- Email: [email protected]
Prophylactic Cranial Irradiation for Resectable Small-Cell Lung Cancer
Accepted Manuscript Prophylactic Cranial Irradiation for Resectable Small Cell Lung Cancer Aditya Halthore, M.D., Anuj Goenka, M.D., Rajiv Sharma, M.D., Jonathan P.S. Knisely, M.D. PII:
S1525-7304(17)30232-2
DOI:
10.1016/j.cllc.2017.08.004
Reference:
CLLC 693
To appear in:
Clinical Lung Cancer
Received Date: 16 June 2017 Revised Date:
8 August 2017
Accepted Date: 18 August 2017
Please cite this article as: Halthore A, Goenka A, Sharma R, Knisely JPS, Prophylactic Cranial Irradiation for Resectable Small Cell Lung Cancer, Clinical Lung Cancer (2017), doi: 10.1016/ j.cllc.2017.08.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Authors: Aditya Halthore, M.D.1, Anuj Goenka, M.D.1, Rajiv Sharma, M.D.1, Jonathan P.S. Knisely, M.D.2 1
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Department of Radiation Medicine, Northwell Health and Hofstra Northwell School of Medicine, Lake Success, NY 2 Department of Radiation Oncology, Weill Cornell Medicine, New York, NY
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Conflicts of Interest: None
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Corresponding author: Anuj Goenka, M.D. Department of Radiation Medicine Northwell Health 450 Lakeville Road, Lake Success, NY. 11040 Email: [email protected] Tel: (516)321-3000 Fax: (718)470-8445
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Author contributions: AH, AG, RS, and JK were all involved in the writing and editing of the submitted manuscript.
Submission: This material has never been published and is not currently under evaluation in any other peer-reviewed publication. All authors have participated in the review and preparation of this manuscript. There was no funding provided for this work.
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Prophylactic Cranial Irradiation for Resectable Small Cell Lung Cancer
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Abstract Following definitive chemoradiation for small cell lung cancer (SCLC), prophylactic cranial irradiation (PCI) has been established as standard of care in those patients whose tumors
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respond to treatment. In the modern era, however, a subset of patients may receive upfront
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resection for SCLC, yet the role of PCI in these patients has not been elucidated. In this review,
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we examined the literature to better define the role of PCI in this subset of patients. For patients
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with T2 or higher disease, incomplete resection, or those not receiving adjuvant chemotherapy,
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PCI is expected to offer a clinical benefit. For patients with T1 tumors treated with R0 resection,
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however, the rate of intracranial metastasis may be less than 10%. In these patients, deferral of
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PCI may be appropriate as it would avoid known neurocognitive sequelae of cranial irradiation.
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Introduction
Small cell lung cancer (SCLC), its characteristic patterns of spread, and its response to
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chemoradiation have been well studied in clinical trials, and recommendations for management
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have been codified within the National Comprehensive Cancer Network (NCCN) and American
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Society of Clinical Oncology (ASCO) guidelines.1,2 Following definitive chemoradiation for
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SCLC, multiple studies have established prophylactic cranial irradiation (PCI) as a standard of
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care for patients with limited-stage disease who have demonstrated a radiographic response to
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initial treatment.3–5 PCI is able to decrease the rates of central nervous system (CNS) failure in
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patients by sterilizing clinically occult cancer cells that were able to avoid eradication by virtue
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of their location behind the blood-brain barrier.3,6–7 In one landmark meta-analysis of patients
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with limited-stage disease who responded to initial chemoradiation, absolute overall survival
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rates increased by over 5% and relative disease-free survival increased by 25% with PCI.3
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Two-thirds of patients with SCLC present at a relatively advanced, symptomatic stage that historically has precluded surgery as part of the treatment paradigm. Even in those patients
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who present with limited-stage disease, surgery has been avoided largely on the basis of one
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randomized controlled trial published over 20 years ago that showed no improvement with the
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addition of surgery to chemoradiation.8 In the modern era of CT screening of high risk patients
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with smoking histories, however, patients are more frequently presenting with very localized
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limited-stage SCLC when compared to historical cohorts.9 In one analysis by Austin et al., CT
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screening led to a significant shift in the percent of patients diagnosed with stage IA or IB SCLC
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(33% of all SCLC cases diagnosed) when compared to historical controls (7% of all SCLC cases
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diagnosed).10 Associated with the increase in the diagnosis of early lesions, a growing subset of
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patients are being offered definitive surgical resection.10,11 The increased use of definitive
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surgery for patients with T1-2N0M0 SCLC is reflected in the most recently updated versions of
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the NCCN and ASCO guidelines.1,2 However, in this population of patients with very limited
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burden of disease, the optimal role for PCI has not been elucidated. In this review, we examine
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the existing literature regarding the role of PCI in patients with SCLC whose primary tumor has
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been treated by resection. In so doing, we have sought to refine the current NCCN
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recommendations by developing a framework for identifying subgroups of patients with low risk
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of CNS failure who may have reduced benefit from PCI.
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Methods
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The literature search strategy employed entered key terms into the PubMed database to
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identify peer-reviewed, English-language papers published between January 1st, 1980 and April
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1st, 2017, pertaining to resected small cell lung cancer and prophylactic cranial irradiation.
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Search terms included: (1) “small cell lung cancer” AND “surgery” AND (“prophylactic cranial
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irradiation” NOT “non-small” (70 results); “small cell lung cancer” AND “surgery” AND
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“prophylactic cranial irradiation” NOT “non-small” (70 results); (2) “small cell lung cancer”
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AND “surgery” AND “brain metastasis” NOT “non-small” (29 results); (3) “small cell lung
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cancer” AND “resection” AND “brain metastasis” NOT “non-small” (15 results); (4) “small cell
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lung cancer” AND “resection” AND “prophylactic cranial irradiation” NOT “non-small” (18
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results); . Author AH then individually reviewed each paper to eliminate duplicate results,
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results pertaining to NSCLC or other pathologies, and to verify applicability to surgically
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resected SCLC.
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Role of PCI in Surgically Resected Patients
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stage SCLC. Tri-modality therapy fell out of favor following the results of a landmark study
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published in 1994 by Lad et al., which demonstrated that resection did not improve survival
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when added to cyclophosphamide, doxorubicin, and vincristine followed by thoracic radiation
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for limited-stage SCLC.8 However, the applicability of this study to the subset of patients
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established to have cT1-2N0M0 SCLC with modern extent of disease workup including PET-CT
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has been questioned.12
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Surgery has historically not been considered part of the treatment paradigm for limited-
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Over the previous ten years, more published experiences have been reported showing outcomes following definitive surgical resection for SCLC. A retrospective report by Yang et al.
