weakness that more than half of the patient data for two of the outcomes (Responses of BM and Progression-free survival) were missing and that the reasons for this is not specified as it is more than can be accounted for by the number of early deaths occurring in each treatment group. Finally, the inclusion of patients with either unknown ECOG scores or ECOG scores >2 against is a concern as it is against the inclusion criteria of the trial.

Therefore, on the basis of the above evaluation in combination with the low patient numbers in each treatment group, this study cannot be considered high quality evidence. References of Included Studies (For systematic reviews): N/A

Citation: Pöttgen, C., Eberhardt, W., Grannass, A., Korfee, S., Stüben, G., Teschler, H., Stamatis, G., Wagner, H., Passlick, B., Petersen, V., Budach, V., Wilhelm, H., Wanke, I., Hirche, H., Wilke, H. J., and Stuschke, M. Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 25[31], 4987-4992. 2007. Design: Multi-centre RCT Country: German

Aim: To examine the effectiveness of prophylactic cranial irradiation (PCI) within multimodality treatment of patients with operable stage IIIA NSCLC Inclusion criteria Patients with - histologically proven primarily resectable locally advanced NSCLC (i.e., Central T3 N0-1, 1 to 2 mediastinal lymph nodes involved without bulky or microscopically extranodal disease at mediastinoscopy, no clinical N2 and no superior sulcus tumor) - age < 70 years WHO PS > 0; 1 if age > 65 years WHO PS > 0; 1 or 2 if age < 60 years - fulfilment of criteria of medical operability with respect to cardiorespiratory parameters - sufficient bone marrow reserve, WBC > 4.0/nL, PLT > 100/nL - physiologic hepatic function, serum bilirubin < 30 g/dL Exclusion criteria Population

All patients: N = 106; N = 51 in arm A and N = 55 in arm B; 90 males/ 16 females, median age = 57 years (range 37-71 years). 50 patients had squamous cell, 35 patients had adenocarcinoma, 5 patients had adenosquamous histology, and 16 patients had large cell histology. Interventions Arm A: Primary curative resection (lobectomy, pneumonectomy, combined with ipsilateral mediastinal lymph node dissection) followed by postoperative thoracic radiation therapy consisting of 50 Gy, in daily fractions of 2 Gy, 5 times per week or 60 Gy in case of R1 resection. Arm B: Induction therapy consisting of 3 cycles of cisplatin (60 mg/m2, days 1 and 7, every 21 days) and etoposide (150 mg/m2 on days 3-5). 3 weeks after administration of the 3rd cycle, concurrent chemoradiotherapy commenced consisting of hyperfractionated and accelerated irradiation of 1.5 Gy twice daily (≥ 6 hours, interfraction interval, 5 times per week) to a total dose of 45 Gy and cisplatin (50 mg/m2, days 2 and 9) with etoposide (100 mg/m2, days 4-6). Following completion of the 4th cycle (≥ 4 hours after the last drug application) PCI consisting of a total dose of 30 Gy in 2 Gy fractions 5 times per week was administered. After completion of chemo- and radiotherapy the patients were referred to thoracic surgery aiming at resection with curative intent.

All long-term survivors were invited to undergo neuropsychological testing. Outcomes See Results section Results Trial terminated early due to slow accrual -Median follow-up = 116 months (range 66-148 months -5-year overall survival = 18% in arm A and 16% in arm B (p = .15). -5-year event-free survival = 20% in arm A and 24% in arm B (p =.12). -9 patients in arm A and 4 patients in arm B patients developed brain metastases (BM) -Extracerebral relapses during the first 36 months after treatment: N = 28 in both arms A and B -Intercurrent deaths during the first 36 months after treatment: N = 2 in arm A and N = 7 in arm B (p = .2) -Extracerebral relapses after the first 36 months after treatment: N = 3 in arm A and N = 6 in arm B -Intercurrent deaths after the first 36 months after treatment: N = 3 in arm A and N = 4 in arm B

Brain Relapses - Treatment delivery: 43 patients (78%) received PCI as planned. - Incidences of brain metastases at first site of failure (intention-to-treat analysis): 2- and 5-year probability of BM = 23.7% (95% CI 8.8- 38.7%) and 30.7% (95% CI 11.9- 49.5%) in arm A and 8.8% (95% CI 0-18.6%) and 15.8% (95% CI 0- 31.8%) in arm B (P = .02) - Incidences of brain metastases at first site of failure (analysis by treatment given): 2- and 5-year probability of BM = 22.8% (95% CI 9.3-36.4%) and 34.7% (95% CI 15.7- 53.7%) for patients without PCI and 7.8% (95% CI 0- 18.5%) and 7.8% (95% CI 0-18.5%) for patients who received PCI (p =.01). - Probability of overall brain-relapse at 5 years = 9.1% with PCI and 27.2% without PCI (p =.04).

“Tumor-Dependent Prognostic Factors In an exploratory analysis of prognostic parameters using a Cox proportional hazards model in the patients of arm A, neither histology (squamous cell histology v all others) nor T stage (T1/2 v T3/4) nor lymph node status (N0 andN1v N2) revealed a statistically significant difference between the probability of brain metastasis at 2 years at first site of relapse.” (page 4990) The authors provide no further details on the nature of this analysis/these analyses (e.g., univariate or multivariate) and the results must therefore be interpreted with extreme caution; this is further underscored by the small sample size.

Neurocognition: N = 17 were long term survivors. Due to the small sample the results are therefore not reported further here. General comments This RCT terminated early and is therefore likely to be underpowered. In addition, no details are provided regarding the method of randomization employed and whether allocation concealment and/or any level of blinding was used. The evidence provided by this study can therefore only be regarded as low quality evidence. References of Included Studies: N/A

Citation: Quantin, X., Bozonnat, M. C., and Pujol, J. L. Recursive Partitioning Analysis Groups II-III Brain Metastases of Non-small Cell Lung Cancer A Phase II Randomized Study Comparing Two Concurrent Chemoradiotherapy Regimens. Journal of Thoracic Oncology 5[6], 846-851. 2010. Design: Two-centre randomised phase II study Country: France

