Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicentre randomised trial

doi:10.1016/S0959-8049(97)00135-4

European Journal of Cancer

Volume 33, Issue 11, October 1997, Pages 1752-1758

https://doi.org/10.1016/S0959-8049(97)00135-4 Get rights and content

Abstract

Prophylactic cranial irradiation (PCI) reduces the risk of cranial metastasis in small cell lung can- cer (SCLC), but the magnitude and value of this reduction, the risks of radiation morbidity and whether PCI influences survival are unclear. We conducted a randomised trial in patients with lim- ited-stage SCLC who had had a complete response to induction therapy. Initially, patients were ran- domised equally to (1) PCI 36 Gy in 18 daily fractions, (2) PCI 24 Gy in 12 fractions and (3) no PCI; subsequently, to increase the rate of accrual, randomisation was to clinicians' choice of PCI regi- men versus no PCI (at a 3:2 ratio). The endpoints were appearance of brain metastases, survival, cognitive function, and quality of life (QoL). Three hundred and fourteen patients (194 PCI, 120 No PCI) were randomised. In the revised design, the most commonly used PCI regimens were 30 Gy in 10 fractions and 8 Gy in a single dose. With PCI, there was a large and highly significant reduction in brain metastases (HR = 0.44, 95% CI 0.29–0.67), a significant advantage in brain-metastasis-free survival (HR = 0.75, 95% CI 0.58–0.96) and a non-significant overall survival advantage (HR = 0.86, 95% CI 0.66–1.12). In both groups, there was impairment of cognitive function and QoL before PCI and additional impairment at 6 months and 1 year, but no consistent difference between the two groups and thus no evidence over 1 year of major impairment attributable to PCI. PCI can safely reduce the risk of brain metastases. Further research is needed to define optimal dose and fraction- ation and to clarify the effect on survival. Patients with SCLC achieving a complete response to in- duction therapy should be offered PCI.

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Cited by (359)

