Prophylactic Cranial Irradiation in Small Cell Lung Cancer

Cécile Le Péchoux

Aaron H. Wolfson

Small cell lung cancer (SCLC) has several features that distinguish it from other tumor types of lung cancer: the risk of early hematogenous dissemination, its marked radiosensibility and chemosensibility but also its particular propensity to disseminate in the brain. Even if chemotherapy is the cornerstone treatment in both limited and extensive disease, thoracic radiotherapy and prophylactic cranial irradiation (PCI) should be part of the therapeutic strategy in a subset of patients with limited disease (LD) as shown in two metaanalyses.¹,² PCI should be considered among patients with extensive disease who respond to treatment.²,³ In the past years, there has been improvement of both systemic and local control so that about two thirds of these patients, mainly those with LD, treated with aggressive induction therapy combining multidrug chemotherapy and thoracic radiation therapy will be put in complete remission. However, there is a high risk of relapse, so that only 15% to 25% of complete responders will be long-term survivors. Brain failures, for instance, have become a significant cause of relapse as the risk of developing brain metastases increases with length of survival to a cumulative risk that can be as high as 80%.⁴,⁵ PCI has been developed as a strategy to prevent dissemination to the uninvolved brain, where systemic agents do not cross the blood-brain barrier effectively.⁶ Thus, several studies have been undertaken that proved PCI would significantly reduce the incidence of a central nervous system (CNS) relapse compared with patients who did not receive PCI. However, in spite of the positive results of several retrospective and prospective studies, the utility of PCI has been a controversial issue for several years because of the lack of improvement in survival in individual trials and a possible risk of neurotoxicity and cognitive deficits in long-term survivors.⁷,⁸,⁹,¹⁰ Since the publication of a metaanalysis on PCI in SCLC complete responders, showing the benefit of PCI not only in terms of brain control but also in terms of survival, PCI is now considered by most clinicians as standard treatment.²

Because brain metastases are frequent and difficult to treat, accompanied by distressing and sometimes life-threatening symptoms, prophylactic treatment seems a good alternative. At the time of initial diagnosis, up to 24% of patients may have brain metastases if magnetic resonance imaging (MRI) is used as initial workup.⁵,⁶,¹¹ Brain metastases may occur in 50% to 80% of 2-year survivors; in patients who achieve a complete response, the incidence of cerebral metastasis as sole site of initial relapse varies between 14% and 45% at 2 years.¹²,¹³,¹⁴ Historically, chemotherapeutic agents have had a limited role in the treatment of cerebral metastases because of the inability of cytostatic drugs to cross the blood-brain barrier, situated in the endothelium of cerebral microvessels. However, more recent studies have reported efficacy of chemotherapy alone, with response rates on brain metastases ranging from 40% to 76%.¹⁵,¹⁶,¹⁷,¹⁸ Chemotherapy-administered postradiation could also be more effective by abrogation of the blood-brain barrier¹⁹; however, that may also increase toxicity as well. Radiation therapy has remained the most widely accepted treatment modality for brain metastases with improvement of neurological symptoms in 56% to 92% of patients.⁵,²⁰,²¹,²²,²³ However, even if the symptomatic relief is of some benefit, quality of life (QOL) after overt brain metastasis is poor, and overall survival after development of brain metastases is low with median survival times ranging from 1.5 to 4.5 months.²¹,²³,²⁴,²⁵,²⁶,²⁷

STUDIES EVALUATING PROPHYLACTIC CRANIAL IRRADIATION

PCI has been used irregularly in the past 20 years, but since the metaanalysis, it has been accepted more generally, that PCI would delay the symptomatic cerebral metastases and would reduce the lifetime risk of brain relapse by 30% to 50%.⁴,⁵ Several randomized trials listed on Table 60.1 have been published showing a significant twofold to threefold decrease in brain metastases incidence in the PCI arm compared to the control arm.²⁴,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴,³⁵,³⁶ However, they included a very heterogeneous patient population: patients who failed to achieve a complete remission, patients with limited and extensive disease, patients who had concomitant chemotherapy and different PCI doses and fractionations, which can explain the differences observed in brain failure reduction. None of these randomized studies could show an impact on the survival rate. However, in 1983, Rosen et al.¹² were the first one to report than PCI could have an impact on survival in a subgroup of patients and since then, several retrospective studies have suggested that PCI could not only reduce brain failure rates but also improve survival in complete responders to induction treatment.³⁷,³⁸ Subsequently, only patients with complete remission were included in randomized trials. In these more recent trials listed in Table 60.2, the rates of brain failures seem higher than in older trials probably because they are reported as actuarial and not as crude brain metastasis rates.¹³,³⁹,⁴⁰,⁴¹,⁴² The overall 2-year actuarial brain failure rates are 40% and 67%, respectively, in the trial reported by Arriagada et al.,¹³ 30% and 54% in the trial reported by Gregor et al.³⁹ Even if there was a trend in favor of PCI, none of these more recent randomized trials were large enough to confirm statistically the survival benefit suggested in retrospective studies.¹²,³⁷,³⁸,⁴³

