Lung Cancer 89 (2015) 4–7
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Commentary
Prophylactic cranial irradiation (PCI). Still a no-brainer? Phillip Davey a,b,c,∗ , Marguerite Ennis b , Richard Aviv b,d a
Odette Cancer Centre, Toronto, Ontario, Canada Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada c Department of Radiation Oncology, University of Toronto d Department of Medical Imaging, University of Toronto b
a r t i c l e
i n f o
Article history: Received 31 January 2015 Received in revised form 30 March 2015 Accepted 20 April 2015 Keyword: PCI small cell lung cancer
a b s t r a c t Although prophylactic cranial irradiation (PCI) has been the standard of practice for patients successfully treated for limited stage small cell lung cancer for decades, subsequent changes in patient selection, updated brain imaging guidelines, an increased understanding of the mechanisms underlying the deleterious effects of whole brain irradiation as well as ongoing investigations into improving radiation treatment delivery have begun to question the current role of PCI. Who should be treated and how? This review attempts to gather together evidence for improving patient selection and describe potential improvements in treatment delivery. © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction The original rationale for prophylactic cranial irradiation (PCI) as advocated by Hansen [1] in 1973 is that CNS relapse in small cell lung cancer is analogous to isolated CNS relapse in acute lymphoblastic leukaemia (ALL). Now most patients with ALL can expect to celebrate becoming a cancer survivor five years later typically without PCI. The outlook for patients diagnosed with small cell lung cancer, most of whom do undergo PCI, remains far more guarded with only ∼6–7% of patients alive 5 years following their diagnosis [2]. Nevertheless, PCI had become the standard of care for many patients treated for small cell lung cancer before the first metaanalysis supporting its use was published in 1999 [3] particularly in patients with limited stage disease achieving a complete response. PCI halves the rate of intracranial relapse (especially if it is to be the first site of relapse) from around 30% in limited stage disease and ∼50% in extensive stage disease and also provides a small incremental improvement in the prospect for survival – although that benefit has recently been called into question [4]. National treatment guidelines [5,6] continue to recommend PCI even though there have been significant advances in the imaging and treatment of brain metastases [7] since many of the original studies advocating the use of PCI were published. In addition, there is now a greater awareness of the potential deleterious effects of whole
∗ Corresponding author at:, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 1275 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. +1 416 480 4834. E-mail address: [email protected] (P. Davey).
brain irradiation on stem cell compartments within the brain, the presence of which in humans was originally reported in 1998 [8]. This observation encouraged the development of techniques to limit radiation dose to critical structures such as the hippocampus [9] and subventricular zone [10]. With the accumulation of more recent information it seems timely to review the indications for PCI. In particular the possibility that some of the early randomized studies of PCI may have failed to exclude patients with early metastatic disease in the brain resulting in exaggerated relapse rates in untreated controls will be addressed. In the current era of personalized medicine, a one size fits all approach may no longer apply to PCI especially since for most patients with small cell lung cancer this prescriptive still has more to do with the quality of remaining life rather than long term survival. 2. Discussion Studies considered pivotal in supporting the use of PCI (Table 1) have been identified in three meta-analyses [1,11,12] and two current national guidelines [5,6]. Over time there has been an evolution in the use of brain imaging in these studies ranging from none to CT. Current appropriateness criteria® from the American College of Radiology recommend contiguous thin slice MRI with newer contrast agents with high relaxivity such as gadobenate (MultiHance® ) to ensure that small metastases are not missed [13,14]. Such techniques were unavailable at the time the clinical trials in Table 1 were carried out. We performed a fixed effects meta-analysis of the 13 trials recording the use of brain imaging, comparing 3 trials in which only a minority of patients underwent brain imaging versus
http://dx.doi.org/10.1016/j.lungcan.2015.04.006 0169-5002/© 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
P. Davey et al. / Lung Cancer 89 (2015) 4–7
5
Table 1 CNS relapse rates in untreated controls and treated patients categorized according to the extent that brain imaging was performed at diagnosis or prior to randomization to exclude early metastatic disease in the brain. Proportion with brain imaging
Modality
Not stated Slotman(† E) Wagner(† E + ‡ L) * The minority Gregor(‡ L) Hansen(† E + ‡ L) Laplanche(† E + ‡ L)
* The majority Aroney(† E + ‡ L) Arriagada(† E + ‡ L) Beiler(† E + ‡ L) Cao(‡ L) Eagen(‡ L) Jackson(† E + ‡ L) Maurer(† E + ‡ L) Niranen(‡ L) Ohonoshi(† E + ‡ L) Seydell(‡ L)
CT (13%) None if asymptomatic None
CT CT Nuclear medicine CT CT Nuclear medicine CT/nuclear medicine Nuclear medicine CT CT
CNS relapses without PCI
Percent
CNS relapses with PCI
Percent
Timing of relapse
59/143 8/15
41% 53%
24/143 3/16
17% 19%
Initial and late Initial and late
65/120 Not stated 57/111
54%
38%
Initial and late
51%
74/194 Not stated 44/100
44%
Initial and late
Total 122/231
53%
Total 118/294
40%
57/139 67/149 5/31 8/25 11/15 4/15 15/84 7/26 12/23 22/122
41% 45% 16% 32% 73% 27% 18% 27% 52% 18%
