Prophylactic cranial irradiation (PCI) or magnetic resonance imaging (MRI) monitoring in limited small cell lung cancer: is it a question?

Neurological disorders represent a major challenge in the management of small cell lung cancer (SCLC). In an old series including 641 patients, 189 (29.5%) had at least one neurologic disorder either at the time of presentation or during the subsequent clinical course of the disease. The total number of neurologic disorders was 210, including brain metastases (75.7%), epidural metastases (11.0%), meningeal carcinomatosis (6.7%) and intramedullary metastases (2.4%) (1). Clearly, brain metastases are a major issue with an incidence as high as 50% at 2 years (2). The brain was considered a sanctuary site due to the blood brain barrier and the limited access for most available drugs. Following the experience in the management of leukemia, Heine Hansen introduced in 1973 the concept of prophylactic cranial irradiation (PCI) for SCLC (3). The goal was to prevent brain metastases, avoiding the possible neurological complications and ultimately improving survival. PCI was tested through a series of randomized trials which showed very early that PCI decreased the incidence of brain metastases but they all failed to show a survival benefit probably due to the limited number of patients included in those trials. The response was provided by the analysis of Auperin et al. who included the individual data of 987 patients from seven randomized trials (2). This meta-analysis demonstrated a 25% reduction in brain metastases leading to a 5% survival benefit at 3 years for patients considered in complete response to the initial therapy. Most of these patients had a limited disease (85%). A more recent meta-analysis including 1983 patients from 16 randomized trials showed a similar survival benefit of 4.4%, especially among patients with a complete response. However, there was no correlation with the disease extent, i.e., limited vs. extensive (4). An interesting observation was reported by Arriagada et al.: in trials comparing PCI (24 Gy in 8 fractions) to no PCI, at 5 years the rate of brain metastases was 37% vs. 59%, respectively, but the interesting figure was the number of patients with only a relapse in the brain, 20 vs. 43%, leading to a 3% survival benefit in favor of PCI (5). This outlines the competing events, brain metastases being only one issue besides control of the primary tumor and extra-cerebral metastatic sites.

Today, PCI is recommended for patients in complete remission after systemic treatment for limited or even disseminated disease (6). In a recent survey amongst US radiation oncologist, 98% will recommend PCI but only after a brain magnetic resonance imaging (MRI) in the initial staging (7). In another survey including 295 responses, 35% from the United States and Europe and mainly including radiation (45%) and medical (43%) oncologists, the picture is a little more contrasted: 88% and 50% would recommend PCI to a 50- and 70-year-old patient, respectively. In contrast, this is not the case in Japan where less than 15% of patients have a PCI (8). Should all patients receive PCI, this question is also raised among elderly patients, especially as in the experience of the MD Anderson no survival benefit was observed for patients older than 70 (9)

So, what is the reason to reopen today the debate on the usefulness of PCI? The goals of PCI are to reduce the incidence of brain metastases, avoiding central nervous system (CNS) symptoms and improving survival being clearly achieved according to the trials and meta-analysis. Therefore, we should first look at the design and limitations of those randomized trials: there was a wide range of radiation schedules (from 8 Gy in one fraction to 40 Gy in 20 fractions), the timing of PCI, the definition of a complete response was based on a chest X-ray, and most trials did not include a brain imaging at the staging, before the PCI or during the follow-up of the patients.

Regarding the issue of the radiation schedule, a large-scale trial has compared 25 to 36 Gy but failed to show any benefit from a higher radiation dose neither on the incidence of brain metastases (which remained high, around 35% at 3 years) nor on survival (10). This confirms the results of a pooled analysis of patients included in four phase II and III trials from the North Cancer Center treatment group: for limited disease 25 Gy in 10 fractions was associated with significantly better survival compared with 30 Gy in 15 fractions (11). So, 25 Gy in 10 fractions is now the recommended radiation schedule.

