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Prophylactic cranial irradiation in lung cancer
Cancer Treatment Reviews 37 (2011) 261–265
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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumour Treatment
Prophylactic cranial irradiation in lung cancer A. Paumier, X. Cuenca, C. Le Péchoux * Radiation Oncology Department, Gustave-Roussy Institute, Villejuif, France
a r t i c l e
i n f o
Article history: Received 19 May 2010 Received in revised form 16 August 2010 Accepted 25 August 2010
Keywords: Lung cancer Prophylactic cranial irradiation Small-cell lung cancer Non-small-cell lung cancer Combined modality treatment
s u m m a r y As multi-modality treatments are now able to ensure better local control and a lower rate of extra cranial metastases, brain relapse has become a major concern in lung cancer. As survival is poor after development of brain metastases in spite of specific treatment, prophylactic cranial irradiation (PCI) has been introduced in the 70’s. PCI has been evaluated in randomized trials in both small-cell (SCLC) and nonsmall-cell (NSCLC) lung cancers to reduce the incidence of brain metastases and possibly increase survival. PCI reduces significantly the BM rate in both limited disease (LD) and extensive disease (ED) SCLC and in non-metastatic NSCLC. Considering SCLC, PCI significantly improves overall survival in LD (from 15% to 20% at 3 years) and ED (from 13% to 27% at 1 year) in patients who respond to first-line treatment; it should thus be part of the standard treatment in all responders in ED and in good responders in LD. No dose-effect relationship for PCI was demonstrated in LD SCLC patients so that the recommended dose is 25 Gy in 10 fractions. In NSCLC, even if the risk of brain dissemination is lower than in SCLC, it has become a challenging issue. Studies have identified subgroups at higher risk of brain failure. There are more local treatment possibilities for NSCLC patients with BM, but most of them will eventually recur so that PCI should be reconsidered. Few randomized trials have been performed and they were not able to show an effect on survival as they were underpowered. New trials are needed. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Brain failures, have become a significant cause of relapse in lung cancer, in both small-cell and non-small-cell lung cancer, as other causes of failure such as loco-regional failure and extra-cerebral metastases are better controlled with multi-modality treatments. Median survival after brain failure is less than 6 months. As systemic agents do not cross the blood–brain barrier effectively to prevent brain metastases (BM), prophylactic cranial irradiation (PCI) has been discussed as a strategy to reduce the risk of brain failure, in the 70’s first in leukemia then lung cancer. We will sequentially develop prophylactic cranial irradiation (PCI) in small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC) and then speak about potential toxicity of PCI. Small-cell lung carcinomas (SCLC) Limited disease Brain metastases (BM) are frequent in SCLC and responsible for serious impairment of patient’s survival and quality of life. About ⇑ Corresponding author. Address: Radiation Oncology Department, GustaveRoussy Institute, 114 Rue Edouard Vaillant, Villejuif 94800, France. Tel.: +33 0 142114757; fax: +33 0 142115253. E-mail address: [email protected] (C. Le Péchoux). 0305-7372/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2010.08.009
15% of patients have brain metastasis at the time of diagnosis, and this rate is even higher with more accurate imaging, such as MRI.1 Moreover, about half of patients in complete remission after treatment for limited disease SCLC will develop brain relapse.2 In the early 80s, PCI was therefore introduced to prevent BM. Most of the randomized trials testing PCI showed a significant decrease of BM incidence in favour of PCI, however, none of them individually could demonstrate a significant improvement in overall survival. Thus a meta-analysis was undertaken, based on individual data of almost one thousand patients in complete remission included in seven randomized phase III studies.3 Thoracic complete remission corresponded to at least normalisation of chest X-ray in most trials. In this meta-analysis, 85% of the patients had limited disease and 15% had extensive disease SCLC; the PCI dose ranged from 8 Gy in 1 fraction to 40 Gy in 20 fractions. At 3 years, there was an absolute decrease of 25.3% in the cumulative incidence of BM (59% in the control arm vs. 33% in the PCI arm, p < 0.001), and an absolute increase in survival of 5.4% from 15.3% in the control group to 20.7% in the treatment group (p = 0.01). Interestingly, an indirect comparison of four total dose groups (8, 24, 25, 30 and 36–40 Gy) showed a significant trend (p = 0.02) towards a decrease in the risk of brain metastasis with higher PCI dose. The authors also identified a trend (p = 0.01) toward a lower risk of brain metastasis with earlier administration of PCI after start of the treatment. Therefore, PCI became part of the standard of care for complete and good responders based on CT scan evaluation.
