Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission

doi:10.1016/S0169-5002(98)00056-7

Lung Cancer

Volume 21, Issue 3, 1 September 1998, Pages 193-201

https://doi.org/10.1016/S0169-5002(98)00056-7 Get rights and content

Abstract

We conducted a randomised clinical trial on 211 patients with small-cell lung cancer in complete remission (CR). The aim of this trial was to evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival. Eligible patients were randomly assigned to receive either PCI (100 patients) or no PCI (111 patients). Each centre was allowed to use its own PCI protocol as long as the total dose was within the range of 24–30 Gy and delivered in less than 3 weeks with fractions of 3 Gy or less. The mean follow-up is 5 years. The survival curves do not differ significantly (P=0.25) between the two groups. The 4-year overall survival rate (95% confidence interval) is 22% [15–32%] in the PCI group versus 16% [10–25%] in the control group. The relative risk of death in the PCI group compared to the control group is 0.84 (95% CI=[0.62–1.13]). The incidence of brain metastasis is lower in the PCI group, but the difference is not statistically significant (P=0.14). The 4-year cumulative rate of brain metastasis is 44% [32–57%] in the PCI group compared to 51% [38–63%] in the control group. In conclusion, in this study, which had to be closed prematurely, no significant difference was found in terms of the incidence of brain metastases nor in survival.

Introduction

There is still controversy over the indications for prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) despite the high incidence of brain metastasis. Randomised trials conducted during the last twenty years 5, 9, 10, 14, 16, 19, 26, 27, 33concluded that PCI was effective in decreasing the risk of brain metastasis, but offered no significant benefit for overall survival. Some published retrospective studies [30], however, suggested that a gain in survival was restricted to patients in complete remission (CR). Prophylactic cranial irradiation was therefore started at doses between 25 and 30 Gy, exclusively in this subgroup of patients. More recent trials, including only patients in CR, have also attempted to evaluate neurotoxicity prospectively, since it was suggested that PCI could cause neuropsychological deterioration (loss of memory and intellectual deficit) and brain abnormalities (ventricular dilatation, periventricular hypodensities and parenchymal calcifications), as determined by CT scan. In France, a PCI trial [3]was initiated in May 1985 (IPC85) to evaluate the effects of PCI on brain metastases and late toxic effects in patients with small cell lung cancer in complete remission; survival was a secondary end-point. It was calculated that a total of 300 patients had to be enrolled to show a minimum decrease of 15% in the rate of isolated brain metastasis at 2 years. In 1988, while inclusion in the IPC85 trial was still ongoing (the 300 patients were included between May 1985 and March 1993), another trial (IPC88) was initiated focusing exclusively on overall survival. The design and follow-up requirements of the latter trial were very simple and more flexible in order to facilitate collaboration with new investigators who could not include patients in the IPC85 trial because of the complexity of its requirements. Neurological assessment was therefore not mandatory and each centre was allowed to use its own PCI protocol. This article presents the results of this last trial.

Section snippets

Patients

Only patients with histologically confirmed small-cell lung cancer, in complete remission after induction treatment were included. Complete remission was confirmed by a chest X-ray, fiberoptic bronchoscopy and a chest CT scan in patients with limited disease. Patients with extensive disease were also eligible provided they had no brain metastases at presentation. In this latter group of patients, complete remission was established by repeating any previous diagnostic examination (liver

Results

From October 1988 to April 1994, 211 patients were enrolled in 24 centres (Appendix A). In April 1994, enrolment was stopped when the results of the IPC85 trial were published [3]. One hundred patients were assigned to the PCI group and 111 to the group without PCI. In the PCI group, one patient should not have been included because he had liver metastases at the pre-randomisation assessment. Nevertheless, this patient was analysed in the PCI group. The demographic and clinical characteristics

Discussion

This trial was initiated to see whether survival could be increased among patients with small-cell lung cancer in complete remission who had undergone prophylactic cranial irradiation. Since it was obvious that any potential gain in survival afforded by PCI would only be moderate, a 1000 patients were to be accrued. In order to accrue such a large number of patients, the design was flexible (each centre was allowed to use its own local radiation protocol) and follow-up requirements were very

Acknowledgements

We thank Lorna Saint-Ange for manuscript editing.