Impact of brain imaging

Brain imaging was not part of the initial staging in many trials and this has a direct impact on the reported incidence of brain metastases: in the absence of brain imaging PCI reduces the incidence of brain metastases from 53% to 40% and in case of a brain imaging from 33% to 10% (12). We should point out that in these studies brain imaging was done by CT or nuclear imaging. Nowadays MRI is available and its introduction has increased the detection of brain metastases from 10% to 24% (13). However, in a recent published trial conducted between 2008 and 2013 baseline imaging of the brain was still done by CT scan in 79% of the 449 patients (14). Furthermore, patients detected with brain metastases through CT had symptoms while they were asymptomatic in case of MRI. Therefore, the proportion of patients eligible for PCI is lower in the MRI era. Another problem is the delay between the initial staging and the time of the PCI: in a series of 40 patients treated by chemoradiotherapy for a limited disease, an MRI repeated before the PCI showed 13 patients (33%) to have developed brain metastases of whom 11 were fully asymptomatic (15).

Side effects of PCI

Another concern with PCI, as it is whole brain radiotherapy (WBRT), is the risk of acute and late toxicities: hair loss, fatigue, hearing impairment, dementia, leukoencephalopathy… Already in 1985, Bruce Johnson reviewed 20 long-term survivors, alive and free of cancer 2.4 to 10.6 years after the initial treatment; 15 (75%) had neurological late effects with also an abnormal CT scan (16). Several risk factors were identified including the dose per fraction above 3 Gy, and the administration of concurrent chemotherapy including methotrexate used in the past. However, the major problem was the absence of a baseline evaluation. Indeed, different studies have also tested the patients before PCI. In a study of the MD Anderson, 97% of the 30 patients evaluated before PCI presented abnormalities in the cognitive functions, mainly alteration of verbal memory, frontal function and fine coordination; the intellectual capacity, the language and the visual perception were preserved (17). The concern with PCI is the risk of (further) altering those cognitive functions leading to an impaired quality of life. The RTOG has evaluated patients before and 6 and 12 months after PCI using the Hopkins Verbal Learning Test-Revised (HVLT-R) test from Harvard and the self-reported cognitive functioning tests of the European Organisation for the Research and Treatment of Cancer (EORTC): a three-fold decrease was observed both at 6 and 12 months after PCI (18).

In order to handle these important side effects, one might think of two solutions. The first solution can be to omit PCI and to only treat the metastases when they appear, alternatively new radiotherapy techniques have been developed in order to safely spare the critical zones in the brain out of the high dose zones.

WBRT vs. radiosurgery (RS) for brain relapses

When considering PCI avoidance, we also need to look at the treatment available for a brain relapse. In the past and still today, the classical approach of such metastases is WBRT with mainly a palliative goal, many patients dying with progressive CNS disease regardless of the radiation schedule used, including 20 Gy in 5 fractions to 30 Gy in 10 fractions (19). In a large series, median survival after WBRT was 17 months for patients in recursive partitioning analysis (RPA) class I; 7 months in class II; and 3 months in class III (20). Important prognostic factors were the performance status (PS), metachronous disease and initial response to chemotherapy. Nevertheless, survival not only depends on the brain disease but also on the extracranial progression: in a study of Gerdan et al. the 6-month survival rate dropped from 52% in the absence of extracranial disease to 0% when 3 or more organs are affected (21). RS is now largely available and is becoming more and more popular in the treatment of brain metastases. RS may allow avoiding toxicity risks and might be more efficacious: in a randomized trial, patients were operated followed by either WBRT or RS limited to the surgical cavity; there was less cognitive deterioration after RS (22). RS is now also used for brain metastases from SCLC: this is a very effective local treatment to control the disease but many patients will develop new brain metastases. As an example, one large series included 70 consecutive patients with brain metastases either after surgery, PCI or WBRT who were treated with RS between 2009 and 2015. Only three patients had an intracranial progression and 9 developed a meningeal carcinomatosis but 40 patients required repeated brain treatment. Indeed, at 12 months the rate of distant intracranial recurrence was 47% (23).