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More recently, in a retrospective study based on the National Cancer Institute’s Surveillance, Epidemiology, and End-Results Program (SEER), which involved almost 8000 patients, Patel et al.4 have reported similar results, with a significant improvement in both overall and cause-specific survival in favour of PCI. One of the challenges raised by the meta-analysis3 was the optimal timing and optimal dose for PCI. The PCI Collaborative Group has recently published an international trial addressing the question of dose-effect for the prevention of metastases in patients with limited disease who achieved a complete response (i.e. at least a normal chest radiograph).5 It compared a standard dose of 25 Gy in 10 fractions to a higher dose of 36 Gy (36 Gy/18 fractions or 36 Gy in 24 twice-daily fractions). It is noteworthy that in order to evaluate a possible increased neurological toxicity, quality of life and neurological assessment both before and after PCI were performed. Toxicities and treatment delivery were not different between the two arms. Patients who received the high dose had a non-significant decrease in brain metastases compared to patients who received the standard dose: incidence of BM at 2 years was 29% and 23% in the high dose and in the standard dose groups, respectively (p = 0.18). For unclear reasons, overall survival was significantly worse among patients in the high dose PCI group (HR for death: 1.2 [1.00, 1.44]). The importance of fractionation in terms of efficacy, tolerance and possible neurological sequelae could be determined by a phase II/III trial (RTOG 0212) which compares conventional fractionation (36 Gy in 18 fractions) to hyperfractionated accelerated radiotherapy (36 Gy in 24 twice-daily fractions). PCI at 25 Gy in 10 fractions is now recommended for LD SCLC good responders. Extensive disease Even if the PCI meta-analysis, which included 15% of patients with extensive disease, supported PCI in extensive disease for complete responders, the question remained unanswered for patients with partial response.3 The EORTC thus decided to undertake a phase III trial randomising patients with extensive disease who had partial or complete response to first-line treatment. They would be randomly assigned PCI (20–30 Gy) or no PCI.6 Patients in the PCI arm were mostly treated with a short course schedule: among the 143 irradiated patients, 89 received 20 Gy in 5 fractions, the others were treated with various fractionation schedules (30 Gy given in 10 fractions, 30 Gy given in 12 fractions or 25 Gy given in 10 fractions). The results of this study are strongly in favour of PCI: not only does PCI significantly reduce the risk of symptomatic brain failure but it also significantly improves overall survival. The cumulative risk of symptomatic brain metastases at 1 year was 14.6% in the PCI arm and 40.4% in the control arm (p < 0.001) and the 1-year survival rate was 13.3% in the control arm and 27.1% in the PCI arm (p = 0.003). Due to the low median survival in this setting, long-term toxicity is not of major concern, and the short course schedule (20 Gy in 5 fractions) should be favoured. However, less hypofractionated schedules (such as the schedule applied to limited disease) could be offered to patients with higher life expectancy. PCI has now become a standard of care for patients with ED SCLC who respond to first-line chemotherapy. Non-small-cell lung cancer Even if the risk of brain failure is not as high as in SCLC, brain metastases are also quite common in NSCLC especially in certain groups of patients. The BM incidence ranges from 17% to 54%7–10 and it is the first site of recurrence in 15–40% of cases.7,11–13 As in small-cell lung cancer, brain MRI can detect smaller BM (12.8 ± 9.1 mm) than CT scan (20.3 ± 7.0 mm).14 The prognosis of
patients with non-metastatic NSCLC has substantially been improved in the past 10 years. Better selection of patients, optimized loco-regional control as well as the addition of platinum-based chemotherapy to surgery and/or radiotherapy have contributed to improve survival.15,16 However these advances do not seem to alter brain relapse rates, on the contrary.8–11 As there are less prospective studies evaluating PCI in NSCLC, we will briefly expose studies trying to identify groups of NSCLC patients at higher risk of brain failure, treatments, and finally randomized trials evaluating PCI in NSCLC. Predictive factors of brain failure in NSCLC Adenocarcinoma, advanced nodal status and tumor stage are associated with higher risk of BM.8,11,17,18 BM also appear more frequent among younger patients (<60 years),13,19–21 and in patients receiving preoperative chemotherapy or EGFR-TKI as shown in some studies.8,22 There are studies evaluating the risk of brain failure after surgery for NSCLC. In a large series of 1532 patients who underwent complete resection, mostly for stage I and II NSCLC,23 only 6.8% of the patients had documented first recurrences involving the brain. The risk of brain recurrence was higher in T2N0/T1N1/ T2N1 than in T1N0 patients. In a retrospective study of surgical patients with N2 nodal involvement, preoperative chemotherapy was associated with an increased isolated BM rate (22% vs. 11%) as well as adenocarcinoma histology.2 Patients who had preoperative chemotherapy for adenocarcinoma had the highest risk to develop isolated BM (33%). Similar conclusions were reported in another retrospective study of Mamon et al. [24]. Among 177 patients with stage IIIA (N2) treated with surgery, chemotherapy and/or radiotherapy, 34% presented BM as first site of failure, and 40% developed BM at some point during the follow-up. Patients with nonsquamous histology and nodal involvement persistent after neoadjuvant therapy had the greater risk of BM in this cohort (53% at 3 years). It should be outlined that superior sulcus tumors have a particularly high risk of brain failure. In the intergroup study of chemoradiotherapy followed by surgery,25 up to 41% 20% of the patients presented a recurrence in the brain only, whereas local control was satisfactory. Other studies have evaluated the risk of brain failure in more advanced NSCLC. In a retrospective study of inoperable nonsmall-cell lung cancer patients treated within four RTOG trials with definitive radiotherapy, BM represented the first site of relapse in 15–18% of good prognostic patients (RPA classes I and II).26 Robnett et al. [13] performed a retrospective analysis from 150 consecutive patients with stage II/III NSCLC treated with definitive chemoradiation. Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Stage IIIB patients had a 2-year actuarial incidence of BM of 36% whereas it was 29% for stage II/IIIA patients (p < 0.04). The 2-year actuarial rate of BM reached 42% for stage IIIB patients with non-squamous histology. In a retrospective study, Lee et al. have reported the outcome of 232 patients with recurrent or metastatic disease treated with EGFR-TKI.22 Among responders to TKI, the authors observed both a higher rate of BM as first site of recurrence and higher rate of isolated brain relapse compared to patients with no clinical benefit with EGFR-TKI (26% vs. 4% and 13% vs. 1%, p < 0.001). These findings have leaded the Korean Radiation Oncology Group to start a randomized trial for patients with advanced NSCLC responsive to EGFR-TKI. Treatment and outcome in NSCLC Among patients with BM, the overall survival is poor ranging from 1.5 to 9.5 months according to several prognostic variables.27,28 There are several scales including factors predictive