Aim: To compare the effectiveness of two different chemotherapy regimens delivered concurrently with whole brain radiotherapy (WBRT) in chemotherapy-naive patients with stage IV non small cell lung cancer (NSCLC) and brain metastasis (BM). Inclusion criteria Patients with - pathologically confirmed stage IV NSCLC, - BM at the time of presentation for which surgery or curative RT was not deemed appropriate. - group II and III of the Recursive Partitioning Analysis of prognostic factors from the Radiation Therapy Oncology Group (RTOG-RPA) - aged 18-75 years - Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 - measurable diseased on brain CT and at least one other site of measurable disease (primary or other non-brain metastases) - adequate bone marrow reserve, adequate hepatic and renal functions and normal serum calcium - no prior chemotherapy - life expectance ≥ 3 months - weight loss in past 3 months < 10% Exclusion criteria Patients with: - previous malignant disease (apart from well-controlled basal cell skin cancer or in situ cervix carcinoma), - history of ileus, - active infection, - pregnancy or breast-feeding, - grade 3-4 peripheral neuropathy or deafness as per NCI Common Toxicity Criteria - contraindication to corticosteroids Population Group A: N = 37, 28 males, mean age = 59.1 (SD = 7.8) years. ECOG PS 0-1/2-3: N = 33/4; Histology adeno/squamous/ADC with bronchoalveolar component: N = 18/14/2; BM missing/1/2/3: N = 2/20/12/3; BM supratentorial / infratentorial / both supra & infra: N = 30/2/3. Group B: N = 33, 25 males, mean age = 56 (SD = 9.5) years. ECOG PS 0-1/2-3: N = 28/5; Histology adeno/squamous/ADC with bronchoalveolar component/ adenosquamous: N = 14/12/3/2; BM missing/1/2/3: N = 1/16/12/4; BM supratentorial / infratentorial / both supra & infra: N = 19/3/10.

The two treatment groups did not differ significantly on any of these baseline characteristics or on neurologic symptoms or other metastatic sites (when a bonferroni correction was applied for multiple comparisons). Interventions All patients:Two X WBRT consisting of 2 weeks of 1.8 Gy in 10 fractions, interspersed by 2 weeks rest. Group A: Chemotherapy delivered concurrently with WBRT and consisting of 3 4-week cycles of vinorelbine 30 mg/m2 on days 1 and 8 of WBRT + ifosfamide 1.5 g/m2 given as a 5-hour infusion daily on days 1-3 + uroprotection by uromitexan 2 g/m2 + cisplatin 100 mg/m2 on day 2 with hyper-hydration methyl-prednisone 120 mg per day on days 1-4 and methyl- prednisone 40 mg per day on days 5-12 Group B: Chemotherapy delivered concurrently with WBRT and consisting of 3 4-week cycles of ifosfamide 3 g/m2 given intravenously on days 1-4 of WBRT + uroprotection by uromitexan 3.5 g/m2 + methyl-prednisone on days 1-12 + haemotopoietic support (r-HuG-CSF administered subcutaneously on days 5-14).

Chemotherapy could be delayed depending on neutrophil/platelet counts, but the WBRT schedule remained unchanged. Drug dose reductions were permitted depending on toxicity.

Outcomes Response, survival, toxicity Results Treatment delivery: -All patients received ≥ 1 cycle and compliance did not differ significantly between the two groups. -67.6% of the group A patients and 57.6% of the group B patients received 3 cycles of chemotherapy. - 27.3% of group B patients and 5.4% group A patients discontinued treatment due to progressive disease (p = .01). - 9% of group B patients and 9.8% group A patients discontinued treatment due to toxicity or intercurrent disease (ns). Overall response rate: Group A patients (1 CR, 16 PR, 9 SD, 4 PD, 7 unavailable) = Group B patients (1 CR, 10 PR, 11 SD, 5 PD, 6 unavailable), whether or not the analyses were restricted to BM. Non significant Survival: Group A (median = 8.5, 95% CI 6.4-10.8 months) = Group B (median = 5.7, 95% CI 4.6-11.9 months; p = .82) Measured after a minimum follow-up of 21 months. Multivariate analysis indicated that a high serum neuron- specific enolase level was the only significant prognostic factor associated with poorer survival (HR = 2.02, 95% CI 1.01-4.03, p = .046). Grade 3 or 4 anaemia: Group A (N = 11) = Group B (N = 5, p =.24). Grade 3 or 4 leucopenia: Group A (N = 32) = Group B (N = 23, p =.12). Grade 3 or 4 thrombocytopenia: Group A (N = 17) > Group B (N = 6, p =.009). Grade 3 or 4 neutropenia: Group A (N = 33) > Group B (N = 21 p =.02). Clinically significant febrile neutropenia: Group A (N = 19) = Group B (N = 12, p =.13). Clinically significant documented infections: Group A (25%) = Group B (9.4%, p =.09). Red blood cell transfusions: Group A (25.7%) = Group B (9.1%, p =.07). Platelet transfusions: Group A = Group B (ns). Other toxicities: No severe modifications in hepatic or renal functions were observed. The frequencies of other severe toxicities did not differ between the groups, and no toxicity-related deaths occurred. General comments Patients in this trial were randomised centrally according to computer generated lists with “a stratification was carried out by the centre” (p 848). With no further details provided regarding the stratification it is therefore unclear how the patients were stratified and whether allocation concealment was used. Furthermore, no level of blinding appears to have been employed, and although initial power analyses were carried out a lower-than-anticipated response rate suggests that the study may be under-powered. The evidence provided by the current trial can therefore be regarded as low quality evidence. References of Included Studies: N/A

Citation: Rades,D.; Schild,S.E.; Lohynska,R.; Veninga,T.; Stalpers,L.J.; Dunst,J. (2007). Two radiation regimens and prognostic factors for brain metastases in nonsmall cell lung cancer patients. Cancer, 110, 1077-82. Design: Retrospective observational study Country: International

Aim: To evaluate the association between survival and potential prognostic factors in patients with brain metastases (BM) from non-small cell lung cancer (NSCLC) who have received either short-course whole brain radiotherapy (WBRT) with 5 X 4 Gy given in 5 days or a long-course WBRT with either 30 Gy given in 2 weeks or 40 Gy given in 4 weeks. Inclusion criteria NSCLC patients treated with WBRT for brain metastases between 1992 and 2005. BM had been confirmed by CT or MRI, and the patients had received dexamethasone during WBRT, and had no prior radiotherapy to the brain. Exclusion criteria Population 404 patients (241 men/163 women): 206/404 were below 60 years old and 198/404 were aged 60 or above. 169/404 had a Karnofsky performance status (KPS) below 70, and 235 had a KPS of 70 or above. 65/404 had single BM and 339/404 had multiple BM. 187/404 had no extracranial metastases whereas 217/404 had. 310/404 had an interval between tumour diagnosis and WBRT of 12 months or less whereas the interval was above 12 months for 94/404 patients. 94/404 patients had a recursive partioning analysis (RPA) class of 1, 141/404 had an RPA class of 2, and 169/404 had an RPA class of 3 (RPA 1 = KPS ≥ 70, age < 65 years, no extracranial metastases, and a controlled primary tumor; RPA 2 = KPS ≥ 70, + 1 or more unfavorable prognostic factor (age ≥ 65 years, extracranial metastases, or uncontrolled primary tumor); RPA 3 = KPS <70).