Extensive disease SCLC

PCI has also been proposed for extensive disease SCLC: in a meta-analysis of 14 clinical studies including 1,221 patients treated with PCI and with 5,074 patients in the control group, PCI reduced the incidence of brain metastases but also prolong survival (24). Nevertheless, a recent phase III trial has challenged this point of view and opened the debate on the place of PCI both for extensive and limited disease. This Japanese phase III trial randomized patients between PCI and no PCI after any response to the initial chemotherapy but only when a new MRI showed no brain metastases. The PCI schedule was 25 Gy in 10 fractions. The no PCI arm included an active surveillance with an MRI every 3 months. PCI reduced the incidence of brain metastases but without any benefit in term of survival and this was also observed for patients with a complete response to the initial treatment (25,26). The median survival in these 163 patients was even lower in the PCI arm (11.6 months) than in the control group (13.7 months). In contrast, the EORTC trial who also randomized PCI vs. no PCI for patients with any response to chemotherapy observed a reduction of the incidence of symptomatic brain metastases at 1 year from 40% to 16% and a statistically significant survival benefit from 13% to 27% (27). The PCI dose most commonly used was 20 Gy in 5 fractions but varied with 25 or 30 Gy in 10 fractions. So, what are the main differences between those trials? First, the EORTC trial did not include a brain imaging in the staging or at the time of PCI, it was only performed in presence of symptoms. In the Japanese trial, 64 out of 77 patients (83%) with brain metastases, even when asymptomatic, received radiotherapy and in the EORTC trial 35 out of the 59 patients (59%) were treated for a symptomatic brain disease. Furthermore, the Japanese trial often used RS. So, the main differences are an earlier diagnosis and a more aggressive approach in case of disease progression by the Japanese colleagues. We should also notice the clear difference in median survival between the two trials: between 11 and 13 months for the Japanese trial vs. 6 months for the European trial; reflecting a different patient population and probably also a very selected group of patients.

Limited disease SCLC

Do we have data in case of limited disease? There are several reports but always with a very limited number of patients. In the series of Ozawa et al., patients had MRI just before PCI: 29 patients received PCI and 95 not (28). At 2 years the incidence of brain metastases was respectively 45.5% and 30.8% in the group with and without PCI; without any difference in survival. In the non-PCI group 25 patients (26%) developed brain metastases of whom 17 (18%) relapsed only at the brain. All were treated with RS. In the series of Sakaguchi et al., 60 patients with an almost complete response after chemoradiotherapy were just followed and only 13 (22%) developed brain metastases; treated by WBRT the ultimately cause of death was brain progression (29). However, the most common site of relapse was still locally, i.e., the lung. In the series of Mamesaya et al., no difference was observed in terms of 3-year survival after PCI (60 patients) vs. no PCI (20 patients), the incidence of brain metastases being respectively 28% and 40% (30). In contrast, Giuliani et al. observed a higher number of patients without brain failure at 3 years and a better survival after PCI compared to the observation arm, respectively 40% vs. 28%. This series included 127 patients with PCI and 80 without (31). The key question is the selection of patients: those are retrospective studies and patients included in the no-PCI arm may have been selected by old age, poor PS or patient refusal.

Another interesting question is the role of PCI for surgically resected patients minimizing the risk of local progression. The current guidelines recommend adjuvant chemotherapy and PCI for early stage SCLC. The risk of brain metastases is related to the extent of the primary lung disease: in the largest series, the rates of brain metastases were respectively 13.6%, 22.4% and 27.8% for pathological stage I, II and III. PCI did not reduce brain relapse for stage I and a survival impact was only seen for stage III (32).

Hippocampus sparing radiotherapy

Finally, one might wonder whether it is possible to decrease the potential brain toxicity induced by PCI. The neurocognitive function highly depends on the sparing of the hippocampus area: doses above 7 Gy may alter the neurocognitive functions. Most of the brain metastases in case of non-small cell lung cancer (NSCLC) are located at distance from this area: amongst 1,133 brain metastases less than 100 (9%) were located within 1 cm from this area (33). Using modern radiation techniques, it is possible to deliver a dose of 25 Gy to the brain while keeping the dose to the hippocampus below 7 Gy. Randomized trials are on-going to show the safety and efficacy of sparing hippocampal sparing PCI. On the one hand, safety is certainly a concern. In contrast to Gondi et al. for NSCLC, the rate of hippocampal metastasis may be higher in SCLC: Korkmaz et al. observed a hippocampal metastasis rate of 32% in a series of 44 patients (34). On the other hand, some small published series have shown a clear potential benefit: Redmond et al. followed 20 patients without any decline in memory using the HVLT-R delayed recall and only two patients developed metastases in the under-dosed regions but both had additionally other brain metastases (35). On-going randomized trials may also give some additional information on the MRI.