6/30 28/145 0/23 1/26 2/15 0/14 3/79 0/25 5/23 5/107
20% 19% 0% 3.8% 13% 0% 4% 0% 22% 5%
Total 208/629
33%
50/487
10%
Initial and late Initial Initial Initial and late Initial and late Initial and late Initial and late Initial and late Initial and late Initial and late
Relapse pooled proportions compared according to imaging (minority versus majority of observed patients) 2 test statistic = 27.86, degrees of freedom = 1, (p < 0.0001), (minority versus majority of treated patients) 2 test statistic = 96.87, degrees of freedom = 1, (p < 0.0001). † E = extensive disease. ‡ L = limited disease. *
10 where the majority of patients had brain imaging as part of staging or follow up prior to randomization to PCI or observation. The pooled relapse rate in untreated controls was significantly higher in the former group (53% versus 33%, 2 p < 0.0001). The difference was even greater between the treated groups, possibly reflecting a more limited effect of low dose PCI radiation prescriptions delivered to patients who already had subclinical brain metastases (undetected by the lack of imaging). Notably there was no difference in the two groups in the proportion of trials including or excluding patients with extensive disease (67% versus 60%, Fisher exact probability test p = 1.0). The impact of switching from CT to MR imaging in staging patients with small cell lung cancer at presentation has been reported to increase the detection rate of brain metastases from 10% to 24% [15]. The utility of contemporary MRI methodology in selecting patients for PCI in whom no evidence of brain metastases can be found may be revealed in pending investigations such as NRG CC003 (which is an NRG Oncology study of hippocampal sparing PCI) that mandates volumetric MR imaging at the time of patient registration. One of the key justifications for PCI was the premise that the treatment of brain metastases from small cell lung cancer was relatively ineffective. In the 1970s palliative whole brain irradiation was the mainstay of treatment. Since a landmark publication in 1987 describing radiosurgery in the treatment of brain metastases in general [16], radiosurgery has become commonplace. The potential improvement in local control achievable with fractionation as is used with extracranial stereotactic body radiation therapy has yet to be exploited [17]. As far as small cell lung cancer is concerned, radiosurgery appears to provide excellent local control but patients remain at significant risk from subsequent distant failure elsewhere in the brain [18], and often in the context of relapsed extracranial disease [19]. Alternative schedules of whole brain irradiation may provide superior local control than previously reported in patients unsuitable for radiosurgery [20]. One of the principal limitations of the PCI studies is the absence of or limited radiological surveillance reported in the no PCI arms. The efficacy of salvage treatment reflected the therapeutic options available at that time for patients who had relapsed clinically and was generally
not well documented. Nevertheless, the limited data available [21] from the era of CT imaging have shown that palliative whole brain irradiation given at the time of asymptomatic relapse may halve the risk of death with active CNS disease (20%) compared to patients treated at the time of clinical relapse (38%) and could lead to prolonged tumour control and survival. The clinical equipoise still lies between the merits of careful surveillance and the need to treat previously undetected brain metastases sooner in a minority of patients, versus the potential morbidity of (unnecessary) prophylactic whole brain irradiation in those patients who were destined never to experience an initial intracranial relapse in the first place [21]. There is now a large body of evidence documenting the detrimental effects of whole brain irradiation [22]. The relevance of this information to PCI is tempered by the observation that many studies describe patients receiving therapeutic doses of whole brain irradiation rather than the lower prophylactic doses commonly used in PCI. Nevertheless, the question of radiation dose has been addressed in dose escalation studies using PCI. Gregor and colleagues were the first to report improved local control with a higher dose of radiotherapy. Notably Le Pechoux and colleagues [23], in a larger collaborative study, were unable to replicate the improvement in local control reported by Gregor using the same modest increase in total radiation dose from 2500 cGy in 10 daily fractions to 3600 cGy in 18 daily fractions. It should be noted that the primary end point in that study was the incidence of all brain metastases at 2 years. A subset analysis of patients with brain metastases as the first isolated site of failure showed a highly significant reduction in brain metastases as the first isolated site of failure in patients in the high dose arm. In addition Wolfson and colleagues [24], who participated in that collaborative study for the RTOG (protocol 0212), prospectively performed neurocognitive and quality of life testing on their patients and found significantly greater neurocognitive decline among patients receiving 3600 cGy including a subset who received that dose using an accelerated hyperfractionated schedule (150 cGy b.i.d.). Assuming 80% recovery between fractions and an alpha/beta ratio of 2, this schedule would be equivalent to a total dose of ∼4400 cGy in daily fractions of 200 cGy. Further analysis
6
P. Davey et al. / Lung Cancer 89 (2015) 4–7
Table 2 Relaxivity of gadolinium chelates at 1.5 T. R1 (L-mmol−1 s−1 )
Gadolinium chelate ®
a
Gadofosveset Ablavar Gadobenate MultiHance® b Gadoxetate Primovist® Gadobutrol Gadavist® Gadoteridol Prohance® Gadopentetate Magnevist® Gadodiamide Omniscan® a b
19 6.3–7.9 6.9 4.7–5.2 4.1 3.9–4.1 3.3–4.3
FDA approved for angiography only. FDA approved for liver imaging only.