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of survival outcome: they often include good performance status, age younger than 65 years, control of the primary tumor, absence of extracranial metastases, favorable tumor histology, and number of BM. NSCLC is considered more favourable tumor histology then SCLC partly because there are more treatment options. Whole brain irradiation (WBI) still is the standard treatment for symptomatic BM. Median survival after WBI is around 4 months.29 In a selected subgroup of patients surgery or stereotactic radiotherapy can be proposed with better results with median survival rates exceeding 12 months. Unfortunately, few patients can benefit from these approaches and they usually relapse again in the brain within 6–8 months.30 Response rates to chemotherapy range between 30% and 50%.27,31 The are some interesting data about tyrosine kinase inhibitors of the epidermal growth factor receptor (TKI-EGFR) in BM.32,33 Despite treatment, approximately half of these patients will die from BM progression and many clinicians agree that improving neurologic and neurocognitive function or preventing its deterioration is more important than prolonging survival.27 With improved survival rate and better local control in NSCLC, the risk of BM seems to become a more problematic issue, thus the concept of PCI has also been developed in NSCLC. PCI Randomized trials in NSCLC In the literature, there are few randomized trials evaluating PCI in locally advanced NSCLC. In most trials, the cumulative incidence of BM was reduced in the PCI arm as compared to the control arm, but there was no impact on overall survival (see Table 1). The first trial was conducted by the Veterans Administration Lung Group (VALG) which included 323 inoperable lung cancer patients, out of which 281 had NSCLC, and almost 50% had squamous cell carcinoma.34 Patients were randomized to receive PCI (20 Gy in 2 weeks) or no PCI, and different regimens of thoracic irradiation (50 Gy in 25 fractions vs. 42 Gy in 15 fractions). The incidence of BM was significantly lower in the PCI arm compared to the observation arm (6% vs. 13%, p = 0.038). There was no effect of PCI on overall survival (OS). The median time to development of BM seemed however longer in the PCI group (34 weeks vs. 29 weeks). Umsawasdi et al. published the second randomized trial which included 100 patients with locally advanced NSCLC of any cell type.35 The majority of patients were stage III (87%) and 13% were stage I and II. All patients received combination chemotherapy (cyclophosphamide + doxorubicin + cisplatin = CAP) or CAP plus radiotherapy as the initial treatment for their active tumor or as an adjuvant therapy after surgery. Patients who were clinically free from lung cancer after combined modality therapy were randomized: 47% received PCI at the dose of 30 Gy in 10 fractions. BM were less frequent in the PCI arm compared to the observation arm (4% vs. 27%; p = 0.02). In the multivariate analysis, PCI was only beneficial to females, patients with good performance status, weight loss less than 6%, squamous histology, and Stage III disease. PCI prolonged significantly median time to brain failure (50.5 weeks vs. 23 weeks, p = 0.002). As expected, considering the low number
of patients, overall survival at 3 years was not different in the two arms (22% vs. 23.5%). The Radiation Therapy Oncology Group (RTOG) has lead a randomized trial comparing PCI at the dose of 30 Gy in 10 fractions to no PCI in patients with unresectable adenocarcinoma or large-cell carcinoma confined to the chest and in resected patients.36 One hundred and eighty-seven patients were enrolled and analyzed. Twenty-six were operated, and all patients underwent chest radiotherapy (CRT). PCI did not significantly reduce the incidence of brain metastases compared to the observation arm (9% vs. 19%, p = 0.10). In a subgroup analysis, there was no differential effect of PCI between resected and unresected patients. PCI did not prolong the median time to BM and there was no difference in terms of overall survival (8.4 vs. 8.1 months, p = 0.36). Another randomized trial conducted by the South West Oncology Group (SWOG)37 included 254 patients with inoperable Stage III NSCLC, but 226 were evaluable. Two loco-regional treatments were tested: thoracic radiotherapy vs. chemoradiotherapy. Then there was a second randomization concerning PCI (at the dose of 30–37.5 Gy in 10–15 fractions) vs. observation. The incidence of BM in the PCI arm was 1% compared with 11% in the observation arm (p = 0.003) but overall survival was higher in the observation arm (8 vs. 11 months, p = 0.004). Finally, Gore et al. presented at the American Society of Clinical Oncology 2009 annual meeting, preliminary results from a RTOG randomized phase III trial.38 After completing loco-regional treatment (surgery, radiation therapy with or without chemotherapy) for locally advanced NSCLC (stage IIIA or IIIB), patients without distant metastasis or progressive disease were randomized between PCI (30 Gy in 15 fractions) or no PCI. The trial was closed because of a poor accrual (358/1058 patients needed) and definitive results are not yet published. Significant reduction of brain metastases was observed in PCI group at 1 year (18% vs. 7.7%, p = 0.004). There was no difference in OS between the two groups. Even if it did not address directly PCI exclusively, Pöttgen et al. published an interesting multicenter study comparing two different therapeutic strategies in operable stage III NSCLC patients, one of the two arms including PCI.39 In the standard arm, patients underwent surgery followed by post-operative thoracic radiotherapy. In the experimental arm, patients received preoperative chemotherapy followed by concurrent chemoradiotherapy before surgery and then PCI (30 Gy in 2 Gy fractions). At 5 years, the probability of developing BM as first site of failure was decreased in the experimental arm with PCI as compared with the control arm (7.8% vs. 34.7%; p = 0 .02), and the overall brain relapse rate was reduced comparably (9.1% vs. 27.2%; p = 0 .04). The interpretation of these results is difficult since the trial did not address directly the benefit of PCI. Patients in the experimental arm had also a more aggressive loco-regional treatment in the experimental arm as compared to the control arm. In conclusion, in most studies, PCI in NSCLC reduces the incidence of brain metastases by 50% and seems to delay their appearance. Unfortunately, as most of these trials were small thereby underpowered, the overall survival was not positively modified
Table 1 Randomized studies evaluating PCI in NSCLC. Reference
Patients (n)
Stage
Dose (n fraction)
PCI
No PCI
p
PCI
No PCI
p
Cox et al. [34] Umsawasdi et al. [35] Mira et al. [36]
281 97 254 229 eval 187 358
Inoperable I, II or III III
20 Gy (10) 30 Gy (10) 37.5 Gy (15) or 30 Gy (15)
7/136 (6) 2/45 (4) 0%
16/145 (13) 14/51 (27) 11%
0038 0002 0002
35.4 weeks _ Median: 7.9 months
41.4 weeks – median: 11.5 months
0.5 ns 0.01
II/III III
30 Gy (10) 30 Gy (15)
3/93 (9) 7.7%
18/94 (19) 18%
0.1 0.004
13% at 2 years
21% at 2 years
0.36 ns
Russel et al. [37] Gore et al. [38]
n: Number; eval: patients evaluated.
Brain metastases (%)
Overall survival
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in these trials. Furthermore, most of them are old and heterogeneous in terms of disease (stage and histology), loco-regional treatment (surgery, radiation modalities, chemotherapy), and whole brain radiation dose. New phase III trials are also needed to determine the place of PCI in NSCLC. There is at present an on-going phase III study in the Netherlands (NVALT-11/DLCRG-02).