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recently published in the Journal of Clinical Oncology examined 954 patients from the National
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Cancer Data Base (NCDB) with T1-2N0M0 SCLC who had received R0 resection after which
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60% received some form of adjuvant therapy.13 When compared to surgery alone, patients
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receiving adjuvant therapy had a significantly improved 5-year overall survival. The use of PCI,
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however, has not been consistent in this literature (Table 1).13–20 In this same study, the authors
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reported that roughly 10% of the entire cohort received radiotherapy directed to the brain
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(presumed by the authors to be prophylactic), of which the vast majority also received adjuvant
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chemotherapy. No direct comparison was made between those receiving adjuvant chemotherapy
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only and those receiving adjuvant chemotherapy and PCI, but the hazard ratio for improvement
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in 5-year OS when compared to surgery only was lower in the adjuvant chemotherapy/PCI group
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(0.52) than in the chemotherapy alone group (0.78). While the authors do not comment
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specifically on incidence of brain metastasis in cohort subsets, they conclude that their findings
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support the recommendations delineated by the NCCN, that all patients undergoing resection for
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localized, non-disseminated SCLC (i.e. stage T1-2N0M0 disease) should receive adjuvant
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chemotherapy and PCI.
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Gong et al. published a single-institution retrospective review of 126 patients who underwent surgical resection without PCI for SCLC.14 In this study, over 90% of cancers were
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pathologic T1 or T2, 56% were pathologic stage I or II, 47% were SCLC only, and 53% were
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combined SCLC and NSCLC. Pathologic stage III tumors comprised 44% of all cancers and
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61% were pathologically node-positive. Either CT or MRI of the brain were confirmed to be
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negative for metastasis prior to treatment and follow-up included CT or MR of the brain every 3
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months. At 5 years, overall survival for patients with stage I, II, and III disease was 54.8%,
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35.6%, and 14.1%, respectively, and the corresponding incidence of brain metastases was 6.3%,
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28.2%, and 29.1%, respectively. Twenty-nine patients (23%) developed brain metastases during
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the study period. In 22 of these patients (76%), the CNS was the first site of distant recurrence,
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and in 16 patients, the CNS was the only site of distant recurrence. On multivariate analysis,
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pathologic stage and development of brain metastases were found to be independent factors
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predictive of overall survival, while pathologic stage (which is often related to nodal status) and
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completeness of surgical resection were independent factors predictive of brain metastases. The
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brain metastasis rate differed significantly according to whether a complete resection was
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achieved (20.5% with complete resection versus 42.9% with incomplete resection). It is
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important to appreciate that almost half of patients (40.5%) received induction chemotherapy,
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which presumably influenced pathologic staging at the time of surgery. Induction chemotherapy
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was not found to significantly influence survival or brain metastasis rates on multivariate
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analysis. No outcomes based on pre-induction clinical staging were reported. While confirming
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that the risk of brain metastasis correlates with advanced stage, and that the CNS is a primary site
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of isolated failure for a subset of patients, this paper also suggested that the risk of developing
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brain metastasis is less than 10% in patients with stage I disease treated with definitive surgical
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resection and systemic therapy.
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The Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101) was a phase II prospective multi-institutional trial in which 61 patients with stage I to IIIA SCLC received
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complete resection, of which 90% also received at least 2 cycles of adjuvant
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cisplatin/etoposide.17 None of the 61 patients in the study received PCI. With a median follow
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up of 65 months, the authors found that the incidence of brain metastasis was 11.4% for stage I
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patients (4 of 35 patients), as compared to 38% (3 of 8 patients) for stage II patients. The sample
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size was small making accurate determination of intracranial failure rates difficult.
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Xu et al. recently published the largest retrospective analysis of PCI in surgically resected
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SCLC from a single institution.20 In this series of 349 patients with completely resected SCLC,
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115 patients received PCI and 234 did not. A significant majority received adjuvant
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chemotherapy (83.1%). When the two groups (those who received PCI versus those who did
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not) were compared, there was a significant benefit in OS in the PCI cohort (36 months versus 25
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months). PCI improved OS in stage II patients (36 months versus 24 months) and in stage III
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patients (29 months versus 21 months), however there was no statistically significant difference
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in OS among stage I patients (HR 1.61, 95% CI 0.68-3.83). Cerebral recurrence was improved
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in the overall cohort that received PCI (13% versus 23%). Among stage III patients, the cerebral
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recurrence rate was 14% and 28% (p = 0.018) in the PCI and non-PCI groups, respectively. For
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stage II patients, brain metastasis rates were 12.8% versus 22.4% in patients receiving PCI
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versus no PCI, respectively (no significance reported). The brain metastasis rate for stage I
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patients receiving PCI versus no PCI was 10.5% versus 13.6%, respectively (significance not
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reported). Of note, there were no statistically significant differences in time to cerebral
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recurrence between PCI and non-PCI groups among stage I or stage II subsets.
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Zhu et al. in 2014 reported on the role of PCI and brain metastasis rate in 193 patients with R0 resected SCLC, all of whom received adjuvant platinum-based chemotherapy.21
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Exclusion criteria for this single institution retrospective study included R1 or R2 resection, but
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T3 and stage III patients were considered for inclusion. Approximately 1/3 of patients received
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PCI. Statistical analysis did not find any differences in patient characteristics between those that
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received PCI and those that did not in terms of gender, smoking status, KPS, stage, age, and
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number of chemotherapy cycles. PCI appeared to be associated with greater 2- and 5-year
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overall survival and brain metastasis-free survival, except in the subset of stage I patients, where
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no differences were noted. In a related publication, Zhu and colleagues examined 126 patients
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who did not receive PCI after R0 resection of SCLC and found that the three-year risk of
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developing brain metastases was about 10% in pathologic stage I patients compared with 19-
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35% in patients with pathologic stage II-III disease.15 Tumors with lymphovascular invasion
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(LVI) were also associated with a higher risk for brain metastasis. These publications suggest
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that the incidence of developing brain metastases in completely resected T1N0 small cell lung
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cancer is lower than that in more advanced SCLC, and as such, the benefit of PCI in this subset
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of patients may be limited. Some studies have, however, suggested a benefit of PCI in patients with limited disease
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SCLC that have been surgically resected. In a retrospective analysis by Bischof and colleagues,
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39 stage I and II SCLC patients received R0 resections, of which 90% received a minimum of 2
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cycles of platinum-based chemotherapy and 46% (18 of 39 patients) received PCI.16 The 5-year
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disease-specific survival was 54%. Brain metastasis-free survival was significantly higher in
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patients receiving PCI (100%) compared to those not receiving PCI (70%), however the study
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did not assess the risk of brain metastasis by stage. Overall survival was improved significantly
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in those who received PCI (p = 0.01), but details regarding the absolute difference in OS were
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not reported. It is unclear from the study whether any selection bias existed in the decision to
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select PCI, such as extent of disease, age, or co-morbidities, which may confound the results
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seen. Furthermore, if we assume that most patients in this cohort did not receive MRI of the
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brain for staging (MRI utilization was not reported in this paper), many likely had subclinical
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intracranial disease that was successfully treated by PCI. Of course, though, all retrospective
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series (including those we cite above that appear to show no benefit for PCI in early stage
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resected SCLC) are potentially subject to bias in how patient management decisions were made,
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and this compromises any attempt to draw conclusions from these works.