showed that chronic neurotoxicity was more likely to be seen in the elderly when age was introduced as a continuous variable. Additional potentially confounding observations include reports that patients with small cell lung cancer are more cognitively impaired at diagnosis than the general population [25], that patients with small cell lung cancer are cognitively impaired following treatment of their extracranial disease before commencing PCI [26,27], and that cognitive function in patients with malignant disease in general deteriorates further in the weeks immediately preceding death [28]. Current guidelines recommend low dose PCI, typically 2500 cGy in 10 daily fractions in order to minimize late sequelae in long-term survivors. However conservative radiation prescriptions may not entirely eliminate the chance of radiation injury notably in subsets of high risk patients such as the elderly [29] and patients who have been exposed to cis-platin [30]. Whether or not radiation dose painting which can reduce exposure of structures such as the hippocampus to radiation results in meaningful benefit to patients is the subject of on going trials (ClinicalTrials.gov identifier: NCT01780675, NCT01797159, NCT02058056). 3. Conclusion So, where does this leave us when having a discussion with patients regarding the merits of PCI? Firstly we should acknowledge that the risk of intracranial relapse has likely been overestimated in the past and the efficacy of contemporary salvage treatments for intracranial relapse may be underestimated especially if provided before patients become symptomatic [21]. Treatment guidelines recommend that only patients who have responded to systemic treatment should be considered for PCI. PCI should be administered only after all of the planned induction chemotherapy has been completed [31]. We should only be offering PCI to patients in whom asymptomatic small volume brain metastases have recently been excluded by volumetric MR imaging preferably using gadolinium chelates with high relaxivity (Table 2). If asymptomatic brain metastases are discovered they should be managed on their merits according to generally accepted treatment guidelines. We should record whether there is any pre-existing cognitive or hearing loss, especially in the elderly. We should be aware of the possibility of a patient being non-compliant with close surveillance over the first two years of follow-up which is the time-frame when almost all intracranial relapses are expected to occur. Patients can be MRI averse due to claustrophobia. They may have renal impairment following chemotherapy and cannot be given gadolinium. Are sophisticated salvage treatments available in a timely manner? When PCI is recommended, should patients be treated with hippocampal sparing as a matter of routine in the absence of level I evidence? And what of the inner ear and subventricular zone? Do these locations deserve radiation dose sparing too? In the authors’ view, one size does not fit all and there remain many opportunities to research PCI and finesse the selection of patients and the delivery of treatment. Ideally the primary
endpoints should be the rate of isolated first relapse in the brain and measures of quality of life in patients in whom the brain is the first site of failure. Patients with extracranial first site of failure or progression become a source of confounding variates reflecting the need to offer second line therapies for systemic disease as well as being the origin of subsequent reseeding of the brain with new metastases. The use of overall survival as the primary endpoint should be avoided. The economic cost of incremental surveillance as well as the psychological impact on patients should be noted. Nevertheless, any future improvement in the salvage of extracranial relapse could potentially increase rather than reduce the utility of PCI in controlling occult metastatic disease at presentation in the brain of patients with a diagnosis of small cell lung cancer [32]. Conflict of interest The authors have no conflict of interest. Acknowledgement The authors are grateful to Dr. M. Doherty and Dr. J. Balogh who critically reviewed previous drafts of the manuscript. P.D. and M.E are supported by the Sunnybrook Foundation through the generosity of Christine Wei-Ren Molson. References [1] Hansen HH. Should initial treatment of small cell carcinoma include systemic chemotherapy and brain irradiation? Cancer Chem Rep 