Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA–N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy

Li, N.; Zeng, Zhifan; Wang, Si Yu; Ou, Wei; Ye, X.; Li, J.; He, Xia; Zhang, B. B.; Yang, Hua; Sun, Hai; Fang, Qin; Wang, B. X.

doi:10.1093/annonc/mdu567

Cited by 62 publications

(98 citation statements)

References 27 publications

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“…Five out of the six RCTs reported a significant decrease in BM incidence (14,15,17,18,22). A reduction in BM was seen following PCI in the Veterans Administration Lung Group (VALG) trial (6% vs. 13%; p=0.038) (17) and the MD Anderson Cancer Center (MDACC) trial (4% vs. 23%; p=0.002) (15).…”

Section: Resultsmentioning

confidence: 97%

“…All studies investigating the incidence of BM reported a decrease with the use of PCI and seven studies reported this decrease as being statistically significant (11,(14)(15)(16)(17)(18)22) (Table I). The greatest difference in the incidence rate of BM between PCI and observation was seen in the trial by Stuschke et al (11) (incidence rate of BM at 4 years 13% vs. 54%, respectively; p=0.0004).…”

Section: Resultsmentioning

confidence: 99%

“…The literature search identified six RCTs (14-18, 21, 22) and six retrospective or non-randomised prospective trials investigating survival benefits and the incidence of BM of PCI in patients with NSCLC (7,8,11,16,19,23) (Table I). Five articles assessed the effects of PCI on NF and QOL (11,12,16,18,20) (Table II). Gore et al (14) and Sun et al (20) both reported on analysis from the RTOG 0214 trial.…”

Section: Resultsmentioning

confidence: 99%

“…Four out of the six RTCs analysed survival benefit; three reported no significant survival advantage for PCI over observation (14,17,18 (22). An MDACC trial reported the 3-year survival in the PCI-treated and control groups as 22% and 23.5%, respectively, but no statistical analysis of this data was recorded (15).…”

Section: Resultsmentioning

confidence: 99%

“…PCI for patients with NSCLC is not widely used due to the lack of established evidence for OS benefit and the potential for neurological toxicity post RT. PCI for NSCLC may not have an impact on OS or disease-free survival (DFS) but it has been shown to reduce the incidence of BM (11,(14)(15)(16)(17)(18)(19), therefore it is a matter of debate if these patients benefit from PCI.…”

Section: Abstract Background: the Use Of Prophylactic Cranial Irradimentioning

confidence: 99%

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The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer

Precival

Landy

Poole

et al. 2018

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Abstract. Background: The use of prophylactic cranial irradiation (PCI) to treat brain metastases (BM) in non-small cell lung cancer (NSCLC) is restricted due to the potential associated toxicity and lack of survival benefit. BM can have a negative impact on neurocognitive function (NF) and quality of life (QOLProphylactic cranial irradiation (PCI) is a technique that delivers radiation therapy (RT) to the whole brain to prevent the occurrence of brain metastases (BM) in aggressive cancer types that commonly metastasise to the brain (1). The rationale behind PCI is to eliminate undetectable micrometastases before they become clinically apparent (1).According to the American Cancer Society, about 85-95% of all lung cancer cases are non-small cell lung cancer (NSCLC) (2). The brain is the first site of metastases for up to 30% of these patients (3), with 60% of BM occurring in the first 6 months (4). With modern advances in the management of NSCLC, the risk of developing BM increases as survival is prolonged (5). The reported incidence of BM from NSCLC ranges from 17% to 54%, with younger patients, those with locally advanced-stage disease, adenocarcinoma and large cell types at the higher end of this range of incidence (4, 6-9). BM are associated with high morbidity, poor prognosis (10) and neurocognitive and quality of life (QOL) deficits (10-12).Patients with small cell lung cancer derive an overall (OS) and BM-free survival benefit from PCI (13). PCI for patients with NSCLC is not widely used due to the lack of established evidence for OS benefit and the potential for neurological toxicity post RT. PCI for NSCLC may not have an impact on OS or disease-free survival (DFS) but it has been shown to reduce the incidence of BM (11,(14)(15)(16)(17)(18)(19), therefore it is a matter of debate if these patients benefit from PCI.Late cognitive toxicities are suggested to be associated with PCI and these may be a factor in the prescribing of this treatment. The Radiation Therapy Oncology Group trial (RTOG)-0214 reported a significant decline in memory at 1 year with PCI use (20). Neurocognitive function (NF) decline may occur as a direct result of vascular injury, demyelination or radionecrosis (20).This review aimed to investigate published literature on the use of PCI in patients with NSCLC to assess the impact of PCI on disease-specific outcomes and report the effects of PCI on NF and QOL outcomes. Materials and MethodsTo ensure all appropriate studies were included in this review, a systematic approach was used for searching and selecting relevant publications. As the technique for treating PCI has remained relatively unchanged over the years,

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Abstract Background: the Use Of Prophylactic Cranial Irradimentioning

confidence: 99%

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The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer

Precival

Landy

Poole

et al. 2018

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The Changing Role of Whole-Brain Radiotherapy