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Discussion
The current standard of care for patients with limited-stage small cell lung cancer who obtain a complete response to definitive chemoradiation therapy includes consideration of PCI.
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However, its applicability to “very limited” stage SCLC, a subset of patients with limited disease
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burden amenable to surgical resection and often identified incidentally on radiographic imaging,
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remains unclear. Several retrospective surgical series suggest that the incidence of brain
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metastasis in patients that do not receive PCI is correlated with stage. Because patients with
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stage I disease may have a risk of brain metastasis <10%, these patients may therefore not
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benefit from PCI.
The landmark study that established PCI as standard of care was the Auperin meta-
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analysis, which showed a decrease in incidence of brain metastasis from 59% to 33% with PCI,
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leading to an increase in overall survival of 5.4%. While it is a critical study, the population
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analyzed in the meta-analysis was accrued between 1965 and 1995 and did not have the extent of
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workup typically seen in the modern era and as such, it is unlikely to accurately reflect the
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contemporary population of resectable SCLC. The former group generally did not receive
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staging with PET-CT, or MRI of the brain, and as such, there likely was understaging of disease
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relative to contemporary patients with resectable SCLC. Therefore, the results of the Auperin
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meta-analysis must be carefully applied to current practice patterns—it is highly unlikely that
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patients classified as having early stage SCLC who have undergone PET-CT and MRI for
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staging, particularly those with T1 disease found incidentally on CT screening, have an incidence
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of brain metastasis as high as 59%. Similarly, heterogeneity of MRI use and timing across and
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within studies of resected SCLC confounds and may generally exaggerate the benefit of PCI, as
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many patients in some studies were not staged by MRI, potentially leading to a failure to detect
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subclinical intracranial disease.
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While our review demonstrates that the risk of brain metastasis in select patients with early stage disease treated with surgery without cranial irradiation is low, i.e. < 10% in patients
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with stage I disease, prospective data is needed to confirm this value as well as to assess the
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impact this may have on overall survival. To put the risk of recurrence in context, we can
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compare this data with that seen in prospective studies examining the incidence of brain
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metastasis in NSCLC. In RTOG 0214, the incidence of brain metastasis was 26.8% in those
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with NSCLC that did not receive PCI, compared to 17.3% for those that did receive PCI at 5
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years.22 Despite a relative improvement in brain metastasis risk with PCI, OS did not
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significantly improve (26.1% versus 24.6%). The trial accrued only about one-third of the
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planned 1058 patients, and may have therefore been underpowered to show improvement in OS.
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However, another possible explanation for the lack of OS benefit is that the absolute risk of brain
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metastasis must be higher to yield a survival advantage. If the latter is true, it would be unlikely
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that PCI would confer a sufficient reduction in intracranial metastasis rates to produce a survival
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advantage in this population.
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On the other hand, our review shows that some patients undergoing resection for SCLC
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may be at sufficiently elevated risk of developing brain metastasis such that PCI should not be
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omitted. In such patients with a high risk for intracranial spread, there is limited evidence for
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salvage stereotactic radiosurgery (SRS), as the likelihood of developing additional brain
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metastases is high, and as such therapeutic whole-brain radiotherapy is considered the default. In
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particular, we would feel less confident deferring PCI in those with stage II or higher disease,
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incompletely resected disease, or lymphovascular invasion. Finally, most modern surgical series
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have included patients who receive resection followed by adjuvant chemotherapy—for patients
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who refuse or are unable to receive adjuvant platinum-based chemotherapy due to comorbidity,
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the role of PCI in decreasing intracranial failures should be discussed separately from systemic
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therapy.
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These discussions should include the anticipated morbidities associated with PCI. Several studies have demonstrated that a large fraction of patients receiving standard whole-brain PCI
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will experience neurocognitive sequelae, as measured by quantifiable testing such as the Hopkins
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Verbal Learning Test (HVLT).5,23 For example, in RTOG 0214 looking at PCI in NSCLC, those
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patients that received PCI had a significantly greater decline in immediate recall and delayed
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recall as measured by the HVLT at 1 year compared to those who did not receive PCI. In RTOG
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0212, the higher-dose PCI arm had 25% greater long-term cognitive toxicity compared to
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standard-dose PCI. The standard-dose PCI arm itself (25 Gy in 10 fractions) had a rate of
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neurologic deterioration of 62% at 12 months, implying that even standard doses of PCI can
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result in a majority of patients developing cognitive toxicity. As such, in patients that are
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recommended whole brain radiation, there are ongoing efforts to find ways to shift the
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therapeutic ratio of PCI by lowering the risk of cognitive injury. One such study is the NRG-
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CC003, which is a phase II/III trial randomizing patients with SCLC who demonstrate response
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to initial treatment to standard PCI versus hippocampal-sparing PCI with or without memantine,
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a drug that appears to reduce neuronal excitotoxicity after irradiation. If the results from this
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study are positive, it is possible that the paradigm for SCLC may shift towards using more PCI,
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which may reduce some of the current concern regarding neurocognitive sequelae.
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Conclusions
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Our review of the literature suggests that the incidence of brain metastasis for patients
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with stage I SCLC that have been staged with modern imaging including PET/CT and/or brain
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MRI and treated by complete resection and adjuvant chemotherapy without PCI is likely <10%.
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Strategies deferring PCI may be appropriate in this select population. This may help limit known
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long term cognitive sequelae associated with standard PCI.
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Table Legend
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Table 1. Summary of literature reporting rates of brain metastasis by pathologic stage for
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resected SCLC. **site of first relapse; PCI = prophylactic cranial irradiation; RT = radiotherapy.
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References
287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318
1.
5.
6.
7.
8.
9.
M AN U
TE D
4.
EP
3.