1973;4(2):239–41. [2] http://seer.cancer.gov/csr/1975 2011/results merged/sect 15 lung bronchus. pdf [3] Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, 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. [4] Seto T, Takahashi T, Yamanaka T, Harada H, Nokihara H, Saka H, et al. Prophylactic cranial irradiation has a detrimental effect on the overall survival of patients with extensive disease small cell lung cancer: results of a Japanese randomized phase III trial. J Clin Oncol 2014;32:5s (suppl.; Abstr 7503). [5] National Comprehensive Cancer Network. Small cell lung cancer (vl.2015). https://www.nccn.org/professionals/physician gls/pdf/scls.pdf [6] National Institute for Health and Care Excellence [CG121]. https://www.nice. org.uk/guidance/CG121/chapter/1-Guidance [7] Davey P. Brain metastases. Curr Probl Cancer 1999;23:53–100. [8] Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn A, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:1313–7. [9] Gondi V, Tolakanahalli R, Mehta MP, Tewatia D, Rowley H, Kuo JS, et al. Hippocampal-sparing whole-brain radiotherapy: a how-to technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:1244–52. [10] Sanghera P, Gardner SL, Scora D, Davey P. Early expansion of the intracranial CSF volume after palliative whole-brain radiotherapy: results of a longitudinal CT segmentation analysis. Int J Radiat Oncol Biol Phys 2010;76:1171–6. [11] Meert AP, Paesmans M, Berghmans T, Martin B, Mascaux C, Vallot F, et al. Prophylactic cranial irradiation in small cell lung cancer: a systematic review of the literature with meta-analysis. BMC Cancer 2001;1:5. [12] Viani GA, Boin AC, Ikeda VY, Vianna BS, Silva RS, Santanella F. Thirty years of prophylactic cranial irradiation in patients with small cell lung cancer: a meta-analysis of randomized clinical trials. Jornal Brasileiro De Pneumologia: Publicacao Oficial Da Sociedade Brasileira De Pneumologia E Tisilogia 2012;38:372–81. [13] Lo SS, Gore EM, Bradley JD, Buatti JM, Germano I, Ghafoori AP, et al. ACR Appropriateness Criteria® pre-irradiation evaluation and management of brain metastases; 2014. Available at https://acsearch.acr.org/docs/69384/Narrative/ (accessed 20.01.15). [14] Rowley HA, Scialfa G, Gao PY, Maldjian JA, Hassell D, Kuhn MJ, et al. Contrastenhanced MR imaging of brain lesions: a large-scale intraindividual crossover comparison of gadobenate dimeglumine versus gadodiamide. AJNR Am J Neuroradiol 2008;29:1684–91. [15] Seute T, Leffers P, ten Velde GPM, Twijnstra A. Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI). Cancer 2008;112:1827–34. [16] Sturm V, Kober B, Hover KH, Schlegel W, Boesecke R, Pastyr O, et al. Stereotactic percutaneous single dose irradiation of brain metastases with a linear accelerator. Int J Radiat Oncol Biol Phys 1987;13:279–82. [17] Saitoh J, Saito Y, Kazumoto T, Kudo S, Ichikawa A, Hayase N, et al. Therapeutic effect of linac-based stereotactic radiotherapy with a micro-multileaf
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[18]
[19]
[20]
[21]
[22] [23]
collimator for the treatment of patients with brain metastases from lung cancer. Jpn J Clin Oncol 2010;40:119–24. Kuremsky JG, Urbanic JJ, Petty WJ, Lovato JF, Bourland JD, Tatter SB, et al. Tumor histology predicts patterns of failure and survival in patients with brain metastases from lung cancer treated with gamma knife radiosurgery. Neurosurgery 2013;73:641–7. Harris S, Chan MD, Lovato JF, Ellis TL, Tatter SB, Bourland JD, et al. Gamma knife stereotactic radiosurgery as salvage therapy after failure of whole-brain radiotherapy in patients with small-cell lung cancer. Int J Radiat Oncol Biol Phys 2012;83:e53–9. Graham PH, Bucci J, Browne L. Randomized comparison of whole brain radiotherapy, 20 Gy in four daily fractions versus 40 Gy in 20 twice-daily fractions, for brain metastases. Int J Radiat Oncol Biol Phys 2010;77: 648–54. Hardy J, Smith I, Cherryman G, Vincent M, Judson I, Perren T, et al. The value of computed tomographic (CT) surveillance in the detection and management of brain metastases in patients with small cell lung cancer. Br J Cancer 1980;62:684–6. McTyre E, Scott J, Chinnaiyan P. Whole brain radiotherapy for brain metastasis. Surg Neurol Int 2013;4(Suppl. 4):S236–44. Le Pechoux C, Dunant A, Senan S, Wolfson A, Quoix E, Faivre-Finn C, et al. Prophylactic Cranial Irradiation (PCI) Collaborative Group. 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 randomized clinical trial. Lancet Oncol 2009;10: 467–74.