WBRT: N = 140 received short-course WBRT with 20 Gy in 5 fractions (5 X 4 Gy; treatment time = 5 days) and N = 264 received long course WBRT with either 30 Gy in 10 fractions (10 X 3 Gy; treatment time = 2 weeks) or 40 Gy in 20 fractions (20 X 2 Gy; treatment time = 4 weeks). Interventions Prognostic factors evaluated: - age (< 60 vs ≥ 60), - sex, - KPS (< 70 vs ≥ 70), - number of BM (single vs multiple), - extracranial metastases at time of WBRT (no vs yes), - interval from tumour diagnosis to WBRT (≤ 12 months vs > 12 months), - RPA class (1 vs 2 vs 3) Outcomes Survival Results All patients: Multivariate analysis (included all significant factors in the univariate analysis). - The following two prognostic factors were significantly associated with survival: RPA class (relative risk (RR) = 1.74 [for ≥ 60]; 95% confidence interval (CI) 1.16–2.62; p = .007) and interval from tumor diagnosis to WBRT (RR = 1.41 [for ≤ 12 months]; 95% CI 1.09–1.85; p = .008). A second multivariate analysis excluding RPA class (because the RPA class takes into account age, KPS, and extracranial metastases) revealed the following significant prognostic factors: - age (RR = 1.30 [for ≥ 60]; 95% CI 1.04–1.61; p = .020), KPS (RR = 3.04 [for < 70]; 95% CI 2.40–3.86; p <.001), extracranial metastases (RR = 1.72 [for present, not absent]; 95% CI 1.37–2.16; p <.001), and interval from tumor diagnosis to WBRT (RR = 1.42 [for ≤ 12 months]; 95% CI 1.10–1.86; p = .007) were significant. - sex (RR = 1.13; 95% CI 0.94–1.39; P 5.20) and the number of brain metastases (RR = 1.06; 95% CI 0.96 -1.19; p = .26) were not significant.

Patients split by RPA class: - RPA class 1: The WBRT schedule, age, sex and interval from tumor diagnosis to WBRT had no significant impact on survival (all ps > .08). - RPA class 2: Being female (RR = 1.54; 95% CI 1.07–2.25; p = .021) and having a single BM (RR = 1.21; 95% CI 1.04–1.44; p = .012) were significantly associated with improved survival. The WBRT schedule, age, extracranial metastases and interval between tumour diagnosis and WBRT had no significant impact on survival (all ps ≥ .1). - RPA class 3: No extracranial metastases (RR = 1.40; 95% CI 1.02–1.94; p = .04) was significantly associated with improved survival. The WBRT schedule, age, sex, number of BM and interval between tumour diagnosis and WBRT had no significant impact on survival (all ps ≥ .11). General comments The number of participants in this study is likely to mean that the study is adequately powered at least for the analyses calculated on all the participants. However, the retrospective nature of this study and the variation in WBRT schedule by participating centre (resulting in clustered data that was not controlled for in the analyses) mean that this evidence cannot be considered of high quality. References of Included Studies (For systematic reviews): N/A

Citation: Serizawa,T. (2009). Metastatic brain tumors: lung cancer. Progress in Neurological Surgery, 22, 142-53. Design: Retrospective observational study Country: Japan

Aim: To present the results of gamma-knife surgery (GKS) for brain metastases (BM) from lung cancer in patients that have not received whole brain radiation therapy (WBRT).

Inclusion criteria Lung cancer patients treated with GKS for BM from January 1998 through December 2003 with - no prior WBRT, - estimated life expectancy ≥ 3 months, - ≤ 25 lesions, - ≤ 4 tumours with a diameter ≥ 20 mm, - no surgically inaccessible large (≥ 35 mm) tumours. Exclusion criteria Population 443 patients (331 males): Age: ≥ 65 (n = 235), < 65 years (n = 208). Pretreatment KPS: < 70 (n = 62), ≥ 70 (n = 381). Oncotype of primary tumour: Non-small (n = 387; adenocarcinoma (n = 294), squamous cell carcinoma (n = 52), large cell carcinoma (n = 9), others/undetermined (n = 32)), small cell (n = 56). Extracranial lesion status: Controlled (n = 56), active (n = 387). Detection of BM: Synchronous (n = 268), metachronous (n = 175). Number of BM: > 10 (n = 78), ≤ 10 (n = 365, single: n = 94). Max lesion size: ≥ 25 mm (n = 334), < 25 mm (n = 109). Total tumour volume: > 10 cm3 (n = 78), ≤ 10 cm3 (n = 365). Presence of carcinomatous meningitis at initial enhanced MRI: Yes (n = 40), no (n = 403). Presence of posterior fossa lesion: Yes (n = 194), no (n = 249). Chemotherapy: Yes (n = 156), no (n = 287). Craniotomy: Yes (n = 66), no (n = 377). Interventions Large tumours (≥ 35 mm) tumours were all surgically removed while smaller (< 35 mm) tumours were treated with GKS. Additional GKS to the tumour bed was performed with 18-20 Gy when incomplete resection of the lesion was considered to have taken place. New distant lesions were re-treated, as appropriate, with GKS. Total skull internal dose calculated with the Leksell GammaPlan for each radiosurgical procedure was less than 10 000 mJ which is equivalent to 3 Gy of whole brain irradiation.

Prognostic factors evaluated: - age (≥ 65 vs < 65 years), - pretreatment Karnofsky Performance Status (KPS; < 70 vs ≥ 70), - gender, - oncotype of primary tumour (non-small vs small cell), - extracranial lesion status (controlled vs active), - detection of BM (synchronous vs metachronous), - number of BM (> 10 vs ≤ 10), - max lesion diameter (≥ 25 vs < 25 mm), - initial tumour volume (> 10 vs ≤ 10 cm3), - presence of carcinomatous meningitis at initial enhanced MRI (yes vs no), - presence of posterior fossa lesion (yes vs no) - chemotherapy (yes vs no) - craniotomy (yes vs no) Outcomes Survival Neurological survival (Impaired) activities of daily living/qualitative survival New lesion-free survival Tumour progression-free survival Results GKS: - A total of 4 626 lesions were treated by 805 separate procedures. - Median number of lesions treated initially = 4 (range 1-25). - Follow-up average = 1.9 ±1.5 (range 1-13) GKS procedures. - Mean number of lesions per patient treated with GKS = 10.4 ±14 (range 1-69). - Mean calculated lesions volume = .72 ± 2.1 cm3. - Min dose applied to tumour margin = 15-33.3 Gy (mean ± standard deviation: 20.8 ± 2.1 Gy, median = 20 Gy) with a 74.3% isodose contour (range 23-99%). Overall survival: Median = 8.9 months. Multivariate analysis showed that (better) survival was associated with the