Kalemkerian GP, Akerley W, Bogner P, et al. Small Cell Lung Cancer. J Natl Compr Canc Netw 2013;11(1):78-98. Rudin CM, Ismaila N, Hann CL, et al. Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. Journal of Clinical Oncology 2015;33(34):4106-11. doi:10.1200/JCO.2015.63.7918. Auperin A, Arriagada R, Pignon J-PP, et al. Prophylactic Cranial Irradiation for Patients with Small-Cell Lung Cancer in Complete Remission. Prophylactic Cranial Irradiation Overview Collaborative Group. New England Journal of Medicine 1999;341(7):476-84. doi:10.1056/NEJM199908123410703. 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. European Journal of Cancer 1997;33(11):1752-1758. doi:10.1016/S0959-8049(97)00135-4. Le Péchoux C, Dunant A, Senan S, et al. Standard-Dose versus Higher-Dose Prophylactic Cranial Irradiation (PCI) in Patients with Limited-Stage Small-Cell Lung Cancer in Complete Remission after Chemotherapy and Thoracic Radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a Randomised Clinical Trial. Lancet Oncology 2009;10(5):467-74. doi:10.1016/S1470-2045(09)70101-9. Arriagada R, Le Chevalier T, Riviere A, et al. Patterns of Failure after Prophylactic Cranial Irradiation in Small-Cell Lung Cancer: Analysis of 505 Randomized Patients. Annals of Oncology 2002;13:748-754. doi:http://dx.doi.org/10.1093/annonc/mdf123. Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic Cranial Irradiation for Patients With Small-Cell Lung Cancer in Complete Remission. Journal of the National Cancer Institute 1995;87(3):183-190. doi:10.1093/jnci/87.3.183. Lad T, Piantadosi S, Thomas P, Payne D, Ruckdeschel J, Giaccone G. A Prospective Randomized Trial to Determine the Benefit of Surgical Resection of Residual Disease following Response of Small Cell Lung Cancer to Combination Chemotherapy. Chest 1994;106(6 Suppl):320S-323S. Veronesi G, Bottoni E, Finocchiaro G, Alloisio M. When is Surgery Indicated for SmallCell Lung Cancer? Lung Cancer (Amsterdam, Netherlands) 2015;90(3):582-9. doi:10.1016/j.lungcan.2015.10.019.
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SC
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15.
16.
17.
18.
19.
20.
21.
22.
23.
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14.
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13.
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12.
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Austin JHM, Yip R, D’Souza BM, Yankelevitz DF, Henschke CI. Small-Cell Carcinoma of the Lung Detected by CT Screening: Stage Distribution and Curability. Lung Cancer (Amsterdam, Netherlands) 2012;76(3):339-43. doi:10.1016/j.lungcan.2011.11.017. Combs SE, Hancock JG, Boffa DJ, Decker RH, Detterbeck FC, Kim AW. Bolstering the Case for Lobectomy in Stages I, II, and IIIA Small-Cell Lung Cancer Using the National Cancer Data Base. Journal of Thoracic Oncology 2015;10(2):316-323. doi:10.1097/JTO.0000000000000402. de Hoyos A, DeCamp MM. Surgery for Small Cell Lung Cancer. Thoracic Surgery Clinics 2014;24(4):399-409. doi:10.1016/j.thorsurg.2014.07.005. Yang C-FJ, Chan DY, Speicher PJ, et al. Role of Adjuvant Therapy in a Population-Based Cohort of Patients With Early-Stage Small-Cell Lung Cancer. Journal of Clinical Oncology 2016. doi:10.1200/JCO.2015.63.8171. Gong L, Wang QI, Zhao L, Yuan Z, Li R, Wang P. Factors Affecting the Risk of Brain Metastasis in Small Cell Lung Cancer with Surgery: is Prophylactic Cranial Irradiation Necessary for Stage I-III Disease? International Journal of Radiation Oncology, Biology, Physics 2013;85(1):196-200. doi:10.1016/j.ijrobp.2012.03.038. Zhu H, Bi Y, Han A, et al. Risk Factors for Brain Metastases in Completely Resected Small Cell Lung Cancer: a Retrospective Study to Identify Patients Most Likely to Benefit from Prophylactic Cranial Irradiation. Radiation Oncology (London, England) 2014;9(1):216. doi:10.1186/1748-717X-9-216. Bischof M, Debus J, Herfarth K, et al. Surgery and Chemotherapy for Small Cell Lung Cancer in Stages I-II with or without Radiotherapy. Strahlentherapie und Onkologie 2007;183(12):679-84. doi:10.1007/s00066-007-1740-z. Tsuchiya R, Suzuki K, Ichinose Y, et al. Phase II Trial of Postoperative Adjuvant Cisplatin and Etoposide in Patients with Completely Resected Stage I-IIIa Small Cell Lung Cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). Journal of Thoracic and Cardiovascular Surgery 2005;129(5):977-83. doi:10.1016/j.jtcvs.2004.05.030. Ogawa S, Horio Y, Yatabe Y, et al. Patterns of Recurrence and Outcome in Patients with Surgically Resected Small Cell Lung Cancer. International Journal of Clinical Oncology 2012;17(3):218-24. doi:10.1007/s10147-011-0277-4. Nakamura H, Kato Y, Kato H. Outcome of Surgery for Small Cell Lung Cancer -Response to Induction Chemotherapy Predicts Survival. Thoracic and Cardiovascular Surgeon 2004;52(4):206-10. doi:10.1055/s-2004-821075. Xu J, Yang H, Fu X, et al. Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer. Journal of Thoracic Oncology 2017;12(2):347-353. doi:10.1016/j.jtho.2016.09.133. Zhu H, Guo H, Shi F, et al. Prophylactic Cranial Irradiation Improved the Overall Survival of Patients with Surgically Resected Small Cell Lung Cancer, but not for Stage I Disease. Lung Cancer (Amsterdam, Netherlands) 2014;86(3):334-8. doi:10.1016/j.lungcan.2014.09.019. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of Prophylactic Cranial Irradiation versus Observation in Patients with Locally Advanced Non-Small-Cell Lung Cancer: Primary Analysis of Radiation Therapy Oncology Group Study RTOG 0214. Journal of Clinical Oncology 2011;29(3):272-8. doi:10.1200/JCO.2010.29.1609. Sun A, Bae K, Gore EM, et al. Phase III Trial of Prophylactic Cranial Irradiation
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Compared With Observation in Patients With Locally Advanced Non-Small-Cell Lung Cancer: Neurocognitive and Quality-of-Life Analysis. Journal of Clinical Oncology 2011;29(3):279-286. doi:10.1200/JCO.2010.29.6053.