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[24] Wolfson AH, Bae K, Komaki R, Meyers C, Movsas B, Le Pechoux C, et al. Primary analysis of a phase II randomized trial radiation therapy oncology group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limiteddisease small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:77–84. [25] Meyers CA, Byrne KS, Komaki R. Cognitive deficits in patients with small cell lung cancer before and after chemotherapy. Lung Cancer 1995;12:231–5. [26] Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tieffenbacher U, Mai SK, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys 2008;72(5):1311–8. [27] Grosshans DR, Meyers CA, Allen PK, Davenport SD, Komaki R. Neurocognitive function in patients with small cell lung cancer. Effect of prophylactic cranial irradiation. Cancer 2008;112:589–95. [28] Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer 1997;79:835–42. [29] Grau JJ, Verger Brandes AA, Rigon A, Monfardini S, DeAngelis LM. Radiotherapy of the brain in elderly patients. Eur J Cancer 2000;36:443–52. [30] Lowe WK, Toh ST, Wee J, Fook-Chong S, Wand DY. Sensorineural hearing loss after radiotherapy and chemotherapy: a single blinded randomized study. J Clin Oncol 2006;24(12):1904–9. [31] Kong FM, Lally BE, Chang JY, Chetty IJ, Decker RH, Ginsburg ME, et al. ACR appropriateness criteria radiation therapy for small-cell lung cancer. Am J Clin Oncol 2013;36:206–13. [32] Lee JJ, Bekele BN, Zhou X, Cantor SB, Komaki R, Lee JS. Decision analysis for prophylactic cranial irradiation for patients with small-cell lung cancer. J Clin Oncol 2006;24:3597–603.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Commentary
Prophylactic cranial irradiation (PCI). Still a no-brainer? Phillip Davey a,b,c,∗ , Marguerite Ennis b , Richard Aviv b,d a
Odette Cancer Centre, Toronto, Ontario, Canada Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada c Department of Radiation Oncology, University of Toronto d Department of Medical Imaging, University of Toronto b
a r t i c l e
i n f o
Article history: Received 31 January 2015 Received in revised form 30 March 2015 Accepted 20 April 2015 Keyword: PCI small cell lung cancer
a b s t r a c t Although prophylactic cranial irradiation (PCI) has been the standard of practice for patients successfully treated for limited stage small cell lung cancer for decades, subsequent changes in patient selection, updated brain imaging guidelines, an increased understanding of the mechanisms underlying the deleterious effects of whole brain irradiation as well as ongoing investigations into improving radiation treatment delivery have begun to question the current role of PCI. Who should be treated and how? This review attempts to gather together evidence for improving patient selection and describe potential improvements in treatment delivery. © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction The original rationale for prophylactic cranial irradiation (PCI) as advocated by Hansen [1] in 1973 is that CNS relapse in small cell lung cancer is analogous to isolated CNS relapse in acute lymphoblastic leukaemia (ALL). Now most patients with ALL can expect to celebrate becoming a cancer survivor five years later typically without PCI. The outlook for patients diagnosed with small cell lung cancer, most of whom do undergo PCI, remains far more guarded with only ∼6–7% of patients alive 5 years following their diagnosis [2]. Nevertheless, PCI had become the standard of care for many patients treated for small cell lung cancer before the first metaanalysis supporting its use was published in 1999 [3] particularly in patients with limited stage disease achieving a complete response. PCI halves the rate of intracranial relapse (especially if it is to be the first site of relapse) from around 30% in limited stage disease and ∼50% in extensive stage disease and also provides a small incremental improvement in the prospect for survival – although that benefit has recently been called into question [4]. National treatment guidelines [5,6] continue to recommend PCI even though there have been significant advances in the imaging and treatment of brain metastases [7] since many of the original studies advocating the use of PCI were published. In addition, there is now a greater awareness of the potential deleterious effects of whole
∗ Corresponding author at:, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 1275 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. +1 416 480 4834. E-mail address: [email protected] (P. Davey).