female gender (hazard ratio (HR) = 1.812 [for male gender]; p < .0001), controlled systemic disease (HR = 3.333 [for active disease]; p < .0001), and a high (≥ 70) pretreatment KPS (HR = 2.734 [for KPS < 70]; p < .0001). Neurological survival: 1-year = 86.1%. 56/306 deaths attributed to neurological death. Multivariate analysis showed that neurological survival was associated with the absence of carcinomatous meningitis (HR = 5.484 [for present carcinomatous meningitis]; p < .0001). 1-year neurological survival in patients without carcinomatous meningitis = 90.5%. (Impaired) activities of daily living/qualitative survival: 1-year = 80.1%. Multivariate analysis showed that (better) qualitative survival was associated with a low (≤ 10) number of lesions (HR = 1.862 [for > 10]; p = .0207), the absence of carcinomatous meningitis (HR = 4.267 [for present carcinomatous meningitis]; p < .0001), and a high (≥ 70) pretreatment KPS (HR = 2.786 [for KPS < 70]; p = .0005). New lesion-free survival: 6-months = 70%. Multivariate analysis showed that longer new lesion-free survival was associated with a higher (≥ 65) age (HR = 1.423 [for < 65]; p = .0165) and controlled systemic disease (HR = 1.946 [for active disease]; p = .0017). Tumour progression-free survival: 1-, and 2-year survival rates = 97.2% and 94.8%, respectively. The tumours were classified according to volume (tiny = ≤ 1 cm3; small = 1 <, but ≤ 4 cm3; medium = 4 < but ≤ 10 cm3; large > 10 cm3), and descriptive survival curves showed progressive lower survival with increasing tumour volume, and inferential survival analysis showed a statistically significant difference in survival according to tumour volume (p < .0001). However, this main effect of tumour volume was not analysed any further, so it is unclear which tumour volume groups differ from each other. Conservatively, we can only assume that survival is better in the tiny tumour volume group than in the large tumour volume group. General comments The authors conclude that “In terms of NS [neurological survival] and QS [qualitative survival], GKS without upfront WBRT for brain metastases from lung cancer provides excellent palliation considering the patients’ short life expectancies. GKS alone is an alternative to WBRT for patients meeting the following four criteria: (1) no surgically inaccessible large (> 35 mm) tumors, (2) no findings of carcinomatous meningitis on initial MRI, (3) limited number of tumors and TSID [total skull internal dose] within 10,000 mJ, and (4) life expectancy exceeding 3 months. However, careful follow-up MRI and appropriate salvage treatment are essential to preventing neurological death and maintaining favourable ADL.” (p. 152).

The number of participants in this study is likely to mean that the study is adequately powered for the analyses calculated on all the participants. However, the absence in the statistical reporting of confidence intervals for the hazard ratios and additional analyses pinpointing the effect of tumour volume on tumour progression-free survival make it difficult to evaluate the precision of the results in detail. In addition, the retrospective nature of this study means that this evidence cannot be considered of high quality. References of Included Studies (For systematic reviews): N/A

Citation: Slotman,B.; Faivre-Finn,C.; Kramer,G.; Rankin,E.; Snee,M.; Hatton,M.; Postmus,P.; Collette,L.; Musat,E.; Senan,S.; EORTC Radiation Oncology Group and Lung Cancer Group (2007). Prophylactic cranial irradiation in extensive small-cell lung cancer. The New England journal of medicine, 357, 664-672. Design: Multi-centre RCT Country: International

Aim: To evaluate prophylactic cranial irradiation (PCI) in patients with extensive small cell lung cancer (SCLC) who had had a response to chemotherapy. Inclusion criteria Patients with: - Histologically/cytologically confirmed extensive SCLC defined as cancer beyond the hemithorax and supraclavicular nodes or pleural effusion containing tumour cells, - a response after 4-6 cycles of systemic chemotherapy, - no brain or leptomeningeal metastases, - no previous radiotherapy to neck or head area, - no history of corticosteroid use,

- no previous or other current cancer, - aged 18 - 75 years, - WHO performance status of 0-2, and - An interval ≤ 5 weeks between last cycle of chemotherapy and randomisation. Exclusion criteria Population Control group: N = 143, 82 males, median age = 63 (range 39-75) years. Median time after diagnosis: 4.2 months. WHO performance status: 0 (n=52), 1 (n = 76), 2 (n=15). Primary persistent disease (n = 110), distant persistent disease (n = 104). N = 1 insisted on undergoing PCI.

PCI group: N = 143, 97 males, median age = 62 (range 37-75) years. Median time after diagnosis: 4.2 months. WHO performance status: 0 (n=52), 1 (n = 80), 2 (n=11). Primary persistent disease (n = 108), distant persistent disease (n = 99). N = 10 did not receive treatment (6 died and 1 had disease progression before treatment commenced, 3 declined treatment).

None of the clinical characteristics listed differed significantly between the groups (no statistics reported). Interventions PCI: Consisted of 4-18 MV photons from linear accelerators or cobalt units. Whole brain irradiation was administered with the use of 2 lateral opposed fields. Each field was treated daily on a schedule of 4-5 fractions/week. The dose was specified to the midline. Each participating centre had to choose one of the following schedules and use that for all their study participants: 20 Gy in 5 or 8 fractions, 24 Gy in 12 fractions, 25 Gy in 10 fractions or 30 Gy in 10 or 12 fractions. The biologically equivalent doses for these schedules ranged from 25 – 39 Gy. PCI started 4 – 6 weeks after chemotherapy. Outcomes Development of symptomatic brain metastases (BM) suggested by the following signs and symptoms: Headache, nausea and vomiting, signs of increased intracranial pressure, seizures, cognitive or affective disturbances, and focal neurological symptoms. Survival Toxic effects Quality of life: Global health status, hair loss, fatigue, role functioning, cognitive functioning, emotional functioning as measured by the EORTC’s QLQ-C30. Results Development of symptomatic BM: 24/143 in PCI group and 59/143 in the control group developed symptomatic BM (p < .001), number needed to treat = 4. Cumulative risks of symptomatic BM at 6 and 12 months = 4.4% and 14.6% in the PCI group and 32% and 40.4% in the control group, respectively. The hazard ratio (HR) for the PCI group (accounting only for the competing risk of death without BM) = .27 (95% CI = .16 - .44, i.e., the risk of BM in the PCI group was significantly lower than in the control group). Disease-free survival: Medians = 14.7 and 12 weeks in the PCI and control groups, respectively (p = .02). HZ = .76 (95% CI .59 - .96, i.e., there was a lower risk of relapse in the PCI than control group). At 6 months, survival rate without disease progression = 23.4% (95% CI 16.6% – 30.9%) and 15.5% (95% CI 10.1% – 22%) in the PCI and control groups, respectively. Overall survival: Medians = 6.7 and 5.4 months in the PCI and control groups, respectively (p = .003). HZ = .68 (95% CI .52 - .88, i.e., there was a lower risk of death in the PCI than control group). At 12 months, survival rate = 27.1% (95% CI 19.4% – 35.5%) and 13.3% (95% CI 8.1% – 19.9%) in the PCI and control groups, respectively. Toxic effects (PCI only): - Acute events: Headache: 41/134 grade 1, 12/134 grade 2, 5/134 grade 3; Nausea and vomiting: 33/134 grade 1, 15/134 grade 2; Fatigue and lethargy: 6/134 grade 1, 7/134 grade 2; and Skin reactions: 3/134 grade 1, 2/134 grade 2. - Late reactions (after 3 months): Mild headache/slight lethargy in 29/134; Moderate headache/severe lethargy in 15/134; Severe headache/central nervous system dysfunction in 3/134. Quality of life (QoL): Response rate = 93.7% at baseline and 46.3% at 9 months. The groups did not differ at any time point on the following measures: Global health status (p = .1), role functioning (p = .17), cognitive functioning (p = .07), and emotional functioning (p = .18). At 6 weeks and 3 months the PCI group experienced significantly more fatigue than the control group (both ps < .001), and at 6 weeks the PCI group experienced significantly more hair loss than the control group (p < .001). Further QoL exploratory analyses also revealed increased rates of appetite loss, nausea and