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Patients (n)
PCI (y/n) Induction
Adjuvant
69
not reported
32/69
41/69
7/69
Tsuchiya17
61
no
0
60/61
0/61
Bischof16
39
0
35/39
no
8/28
Gong14
126
no
51/126
Zhu21
126
no
not reported
Xu20
349
115—yes
not reported
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234—no
16/39
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Stage II
Stage III
7% (2/30)
25% (3/12)
27% (7/26)
11% (4/35)**
38% (3/8)
11% (2/18)
22% (4/18, stages I & II combined)
29% (4/14, both II/III)
21/28
2/28
0% (0/14)
112/126
50/126
6% (2/32)
28% (11/39)
29% (16/55)
126/126
55/126
10%
19%
35% (actuarial risks)
290/349 (at least 4 cycles)
10%—PCI
13%—PCI
14%—PCI
229/349 14%—no PCI
22%—no PCI
28%—no PCI
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Ogawa18
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18—no
Stage I
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Nakamura19
21—yes
Brain Metastasis Rates
Thoracic RT (n)
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Chemotherapy (n) Author
S1525-7304(17)30232-2
DOI:
10.1016/j.cllc.2017.08.004
Reference:
CLLC 693
To appear in:
Clinical Lung Cancer
Received Date: 16 June 2017 Revised Date:
8 August 2017
Accepted Date: 18 August 2017
Please cite this article as: Halthore A, Goenka A, Sharma R, Knisely JPS, Prophylactic Cranial Irradiation for Resectable Small Cell Lung Cancer, Clinical Lung Cancer (2017), doi: 10.1016/ j.cllc.2017.08.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Authors: Aditya Halthore, M.D.1, Anuj Goenka, M.D.1, Rajiv Sharma, M.D.1, Jonathan P.S. Knisely, M.D.2 1
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Department of Radiation Medicine, Northwell Health and Hofstra Northwell School of Medicine, Lake Success, NY 2 Department of Radiation Oncology, Weill Cornell Medicine, New York, NY
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Conflicts of Interest: None
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Corresponding author: Anuj Goenka, M.D. Department of Radiation Medicine Northwell Health 450 Lakeville Road, Lake Success, NY. 11040 Email: [email protected] Tel: (516)321-3000 Fax: (718)470-8445
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Author contributions: AH, AG, RS, and JK were all involved in the writing and editing of the submitted manuscript.
Submission: This material has never been published and is not currently under evaluation in any other peer-reviewed publication. All authors have participated in the review and preparation of this manuscript. There was no funding provided for this work.
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Prophylactic Cranial Irradiation for Resectable Small Cell Lung Cancer
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Abstract Following definitive chemoradiation for small cell lung cancer (SCLC), prophylactic cranial irradiation (PCI) has been established as standard of care in those patients whose tumors
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respond to treatment. In the modern era, however, a subset of patients may receive upfront
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resection for SCLC, yet the role of PCI in these patients has not been elucidated. In this review,
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we examined the literature to better define the role of PCI in this subset of patients. For patients
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with T2 or higher disease, incomplete resection, or those not receiving adjuvant chemotherapy,
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PCI is expected to offer a clinical benefit. For patients with T1 tumors treated with R0 resection,
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however, the rate of intracranial metastasis may be less than 10%. In these patients, deferral of
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PCI may be appropriate as it would avoid known neurocognitive sequelae of cranial irradiation.
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Introduction
Small cell lung cancer (SCLC), its characteristic patterns of spread, and its response to
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chemoradiation have been well studied in clinical trials, and recommendations for management
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have been codified within the National Comprehensive Cancer Network (NCCN) and American
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Society of Clinical Oncology (ASCO) guidelines.1,2 Following definitive chemoradiation for
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SCLC, multiple studies have established prophylactic cranial irradiation (PCI) as a standard of
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care for patients with limited-stage disease who have demonstrated a radiographic response to
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initial treatment.3–5 PCI is able to decrease the rates of central nervous system (CNS) failure in
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patients by sterilizing clinically occult cancer cells that were able to avoid eradication by virtue
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of their location behind the blood-brain barrier.3,6–7 In one landmark meta-analysis of patients
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with limited-stage disease who responded to initial chemoradiation, absolute overall survival
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rates increased by over 5% and relative disease-free survival increased by 25% with PCI.3
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Two-thirds of patients with SCLC present at a relatively advanced, symptomatic stage that historically has precluded surgery as part of the treatment paradigm. Even in those patients
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who present with limited-stage disease, surgery has been avoided largely on the basis of one
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randomized controlled trial published over 20 years ago that showed no improvement with the
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addition of surgery to chemoradiation.8 In the modern era of CT screening of high risk patients
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with smoking histories, however, patients are more frequently presenting with very localized
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limited-stage SCLC when compared to historical cohorts.9 In one analysis by Austin et al., CT
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screening led to a significant shift in the percent of patients diagnosed with stage IA or IB SCLC
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(33% of all SCLC cases diagnosed) when compared to historical controls (7% of all SCLC cases
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diagnosed).10 Associated with the increase in the diagnosis of early lesions, a growing subset of
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patients are being offered definitive surgical resection.10,11 The increased use of definitive
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surgery for patients with T1-2N0M0 SCLC is reflected in the most recently updated versions of
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the NCCN and ASCO guidelines.1,2 However, in this population of patients with very limited
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burden of disease, the optimal role for PCI has not been elucidated. In this review, we examine
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the existing literature regarding the role of PCI in patients with SCLC whose primary tumor has
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been treated by resection. In so doing, we have sought to refine the current NCCN
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recommendations by developing a framework for identifying subgroups of patients with low risk
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of CNS failure who may have reduced benefit from PCI.
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Methods
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The literature search strategy employed entered key terms into the PubMed database to
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identify peer-reviewed, English-language papers published between January 1st, 1980 and April
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1st, 2017, pertaining to resected small cell lung cancer and prophylactic cranial irradiation.
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Search terms included: (1) “small cell lung cancer” AND “surgery” AND (“prophylactic cranial
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irradiation” NOT “non-small” (70 results); “small cell lung cancer” AND “surgery” AND
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“prophylactic cranial irradiation” NOT “non-small” (70 results); (2) “small cell lung cancer”
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AND “surgery” AND “brain metastasis” NOT “non-small” (29 results); (3) “small cell lung
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cancer” AND “resection” AND “brain metastasis” NOT “non-small” (15 results); (4) “small cell
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lung cancer” AND “resection” AND “prophylactic cranial irradiation” NOT “non-small” (18
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results); . Author AH then individually reviewed each paper to eliminate duplicate results,
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results pertaining to NSCLC or other pathologies, and to verify applicability to surgically
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resected SCLC.
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Role of PCI in Surgically Resected Patients
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stage SCLC. Tri-modality therapy fell out of favor following the results of a landmark study
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published in 1994 by Lad et al., which demonstrated that resection did not improve survival
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when added to cyclophosphamide, doxorubicin, and vincristine followed by thoracic radiation
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for limited-stage SCLC.8 However, the applicability of this study to the subset of patients
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established to have cT1-2N0M0 SCLC with modern extent of disease workup including PET-CT
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has been questioned.12
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Surgery has historically not been considered part of the treatment paradigm for limited-
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Over the previous ten years, more published experiences have been reported showing outcomes following definitive surgical resection for SCLC. A retrospective report by Yang et al.