Conclusions

Today, the question whether MRI monitoring and surveillance can be an alternative to PCI for patients with limited disease remains unanswered. There is no randomized trial comparing MRI surveillance vs. PCI using a hippocampus sparing approach but some series suggesting the feasibility of such an approach challenge the PCI dogma. Quality of life and an economic analysis should be part of a phase III trial. However, there is also a major problem due to the limited MRI resources in many countries. In the absence of a clear cut answer, PCI may still be proposed to patients but only after a clear explanation of benefits and risks while avoiding patients at high risk such as old patients and patients in poor condition.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor Nir Peled for the series dedicated to the Congress on Clinical Controversies in Lung Cancer (CCLC 2018) published in Precision Cancer Medicine. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/pcm.2019.03.02). The series dedicated to the Congress on Clinical Controversies in Lung Cancer (CCLC 2018) was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sculier JP, Feld R, Evans WK, et al. Neurologic disorders in patients with small cell lung cancer. Cancer 1987;60:2275-83. [Crossref] [PubMed]
2. Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476-84. [Crossref] [PubMed]
3. Hansen HH. Should initial treatment of small cell lung cancer carcinoma include systemic chemotherapy and brain irradiation? Cancer Chemother Rep 3 1973;4:239-41. [PubMed]
4. Viani GA, Boin AC, Ikeda VY, et al. Thirty years of prophylactic cranial irradiation in patients with small cell lung cancer: a meta-analysis of randomized clinical trials. J Bras Pneumol 2012;38:372-81. [Crossref] [PubMed]
5. Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995;87:183-90. [Crossref] [PubMed]
6. Kalemkerian GP, Loo BW, Akerley W, et al. NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018. J Natl Compr Canc Netw 2018;16:1171-82. [Crossref] [PubMed]
7. Farrell MJ, Yahya JB, Degnin C, et al. Prophylactic cranial irradiation for limited-stage small-cell lung cancer: survey of US radiation oncologists on current practice pattern. Clin Lung Cancer 2018;19:371-6. [Crossref] [PubMed]
8. Robin TP, Sannes TS, Spring Kong FM, et al. Physician Bias in Prophylactic Cranial Irradiation Decision Making-An Opportunity for a Patient Decision Aid. Clin Lung Cancer 2018;19:476-83. [Crossref] [PubMed]
9. Farooqi AS, Holliday EB, Allen PK, et al. Prophylactic cranial irradiation after definitive chemoradiotherapy for limited-stage small cell lung cancer: do all patients benefit? Radiother Oncol 2017;122:307-12. [Crossref] [PubMed]
10. Le Péchoux C, Dunant A, Senan S, et al. 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. Lancet Oncol 2009;10:467-74. [Crossref] [PubMed]
11. Schild SE, Foster NR, Meyers JP, et al. Prophylactic cranial irradiation in small-cell lung cancer: Findings from a North Central Cancer Treatment Group Pooled Analysis. Ann Oncol 2012;23:2919-24. [Crossref] [PubMed]
12. Davey P, Ennis M, Aviv R. Prophylactic cranial irradiation (PCI). Still a no-brainer? Lung Cancer 2015;89:4-7. [Crossref] [PubMed]
13. Seute T, Leffers P, ten Velde GP, et al. Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI). Cancer 2008;112:1827-34. [Crossref] [PubMed]
14. Levy A, Le Péchoux C, Mistry H, et al. Prophylactic cranial irradiation for limited stage small=cell lung cancer patients: secondary findings from the prospective randomized phase 3 Concert trial. J Thorac Oncol 2019;14:294-7. [Crossref] [PubMed]
15. Manapov F, Klautke G, Fietkau R. Prevalence of brain metastases immediately before prophylactic cranial irradiation in limited disease small cell lung cancer patients with complete remission to chemoradiotherapy: a single institution experience. J Thorac Oncol 2008;3:652-5. [Crossref] [PubMed]