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Cited by (83)

The overall survival impact of prophylactic cranial irradiation in limited-stage small-cell lung cancer: A systematic review and meta-analysis
2022, Clinical and Translational Radiation Oncology
Prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (LS-SCLC) patients has become more controversial. Since the publication of the systematic review by Aupérin et al. in 1999, no randomized controlled trials regarding PCI in LS-SCLC have been completed. The aim of this study was to systematically review and meta-analyze the effect of PCI on overall survival (OS) in patients with LS-SCLC.
A systematic search was conducted in the databases of MEDLINE (PubMed), Embase and the Cochrane library. Only studies that reported an adjusted hazard ratio (aHR), indicating the effect of PCI versus no PCI on OS (adjusted for confounders) in patients with LS-SCLC were included for critical appraisal and meta-analysis. A pooled aHR estimate was calculated using a random-effects model.
Pooling of 28 retrospective studies including a total of 18,575 patients demonstrated a significant beneficial effect of PCI versus no PCI on OS with a pooled aHR of 0.62 (95% CI: 0.57–0.69). Substantial heterogeneity of reported aHRs among studies was observed (I² = 65.9%). Subgroup analyses revealed that this heterogeneity could partly be explained by study sample size. The pooled aHR among 7 versus 21 studies with a sample size of > 300 versus ≤ 300 patients was 0.79 (95% CI: 0.64–0.97) versus 0.56 (95% CI: 0.46–0.69; p < 0.001), respectively.
This meta-analysis demonstrates a significant beneficial effect of PCI on OS in patients with LS-SCLC. Larger studies reported a milder beneficial effect, possibly due to a decreased risk of model overfitting. Serious risk of selection and confounding bias were of concern due to the lack of prospective trials. These results support the role of PCI in standard clinical practice in patients with LS-SCLC while awaiting results of prospective trials on alternative strategies.
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.
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%).
Limited-Stage Small Cell Lung Cancer: Is Prophylactic Cranial Irradiation Necessary?
2019, Practical Radiation Oncology
Citation Excerpt :
Patients with no initial brain imaging (N = 5), those with progressive disease by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria8,9 in the brain (N = 6) or in the chest (N = 5) after initial therapy, those who did not complete initial therapy, and those without adequate follow-up were excluded. Patients who progressed immediately after curative therapy were excluded, as in multiple prior studies of patients with both limited and extensive-stage disease.1,10-13 Baseline patient demographic characteristics, treatment details, and clinical outcomes were abstracted from the medical record.
Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases in patients with limited stage small cell lung cancer (LS-SCLC). However, PCI is associated with neurotoxicity. Previous studies have not consistently used pretreatment magnetic resonance imaging. Modern imaging improvements continue to enhance early metastasis detection, potentially decreasing the utility of PCI. We sought to determine whether PCI was associated with improved outcomes in LS-SCLC patients with modern imaging.
We identified LS-SCLC patients with no intracranial disease who were treated between 2007 and 2018. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated and multivariate Cox proportional hazards models were generated. The cumulative incidence of brain metastases was estimated using competing risks methodology.
Ninety-two patients were identified without intracranial disease at initial staging, 39 of whom received PCI. Median follow-up was 56.7 months. The median OS for the cohort was 35.5 months (95% CI, 25.8-49.3), and median PFS was 19.1 months (95% CI, 12.3-30.5). Median OS with PCI versus observation was 37.9 months (95% CI, 31.8-not reached) versus 30.5 months (95% CI, 14.6-56.1; P = .07), whereas median PFS was 26.3 months (95% CI 19.1-not reached) versus 12.3 months (95% CI, 8.5-30.5; P = .02), respectively. Overall, at 2 years, the cumulative incidence of brain metastases was 10% with PCI and 29% without; this increased to 32% and 29% by 4 years (P = .66). In those patients who had negative magnetic resonance imaging of the brain after completing initial treatment, the 1-year cumulative incidence of brain metastasis was not significantly different at 8% versus 11% (P = .46) respectively. Both PCI and treatment response were independent predictors for PFS on multivariate analysis. Stratified by disease response, patients with a complete response did not benefit from PCI (P = .50), whereas those with partial response or stable disease experienced improved PFS (P = .01).
Overall, PCI was associated with improved PFS and reduced early incidence of brain metastases. Patients achieving a complete response to initial therapy did not experience a PFS benefit with PCI. This may indicate that subsets of LS-SCLC patients can potentially be spared from PCI in the era of modern imaging.
Prophylactic Cranial Irradiation Versus Surveillance: Physician Bias and Patient-centered Decision-making
2018, Clinical Lung Cancer
An original work in this month’s issue of Clinical Lung Cancer highlights the role of physician bias in the decision to recommend prophylactic cranial irradiation (PCI) to patients with small-cell lung cancer, and presents a patient decision aid to facilitate discussion. After decades of clinical trials, we’ve learned that PCI can significantly decrease the risk of brain metastases and possibly improve survival. However, PCI is also associated with negative impacts on cognition and quality of life. At present, there is no consensus on how to balance these risks and benefits. Understanding and exploring these issues in a structured fashion offers an opportunity to return decision-making to patients, incorporating their values and priorities.
Is prophylactic cranial irradiation indicated for patients with extensive-stage small cell lung cancer with a complete response to first-line treatment?
2018, Radiotherapy and Oncology
Citation Excerpt :
However, one shortcoming of these studies is that complete response (to chemotherapy) had not been confirmed in most patients. During the period from 1977 through 1995, seven randomized trials were conducted that considered PCI for patients with pathologically proven SCLC that had completely responded to definitive therapy [10–15]. In 1999, Auperin and colleagues published a meta-analysis of the 987 patients treated in those trials and found a statistically significant absolute survival benefit of 5.4% (20.7% vs. 15.3%; hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.73–0.97, P = 0.01) at 3 years among patients given PCI [6].
Prophylactic cranial irradiation (PCI) has been considered standard of care for patients with limited-stage small-cell lung cancer who achieve complete response to definitive treatment after a meta-analysis revealed its favorable effects on survival. In a European trial, PCI was also shown to confer a survival advantage for patients with extensive-stage (ES) SCLC who experienced any positive response after initial chemotherapy, leading to PCI also being considered a standard treatment for these patients as well. However, a recent Japanese trial investigating PCI for patients with ES-SCLC was stopped early when an interim analysis failed to confirm a survival benefit. This finding has motivated the thoracic oncology community to rethink the role of PCI in ES-SCLC.