TABLE 60.1 Older Randomized Trials Evaluating Prophylactic Cranial Irradiation in Small Cell Lung Cancer Patients

Study (Reference)	Patients	PCI Dose Gy/Fraction Timing of PCI	Brain Metastases Rate (%)		p Value	Median Survival or Survival at X Years
Study (Reference)	Patients	PCI Dose Gy/Fraction Timing of PCI	PCI (+)	PCI (−)	p Value	PCI (+)	PCI (−)
Cox et al.²⁸	45	20/10 D1	17%	24%	NS	40 wks
Beiler et al.²⁹	54	24/8 3rd wk	0%	16%	<0.05	>104 wks LD	58 wks LD
Hansen et al.³⁰	110	40/20 12th wk	9%	13%	NS	9.2 mo	10.2 mo
Maurer et al.³¹	163	30/10 9th wk	4%	18%	<0.01	8.4 mo	8.8 mo
Eagan et al.²⁴	30	36/10 20th wk	13%	73%	<0.05	13.6 mo	12.9 mo
Aroney et al.³³	29 R/172^*	30/10 CR	0%	27%	NS	17 mo	13.5 mo
Jackson Jr et al.³⁴	29	30/10 D1	0%	27%	<0.05	9.8 mo	7.2 mo
Seydel et al.³⁵	217	30/10 D1	5%	21%	<0.005	53 wks	52 wks
Niiranen et al.³⁶	51	40/20 4th wk	0%	26%	<0.05	13 mo	10 mo
^*Out of 172 patients evaluated and analyzed, only 29 patients achieving CR were randomized.
CR, PCI given when patients are in complete remission; D1, PCI given on the first day of induction treatment; LD, limited disease; NS, not specified; PCI, prophylactic cranial irradiation.

Current randomized trials have included patients with both limited and extensive disease, usually complete responders. Thus, as anticipated, more patients with LD comprise these studies. The surprising recent EORTC trial addressed the question of PCI exclusively among 286 patients with documented extensive disease having responded to four to six cycles of chemotherapy and with residual local and systemic disease in nearly three quarters of the randomized patients.³ Patients did not undergo brain imaging before randomization if they were not symptomatic, but were screened for predefined key symptoms of brain metastases. The primary end point was the time to symptomatic brain metastases. The results reported in 2007 strongly support PCI; the authors conclude that it should be part of standard care, not only among complete responders, but also extended to all responders. The majority of patients (61%) received a dose of 20 Gy in five fractions. The cumulative risk of brain metastases at 1 year is 14.6% in PCI group, whereas it is 40.4% in the control group (hazard ratio [HR] = 0.27; p <0.001). Furthermore, irradiated patients also had significantly (HR = 0.68; p = 0.003) longer overall survival (median survival of 6.7 months and survival rate at 1 year of 27.1%) than those in the control group (median survival of 5.4 months; survival rate at 1 year of 13.3%). The difference in survival may be explained also by the fact that patients with extracranial progression were more often treated than those in the control group.

TABLE 60.2 Randomized Trials Evaluating Prophylactic Cranial Irradiation in Small Cell Lung Cancer Complete Responders Included in the Metaanalysis and Results of the Metaanalysis

Study (Reference)	Patients	PCI Dose Gy/Fraction Timing of PCI	Brain Metastases Rate (%)		p Value	Median Survival or Survival at X Years
Study (Reference)	Patients	PCI Dose Gy/Fraction Timing of PCI	PCI (+)	PCI (−)	p Value	PCI (+)	PCI (−)
Aroney et al.³³	29^*	30/3	0%	36%	0.02	—	—
Ohonoshi et al.⁴¹	46	40/20 CR	22%	52%	<0.05	21 mo	15 mo
Arriagada et al.¹³	300	24/8 CR	2-yr rate 40%	2-yr rate 67%	<10^-13	2-yr SR 29%	2-yr SR 21.5%
Wagner et al.⁴²	31	25/10 CR	20%	50%	NS	15.3 mo	8.8 mo
Gregor et al.³⁹^†	314 LD only	Various CR	2-yr rate 30%	2-yr rate 54%	0.00004	305 days 3-yr SR 21%	300 days 3-yr SR 11%
Laplanche et al.⁴⁰	211	24/8-30/10 CR	4-yr rate 44%	4-yr rate 51%	0.14	4-yr SR 22%	4-yr SR 16%
Metaanalysis Aupérin et al.²	987	Various	3-yr rate 33.3%	3-yr rate 58.6%	<0.001	3-yr SR 20.7%	3-yr SR 15.3%
^*Out of 172 patients evaluated and analyzed, only 29 patients achieving CR were randomized.
^†The Gregor study is the only one restricted to patients with limited disease.
CR, PCI given when patients are in complete remission; D1, PCI given on the first day of induction treatment; LD, limited disease; NS, not specified; PCI, prophylactic cranial irradiation; SR, survival rate.