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recently published in the Journal of Clinical Oncology examined 954 patients from the National
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Cancer Data Base (NCDB) with T1-2N0M0 SCLC who had received R0 resection after which
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60% received some form of adjuvant therapy.13 When compared to surgery alone, patients
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receiving adjuvant therapy had a significantly improved 5-year overall survival. The use of PCI,
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however, has not been consistent in this literature (Table 1).13–20 In this same study, the authors
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reported that roughly 10% of the entire cohort received radiotherapy directed to the brain
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(presumed by the authors to be prophylactic), of which the vast majority also received adjuvant
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chemotherapy. No direct comparison was made between those receiving adjuvant chemotherapy
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only and those receiving adjuvant chemotherapy and PCI, but the hazard ratio for improvement
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in 5-year OS when compared to surgery only was lower in the adjuvant chemotherapy/PCI group
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(0.52) than in the chemotherapy alone group (0.78). While the authors do not comment
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specifically on incidence of brain metastasis in cohort subsets, they conclude that their findings
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support the recommendations delineated by the NCCN, that all patients undergoing resection for
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localized, non-disseminated SCLC (i.e. stage T1-2N0M0 disease) should receive adjuvant
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chemotherapy and PCI.
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Gong et al. published a single-institution retrospective review of 126 patients who underwent surgical resection without PCI for SCLC.14 In this study, over 90% of cancers were
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pathologic T1 or T2, 56% were pathologic stage I or II, 47% were SCLC only, and 53% were
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combined SCLC and NSCLC. Pathologic stage III tumors comprised 44% of all cancers and
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61% were pathologically node-positive. Either CT or MRI of the brain were confirmed to be
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negative for metastasis prior to treatment and follow-up included CT or MR of the brain every 3
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months. At 5 years, overall survival for patients with stage I, II, and III disease was 54.8%,
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35.6%, and 14.1%, respectively, and the corresponding incidence of brain metastases was 6.3%,
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28.2%, and 29.1%, respectively. Twenty-nine patients (23%) developed brain metastases during
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the study period. In 22 of these patients (76%), the CNS was the first site of distant recurrence,
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and in 16 patients, the CNS was the only site of distant recurrence. On multivariate analysis,
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pathologic stage and development of brain metastases were found to be independent factors
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predictive of overall survival, while pathologic stage (which is often related to nodal status) and
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completeness of surgical resection were independent factors predictive of brain metastases. The
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brain metastasis rate differed significantly according to whether a complete resection was
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achieved (20.5% with complete resection versus 42.9% with incomplete resection). It is
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important to appreciate that almost half of patients (40.5%) received induction chemotherapy,
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which presumably influenced pathologic staging at the time of surgery. Induction chemotherapy
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was not found to significantly influence survival or brain metastasis rates on multivariate
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analysis. No outcomes based on pre-induction clinical staging were reported. While confirming
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that the risk of brain metastasis correlates with advanced stage, and that the CNS is a primary site
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of isolated failure for a subset of patients, this paper also suggested that the risk of developing
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brain metastasis is less than 10% in patients with stage I disease treated with definitive surgical
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resection and systemic therapy.
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The Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101) was a phase II prospective multi-institutional trial in which 61 patients with stage I to IIIA SCLC received
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complete resection, of which 90% also received at least 2 cycles of adjuvant
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cisplatin/etoposide.17 None of the 61 patients in the study received PCI. With a median follow
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up of 65 months, the authors found that the incidence of brain metastasis was 11.4% for stage I
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patients (4 of 35 patients), as compared to 38% (3 of 8 patients) for stage II patients. The sample
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size was small making accurate determination of intracranial failure rates difficult.
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Xu et al. recently published the largest retrospective analysis of PCI in surgically resected
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SCLC from a single institution.20 In this series of 349 patients with completely resected SCLC,
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115 patients received PCI and 234 did not. A significant majority received adjuvant
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chemotherapy (83.1%). When the two groups (those who received PCI versus those who did
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not) were compared, there was a significant benefit in OS in the PCI cohort (36 months versus 25
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months). PCI improved OS in stage II patients (36 months versus 24 months) and in stage III
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patients (29 months versus 21 months), however there was no statistically significant difference
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in OS among stage I patients (HR 1.61, 95% CI 0.68-3.83). Cerebral recurrence was improved
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in the overall cohort that received PCI (13% versus 23%). Among stage III patients, the cerebral
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recurrence rate was 14% and 28% (p = 0.018) in the PCI and non-PCI groups, respectively. For
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stage II patients, brain metastasis rates were 12.8% versus 22.4% in patients receiving PCI
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versus no PCI, respectively (no significance reported). The brain metastasis rate for stage I
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patients receiving PCI versus no PCI was 10.5% versus 13.6%, respectively (significance not
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reported). Of note, there were no statistically significant differences in time to cerebral
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recurrence between PCI and non-PCI groups among stage I or stage II subsets.
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Zhu et al. in 2014 reported on the role of PCI and brain metastasis rate in 193 patients with R0 resected SCLC, all of whom received adjuvant platinum-based chemotherapy.21
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Exclusion criteria for this single institution retrospective study included R1 or R2 resection, but
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T3 and stage III patients were considered for inclusion. Approximately 1/3 of patients received
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PCI. Statistical analysis did not find any differences in patient characteristics between those that
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received PCI and those that did not in terms of gender, smoking status, KPS, stage, age, and
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number of chemotherapy cycles. PCI appeared to be associated with greater 2- and 5-year
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overall survival and brain metastasis-free survival, except in the subset of stage I patients, where
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no differences were noted. In a related publication, Zhu and colleagues examined 126 patients
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who did not receive PCI after R0 resection of SCLC and found that the three-year risk of
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developing brain metastases was about 10% in pathologic stage I patients compared with 19-
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35% in patients with pathologic stage II-III disease.15 Tumors with lymphovascular invasion
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(LVI) were also associated with a higher risk for brain metastasis. These publications suggest
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that the incidence of developing brain metastases in completely resected T1N0 small cell lung
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cancer is lower than that in more advanced SCLC, and as such, the benefit of PCI in this subset
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of patients may be limited. Some studies have, however, suggested a benefit of PCI in patients with limited disease
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SCLC that have been surgically resected. In a retrospective analysis by Bischof and colleagues,
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39 stage I and II SCLC patients received R0 resections, of which 90% received a minimum of 2
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cycles of platinum-based chemotherapy and 46% (18 of 39 patients) received PCI.16 The 5-year
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disease-specific survival was 54%. Brain metastasis-free survival was significantly higher in
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patients receiving PCI (100%) compared to those not receiving PCI (70%), however the study
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did not assess the risk of brain metastasis by stage. Overall survival was improved significantly
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in those who received PCI (p = 0.01), but details regarding the absolute difference in OS were
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not reported. It is unclear from the study whether any selection bias existed in the decision to
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select PCI, such as extent of disease, age, or co-morbidities, which may confound the results
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seen. Furthermore, if we assume that most patients in this cohort did not receive MRI of the
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brain for staging (MRI utilization was not reported in this paper), many likely had subclinical
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intracranial disease that was successfully treated by PCI. Of course, though, all retrospective
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series (including those we cite above that appear to show no benefit for PCI in early stage
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resected SCLC) are potentially subject to bias in how patient management decisions were made,
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and this compromises any attempt to draw conclusions from these works.