2017

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Is there a role for whole-brain radiation therapy in the treatment of brain metastases?-Yes.Whole-brain radiotherapy (WBRT), has been integral in the management of brain metastases (BrM), but some recent trials have raised important questions regarding WBRT.In the QUARTZ trial, 1 538 patients with non-smallcell lung cancer (NSCLC) BrM were randomized to WBRT or best supportive care. No survival difference was observed (8-9 weeks median overall survival [OS] for both). The obvious conclusion from is that WBRT does not prolong median OS in NSCLC BrM, but the caveat here is the dismal median OS of 8 to 9 weeks, implying selection of an extremely unfavorable cohort of patients, best considered for hospice. They also found no difference in quality of life (QOL). It takes weeks before WBRT translates to clinical benefit and QOL improvement. When more than half the patients die within 8 weeks, there is not enough time for QOL benefit to manifest, underscoring the existing practice that for patients with poor performance status and short survival, best supportive care is ideal, not a practice-changing observation.Another trial that has received attention is Alliance (NCT00377156). 2 Overall, 213 patients with 1 to 3 BrM were randomized to stereotactic radiosurgery (SRS) with or without WBRT. There was no difference in median OS, an important finding, in light of the shorter time to intracranial failure with WBRT (hazard ratio [HR], 3.6; P < .001). One conclusion would be that WBRT does not prolong median OS in spite of improved local control and should not be used. The slippery slope is that SRS has never been shown to improve survival except for those with a single BrM, in spite of enhancing local control. Logic would suggest that SRS should therefore also not be used.A therapy capable of enhancing intracranial control can only improve median OS in patients at high risk of dying from intracranial progression and low risk of succumbing to extracranial progression. This has been amply proven in randomized trials of prophylactic cranial radiation in small-cell lung cancer (SCLC). The majority of the patients in the QUARTZ 1 and Alliance 2 trials had NSCLC. A recent phase 3 trial of prophylactic cranial radiation 3 in NSCLC showed that prophylactic cranial radiation outperformed observation; disease-free survival was significantly lengthened to 28.5 vs 21.2 months (HR, 0.67; P = .04); 5-year brain metastases risk was reduced from 49.9% to 20.3%. Median OS was 31.2 vs 27.4 months (HR, 0.81) but did not reach statistical significance because the trial was terminated early based on achieving the primary objective. A secondary analysis of the JROSG 99-1 randomized trial 4 categorized patients into "unfavorable" vs "favorable" groups using the dis-VIEWPOINT

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Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer

Sun

Wong

et al. 2019

JAMA Oncol

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IMPORTANCE Brain metastasis (BM) rates are high in locally advanced non-small cell lung cancer (LA-NSCLC), approaching rates seen in small cell lung cancer, where prophylactic cranial irradiation (PCI) is standard of care. Although PCI decreases the incidence of BM in LA-NSCLC, a survival advantage has not yet been shown. OBJECTIVE To determine if PCI improves survival in LA-NSCLC. DESIGN, SETTING, AND PARTICIPANTS Radiation Therapy Oncology Group (RTOG) 0214 was a randomized phase 3 clinical trial in stage III NSCLC stratified by stage (IIIA vs IIIB), histologic characteristics (nonsquamous vs squamous) and therapy (no surgery vs surgery). The study took place at 291 institutions in the United States, Canada, and internationally. Of 356 patients with stage III NSCLC entered onto this study, 16 were ineligible; therefore, 340 patients were randomized. INTERVENTION FOR CLINICAL TRIALS Observation vs PCI. MAIN OUTCOMES AND MEASURESThe primary outcome was overall survival (OS). The secondary end points were disease-free survival (DFS) and incidence of BM. RESULTSOf the 340 total participants, mean (SD) age was 61 years; 213 of the participants were men and 127 were women. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The OS for PCI was not significantly better than observation (hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P = .12; 5-and 10-year rates, 24.7% and 17.6% vs 26.0% and 13.3%, respectively), while the DFS (HR, 0.76; 95% CI, 0.59-0.97; P = .03; 5-and 10-year rates, 19.0% and 12.6% vs 16.1% and 7.5% for PCI vs observation) and BM (HR, 0.43; 95% CI, 0.24-0.77; P = .003; 5-and 10-year rates, 16.7% vs 28.3% for PCI vs observation) were significantly different. Patients in the PCI arm were 57% less likely to develop BM than those in the observation arm. Younger patients (<60 years) and patients with nonsquamous disease developed more BM. On multivariable analysis, PCI was associated with decreased BM and improved DFS, but not improved OS. Multivariable analysis within the nonsurgical arm suggests that PCI effectively prolongs OS, DFS, and BM. CONCLUSIONS AND RELEVANCEIn patients with stage III LA-NSCLC without progression of disease after therapy, PCI decreased the 5-and 10-year rate of BM and improved 5-and 10-year DFS, but did not improve OS. Although this study did not meet its primary end point, the long-term results reveal many important findings that will benefit future trials. Identifying the appropriate patient population and a safe intervention is critical.TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00048997

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Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA–N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy

Abstract: In patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases.

Cited by 62 publications

References 27 publications

The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer

The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer

The Changing Role of Whole-Brain Radiotherapy

Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer

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