vomiting as well as leg weakness in the PCI compared to the control group at 6 weeks and 3 months (all ps ≤ .003).

A more recent publication of this QoL data (Slotman et al., 2009) also reported that in their exploratory QoL analyses that the PCI group experienced significantly (p < .01) more constipation, future uncertainty, headaches and motor dysfunction as well as less social functioning at 6 weeks and/or 3 months compared to the control group. General comments This RCT is a well-conducted study that employed a number of RCT design strategies including central randomisation with stratification according to institution and performance status, intention-to-treat analysis and statistical correction for multiple comparisons that collectively serves to reduce the influence of different kinds of biases and the promotion of statistically spurious results. It does however appear that no level of blinding (e.g., of the outcome assessors) was employed. This study can therefore be regarded as moderate-high quality evidence. References of Included Studies: Slotman,B.J.; Mauer,M.E.; Bottomley,A.; Faivre-Finn,C.; Kramer,G.W.; Rankin,E.M.; Snee,M.; Hatton,M.; Postmus,P.E.; Collette,L.; Senan,S. (2009). Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health- related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. Journal of Clinical Oncology, 27, 78-84.

Citation: Slotman,B.J.; Mauer,M.E.; Bottomley,A.; Faivre-Finn,C.; Kramer,G.W.; Rankin,E.M.; Snee,M.; Hatton,M.; Postmus,P.E.; Collette,L.; Senan,S. (2009). Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. Journal of Clinical Oncology, 27, 78-84. Design: See review of Slotman et al. (2007) Country: Aim: Inclusion criteria Exclusion criteria Population Interventions Outcomes Results General comments References of Included Studies (For systematic reviews):

Citation: Sperduto,P.W.; Chao,S.T.; Sneed,P.K.; Luo,X.H.; Suh,J.; Roberge,D.; Bhatt,A.; Jensen,A.W.; Brown,P.D.; Shih,H.; Kirkpatrick,J.; Schwer,A.; Gaspar,L.E.; Fiveash,J.B.; Chiang,V.; Knisely,J.; Sperduto,C.M.; Mehta,M. (2010). Diagnosis- Specific Prognostic Factors, Indexes, and Treatment Outcomes for Patients with Newly Diagnosed Brain Metastases: A Multi-Institutional Analysis of 4,259 Patients. International Journal of Radiation Oncology Biology Physics, 77, 655-661. Design: Retrospective study Country: USA

Aim: To identify significant diagnosis-specific prognostic factors and indexes for the treatment of brain metastases (BM). Inclusion criteria Retrospective review of newly diagnosed patients with lung cancer treated for BM between July 1985 and August 2007 for whom accurate dates of treatment and follow-up/death were available. Exclusion criteria Patients treated for recurrent BMs after previous initial therapy elsewhere. Patients with treatment dates that were >2 months from the date of initial treatment.

Population NSCLC: N = 1888; age ≥ 60 / 50-59 / < 50: N = 1066 / 525 / 297; Karnofsky performance score < 70 / 70-80 / 90/100: N = 278 / 839 / 755; no of BMs >3 / 2-3 / 1: N = 449 / 618 / 781; extracranial metastases present: N = 627. SCLC: N = 299; age ≥ 60 / 50-59 / < 50: N = 195 / 84 / 20; Karnofsky performance score < 70 / 70-80 / 90/100: N = 79 / 130 / 88; no of BMs >3 / 2-3 / 1: N = 110 / 91 / 82; extracranial metastases present: N = 82. Interventions Stereotactic radio surgery (SRS), WBRT + SRS, surgery + SRS, surgery + WBRT and surgery + WBRT + SRS. Outcomes Survival time from the date of diagnosis of BMs. Results Survival: NSCLC: Multivariate analysis showed that age, extracranial metastases, Karnofsky performance score and number of BMs (all ps ≤ .017) were significant predictors of survival. SCLC: Multivariate analysis showed that age, extracranial metastases, Karnofsky performance score and number of BMs (all ps ≤ .0222) were significant predictors of survival. Diagnosis –specific graded prognostic index (DS-GPA) for NSCLC and SCLC (0 (poor prognosis) – 4 (best prognosis)): GPA score of 0 given to age ≥ 60, Karnofsky performance score < 70, extracranial metastases present and > 3 BMs. GPA score of 0.5 given to age 50-60, Karnofsky performance score 70-80, and 2-3 BMs. GPA score of 1 given to age < 50, Karnofsky performance score 90-100, extracranial metastases absent and 1 BM. Survival were significantly different between the patients with DS-GPA scores of 0-1, 1.5-2.5, 3 and 3.5-4 for both the NSCLC and SCLC diagnoses. NSCLC: Compared to patients treated for BMs with WBRT, patients treated with stereotactic radio surgery (SRS; HR = .62, 95% CI .51-.75), WBRT + SRS (HR = .53, 95% CI .45-.63), surgery + SRS (HR = .42, 95% CI .3-.61), surgery + WBRT (HR = .46, 95% CI .39-.55), and surgery + WBRT + SRS (HR = .39, 95% CI .28-.55) all had a reduced hazard of death., General comments This study examined a limited number of variables in the prognostic analyses and a number of interventions retrospectively. The results of this study must therefore be interpreted with caution also in light of the fact that it involved a small sample size at least for the SCLC analyses. This evidence can therefore be considered of low quality. References of Included Studies (For systematic reviews): N/A

Citation: Suh,J.H.; Stea,B.; Nabid,A.; Kresl,J.J.; Fortin,A.; Mercier,J.P.; Senzer,N.; Chang,E.L.; Boyd,A.P.; Cagnoni,P.J.; Shaw,E. (2006). Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 24, 106-114. Design: Multi-centre RCT Country: International

Aim: To evaluate whether efaproxiral (an allosteric modifier of haemoglobin) improves survival in patients with brain metastases (BM) when used as an adjunct to whole brain radiation therapy (WBRT).