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Discussion
The current standard of care for patients with limited-stage small cell lung cancer who obtain a complete response to definitive chemoradiation therapy includes consideration of PCI.
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However, its applicability to “very limited” stage SCLC, a subset of patients with limited disease
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burden amenable to surgical resection and often identified incidentally on radiographic imaging,
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remains unclear. Several retrospective surgical series suggest that the incidence of brain
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metastasis in patients that do not receive PCI is correlated with stage. Because patients with
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stage I disease may have a risk of brain metastasis <10%, these patients may therefore not
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benefit from PCI.
The landmark study that established PCI as standard of care was the Auperin meta-
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analysis, which showed a decrease in incidence of brain metastasis from 59% to 33% with PCI,
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leading to an increase in overall survival of 5.4%. While it is a critical study, the population
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analyzed in the meta-analysis was accrued between 1965 and 1995 and did not have the extent of
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workup typically seen in the modern era and as such, it is unlikely to accurately reflect the
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contemporary population of resectable SCLC. The former group generally did not receive
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staging with PET-CT, or MRI of the brain, and as such, there likely was understaging of disease
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relative to contemporary patients with resectable SCLC. Therefore, the results of the Auperin
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meta-analysis must be carefully applied to current practice patterns—it is highly unlikely that
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patients classified as having early stage SCLC who have undergone PET-CT and MRI for
227
staging, particularly those with T1 disease found incidentally on CT screening, have an incidence
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of brain metastasis as high as 59%. Similarly, heterogeneity of MRI use and timing across and
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within studies of resected SCLC confounds and may generally exaggerate the benefit of PCI, as
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many patients in some studies were not staged by MRI, potentially leading to a failure to detect
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subclinical intracranial disease.
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While our review demonstrates that the risk of brain metastasis in select patients with early stage disease treated with surgery without cranial irradiation is low, i.e. < 10% in patients
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with stage I disease, prospective data is needed to confirm this value as well as to assess the
235
impact this may have on overall survival. To put the risk of recurrence in context, we can
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compare this data with that seen in prospective studies examining the incidence of brain
237
metastasis in NSCLC. In RTOG 0214, the incidence of brain metastasis was 26.8% in those
238
with NSCLC that did not receive PCI, compared to 17.3% for those that did receive PCI at 5
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years.22 Despite a relative improvement in brain metastasis risk with PCI, OS did not
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significantly improve (26.1% versus 24.6%). The trial accrued only about one-third of the
241
planned 1058 patients, and may have therefore been underpowered to show improvement in OS.
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However, another possible explanation for the lack of OS benefit is that the absolute risk of brain
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metastasis must be higher to yield a survival advantage. If the latter is true, it would be unlikely
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that PCI would confer a sufficient reduction in intracranial metastasis rates to produce a survival
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advantage in this population.
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On the other hand, our review shows that some patients undergoing resection for SCLC
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may be at sufficiently elevated risk of developing brain metastasis such that PCI should not be
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omitted. In such patients with a high risk for intracranial spread, there is limited evidence for
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salvage stereotactic radiosurgery (SRS), as the likelihood of developing additional brain
250
metastases is high, and as such therapeutic whole-brain radiotherapy is considered the default. In
251
particular, we would feel less confident deferring PCI in those with stage II or higher disease,
252
incompletely resected disease, or lymphovascular invasion. Finally, most modern surgical series
253
have included patients who receive resection followed by adjuvant chemotherapy—for patients
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who refuse or are unable to receive adjuvant platinum-based chemotherapy due to comorbidity,
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the role of PCI in decreasing intracranial failures should be discussed separately from systemic
256
therapy.
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These discussions should include the anticipated morbidities associated with PCI. Several studies have demonstrated that a large fraction of patients receiving standard whole-brain PCI
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will experience neurocognitive sequelae, as measured by quantifiable testing such as the Hopkins
260
Verbal Learning Test (HVLT).5,23 For example, in RTOG 0214 looking at PCI in NSCLC, those
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patients that received PCI had a significantly greater decline in immediate recall and delayed
262
recall as measured by the HVLT at 1 year compared to those who did not receive PCI. In RTOG
263
0212, the higher-dose PCI arm had 25% greater long-term cognitive toxicity compared to
264
standard-dose PCI. The standard-dose PCI arm itself (25 Gy in 10 fractions) had a rate of
265
neurologic deterioration of 62% at 12 months, implying that even standard doses of PCI can
266
result in a majority of patients developing cognitive toxicity. As such, in patients that are
267
recommended whole brain radiation, there are ongoing efforts to find ways to shift the
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therapeutic ratio of PCI by lowering the risk of cognitive injury. One such study is the NRG-
269
CC003, which is a phase II/III trial randomizing patients with SCLC who demonstrate response
270
to initial treatment to standard PCI versus hippocampal-sparing PCI with or without memantine,
271
a drug that appears to reduce neuronal excitotoxicity after irradiation. If the results from this
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study are positive, it is possible that the paradigm for SCLC may shift towards using more PCI,
273
which may reduce some of the current concern regarding neurocognitive sequelae.
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Conclusions
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Our review of the literature suggests that the incidence of brain metastasis for patients
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with stage I SCLC that have been staged with modern imaging including PET/CT and/or brain
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MRI and treated by complete resection and adjuvant chemotherapy without PCI is likely <10%.
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Strategies deferring PCI may be appropriate in this select population. This may help limit known
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long term cognitive sequelae associated with standard PCI.
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Table Legend
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Table 1. Summary of literature reporting rates of brain metastasis by pathologic stage for
283
resected SCLC. **site of first relapse; PCI = prophylactic cranial irradiation; RT = radiotherapy.