brain irradiation on stem cell compartments within the brain, the presence of which in humans was originally reported in 1998 [8]. This observation encouraged the development of techniques to limit radiation dose to critical structures such as the hippocampus [9] and subventricular zone [10]. With the accumulation of more recent information it seems timely to review the indications for PCI. In particular the possibility that some of the early randomized studies of PCI may have failed to exclude patients with early metastatic disease in the brain resulting in exaggerated relapse rates in untreated controls will be addressed. In the current era of personalized medicine, a one size fits all approach may no longer apply to PCI especially since for most patients with small cell lung cancer this prescriptive still has more to do with the quality of remaining life rather than long term survival. 2. Discussion Studies considered pivotal in supporting the use of PCI (Table 1) have been identified in three meta-analyses [1,11,12] and two current national guidelines [5,6]. Over time there has been an evolution in the use of brain imaging in these studies ranging from none to CT. Current appropriateness criteria® from the American College of Radiology recommend contiguous thin slice MRI with newer contrast agents with high relaxivity such as gadobenate (MultiHance® ) to ensure that small metastases are not missed [13,14]. Such techniques were unavailable at the time the clinical trials in Table 1 were carried out. We performed a fixed effects meta-analysis of the 13 trials recording the use of brain imaging, comparing 3 trials in which only a minority of patients underwent brain imaging versus
http://dx.doi.org/10.1016/j.lungcan.2015.04.006 0169-5002/© 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
P. Davey et al. / Lung Cancer 89 (2015) 4–7
5
Table 1 CNS relapse rates in untreated controls and treated patients categorized according to the extent that brain imaging was performed at diagnosis or prior to randomization to exclude early metastatic disease in the brain. Proportion with brain imaging
Modality
Not stated Slotman(† E) Wagner(† E + ‡ L) * The minority Gregor(‡ L) Hansen(† E + ‡ L) Laplanche(† E + ‡ L)
* The majority Aroney(† E + ‡ L) Arriagada(† E + ‡ L) Beiler(† E + ‡ L) Cao(‡ L) Eagen(‡ L) Jackson(† E + ‡ L) Maurer(† E + ‡ L) Niranen(‡ L) Ohonoshi(† E + ‡ L) Seydell(‡ L)
CT (13%) None if asymptomatic None
CT CT Nuclear medicine CT CT Nuclear medicine CT/nuclear medicine Nuclear medicine CT CT
CNS relapses without PCI
Percent
CNS relapses with PCI
Percent
Timing of relapse
59/143 8/15
41% 53%
24/143 3/16
17% 19%
Initial and late Initial and late
65/120 Not stated 57/111
54%
38%
Initial and late
51%
74/194 Not stated 44/100
44%
Initial and late
Total 122/231
53%
Total 118/294
40%
57/139 67/149 5/31 8/25 11/15 4/15 15/84 7/26 12/23 22/122
41% 45% 16% 32% 73% 27% 18% 27% 52% 18%
6/30 28/145 0/23 1/26 2/15 0/14 3/79 0/25 5/23 5/107
20% 19% 0% 3.8% 13% 0% 4% 0% 22% 5%
Total 208/629
33%
50/487
10%
Initial and late Initial Initial Initial and late Initial and late Initial and late Initial and late Initial and late Initial and late Initial and late
Relapse pooled proportions compared according to imaging (minority versus majority of observed patients) 2 test statistic = 27.86, degrees of freedom = 1, (p < 0.0001), (minority versus majority of treated patients) 2 test statistic = 96.87, degrees of freedom = 1, (p < 0.0001). † E = extensive disease. ‡ L = limited disease. *
10 where the majority of patients had brain imaging as part of staging or follow up prior to randomization to PCI or observation. The pooled relapse rate in untreated controls was significantly higher in the former group (53% versus 33%, 2 p < 0.0001). The difference was even greater between the treated groups, possibly reflecting a more limited effect of low dose PCI radiation prescriptions delivered to patients who already had subclinical brain metastases (undetected by the lack of imaging). Notably there was no difference in the two groups in the proportion of trials including or excluding patients with extensive disease (67% versus 60%, Fisher exact probability test p = 1.0). The impact of switching from CT to MR imaging in staging patients with small cell lung cancer at presentation has been reported to increase the detection rate of brain metastases from 10% to 24% [15]. The utility of contemporary MRI methodology in selecting patients for PCI in whom no evidence of brain metastases can be found may be revealed in pending investigations such as NRG CC003 (which is an NRG Oncology study of hippocampal sparing PCI) that mandates volumetric MR imaging at the time of patient registration. One of the key justifications for PCI was the premise that the treatment of brain metastases from small cell lung cancer was relatively ineffective. In the 1970s palliative whole brain irradiation was the mainstay of treatment. Since a landmark publication in 1987 describing radiosurgery in the treatment of brain metastases in general [16], radiosurgery has become commonplace. The potential improvement in local control achievable with fractionation as is used with extracranial stereotactic body radiation therapy has yet to be exploited [17]. As far as small cell lung cancer is concerned, radiosurgery appears to provide excellent local control but patients remain at significant risk from subsequent distant failure elsewhere in the brain [18], and often in the context of relapsed extracranial disease [19]. Alternative schedules of whole brain irradiation may provide superior local control than previously reported in patients unsuitable for radiosurgery [20]. One of the principal limitations of the PCI studies is the absence of or limited radiological surveillance reported in the no PCI arms. The efficacy of salvage treatment reflected the therapeutic options available at that time for patients who had relapsed clinically and was generally