Inclusion criteria Patients with: - RPA class I or II who had BM originating from solid tumors that were not small-cell lung cancer, germ cell tumors, and lymphomas, - age ≥ 18 years, - no prior treatment for BM (other than resection with measurable lesions remaining), - transaminase 3 X upper limit of normal, - bilirubin ≤ 2 mg/dL - platelet counts ≥ 75 000 cells/μL, - haemoglobin counts ≥ 10g dL, - WBC count ≥2,000 cells/μL, - creatinine concentration ≤ 2 mg/dL, and - standard pulse oximetry (SpO2) measurement (resting and exercise) ≥ 90%.

Exclusion criteria - Other concurrent active malignancy, - planned therapy for BM during the 1-month post-WBRT follow-up visit - breastfeeding or pregnant women - prior exposure to efaproxiral, - chemotherapy within 7 days, - investigational agents within 28 days before WBRT Population Randomisation stratified by (1) RPA class I; (2) RPA class II non–small-cell lung cancer (NSCLC); (3) RPA class II breast cancer; and (4) RPA class II other cancer sites.

Controls: 145/250 patients had NSCLC.

Efaproxiral: 145/265patients had NSCLC. Interventions Control: 2-week course of WBRT (3 Gy/fraction for 10 days) plus supplemental oxygen (4 L/min via nasal cannula). Oxygen was administered beginning 35 minutes before, during, and for at least 15 minutes after daily WBRT.

Efaproxiral: As controls + efaproxiral: The intended daily dose of efaproxiral was 75 or 100 mg/kg and it was administered intravenously via a central venous access device over 30 minutes and the infusion was completed no more than 30 minutes before WBRT. Efaproxiral administration began on the first day of WBRT and continued every day of the 2-week WBRT course for a total of 10 doses. The initial efaproxiral dose was dependent on sex and body weight. If the SpO2 while breathing room air at screening (at rest and during exercise) and on WBRT day 1 was ≥ 93%, efaproxiral was administered as follows: males with a body weight of ≤ 95 kg and females weighing ≤ 70 kg were initially administered 100 mg/kg of efaproxiral; and males with a body weight of more than 95 kg and females weighing more than 70 kg were given 75 mg/kg of efaproxiral. If the SpO2 while breathing room air onWBRTday 1 was less than 93%, no efaproxiral was administered that day. Outcomes Overall survival Results Only the results pertaining directly to NSCLC are reported. Overall survival: Univariate analysis indicated no difference in survival between the two treatment groups when the analysis was limited to the patients with NSCLC (hazard ratio = .97, p = .83). General comments Although this RCT appears to be well-conducted by, for example, employing blind evaluation of some of the outcomes (i.e., BM response rate), the mixed nature of the patient population and analysis strategy of collapsing across more than one patient group (i.e., breast and lung) makes the contribution of this study to the present review limited because the only analysis calculated on exclusively the NSCLC patients was univariate and therefore did not take into account the potential modifying contribution of other prognostic variables as a multivariate analysis would have done.

Another concern pertaining to this RCT relates to the uncertainty of whether there was allocation concealment. On the other hand, although there is no mention of intention-to-treat analysis, the data appear to have been analysed according to this principle. References of Included Studies (For systematic reviews): N/A

Citation: Sundaresan, P., Yeghiaian-Alvandi, R., and Gebski, V. Prognostic index to identify patients who may not benefit from whole brain radiotherapy for multiple brain metastases from lung cancer. Journal of Medical Imaging and Radiation Oncology 54[1], 69-75. 2010. Design: Retrospective study Country: Australia

Aim: To develop a prognostic index (PI) that identifies the subset of patients with lung cancer with multiple brain

metastases (BM) who may not benefit from whole brain radiotherapy WBRT because of death before the benefits of WBRT manifest (early death). Inclusion criteria Patients from the Department of Radiation Oncology at Westmead Hospital’s electronic database of all patients reviewed by the radiation oncology service: - with a primary diagnosis of small-cell lung cancer or non-small-cell lung cancer with histological confirmation of a lung cancer primary at some point in the disease course - who had undergone assessment in the 10-year period between 1 January 1995 and 31 December 2005 - who were recommended for WBRT for the treatment of multiple brain metastases. - with radiological confirmation of multiple parenchymal brain metastases with a brain CT or MRI Exclusion criteria Patients with: - non-parenchymal (leptomeningeal or calvarial) metastases, - solitary (no other metastases) or a single brain metastasis, - previous surgery for brain metastases (including excision biopsy or debulking of dominant lesions) - previous brain radiotherapy, including prophylactic cranial irradiation and stereotactic radiation treatment. Population All patients: N = 271; Age ≤ 65 / > 65 years: N = 171/100; ECOG performance status 0-1 / 2/ 3/ 4: N = 146 / 95 / 30 / 0; weight loss >10% No / Yes: N = 211 / 60; Histology SCLC / NSCLC / Lung cancer unspecified: N = 87 / 182 /2; Primary disease status controlled / uncontrolled: N = 110 / 161; Systemic disease status brain only / Brain + bone metastases / Brain + visceral metastases / Brain + bone + visceral metastases: N = 157 / 45 / 42 / 27 Interventions WBRT consisting of 20 Gy in 5 daily fractions over 5 consecutive days or 30 Gy in 10 daily fractions or 8 Gy in single fraction. WBRT course commenced within 3 weeks of decision to treat. Median time to WBRT commencement from date of decision to treat =9 days; median time to WBRT completion = 16 days. Outcomes Overall survival, CNS progression, toxicity Results -64/275 patients recommended to have WBRT for the management of multiple brain metastases from lung cancer died within 6 weeks of recommendation. - Univariate analysis showed that age > 65 years, > 10% weight loss, NSCLC histology, brain & bone metastases, brain and viscereal metastases, and brain, bone & viscereal metastases were not significantly associated with early death (all ps ≥ .13), however ECOG performance status 3 or 4 (OR = 10, 95% CI 3.54-28.28, p < .01) and uncontrolled primary (OR = 2.37, 95% CI 1.03-5.45, p = .042) were associated with early death although uncontrolled primary was not if a bonferroni correction for multiple comparisons was applied to the alpha-level. - Multivariate analysis confirmed the result by the univariate analyses including that uncontrolled primary was not significantly associated with early death (p = . 07; all other ps ≥ .09) and that ECOG performance status 3 or 4 was significantly associated with early death (OR = 10.14, 95% CI 3.35-30.68, p < .01).