Possible toxicity related to PCI Even if there is strong evidence in favour of PCI as it reduces the incidence of BM both in SCLC and NSCLC and improves OS in SCLC, clinicians may be reluctant to propose it to patients because of its potential neurotoxicity. Retrospective studies have reported neurological and intellectual impairment or abnormalities on brain computed tomography (CT) scan potentially related to PCI that can be of concern to clinicians. Acute toxicity is generally manageable and consists mostly in alopecia, headache, fatigue, nausea, and vomiting. Long-term sequelae such as severe memory loss, intellectual impairment or even dementia and ataxia have been reported in retrospective studies and attributed to PCI. Such risk has to be put into balance with the benefit of PCI in terms of BM incidence and survival. However, most of these studies are small, retrospective and with no baseline evaluations. Evaluating PCI neurological toxicity is difficult because the related symptoms can be caused by many different factors. Treatment modalities such as PCI dose and fractionation scheme (fraction size P3 Gy), or the use of concurrent chemotherapy (ccCT) may contribute to neurotoxicity.40–44 Other studies have suggested that neuropsychological impairment could be attributable to cancer itself or pre-PCI treatment. For instance, baseline evaluation was impaired before PCI in several studies both retrospective and prospective.2,45 Age, effects of chronic cigarette abuse, paraneoplastic syndromes, and undiagnosed micrometastases may also contribute to neurotoxicity or partly explain neurological symptoms.41 Furthermore, patients may have symptoms of depression or anxiety that may interfere with neuropsychological evaluations. Neuropsychological assessment of long-term toxicity is thus difficult in lung cancer. The best evaluation of PCI toxicity comes from long-term follow-up of randomized studies using validated questionnaires for QoL, general health status, and neurological functions. As shown earlier, two trials2,45 did not show any significant decline in neurological functions between PCI and no PCI groups, with a follow-up not exceeding 30 months. A third trial which did not address the issue of PCI directly, comprised a prospective neurocognitive evaluation of all patients randomly assigned to receive irradiation and concomitant chemotherapy with or without warfarin.44 Even if this Cancer and Leukemia Group B trial did not address directly PCI, the authors concluded that the combination of chemotherapy and PCI had a negative impact on cognitive functioning, confirming that chemotherapy and PCI should not be administered concomitantly. Pottgen et al. published a neurocognitive evaluation on 11 out of 17 long-term survivors of stage IIIA NSCLC treated with or without PCI.39 They did not find any difference between the two groups, but their sample size is very small. In SCLC limited disease, the results of neurological follow-up of the PCI dose intergroup trial have been reported recently.46 There was no significant difference between the two groups in any of the 17 selected items assessing quality of life, neurological and cognitive functions. There was a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory. Very few patients had severe deterioration of neuropsychological and cognitive functions. Some items seemed to worsen with age: physical functioning, motor dysfunction, memory and brain imaging abnormalities. Concerning PCI in extensive stage SCLC, quality of life was evaluated in the
EORTC trial.47 The EORTC Health-related Quality of Life (HRQOL) questionnaire and its brain module were used to collect self-reported patient data. The results show a negative but limited impact of PCI, with a significantly decreased QoL in terms of functioning scales among PCI patients at 6 weeks (p 6 0.018), which tended to be not significant at 3 months and afterwards. Fatigue was also significantly higher in PCI patients at 6 weeks and 3 months, which could partly explain some neurocognitive findings. An exploratory analysis of the remaining HRQOL and symptom scales showed statistically significant (p < 0.01) and clinically meaningful mean differences between the two arms for appetite loss, nausea/ vomiting, and social functioning. There are ways to possibly reduce the risk of neurocognitive decline after whole brain irradiation: combination with neuroprotective drugs such as memantine being evaluated, and new approaches using intensity modulated radiotherapy to spare the hippocampus.48,49 They are being evaluated in BM treatment and they could eventually be explored in the future for PCI. Lee et al. have proposed a decision analysis model to evaluate the survival benefit associated with PCI, penalized by its possible neurotoxicity.50 The authors concluded that PCI offered a better quality adjusted life expectancy over no PCI with moderate or low neurotoxicity rates.50 At present based on randomized trials, neurocognitive functions seem to be equivalent or moderately altered after PCI as opposed to no PCI. PCI is now part of the standard treatment in SCLC patients and should continue to be investigated in NSCLC patients with locally advanced disease. An important issue to be outlined concerning neurologic toxicity is that it has clearly been shown that the use of concomitant CT with PCI results in a significant increase of neurotoxicity.43,44 PCI, if prescribed, should always be performed in absence of concomitant CT. PCI should be reconsidered if longterm survival increased dramatically or if neurotoxicity appeared more frequent and more severe. Thus long-term follow-up of patients included in prospective studies is needed.5,38,51 Conflict of interest statement The authors have no conflict of interest concerning the following article. References 1. Hochstenbag MM, Twijnstra A, Wilmink JT, Wouters EF, Velde GP. Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MRimaging is useful at initial diagnosis. J Neurooncol 2000;48:243–8. 2. 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. 3. Auperin 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. 4. Patel S, Macdonald OK, Suntharalingam M. Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer. Cancer 2009;115:842–50. 5. Le Pechoux 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 randomized clinical trial. Lancet Oncol 2009;10:467–74. 6. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–72. 7. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB nons mallcell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880–92. 8. Andre F, Grunenwald D, Pujol JL, et al. Patterns of relapse of N2 nonsmall-cell lung carcinoma patients treated with preoperative chemotherapy: should prophylactic cranial irradiation be reconsidered? Cancer 2001;91:2394–400. 9. Gaspar LE, Chansky K, Albain KS, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III nonsmall-cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol 2005;23:2955–61.