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References
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Kalemkerian GP, Akerley W, Bogner P, et al. Small Cell Lung Cancer. J Natl Compr Canc Netw 2013;11(1):78-98. Rudin CM, Ismaila N, Hann CL, et al. Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. Journal of Clinical Oncology 2015;33(34):4106-11. doi:10.1200/JCO.2015.63.7918. Auperin A, Arriagada R, Pignon J-PP, et al. Prophylactic Cranial Irradiation for Patients with Small-Cell Lung Cancer in Complete Remission. Prophylactic Cranial Irradiation Overview Collaborative Group. New England Journal of Medicine 1999;341(7):476-84. doi:10.1056/NEJM199908123410703. 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. European Journal of Cancer 1997;33(11):1752-1758. doi:10.1016/S0959-8049(97)00135-4. Le Péchoux C, Dunant A, Senan S, et al. Standard-Dose versus Higher-Dose Prophylactic Cranial Irradiation (PCI) in Patients with Limited-Stage Small-Cell Lung Cancer in Complete Remission after Chemotherapy and Thoracic Radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a Randomised Clinical Trial. Lancet Oncology 2009;10(5):467-74. doi:10.1016/S1470-2045(09)70101-9. Arriagada R, Le Chevalier T, Riviere A, et al. Patterns of Failure after Prophylactic Cranial Irradiation in Small-Cell Lung Cancer: Analysis of 505 Randomized Patients. Annals of Oncology 2002;13:748-754. doi:http://dx.doi.org/10.1093/annonc/mdf123. Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic Cranial Irradiation for Patients With Small-Cell Lung Cancer in Complete Remission. Journal of the National Cancer Institute 1995;87(3):183-190. doi:10.1093/jnci/87.3.183. Lad T, Piantadosi S, Thomas P, Payne D, Ruckdeschel J, Giaccone G. A Prospective Randomized Trial to Determine the Benefit of Surgical Resection of Residual Disease following Response of Small Cell Lung Cancer to Combination Chemotherapy. Chest 1994;106(6 Suppl):320S-323S. Veronesi G, Bottoni E, Finocchiaro G, Alloisio M. When is Surgery Indicated for SmallCell Lung Cancer? Lung Cancer (Amsterdam, Netherlands) 2015;90(3):582-9. doi:10.1016/j.lungcan.2015.10.019.
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2.
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285
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14.
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Austin JHM, Yip R, D’Souza BM, Yankelevitz DF, Henschke CI. Small-Cell Carcinoma of the Lung Detected by CT Screening: Stage Distribution and Curability. Lung Cancer (Amsterdam, Netherlands) 2012;76(3):339-43. doi:10.1016/j.lungcan.2011.11.017. Combs SE, Hancock JG, Boffa DJ, Decker RH, Detterbeck FC, Kim AW. Bolstering the Case for Lobectomy in Stages I, II, and IIIA Small-Cell Lung Cancer Using the National Cancer Data Base. Journal of Thoracic Oncology 2015;10(2):316-323. doi:10.1097/JTO.0000000000000402. de Hoyos A, DeCamp MM. Surgery for Small Cell Lung Cancer. Thoracic Surgery Clinics 2014;24(4):399-409. doi:10.1016/j.thorsurg.2014.07.005. Yang C-FJ, Chan DY, Speicher PJ, et al. Role of Adjuvant Therapy in a Population-Based Cohort of Patients With Early-Stage Small-Cell Lung Cancer. Journal of Clinical Oncology 2016. doi:10.1200/JCO.2015.63.8171. Gong L, Wang QI, Zhao L, Yuan Z, Li R, Wang P. Factors Affecting the Risk of Brain Metastasis in Small Cell Lung Cancer with Surgery: is Prophylactic Cranial Irradiation Necessary for Stage I-III Disease? International Journal of Radiation Oncology, Biology, Physics 2013;85(1):196-200. doi:10.1016/j.ijrobp.2012.03.038. Zhu H, Bi Y, Han A, et al. Risk Factors for Brain Metastases in Completely Resected Small Cell Lung Cancer: a Retrospective Study to Identify Patients Most Likely to Benefit from Prophylactic Cranial Irradiation. Radiation Oncology (London, England) 2014;9(1):216. doi:10.1186/1748-717X-9-216. Bischof M, Debus J, Herfarth K, et al. Surgery and Chemotherapy for Small Cell Lung Cancer in Stages I-II with or without Radiotherapy. Strahlentherapie und Onkologie 2007;183(12):679-84. doi:10.1007/s00066-007-1740-z. Tsuchiya R, Suzuki K, Ichinose Y, et al. Phase II Trial of Postoperative Adjuvant Cisplatin and Etoposide in Patients with Completely Resected Stage I-IIIa Small Cell Lung Cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). Journal of Thoracic and Cardiovascular Surgery 2005;129(5):977-83. doi:10.1016/j.jtcvs.2004.05.030. Ogawa S, Horio Y, Yatabe Y, et al. Patterns of Recurrence and Outcome in Patients with Surgically Resected Small Cell Lung Cancer. International Journal of Clinical Oncology 2012;17(3):218-24. doi:10.1007/s10147-011-0277-4. Nakamura H, Kato Y, Kato H. Outcome of Surgery for Small Cell Lung Cancer -Response to Induction Chemotherapy Predicts Survival. Thoracic and Cardiovascular Surgeon 2004;52(4):206-10. doi:10.1055/s-2004-821075. Xu J, Yang H, Fu X, et al. Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer. Journal of Thoracic Oncology 2017;12(2):347-353. doi:10.1016/j.jtho.2016.09.133. Zhu H, Guo H, Shi F, et al. Prophylactic Cranial Irradiation Improved the Overall Survival of Patients with Surgically Resected Small Cell Lung Cancer, but not for Stage I Disease. Lung Cancer (Amsterdam, Netherlands) 2014;86(3):334-8. doi:10.1016/j.lungcan.2014.09.019. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of Prophylactic Cranial Irradiation versus Observation in Patients with Locally Advanced Non-Small-Cell Lung Cancer: Primary Analysis of Radiation Therapy Oncology Group Study RTOG 0214. Journal of Clinical Oncology 2011;29(3):272-8. doi:10.1200/JCO.2010.29.1609. Sun A, Bae K, Gore EM, et al. Phase III Trial of Prophylactic Cranial Irradiation
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Compared With Observation in Patients With Locally Advanced Non-Small-Cell Lung Cancer: Neurocognitive and Quality-of-Life Analysis. Journal of Clinical Oncology 2011;29(3):279-286. doi:10.1200/JCO.2010.29.6053.
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ACCEPTED MANUSCRIPT
Patients (n)
PCI (y/n) Induction
Adjuvant
69
not reported
32/69
41/69
7/69
Tsuchiya17
61
no
0
60/61
0/61
Bischof16
39
0
35/39
no
8/28
Gong14
126
no
51/126
Zhu21
126
no
not reported
Xu20
349
115—yes
not reported
AC C
234—no
16/39
M AN U
28
Stage II
Stage III
7% (2/30)
25% (3/12)
27% (7/26)
11% (4/35)**
38% (3/8)
11% (2/18)
22% (4/18, stages I & II combined)
29% (4/14, both II/III)
21/28
2/28
0% (0/14)
112/126
50/126
6% (2/32)
28% (11/39)
29% (16/55)
126/126
55/126
10%
19%
35% (actuarial risks)
290/349 (at least 4 cycles)
10%—PCI
13%—PCI
14%—PCI
229/349 14%—no PCI
22%—no PCI
28%—no PCI
TE D
Ogawa18
EP
18—no
Stage I
SC
Nakamura19
21—yes
Brain Metastasis Rates
Thoracic RT (n)
RI PT
Chemotherapy (n) Author