not well documented. Nevertheless, the limited data available [21] from the era of CT imaging have shown that palliative whole brain irradiation given at the time of asymptomatic relapse may halve the risk of death with active CNS disease (20%) compared to patients treated at the time of clinical relapse (38%) and could lead to prolonged tumour control and survival. The clinical equipoise still lies between the merits of careful surveillance and the need to treat previously undetected brain metastases sooner in a minority of patients, versus the potential morbidity of (unnecessary) prophylactic whole brain irradiation in those patients who were destined never to experience an initial intracranial relapse in the first place [21]. There is now a large body of evidence documenting the detrimental effects of whole brain irradiation [22]. The relevance of this information to PCI is tempered by the observation that many studies describe patients receiving therapeutic doses of whole brain irradiation rather than the lower prophylactic doses commonly used in PCI. Nevertheless, the question of radiation dose has been addressed in dose escalation studies using PCI. Gregor and colleagues were the first to report improved local control with a higher dose of radiotherapy. Notably Le Pechoux and colleagues [23], in a larger collaborative study, were unable to replicate the improvement in local control reported by Gregor using the same modest increase in total radiation dose from 2500 cGy in 10 daily fractions to 3600 cGy in 18 daily fractions. It should be noted that the primary end point in that study was the incidence of all brain metastases at 2 years. A subset analysis of patients with brain metastases as the first isolated site of failure showed a highly significant reduction in brain metastases as the first isolated site of failure in patients in the high dose arm. In addition Wolfson and colleagues [24], who participated in that collaborative study for the RTOG (protocol 0212), prospectively performed neurocognitive and quality of life testing on their patients and found significantly greater neurocognitive decline among patients receiving 3600 cGy including a subset who received that dose using an accelerated hyperfractionated schedule (150 cGy b.i.d.). Assuming 80% recovery between fractions and an alpha/beta ratio of 2, this schedule would be equivalent to a total dose of ∼4400 cGy in daily fractions of 200 cGy. Further analysis
6
P. Davey et al. / Lung Cancer 89 (2015) 4–7
Table 2 Relaxivity of gadolinium chelates at 1.5 T. R1 (L-mmol−1 s−1 )
Gadolinium chelate ®
a
Gadofosveset Ablavar Gadobenate MultiHance® b Gadoxetate Primovist® Gadobutrol Gadavist® Gadoteridol Prohance® Gadopentetate Magnevist® Gadodiamide Omniscan® a b
19 6.3–7.9 6.9 4.7–5.2 4.1 3.9–4.1 3.3–4.3
FDA approved for angiography only. FDA approved for liver imaging only.
showed that chronic neurotoxicity was more likely to be seen in the elderly when age was introduced as a continuous variable. Additional potentially confounding observations include reports that patients with small cell lung cancer are more cognitively impaired at diagnosis than the general population [25], that patients with small cell lung cancer are cognitively impaired following treatment of their extracranial disease before commencing PCI [26,27], and that cognitive function in patients with malignant disease in general deteriorates further in the weeks immediately preceding death [28]. Current guidelines recommend low dose PCI, typically 2500 cGy in 10 daily fractions in order to minimize late sequelae in long-term survivors. However conservative radiation prescriptions may not entirely eliminate the chance of radiation injury notably in subsets of high risk patients such as the elderly [29] and patients who have been exposed to cis-platin [30]. Whether or not radiation dose painting which can reduce exposure of structures such as the hippocampus to radiation results in meaningful benefit to patients is the subject of on going trials (ClinicalTrials.gov identifier: NCT01780675, NCT01797159, NCT02058056). 