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33. Katayama T, Shimizu J, Suda K. Efficacy of erlotinib for brain metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol 2009;4:1–4. 34. Cox JD, Stanley K, Petrovich Z, Paig C, Yesner R. Cranial irradiation in cancer of the lung of all cell types. JAMA 1981;245:469–72. 35. Umsawasdi T, Valdivieso M, Chen TT, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J Neurooncol 1984;2:253–9. 36. Russell AH, Pajak TE, Selim HM, et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1991;21:637–43. 37. Miller TP, Crowley JJ, Mira J, et al. A randomized trial of chemotherapy and radiotherapy for stage III non-small cell lung cancer. Cancer Ther 1998;4:229–36. 38. Gore EM, Bae K, Wong S, et al. A phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced nonsmall cell lung cancer: initial analysis of Radiation Therapy Oncology Group 0214. J Clin Oncol 2009;27(Suppl.) [abstract #7506]. 39. Pottgen C, Eberhardt W, Grannass A, et al. Prophylactic cranial irradiation in operable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 2007;25:4987–92. 40. Cull A, Gregor A, Hopwood P, et al. Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur J Cancer 1994;30A:1067–74. 41. 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. 42. 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. 43. Van Oosterhout AG, Ganzevles PG, Wilmink JT, De Geus BW, Van Vonderen RG, Twijnstra A. Sequelae in long-term survivors of small cell lung cancer. Int J Radiat Oncol Biol Phys 1996;34:1037–44. 44. Ahles TA, Silberfarb PM, Herndon J, et al. Psychologic and neuropsychologic functioning of patients with limited small-cell lung cancer treated with chemotherapy and radiation therapy with or without warfarin: a study by the Cancer and Leukemia Group B. J Clin Oncol 1998;16:1954–60. 45. Gregor A, Cull A, Stephens RJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer 1997;33:1752–8. 46. Le Pechoux C, Laplanche A, Faivre-Finn C, et al. Neuro-cognitive follow-up among patients with limited small cell cancer (SCLC) treated with two different doses of prophylactic cranial irradiation (PCI) according to the intergroup phase III trial (PCI99-01, IFCT 99-01, EORTC 22003-08004, RTOG 0212). J Thorac Oncol 2009;4:S393. 47. Slotman BJ, Mauer ME, Bottomley A, et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol 2009;27:78–84. 48. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002;33:1834–9. 49. Gutiérrez AN, Westerly DC, Tomé WA, et al. Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. Int J Radiat Oncol Biol Phys 2007;69:589–97. 50. 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. 51. Wolfson AH, Bae K, Komaki R, et al. Secondary endpoints of a phase ii randomized trial (RTOG 0212): impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 2009;75(Suppl. 3).
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumour Treatment
Prophylactic cranial irradiation in lung cancer A. Paumier, X. Cuenca, C. Le Péchoux * Radiation Oncology Department, Gustave-Roussy Institute, Villejuif, France
a r t i c l e
i n f o
Article history: Received 19 May 2010 Received in revised form 16 August 2010 Accepted 25 August 2010
Keywords: Lung cancer Prophylactic cranial irradiation Small-cell lung cancer Non-small-cell lung cancer Combined modality treatment
s u m m a r y As multi-modality treatments are now able to ensure better local control and a lower rate of extra cranial metastases, brain relapse has become a major concern in lung cancer. As survival is poor after development of brain metastases in spite of specific treatment, prophylactic cranial irradiation (PCI) has been introduced in the 70’s. PCI has been evaluated in randomized trials in both small-cell (SCLC) and nonsmall-cell (NSCLC) lung cancers to reduce the incidence of brain metastases and possibly increase survival. PCI reduces significantly the BM rate in both limited disease (LD) and extensive disease (ED) SCLC and in non-metastatic NSCLC. Considering SCLC, PCI significantly improves overall survival in LD (from 15% to 20% at 3 years) and ED (from 13% to 27% at 1 year) in patients who respond to first-line treatment; it should thus be part of the standard treatment in all responders in ED and in good responders in LD. No dose-effect relationship for PCI was demonstrated in LD SCLC patients so that the recommended dose is 25 Gy in 10 fractions. In NSCLC, even if the risk of brain dissemination is lower than in SCLC, it has become a challenging issue. Studies have identified subgroups at higher risk of brain failure. There are more local treatment possibilities for NSCLC patients with BM, but most of them will eventually recur so that PCI should be reconsidered. Few randomized trials have been performed and they were not able to show an effect on survival as they were underpowered. New trials are needed. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Brain failures, have become a significant cause of relapse in lung cancer, in both small-cell and non-small-cell lung cancer, as other causes of failure such as loco-regional failure and extra-cerebral metastases are better controlled with multi-modality treatments. Median survival after brain failure is less than 6 months. As systemic agents do not cross the blood–brain barrier effectively to prevent brain metastases (BM), prophylactic cranial irradiation (PCI) has been discussed as a strategy to reduce the risk of brain failure, in the 70’s first in leukemia then lung cancer. We will sequentially develop prophylactic cranial irradiation (PCI) in small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC) and then speak about potential toxicity of PCI. Small-cell lung carcinomas (SCLC) Limited disease Brain metastases (BM) are frequent in SCLC and responsible for serious impairment of patient’s survival and quality of life. About ⇑ Corresponding author. Address: Radiation Oncology Department, GustaveRoussy Institute, 114 Rue Edouard Vaillant, Villejuif 94800, France. Tel.: +33 0 142114757; fax: +33 0 142115253. E-mail address: [email protected] (C. Le Péchoux). 0305-7372/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2010.08.009
15% of patients have brain metastasis at the time of diagnosis, and this rate is even higher with more accurate imaging, such as MRI.1 Moreover, about half of patients in complete remission after treatment for limited disease SCLC will develop brain relapse.2 In the early 80s, PCI was therefore introduced to prevent BM. Most of the randomized trials testing PCI showed a significant decrease of BM incidence in favour of PCI, however, none of them individually could demonstrate a significant improvement in overall survival. Thus a meta-analysis was undertaken, based on individual data of almost one thousand patients in complete remission included in seven randomized phase III studies.3 Thoracic complete remission corresponded to at least normalisation of chest X-ray in most trials. In this meta-analysis, 85% of the patients had limited disease and 15% had extensive disease SCLC; the PCI dose ranged from 8 Gy in 1 fraction to 40 Gy in 20 fractions. At 3 years, there was an absolute decrease of 25.3% in the cumulative incidence of BM (59% in the control arm vs. 33% in the PCI arm, p < 0.001), and an absolute increase in survival of 5.4% from 15.3% in the control group to 20.7% in the treatment group (p = 0.01). Interestingly, an indirect comparison of four total dose groups (8, 24, 25, 30 and 36–40 Gy) showed a significant trend (p = 0.02) towards a decrease in the risk of brain metastasis with higher PCI dose. The authors also identified a trend (p = 0.01) toward a lower risk of brain metastasis with earlier administration of PCI after start of the treatment. Therefore, PCI became part of the standard of care for complete and good responders based on CT scan evaluation.