Prophylactic cranial irradiation (PCI), hippocampal avoidance (HA) whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) in small cell lung cancer (SCLC): Where do we stand?
2021, Lung Cancer
Small cell lung cancer (SCLC) is an aggressive form of lung cancer associated with an increased risk of develping brain metastases (BM), which are a significant cause of morbidity and mortality. Prophylactic cranial irradiation (PCI) was first introduced in the 1970s with the aim of reducing BM incidence and improving survival and quality of life (QoL). Prospective clinical trials and meta-analyses have demonstrated its effectiveness in reducing BM incidence and improving survival, across all stages of the disease following response to induction chemotherapy.
Despite its long history, “unknowns” surrounding PCI use still exist and there are particular subgroups of patients for which its use remains controversial. PCI is known to cause neurocognitive toxicity which can have a significant impact on a patient’s QoL. Strategies to minimise this, including the use of hippocampal avoidance radiotherapy techniques, neuroprotective drugs and stereotactic radiosurgery in place of whole brain radiotherapy for the treatment of BM, are under evaluation.
This review offers a summary of the key PCI trials published to date and the current treatment recommendations based on available evidence. It also discusses the key questions being addressed in ongoing clinical trials and highlights others where there is currently a knowledge gap and therefore where further data are urgently required.
Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up<sup>☆</sup>
2021, Annals of Oncology
The role of prophylactic cranial irradiation in small cell lung cancer
2021, Revue des Maladies Respiratoires
L’irradiation cérébrale prophylactique (ICP) est considérée comme le standard thérapeutique du traitement des cancers bronchiques à petites cellules (CBPC) sur la base d’anciennes études randomisées, grevées de limitations méthodologiques, notamment l’absence d’évaluation cérébrale par une imagerie par résonance magnétique. Le but de cette étude est d’évaluer le risque à ne pas administrer d’ICP en cas d’imagerie cérébrale systématique.
Étude rétrospective incluant des CBPC non prétraités, sans ICP et bénéficiant d’une imagerie cérébrale au diagnostic. La méthode de Kaplan–Meier et le test statistique du log-rank ont été utilisés pour évaluer la survie.
Sur 150 patients, 75 auraient pu être éligibles pour une ICP. Treize patients ont présenté une récidive cérébrale comme premier site de progression sans autre localisation métastatique associée et 6 patients ont eu le cerveau pour seul site de récidive durant l’ensemble de leur suivi. Parmi les patients éligibles pour une ICP, il n’y a pas de différence statistiquement significative pour la survie entre les patients ayant progressé au niveau cérébral ou non (p = 0,11).
L’impact attendu d’une ICP semble faible en termes de survie globale et de prévention de métastases cérébrales isolées pour des patients ayant une imagerie cérébrale systématique lors des bilans d’évaluation d’un CBPC.
Prophylactic cranial irradiation (PCI) is considered standard therapeutic management in small cell lung cancer (SCLC). This is based on old randomised trials with methodological limitations, namely the absence of magnetic resonance imaging (MRI) of the brain. The aim of this study is to assess the risk not administering PCI when systematic brain imaging is applied.
Retrospective study including untreated SCLC, without PCI and receiving brain imaging at the time of diagnosis. Kaplan–Meier and log-rank statistics were used for survival analyses.
Among 150 patients, 75 were possibly eligible for PCI. Thirteen patients presented with an isolated brain recurrence as the first site of progression with no other metastatic sites apparent, and in 6 patients, the brain was the only recurrent site during the whole follow-up. In the group of patients eligible for PCI, there was no statistically significant survival difference according to the brain progression status (P = 0.11).
The expected impact of PCI seems limited in terms of overall survival and prevention of isolated brain metastases in patients having systematic brain imaging during SCLC work-up.
Risk factors for neurocognitive decline in lung cancer patients treated with prophylactic cranial irradiation: A systematic review
2020, Cancer Treatment Reviews
Citation Excerpt :
In Le Pechoux’s trial, baseline cognitive decline was detected in 23–25% of patients [39]. In the UKCCCR/EORTC trial, 24–42% had baseline cognitive impairment [32]. In Arriagada’s trial, only 94 of 229 (41%) assessed patients did not show abnormalities at the initial neuropsychological examination [31].
Prophylactic cranial irradiation (PCI) reduces brain metastasis incidence in lung cancer, however with risk of neurocognitive decline. Nevertheless, risk factors for neurocognitive decline after PCI remain unclear.
We systematically reviewed the PubMed database according to the PRISMA guideline. Inclusion criteria were: randomized clinical trials (RCTs) and observational/single arm trials evaluating PCI, including ≥20 patients, reporting neurocognitive test results for lung cancer. Primary aim: evaluate risk factors associated with neurocognitive decline after PCI.
Twenty records were eligible (8 different RCTs, 8 observational studies), including 3553 patients in total (858 NSCLC, 2695 SCLC) of which 73.6% received PCI. Incidence of mild/moderate cognitive decline after PCI varied from 8 to 89% (grading not always provided); for those without PCI, this was 3.4–42%. Interestingly, 23–95% had baseline cognitive impairment. Risk factors were often not reported. In one trial, both age (>60 years) and higher PCI dose (36 Gy) including twice-daily PCI were associated with a higher risk of cognitive decline. In one trial, white matter abnormalities were more frequent in the concurrent or sandwiched PCI arm, but without significant neuropsychological differences. One trial identified hippocampal sparing PCI to limit the neurocognitive toxicities of PCI and another reported an association between hippocampal dose volume effects and memory decline. As neurocognition was a secondary endpoint in most RCTs, and was assessed by various instruments with often poor/moderate compliance, high-quality data is lacking.