16. Johnson BE, Becker B, Goff WB 2nd, et al. Neurologic, neuropsychologic, and computed cranial tomography scan abnormalities in 2- to 10-year survivors of small-cell lung cancer. J Clin Oncol 1985;3:1659-67. [Crossref] [PubMed]
17. Komaki R, Meyers CA, Shin DM, et al. Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 1995;33:179-82. [Crossref] [PubMed]
18. Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation in lung cancer: pooled secondary analysis of Radiation Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys 2013;86:656-64. [Crossref] [PubMed]
19. Bohlen G, Meyners T, Kieckebusch S, et al. Short-course whole-brain radiotherapy (WBRT) for brain metastases due to small-cell lung cancer (SCLC). Clin Neurol Neurosurg 2010;112:183-7. [Crossref] [PubMed]
20. Bernhardt D, Adeberg S, Bozorgmehr F, et al. Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy. J Neurooncol 2017;134:205-12. [Crossref] [PubMed]
21. Gerdan L, Šegedin B, Veninga T, et al. Number of involved extracranial organs predicts survival in patients with brain metastasis from small cell lung cancer. Anticancer Res 2013;33:3887-9. [PubMed]
22. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2017;18:1049-60. [Crossref] [PubMed]
23. Yomo S, Hayashi M. Is stereotactic radiosurgery a rational treatment option for brain metastases from small cell lung cancer? A retrospective analysis of 70 consecutive patients. BMC Cancer 2015;15:95. [Crossref] [PubMed]
24. Ge W, Xu H, Yan Y, et al. The effects of prophylactic cranial irradiation versus control on survival of patients with extensive-stage small-cell lung cancer: a meta-analysis of 14 trials. Radiat Oncol 2018;13:155. [Crossref] [PubMed]
25. Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:663-71. [Crossref] [PubMed]
26. Nosaki K, Seto T, Shimokawa M, et al. Is prophylactic cranial irradiation (PCI)needed in patients with extensive-stage small cell lung cancer showing complete response to first-line chemotherapy? Radiother Oncol 2018;127:344-8. [Crossref] [PubMed]
27. Slotman B, Faivre-Finn C, Kramer GEORTC Radiation Oncology and Lung Group Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer, et al. N Engl J Med 2007;357:664-72. [Crossref] [PubMed]
28. Ozawa Y, Omae M, Fujii M, et al. Management of brain metastases with magnetic resonance imaging and stereotactic irradiation attenuated benefits of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer. BMC Cancer 2015;15:589. [Crossref] [PubMed]
29. Sakaguchi M, Maebayashi T, Aizawa T, et al. Treatment outcomes of patients with small cell lung cancer without prophylactic cranial irradiation. J Thorac Dis 2016;8:2571-9. [Crossref] [PubMed]
30. Mamesaya N, Wakuda K, Omae K, et al. Efficacy of prophylactic cranial irradiation in patients with limited-disease small-cell lung cancer who were confirmed to have no brain metastases via magnetic imaging after initial chemoradiotherapy. Oncotarget 2018;9:17664-74. [Crossref] [PubMed]
31. Giuliani M, Sun A, Bezjak A, et al. Utilization of prophylactic cranial irradiation in patients with limited stage small cell lung carcinoma. Cancer 2010;116:5694-9. [Crossref] [PubMed]
32. Xu J, Yang H, Fu X, et al. Prophylactic cranial irradiation for patients with surgically resected small cell lung cancer. J Thorac Oncol 2017;12:347-53. [Crossref] [PubMed]
33. Gondi V, Tome WA, Marsh J, et al. Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol 2010;95:327-31. [Crossref] [PubMed]
34. Korkmaz Kirakli E, Oztekin O. Is Hippocampal Avoidance During Whole-Brain Radiotherapy Risky for Patients With Small-Cell Lung Cancer? Hippocampal Metastasis Rate and Associated Risk Factors. Technol Cancer Res Treat 2017;16:1202-8. [Crossref] [PubMed]
35. Redmond KJ, Hales RK, Anderson-Keightly H, et al. Prospective study of hippocampal-sparing prophylactic cranial irradiation in limited-stage small cell lung cancer. Int J Radiat Oncol Biol Phys 2017;98:603-11. [Crossref] [PubMed]