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More recently, in a retrospective study based on the National Cancer Institute’s Surveillance, Epidemiology, and End-Results Program (SEER), which involved almost 8000 patients, Patel et al.4 have reported similar results, with a significant improvement in both overall and cause-specific survival in favour of PCI. One of the challenges raised by the meta-analysis3 was the optimal timing and optimal dose for PCI. The PCI Collaborative Group has recently published an international trial addressing the question of dose-effect for the prevention of metastases in patients with limited disease who achieved a complete response (i.e. at least a normal chest radiograph).5 It compared a standard dose of 25 Gy in 10 fractions to a higher dose of 36 Gy (36 Gy/18 fractions or 36 Gy in 24 twice-daily fractions). It is noteworthy that in order to evaluate a possible increased neurological toxicity, quality of life and neurological assessment both before and after PCI were performed. Toxicities and treatment delivery were not different between the two arms. Patients who received the high dose had a non-significant decrease in brain metastases compared to patients who received the standard dose: incidence of BM at 2 years was 29% and 23% in the high dose and in the standard dose groups, respectively (p = 0.18). For unclear reasons, overall survival was significantly worse among patients in the high dose PCI group (HR for death: 1.2 [1.00, 1.44]). The importance of fractionation in terms of efficacy, tolerance and possible neurological sequelae could be determined by a phase II/III trial (RTOG 0212) which compares conventional fractionation (36 Gy in 18 fractions) to hyperfractionated accelerated radiotherapy (36 Gy in 24 twice-daily fractions). PCI at 25 Gy in 10 fractions is now recommended for LD SCLC good responders. Extensive disease Even if the PCI meta-analysis, which included 15% of patients with extensive disease, supported PCI in extensive disease for complete responders, the question remained unanswered for patients with partial response.3 The EORTC thus decided to undertake a phase III trial randomising patients with extensive disease who had partial or complete response to first-line treatment. They would be randomly assigned PCI (20–30 Gy) or no PCI.6 Patients in the PCI arm were mostly treated with a short course schedule: among the 143 irradiated patients, 89 received 20 Gy in 5 fractions, the others were treated with various fractionation schedules (30 Gy given in 10 fractions, 30 Gy given in 12 fractions or 25 Gy given in 10 fractions). The results of this study are strongly in favour of PCI: not only does PCI significantly reduce the risk of symptomatic brain failure but it also significantly improves overall survival. The cumulative risk of symptomatic brain metastases at 1 year was 14.6% in the PCI arm and 40.4% in the control arm (p < 0.001) and the 1-year survival rate was 13.3% in the control arm and 27.1% in the PCI arm (p = 0.003). Due to the low median survival in this setting, long-term toxicity is not of major concern, and the short course schedule (20 Gy in 5 fractions) should be favoured. However, less hypofractionated schedules (such as the schedule applied to limited disease) could be offered to patients with higher life expectancy. PCI has now become a standard of care for patients with ED SCLC who respond to first-line chemotherapy. Non-small-cell lung cancer Even if the risk of brain failure is not as high as in SCLC, brain metastases are also quite common in NSCLC especially in certain groups of patients. The BM incidence ranges from 17% to 54%7–10 and it is the first site of recurrence in 15–40% of cases.7,11–13 As in small-cell lung cancer, brain MRI can detect smaller BM (12.8 ± 9.1 mm) than CT scan (20.3 ± 7.0 mm).14 The prognosis of
patients with non-metastatic NSCLC has substantially been improved in the past 10 years. Better selection of patients, optimized loco-regional control as well as the addition of platinum-based chemotherapy to surgery and/or radiotherapy have contributed to improve survival.15,16 However these advances do not seem to alter brain relapse rates, on the contrary.8–11 As there are less prospective studies evaluating PCI in NSCLC, we will briefly expose studies trying to identify groups of NSCLC patients at higher risk of brain failure, treatments, and finally randomized trials evaluating PCI in NSCLC. Predictive factors of brain failure in NSCLC Adenocarcinoma, advanced nodal status and tumor stage are associated with higher risk of BM.8,11,17,18 BM also appear more frequent among younger patients (<60 years),13,19–21 and in patients receiving preoperative chemotherapy or EGFR-TKI as shown in some studies.8,22 There are studies evaluating the risk of brain failure after surgery for NSCLC. In a large series of 1532 patients who underwent complete resection, mostly for stage I and II NSCLC,23 only 6.8% of the patients had documented first recurrences involving the brain. The risk of brain recurrence was higher in T2N0/T1N1/ T2N1 than in T1N0 patients. In a retrospective study of surgical patients with N2 nodal involvement, preoperative chemotherapy was associated with an increased isolated BM rate (22% vs. 11%) as well as adenocarcinoma histology.2 Patients who had preoperative chemotherapy for adenocarcinoma had the highest risk to develop isolated BM (33%). Similar conclusions were reported in another retrospective study of Mamon et al. [24]. Among 177 patients with stage IIIA (N2) treated with surgery, chemotherapy and/or radiotherapy, 34% presented BM as first site of failure, and 40% developed BM at some point during the follow-up. Patients with nonsquamous histology and nodal involvement persistent after neoadjuvant therapy had the greater risk of BM in this cohort (53% at 3 years). It should be outlined that superior sulcus tumors have a particularly high risk of brain failure. In the intergroup study of chemoradiotherapy followed by surgery,25 up to 41% 20% of the patients presented a recurrence in the brain only, whereas local control was satisfactory. Other studies have evaluated the risk of brain failure in more advanced NSCLC. In a retrospective study of inoperable nonsmall-cell lung cancer patients treated within four RTOG trials with definitive radiotherapy, BM represented the first site of relapse in 15–18% of good prognostic patients (RPA classes I and II).26 Robnett et al. [13] performed a retrospective analysis from 150 consecutive patients with stage II/III NSCLC treated with definitive chemoradiation. Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Stage IIIB patients had a 2-year actuarial incidence of BM of 36% whereas it was 29% for stage II/IIIA patients (p < 0.04). The 2-year actuarial rate of BM reached 42% for stage IIIB patients with non-squamous histology. In a retrospective study, Lee et al. have reported the outcome of 232 patients with recurrent or metastatic disease treated with EGFR-TKI.22 Among responders to TKI, the authors observed both a higher rate of BM as first site of recurrence and higher rate of isolated brain relapse compared to patients with no clinical benefit with EGFR-TKI (26% vs. 4% and 13% vs. 1%, p < 0.001). These findings have leaded the Korean Radiation Oncology Group to start a randomized trial for patients with advanced NSCLC responsive to EGFR-TKI. Treatment and outcome in NSCLC Among patients with BM, the overall survival is poor ranging from 1.5 to 9.5 months according to several prognostic variables.27,28 There are several scales including factors predictive