3. Conclusion So, where does this leave us when having a discussion with patients regarding the merits of PCI? Firstly we should acknowledge that the risk of intracranial relapse has likely been overestimated in the past and the efficacy of contemporary salvage treatments for intracranial relapse may be underestimated especially if provided before patients become symptomatic [21]. Treatment guidelines recommend that only patients who have responded to systemic treatment should be considered for PCI. PCI should be administered only after all of the planned induction chemotherapy has been completed [31]. We should only be offering PCI to patients in whom asymptomatic small volume brain metastases have recently been excluded by volumetric MR imaging preferably using gadolinium chelates with high relaxivity (Table 2). If asymptomatic brain metastases are discovered they should be managed on their merits according to generally accepted treatment guidelines. We should record whether there is any pre-existing cognitive or hearing loss, especially in the elderly. We should be aware of the possibility of a patient being non-compliant with close surveillance over the first two years of follow-up which is the time-frame when almost all intracranial relapses are expected to occur. Patients can be MRI averse due to claustrophobia. They may have renal impairment following chemotherapy and cannot be given gadolinium. Are sophisticated salvage treatments available in a timely manner? When PCI is recommended, should patients be treated with hippocampal sparing as a matter of routine in the absence of level I evidence? And what of the inner ear and subventricular zone? Do these locations deserve radiation dose sparing too? In the authors’ view, one size does not fit all and there remain many opportunities to research PCI and finesse the selection of patients and the delivery of treatment. Ideally the primary
endpoints should be the rate of isolated first relapse in the brain and measures of quality of life in patients in whom the brain is the first site of failure. Patients with extracranial first site of failure or progression become a source of confounding variates reflecting the need to offer second line therapies for systemic disease as well as being the origin of subsequent reseeding of the brain with new metastases. The use of overall survival as the primary endpoint should be avoided. The economic cost of incremental surveillance as well as the psychological impact on patients should be noted. Nevertheless, any future improvement in the salvage of extracranial relapse could potentially increase rather than reduce the utility of PCI in controlling occult metastatic disease at presentation in the brain of patients with a diagnosis of small cell lung cancer [32]. Conflict of interest The authors have no conflict of interest. Acknowledgement The authors are grateful to Dr. M. Doherty and Dr. J. Balogh who critically reviewed previous drafts of the manuscript. P.D. and M.E are supported by the Sunnybrook Foundation through the generosity of Christine Wei-Ren Molson. References [1] Hansen HH. Should initial treatment of small cell carcinoma include systemic chemotherapy and brain irradiation? Cancer Chem Rep 1973;4(2):239–41. [2] http://seer.cancer.gov/csr/1975 2011/results merged/sect 15 lung bronchus. pdf [3] Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, 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. [4] Seto T, Takahashi T, Yamanaka T, Harada H, Nokihara H, Saka H, et al. Prophylactic cranial irradiation has a detrimental effect on the overall survival of patients with extensive disease small cell lung cancer: results of a Japanese randomized phase III trial. J Clin Oncol 2014;32:5s (suppl.; Abstr 7503). [5] National Comprehensive Cancer Network. Small cell lung cancer (vl.2015). https://www.nccn.org/professionals/physician gls/pdf/scls.pdf [6] National Institute for Health and Care Excellence [CG121]. https://www.nice. org.uk/guidance/CG121/chapter/1-Guidance [7] Davey P. Brain metastases. Curr Probl Cancer 1999;23:53–100. [8] Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn A, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:1313–7. [9] Gondi V, Tolakanahalli R, Mehta MP, Tewatia D, Rowley H, Kuo JS, et al. Hippocampal-sparing whole-brain radiotherapy: a how-to technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:1244–52. [10] Sanghera P, Gardner SL, Scora D, Davey P. Early expansion of the intracranial CSF volume after palliative whole-brain radiotherapy: results of a longitudinal CT segmentation analysis. Int J Radiat Oncol Biol Phys 2010;76:1171–6. [11] Meert AP, Paesmans M, Berghmans T, Martin B, Mascaux C, Vallot F, et al. Prophylactic cranial irradiation in small cell lung cancer: a systematic review of the literature with meta-analysis. BMC Cancer 2001;1:5. [12] Viani GA, Boin AC, Ikeda VY, Vianna BS, Silva RS, Santanella F. Thirty years of prophylactic cranial irradiation in patients with small cell lung cancer: a meta-analysis of randomized clinical trials. Jornal Brasileiro De Pneumologia: Publicacao Oficial Da Sociedade Brasileira De Pneumologia E Tisilogia 2012;38:372–81. [13] Lo SS, Gore EM, Bradley JD, Buatti JM, Germano I, Ghafoori AP, et al. ACR Appropriateness Criteria® pre-irradiation evaluation and management of brain metastases; 2014. Available at https://acsearch.acr.org/docs/69384/Narrative/ (accessed 20.01.15). [14] Rowley HA, Scialfa G, Gao PY, Maldjian JA, Hassell D, Kuhn MJ, et al. Contrastenhanced MR imaging of brain lesions: a large-scale intraindividual crossover comparison of gadobenate dimeglumine versus gadodiamide. AJNR Am J Neuroradiol 2008;29:1684–91. [15] Seute T, Leffers P, ten Velde GPM, Twijnstra A. Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI). Cancer 2008;112:1827–34. [16] Sturm V, Kober B, Hover KH, Schlegel W, Boesecke R, Pastyr O, et al. Stereotactic percutaneous single dose irradiation of brain metastases with a linear accelerator. Int J Radiat Oncol Biol Phys 1987;13:279–82. [17] Saitoh J, Saito Y, Kazumoto T, Kudo S, Ichikawa A, Hayase N, et al. Therapeutic effect of linac-based stereotactic radiotherapy with a micro-multileaf
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