PI score: - The odds ratios (from the multivariate analysis) for each of the factors were used as weights to develop the PI. In the interests of simplicity, the odds ratios for each of the factors were multiplied by a factor of 2 and rounded to obtain a weighting for each of the factors. The PI score is the sum of the weighting score for each of the prognostic factors from the regression coefficients and is calculated for each patient. - Weight for each prognostic factor in brackets: Age >65 years (3); ECOG 3 and 4 (20); >10% weight loss (3); NSCLC histology (2); Uncontrolled primary (5); Brain and bone metastases (3); Brain and visceral metastases (3); Brain, bone and visceral metastases (4). - Threshold PI score: This optimum value to separate the classification of patients into those predicted to live longer than 6 weeks and those predicted to experience ‘early death’ was 13; Patients with a PI score ≥ 13 had an 8.6 times higher odds of ‘early death’ compared with those who had a PI score < 13. General comments The prognostic index developed in this retrospective study was not validated and appears to be subject to multiple comparisons that have been evaluated without any alpha level correction. This would seriously compromise the results

due to the increased risk of spurious significant results. In this context it is also worth noting that the majority of variables that make up the prognostic index were not found to be significant predictors of early death in either univariate or multivariate analyses. In addition to these limitations, the sample size is small. The evidence provided by this study can therefore be regarded as low quality evidence. References of Included Studies: N/A

Citation: Tang,S.G.; Tseng,C.K.; Tsay,P.K.; Chen,C.H.; Chang,J.W.; Pai,P.C.; Hong,J.H. (2005). Predictors for patterns of brain relapse and overall survival in patients with non-small cell lung cancer. Journal of Neuro-Oncology, 73, 153-161. Design: Retrospective observational study Country: Taiwan

Aim: To investigate prognostic factors for different patterns of brain relapse and overall survival in patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). Inclusion criteria Patients with symptomatic BM from NSCLC who had been referred for radiation therapy (RT). Exclusion criteria Population 292 patients Interventions Prognostic variables assessed (for outcomes 1-4): Age (≤ 50, > 50 / ≤ 60, > 60) Gender ECOG performance status (1-4) T classification (T1, T2, T3, T4) N classification (N0, N1, N2, N3) Treatment response of lung lesions (CR, PR, NR) Pathology (squamous cell carcinoma, adenocarcinoma, bronchioalveolar cell, large cell carcinoma, poorly differentiated or undifferentiated carcinoma, NSCLC, adenosquamous cell carcinoma) Location of lung lesion (right upper lobe (RUL), right middle lobe (RML), right lower lobe (RLL), left upper lobe (LUL), left lower lobe (LLL) Extracranial metastases (None, bone, liver, adrenal, lung to lung, neck lymph nodes, bone+liver+lung to lung) Additional variables assessed for outcome 4: Treatment methods for lung lesion (surgery (S), S + chemotherapy (C/T), S + C/T + RT vs RT only or no treatment) Treatment methods for BM (S, S+R vs whole brain RT) Early (≤ 6 months)/late (> 6 months) brain relapse Brain relapse with/without extra-cranial metastases Outcomes 1. Early (≤ 6 months)/late (> 6 months) brain relapse 2. Brain relapse isolated vs non-isolated from extra-cranial metastases 3. Multiple vs isolated BM 4. Survival Results Multiple logistic regression: Early vs late brain relapse: Performance status and treatment response of lung significantly predicted brain relapse: - Using ECOG performance status 4 as the reference (odds ratio = 1) the odds ratios (OR) and 95% confidence interval (CI) of ECOG 1, 2 and 3 were 18.33 (6.89 - 48.78; p <0.0001), 6.88 (2.35 - 20.15; p <0.0001) and 2.24 (0.75 - 6.64; p = 0.147), respectively; that is, having an ECOG status of 1 or 2 was associated with an 18.33 or 6.88 times, respectively, increased chance of developing late (rather than early) brain relapse compared to having an ECOG status of 4. - Using the NR category of treatment response of the lung as the reference (odds ratio = 1) the OR and 95% CI of CR and PR were 6.711 (2.32 – 19.39; p <0.0001) and 4.435 (1.794 - 10.96; p = 0.001), respectively; that is, CR and

PR were associated with an 6.711 or 4.435 times, respectively, increased chance of developing late (rather than early) brain relapse compared to NR. Brain relapse isolated vs non-isolated from extra-cranial metastases 221/292 patients experienced brain relapse without and 71/292 patients experienced brain relapse with extra- cranial metastases. ECOG performance status was also a significant predictor of isolated BM relapse: - Using ECOG performance status 4 as the reference (odds ratio = 1) the OR and 95%CI of ECOG 1, 2 and 3 were 1.695 (.838 – 3.425; p = .14), 2.92 (1.275 – 6.686; p = .011) and 1.119 (0.496 – 2.523; p = 0.79), respectively; that is, having an ECOG status of 2 was significantly associated with an 2.92 times increased chance of developing isolated (rather than non-isolated) brain relapse compared to having an ECOG performance status of 4. Multiple vs isolated BM 208/292 patients experienced multiple BM and 84/292 patients experienced solitary BM. The location of the primary tumour in the lung was the only significant predictor of multiple BM: - Using LLL as the reference (odds ratio = 1) the OR and 95%CI were: RUL: .901 (.42 – 1.93; p = .79), RML: 1.232 (.35 – 4.27; p = .74), RLL: 2.73 (1 – 7.45; p = .05), and LUL: 2.345 (1 – 5.49; p = .05); that is, a primary tumour location in the RLL and LUL were significantly associated with a 2.73 and 2.345 times, respectively, increased chance of developing multiple (rather than isolated) BM compared to a primary tumour location in the LLL. Cox regression model: Survival: ECOG status, lung response to treatment and pattern of brain relapse were all significant predictors of overall survival: - Using ECOG performance status 1 as the reference (hazard ratio = 1) the hazard ratios (HR) and 95% confidence interval (CI) of ECOG 2, 3 and 4 were 1.904 (1.27- 2.85; p = 0.002), 3.942 (2.69 - 5.762; p < 0.0001) and 5.888 (4.06 - 8.52, p < 0.0001), respectively; that is, having an ECOG status of 2, 3 and 2 were associated with an 1.904, 3.942 and 5.888 times, respectively, increased hazard of dying for each of the 3 ECOG status groups compared to having an ECOG status of 1. - Using the CR category of treatment response of the lung as the reference (HR = 1) the HR and 95% CI of PR and NR were 1.09 (.742 – 1.6; p = .66) and 1.784 (1.47 - 2.77; p = 0.01), respectively; that is, NR was significantly associated with a 1.784 times increased hazard of dying compared to CR. - Using the late brain relapse category as the reference (HR = 1) the HR and 95% CI of early brain relapse were 2.149 (1.59 – 2.89; p < .0001); that is, early brain relapse was significantly associated with a 2.149 times increased hazard of dying compared to late brain relapse. General comments The authors also report a number if univariate analyses that have not been reported in this review because the analysis strategy adopted in this study entailed entering all the significant variables from the univariate analyses into multivariate analyses. Multivariate analysis is a more valid method as it assesses the unique contribution of the entered variables by adjusting for the influence of the other variables and thereby minimises the occurrence of statistically significant results that, in effect, are surrogates for other variables – a common problem with univariate analyses.