Age, PCI dose, regimen and timing might be associated with cognitive impairment after PCI in lung cancer patients, but high-quality data is lacking. Future PCI trials should collect and evaluate possible risk factors systematically.
Prognostic factors for patients with limited-stage small-cell lung cancer without receiving prophylactic cranial irradiation
2020, Radiation Medicine and Protection
This retrospective study aims to explore the risk factors for brain metastasis and the prognostic factors for overall survival (OS) in patients with limited-stage small-cell lung cancer (LS-SCLC) who have no brain metastases according to magnetic resonance imaging (MRI) and have not received prophylactic cranial irradiation (PCI) after first-line chemoradiotherapy.
A total of 107 patients who were treated in the Fourth Hospital of Hebei Medical University from January 2013 to December 2017 were enrolled in this study. The patients were treated with etoposide/platinum chemotherapy and thoracic radiotherapy (TRT) with involved-field irradiation. The median dose of the radiotherapy was 60 Gy (50−64 Gy). The primary study endpoints include BMFS (brain-metastasis-free survival) and OS (overall survival). The Kaplan-Meier method was applied to estimate survival, with a log-rank test used to ascertain statistical significance. The multivariate Cox proportional hazards model was used to determine the prognostic factors for survival.
The median follow-up of all patients was 18.8 months (range: 7.9–65.1 months) and the median follow-up of surviving patients was 26.7 months (range: 18.8–65.1 months). The median OS of the whole cohort was 20.1 months, and the 1-, 2- and 3-year OS rates were 84.9%, 44.9%, and 25.9%, respectively. The 1-, 2-, and 3-year BMFS rates were 69.0%, 49.9%, and 40.7%, respectively. 50 patients (46.7%) developed brain metastases during the follow-up period, and the median time from the start to brain metastasis was 10.7 months (range: 4.8–31.1 months). As shown by multivariate analysis, independent prognostic factors of OS included cycles of chemotherapy (P = 0.019), the response to initial treatment (P = 0.011), and the start time of TRT (P = 0.044). The independent prognostic factors of BMFS included the clinical stage (P = 0.008), the response to initial treatment (P = 0.024), and the start time of TRT (P = 0.028).
For patients with LS-SCLC who have not received PCI, favorable factors for lower brain metastasis and higher survival include early clinical stage, CR to initial chemoradiotherapy, early TRT, and adequate cycles of chemotherapy. PCI is still recommended as the standard modality since the incidence of brain metastases was high (46.7%).
Impact of Lung Cancer Treatment on Cognitive Functioning
2020, Clinical Lung Cancer
The impact of oncologic treatment for (non)–small-cell lung cancer (NSCLC and SCLC, respectively) on cognition is relevant when deciding which treatment is the most preferable option, especially when curation is not possible. A systematic search of Medline and EMBASE for studies on the effect of treatment on cognition in patients with lung cancer was performed. A total of 39 longitudinal articles were included. Study populations were heterogeneous with regards to stage and treatment type. In the 7 studies concerning SCLC, the median age of patients was between 59 and 68 years. Eighty-six percent of these studies had a loss to follow-up > 10%. Six studies used objective tests to assess cognition. Objective measurements showed a negative effect on attention, memory, and fluency after treatment. Thirty-three studies concerning NSCLC were included. The mean age of patients was between 53 and 77 years. Seventy percent of these studies included patients with stage III and IV NSCLC. Over one-half of the studies had a high rate of loss to follow-up. Eighty-eight percent used objective scales to assess cognitive functioning. Subjective decline of cognitive functioning up to 11.1% was experienced, with recovery at 4 to 6 months. Objective measurement of attention showed improvement over the course of chemotherapy. In SCLC, there is a significant negative effect on attention, memory, and fluency. In NSCLC, the longer term impact of treatment on both subjective and objective cognitive functioning appears limited. Thus, there is no evidence directing treatment choice for NSCLC based on longer term cognitive deficits. Further research is needed to precisely assess the impact of lung cancer treatment on cognition.

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Original paperProphylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicentre randomised trial

Abstract

Int J Radiat Oncol Biol Phys

Clin Oncol

Radiother Oncol

Lung Cancer

Am J Med

Lancet

Int J Radiat Oncol Biol Phys

Eur J Cancer

Central nervous system metastases in small-cell bronchogenic carcinoma

Risk of brain metastases from small-cell carcinoma of the lung related to the length of survival and prophylactic irradiation

Cancer Treat Rep

Morbidity of cranial relapse in small-cell lung cancer and the impact of radiation therapy

Cancer Treat Rep

Cranial irradiation in small cell lung cancer

Br J Cancer

Value of prophylactic cranial irradiation given at complete remission in small cell lung carcinoma

Cancer Treat Rep

Neurologic, neuropsychologic and computed cranial tomography scan abnormalities in 2 to 10-year survivors of small cell lung cancer

J Clin Oncol

Original paper
Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicentre randomised trial