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of survival outcome: they often include good performance status, age younger than 65 years, control of the primary tumor, absence of extracranial metastases, favorable tumor histology, and number of BM. NSCLC is considered more favourable tumor histology then SCLC partly because there are more treatment options. Whole brain irradiation (WBI) still is the standard treatment for symptomatic BM. Median survival after WBI is around 4 months.29 In a selected subgroup of patients surgery or stereotactic radiotherapy can be proposed with better results with median survival rates exceeding 12 months. Unfortunately, few patients can benefit from these approaches and they usually relapse again in the brain within 6–8 months.30 Response rates to chemotherapy range between 30% and 50%.27,31 The are some interesting data about tyrosine kinase inhibitors of the epidermal growth factor receptor (TKI-EGFR) in BM.32,33 Despite treatment, approximately half of these patients will die from BM progression and many clinicians agree that improving neurologic and neurocognitive function or preventing its deterioration is more important than prolonging survival.27 With improved survival rate and better local control in NSCLC, the risk of BM seems to become a more problematic issue, thus the concept of PCI has also been developed in NSCLC. PCI Randomized trials in NSCLC In the literature, there are few randomized trials evaluating PCI in locally advanced NSCLC. In most trials, the cumulative incidence of BM was reduced in the PCI arm as compared to the control arm, but there was no impact on overall survival (see Table 1). The first trial was conducted by the Veterans Administration Lung Group (VALG) which included 323 inoperable lung cancer patients, out of which 281 had NSCLC, and almost 50% had squamous cell carcinoma.34 Patients were randomized to receive PCI (20 Gy in 2 weeks) or no PCI, and different regimens of thoracic irradiation (50 Gy in 25 fractions vs. 42 Gy in 15 fractions). The incidence of BM was significantly lower in the PCI arm compared to the observation arm (6% vs. 13%, p = 0.038). There was no effect of PCI on overall survival (OS). The median time to development of BM seemed however longer in the PCI group (34 weeks vs. 29 weeks). Umsawasdi et al. published the second randomized trial which included 100 patients with locally advanced NSCLC of any cell type.35 The majority of patients were stage III (87%) and 13% were stage I and II. All patients received combination chemotherapy (cyclophosphamide + doxorubicin + cisplatin = CAP) or CAP plus radiotherapy as the initial treatment for their active tumor or as an adjuvant therapy after surgery. Patients who were clinically free from lung cancer after combined modality therapy were randomized: 47% received PCI at the dose of 30 Gy in 10 fractions. BM were less frequent in the PCI arm compared to the observation arm (4% vs. 27%; p = 0.02). In the multivariate analysis, PCI was only beneficial to females, patients with good performance status, weight loss less than 6%, squamous histology, and Stage III disease. PCI prolonged significantly median time to brain failure (50.5 weeks vs. 23 weeks, p = 0.002). As expected, considering the low number
of patients, overall survival at 3 years was not different in the two arms (22% vs. 23.5%). The Radiation Therapy Oncology Group (RTOG) has lead a randomized trial comparing PCI at the dose of 30 Gy in 10 fractions to no PCI in patients with unresectable adenocarcinoma or large-cell carcinoma confined to the chest and in resected patients.36 One hundred and eighty-seven patients were enrolled and analyzed. Twenty-six were operated, and all patients underwent chest radiotherapy (CRT). PCI did not significantly reduce the incidence of brain metastases compared to the observation arm (9% vs. 19%, p = 0.10). In a subgroup analysis, there was no differential effect of PCI between resected and unresected patients. PCI did not prolong the median time to BM and there was no difference in terms of overall survival (8.4 vs. 8.1 months, p = 0.36). Another randomized trial conducted by the South West Oncology Group (SWOG)37 included 254 patients with inoperable Stage III NSCLC, but 226 were evaluable. Two loco-regional treatments were tested: thoracic radiotherapy vs. chemoradiotherapy. Then there was a second randomization concerning PCI (at the dose of 30–37.5 Gy in 10–15 fractions) vs. observation. The incidence of BM in the PCI arm was 1% compared with 11% in the observation arm (p = 0.003) but overall survival was higher in the observation arm (8 vs. 11 months, p = 0.004). Finally, Gore et al. presented at the American Society of Clinical Oncology 2009 annual meeting, preliminary results from a RTOG randomized phase III trial.38 After completing loco-regional treatment (surgery, radiation therapy with or without chemotherapy) for locally advanced NSCLC (stage IIIA or IIIB), patients without distant metastasis or progressive disease were randomized between PCI (30 Gy in 15 fractions) or no PCI. The trial was closed because of a poor accrual (358/1058 patients needed) and definitive results are not yet published. Significant reduction of brain metastases was observed in PCI group at 1 year (18% vs. 7.7%, p = 0.004). There was no difference in OS between the two groups. Even if it did not address directly PCI exclusively, Pöttgen et al. published an interesting multicenter study comparing two different therapeutic strategies in operable stage III NSCLC patients, one of the two arms including PCI.39 In the standard arm, patients underwent surgery followed by post-operative thoracic radiotherapy. In the experimental arm, patients received preoperative chemotherapy followed by concurrent chemoradiotherapy before surgery and then PCI (30 Gy in 2 Gy fractions). At 5 years, the probability of developing BM as first site of failure was decreased in the experimental arm with PCI as compared with the control arm (7.8% vs. 34.7%; p = 0 .02), and the overall brain relapse rate was reduced comparably (9.1% vs. 27.2%; p = 0 .04). The interpretation of these results is difficult since the trial did not address directly the benefit of PCI. Patients in the experimental arm had also a more aggressive loco-regional treatment in the experimental arm as compared to the control arm. In conclusion, in most studies, PCI in NSCLC reduces the incidence of brain metastases by 50% and seems to delay their appearance. Unfortunately, as most of these trials were small thereby underpowered, the overall survival was not positively modified
Table 1 Randomized studies evaluating PCI in NSCLC. Reference
Patients (n)
Stage
Dose (n fraction)
PCI
No PCI
p
PCI
No PCI
p
Cox et al. [34] Umsawasdi et al. [35] Mira et al. [36]
281 97 254 229 eval 187 358
Inoperable I, II or III III
20 Gy (10) 30 Gy (10) 37.5 Gy (15) or 30 Gy (15)
7/136 (6) 2/45 (4) 0%
16/145 (13) 14/51 (27) 11%
0038 0002 0002
35.4 weeks _ Median: 7.9 months
41.4 weeks – median: 11.5 months
0.5 ns 0.01
II/III III
30 Gy (10) 30 Gy (15)
3/93 (9) 7.7%
18/94 (19) 18%
0.1 0.004
13% at 2 years
21% at 2 years
0.36 ns
Russel et al. [37] Gore et al. [38]
n: Number; eval: patients evaluated.