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Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgements

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

Cancer Treat Rep

Competiting risks determining event-free survival in early breast cancer

Br J Cancer

Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission

J Natl Cancer Inst

Prophylactic cranial irradiation (PCI) for patients (pts) with small-cell lung cancer (SCLC) in complete response (CR)

Eur J Cancer

Low dose elective brain irradiation in small cell cancer of the lung

Int J Radiat Oncol Biol Phys

An improved approximate formula for calculating sample sizes for comparing two binomial distributions

Biometrics

Adverse effects of brain irradiation correlated with MR and CT imaging

Int J Radiat Oncol Biol Phys

Regression models and life-tables

J R Stat Soc

Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung: preliminary report of a cooperative trial

Cancer

A case for preplanned thoracic and prophylactic whole brain radiation therapy in limited small-cell lung cancer

Cancer Clin Trials

Neurological paraneoplastic syndromes in patients with small cell lung cancer. A prospective survey of 150 patients

J Neurol Neurosurg Psychiatr

A class of K-sample test for comparing the cumulative incidence of competing risk

Ann Stat

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

Eur J Cancer

Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma. A comparative trial of localized versus extensive radiotherapy including prophylactic brain irradiation in patients receiving combination chemotherapy

Cancer

Residual effects of cigarette smoking on cognitive performance in normal aging

Psychol Aging

Prophylactic cranial irradiation in small cell carcinoma of the lung. A randomized study

J Am Med Assoc

Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small cell lung cancer: further follow-up to 6- to 13-year survivors

J Clin Oncol

Non parametric estimation from incomplete observations

J Am Stat Assoc