This study is limited by its retrospective design and low numbers of patients with some of the outcomes, and can therefore not be considered of high quality. References of Included Studies (For systematic reviews): N/A

Citation: Videtic,G.M.; Adelstein,D.J.; Mekhail,T.M.; Rice,T.W.; Stevens,G.H.; Lee,S.Y.; Suh,J.H. (2007). Validation of the RTOG recursive partitioning analysis (RPA) classification for small-cell lung cancer-only brain metastases. International Journal of Radiation Oncology, Biology, Physics, 67, 240-43. Design: Retrospective observational study Country: USA

Aim: To evaluate the validity of the RTOG-RPA prognostic classification system for brain metastases (BM) patients (that is based on patient pre-treatment characteristics from three completed brain metastases randomised trials) in patients with BM from small cell lung cancer (SCLC). Inclusion criteria Patients with BM from SCLC.

Exclusion criteria Patients who had received surgery as part of their treatment. Population 154 patients: Median age = 65 years (range 42-85). Median Karnofsky score (KPS) = 70 (range 40 – 100). Median number of BM at diagnosis = 3 (range 1-30, n = 139). BM treatment: whole brain radiotherapy (WBRT; n = 130), WBRT + stereotactic surgery (SRS; n = 18), WBRT + chemotherapy (n = 3), SRS (n = 2), and intensity-modulated radiotherapy (n = 1).

These patients were then divided into 3 RTOG-RPA classes: Class I: KPS ≥ 70, age < 65 years, controlled primary tumour and no extracranial metastases (n = 8) Class II: All others (n = 95) Class III: KPS < 70 (n = 51) Interventions Outcomes Survival (measured from time of diagnosis until death or last patient contact). Results Median follow up = 4.7 months (range .3 – 40.3 months) Median survival = 8.6, 4.2 and 2.3 months for classes I, II and III, respectively (p = .0023). General comments The authors conclude: “This retrospective analysis of 154 small-cell lung cancer patients stratified by the RTOG RPA class criteria suggests that these classes are valid for the prognostic stratification of brain metastases patients with this histology and support the inclusion of small-cell lung cancer patients in future brain metastases trials to improve on current poor outcomes. This classification may also serve as a basis for historical comparisons.” (p 243)

However, the study is limited by its retrospective design and relatively low patient numbers. References of Included Studies (For systematic reviews): N/A

Citation: Videtic, G. M., Reddy, C. A., Chao, S. T., Rice, T. W., Adelstein, D. J., Barnett, G. H., Mekhail, T. M., Vogelbaum, M. A., and Suh, J. H. Gender, race, and survival: a study in non-small-cell lung cancer brain metastases patients utilizing the radiation therapy oncology group recursive partitioning analysis classification. International Journal of Radiation Oncology, Biology, Physics 75[4], 1141-1147. 15-11-2009. Design: Retrospective study Country: USA

Aim: To explore whether gender, race and RPA class influence survival in patients with non–small-cell lung cancer (NSCLC) and brain metastases (BM). Inclusion criteria Patients with BM from NSCLC registered for the interval January 1982 to September 2004 on the Cleveland Clinic brain tumor database which is an institutional review board–approved registry of more than 1200 patients with brain metastases. Patients recorded in this database were either diagnosed and treated for primary and secondary tumours at the Cleveland Clinic as well as at outside hospitals, or referred to the Cleveland Clinic for treatment of brain metastases Exclusion criteria Population All patients: N = 835; 487 males; Age ≥ 65 / < 65 / na years: N = 339/495/1; Karnofsky performance status ≥ 70 / < 70/ na: N = 646/163/ 26; Race white/black/other: N = 685/143/7; Number of lesions single / multiple / na: N = 346/445/44; Primary disease status controlled Yes/ No/ na: N = 280/548/7; Extracranial metastases Yes/No: N = 368/467; RPA class I/II/III/na: N = 92/552/162/29; Surgery Yes/No: N = 212/623; Chemotherapy Yes/No: N = 16/819; Radiosurgery Yes/No: N = 272/563; WBRT (total dose/fraction in cGY) 3000/10: N = 357

3750/15: N = 155 4000/20: N = 25 2000/5: N = 22 4500/25: N = 20 4000/15: N = 14 Other (n ≤ 15): N = 125 Na: N = 117 Interventions RPA class I: Patients with Karnofsky performance status ≥ 70, age < 65 years, controlled primary tumour and no extracranial metastases RPA class II: All others RPA class III: Karnofsky performance status < 70 Outcomes Survival Results - Median follow-up = 5.4 months (range 0–122.9 months). - No significant differences were identified between gender or race groups in terms of treatments or number of BMs. - Median survival time (MST) from time of brain metastasis diagnosis for all patients = 5.8 months. - MST = 6.3 months for females and 5.5 months for males (p = 0.013) - MST = 6 months for whites and 5.2 months for blacks (p = 0.08). - MST = 13.0 months for RPA class I, 6.2 months for RPA class II and 2.5 months for RPA class III (p < .0001) - MST did not differ within each RPA class between the gender and race groups overall (all ps ≥ .09) or between the gender/race groups when stratified within the race/gender groups and a bonferroni correction had been applied to adjust for multiple comparisons. - Multivariate analysis showed that gender (relative risk (RR) = .83, p = .041) and RPA class (RR = .28 for I v III, p < .0001; RR = .51 for II v III, p < .0001), but not race were significant predictors of survival. General comments Due to the retrospective nature of this study and relatively low patient numbers in some of the groups (e.g., black patients, RPA Class I patients) included in the analyses, this evidence provided by this study can only be considered of low quality. References of Included Studies: N/A