Brain metastases (%)
Overall survival
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in these trials. Furthermore, most of them are old and heterogeneous in terms of disease (stage and histology), loco-regional treatment (surgery, radiation modalities, chemotherapy), and whole brain radiation dose. New phase III trials are also needed to determine the place of PCI in NSCLC. There is at present an on-going phase III study in the Netherlands (NVALT-11/DLCRG-02).
Possible toxicity related to PCI Even if there is strong evidence in favour of PCI as it reduces the incidence of BM both in SCLC and NSCLC and improves OS in SCLC, clinicians may be reluctant to propose it to patients because of its potential neurotoxicity. Retrospective studies have reported neurological and intellectual impairment or abnormalities on brain computed tomography (CT) scan potentially related to PCI that can be of concern to clinicians. Acute toxicity is generally manageable and consists mostly in alopecia, headache, fatigue, nausea, and vomiting. Long-term sequelae such as severe memory loss, intellectual impairment or even dementia and ataxia have been reported in retrospective studies and attributed to PCI. Such risk has to be put into balance with the benefit of PCI in terms of BM incidence and survival. However, most of these studies are small, retrospective and with no baseline evaluations. Evaluating PCI neurological toxicity is difficult because the related symptoms can be caused by many different factors. Treatment modalities such as PCI dose and fractionation scheme (fraction size P3 Gy), or the use of concurrent chemotherapy (ccCT) may contribute to neurotoxicity.40–44 Other studies have suggested that neuropsychological impairment could be attributable to cancer itself or pre-PCI treatment. For instance, baseline evaluation was impaired before PCI in several studies both retrospective and prospective.2,45 Age, effects of chronic cigarette abuse, paraneoplastic syndromes, and undiagnosed micrometastases may also contribute to neurotoxicity or partly explain neurological symptoms.41 Furthermore, patients may have symptoms of depression or anxiety that may interfere with neuropsychological evaluations. Neuropsychological assessment of long-term toxicity is thus difficult in lung cancer. The best evaluation of PCI toxicity comes from long-term follow-up of randomized studies using validated questionnaires for QoL, general health status, and neurological functions. As shown earlier, two trials2,45 did not show any significant decline in neurological functions between PCI and no PCI groups, with a follow-up not exceeding 30 months. A third trial which did not address the issue of PCI directly, comprised a prospective neurocognitive evaluation of all patients randomly assigned to receive irradiation and concomitant chemotherapy with or without warfarin.44 Even if this Cancer and Leukemia Group B trial did not address directly PCI, the authors concluded that the combination of chemotherapy and PCI had a negative impact on cognitive functioning, confirming that chemotherapy and PCI should not be administered concomitantly. Pottgen et al. published a neurocognitive evaluation on 11 out of 17 long-term survivors of stage IIIA NSCLC treated with or without PCI.39 They did not find any difference between the two groups, but their sample size is very small. In SCLC limited disease, the results of neurological follow-up of the PCI dose intergroup trial have been reported recently.46 There was no significant difference between the two groups in any of the 17 selected items assessing quality of life, neurological and cognitive functions. There was a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory. Very few patients had severe deterioration of neuropsychological and cognitive functions. Some items seemed to worsen with age: physical functioning, motor dysfunction, memory and brain imaging abnormalities. Concerning PCI in extensive stage SCLC, quality of life was evaluated in the
EORTC trial.47 The EORTC Health-related Quality of Life (HRQOL) questionnaire and its brain module were used to collect self-reported patient data. The results show a negative but limited impact of PCI, with a significantly decreased QoL in terms of functioning scales among PCI patients at 6 weeks (p 6 0.018), which tended to be not significant at 3 months and afterwards. Fatigue was also significantly higher in PCI patients at 6 weeks and 3 months, which could partly explain some neurocognitive findings. An exploratory analysis of the remaining HRQOL and symptom scales showed statistically significant (p < 0.01) and clinically meaningful mean differences between the two arms for appetite loss, nausea/ vomiting, and social functioning. There are ways to possibly reduce the risk of neurocognitive decline after whole brain irradiation: combination with neuroprotective drugs such as memantine being evaluated, and new approaches using intensity modulated radiotherapy to spare the hippocampus.48,49 They are being evaluated in BM treatment and they could eventually be explored in the future for PCI. Lee et al. have proposed a decision analysis model to evaluate the survival benefit associated with PCI, penalized by its possible neurotoxicity.50 The authors concluded that PCI offered a better quality adjusted life expectancy over no PCI with moderate or low neurotoxicity rates.50 At present based on randomized trials, neurocognitive functions seem to be equivalent or moderately altered after PCI as opposed to no PCI. PCI is now part of the standard treatment in SCLC patients and should continue to be investigated in NSCLC patients with locally advanced disease. An important issue to be outlined concerning neurologic toxicity is that it has clearly been shown that the use of concomitant CT with PCI results in a significant increase of neurotoxicity.43,44 PCI, if prescribed, should always be performed in absence of concomitant CT. PCI should be reconsidered if longterm survival increased dramatically or if neurotoxicity appeared more frequent and more severe. Thus long-term follow-up of patients included in prospective studies is needed.5,38,51 Conflict of interest statement The authors have no conflict of interest concerning the following article. References 1. Hochstenbag MM, Twijnstra A, Wilmink JT, Wouters EF, Velde GP. Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MRimaging is useful at initial diagnosis. J Neurooncol 2000;48:243–8. 2. 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. 3. Auperin 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. 4. Patel S, Macdonald OK, Suntharalingam M. Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer. Cancer 2009;115:842–50. 5. Le Pechoux 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 randomized clinical trial. Lancet Oncol 2009;10:467–74. 6. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–72. 7. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB nons mallcell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880–92. 8. Andre F, Grunenwald D, Pujol JL, et al. Patterns of relapse of N2 nonsmall-cell lung carcinoma patients treated with preoperative chemotherapy: should prophylactic cranial irradiation be reconsidered? Cancer 2001;91:2394–400. 9. Gaspar LE, Chansky K, Albain KS, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III nonsmall-cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol 2005;23:2955–61.
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