ORIGINAL ARTICLE Compliance and Outcome of Elderly Patients Treated in the Concurrent Once-Daily Versus Twice-Daily Radiotherapy (CONVERT) Trial Marianna Christodoulou, MRCP, MRes,a Fiona Blackhall, MD, PhD,b Hitesh Mistry, PhD,a,b Ahmet Leylek, PhD,c Joost Knegjens, MD,d Vincent Remouchamps, MD, PhD,e Isabelle Martel-Lafay, MD,f Núria Farré, MD,g Matjaz Zwitter, MD, PhD,h Delphine Lerouge, MD,i Nicolas Pourel, MD,j Henri Janicot, MD,k Arnaud Scherpereel, MD, PhD,l Caroline Tissing-Tan, MD,m Karin Peignaux, MD,n Xavier Geets, MD, PhD,o Krzysztof Konopa, MD, PhD,p Corinne Faivre-Finn, MD, PhDa,b,* a Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom b Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK c CancerCare Manitoba, Winnipeg, Canada d The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands e CHU UCL Namur, site Ste Elisabeth, Namur, Belgium f Centre Léon Bérard, Lyon, France g Hospital de la Santa Creu i Sant Pau, Barcelona, Spain h Institute of Oncology, Ljubljana, Slovenia i Centre François Baclesse, Caen, France j Institut Sainte-Catherine, Avignon, France k CHU Gabriel Montpied, Clermont-Ferrand, France l Hospital of the University (CHRU) of Lille, Lille, France m Radiotherapiegroep, Arnhem, Netherlands n Georges Francois LECLERC Center, Dijon, France o Cliniques universitaires Saint-Luc, MIRO-IREC-UCL, Brussels, Belgium p Medical University of Gdansk, Gdansk, Poland Received 31 July 2018; revised 20 September 2018; accepted 26 September 2018 Available online - 31 October 2018 ABSTRACT 70–82). Fewer older patients received the optimal number of radiotherapy fractions (73% versus 85%; p ¼ 0.03); Introduction: There is a lack of data on the efficacy and however, chemotherapy compliance was similar in both safety of concurrent chemoradiotherapy in elderly, limited- stage, patients with SCLC. Methods: We compared outcomes of patients 70 years of *Corresponding author. age or older versus younger patients within the Concurrent Disclosure: Dr. Tissing-Tan has a spouse who is employed by Sirtex Medical. Dr. Faivre-Finn has received grants from Cancer Research Once-daily Versus twice-daily RadioTherapy (CONVERT) UK. The remaining authors declare no conflict of interest. trial. Patients were randomized to receive 45 Gy/30 twice- Presented at the IASLC 17th World Conference on Lung Cancer in daily fractions/19 days or 66 Gy/33 once-daily fractions/45 Vienna, Austria, December 4-7, 2016; and the abstract has been awarded the Heine Hansen Lectureship Award. days concurrently with platinum-based chemotherapy. Address for correspondence: Corinne Faivre-Finn, MD, PhD, Division of Overall survival and progression-free survival were evalu- Molecular and Clinical Cancer Sciences, University of Manchester, The ated using Kaplan-Meier methodology and Cox proportional Christie NHS Foundation Trust, Wilmslow Road, M20 4BX, United Kingdom. E-mail: corinne.finn@christie.nhs.uk hazards regression. ª 2018 International Association for the Study of Lung Cancer. Results: Of 547 patients randomized between April 2008 Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). and November 2013, 57 did not receive protocol treatment ISSN: 1556-0864 and were excluded. Of the 490 patients included, 67 (14%) https://doi.org/10.1016/j.jtho.2018.09.027 were 70 years of age or older (median age: 73 years; range: Journal of Thoracic Oncology Vol. 14 No. 1: 63-71 64 Christodoulou et al Journal of Thoracic Oncology Vol. 14 No. 1 groups (p ¼ 0.24). Neutropenia grade 3/4 occurred more good performance status LS-SCLC. Despite no signifi- frequently in the elderly (84% versus 70%; p ¼ 0.02) but cant difference in outcomes in the twice-daily and rates of neutropenic sepsis (4% versus 7%; p ¼ 0.07) and once-daily radiotherapy arms in the CONVERT trial, death (3% versus 1.4%; p ¼ 0.67) were similar in both survival rates in both arms were higher than previ- groups. With a median follow-up of 46 months; median ously reported.6,8 Severe toxicity was less compared to survival in the elderly versus younger groups was 29 (95% that reported in the Intergroup 0096 trial, particularly confidence interval [CI]: 21–39) versus 30 months (95% CI: radiation esophagitis.6,8 The improved outcomes were 26–35), respectively; (hazard ratio: 1.15, 95% CI: 0.84– thought to reflect advances in staging and supportive 1.59; p ¼ 0.38). Median time to progression in the elderly management of LS-SCLC in the last 2 decades, along- versus younger groups was 18 months (95% CI: 13–31) side the use of modern radiotherapy techniques. versus 16 months (95% CI: 14–19), respectively (hazard The optimal treatment for older patients with LS- ratio: 1.04, 95% CI: 0.76–1.41; p ¼ 0.81). SCLC is not established. The prognostic role of age re- Conclusions: Concurrent chemoradiotherapy with modern mains unclear with conflicting results from retrospective radiotherapy techniques should be a treatment option for studies.9-15 Corso et al.16 recently showed an overall fit, older patients. survival (OS) benefit of 6.3 months with modern che-  2018 International Association for the Study of Lung moradiotherapy in a population-based analysis of 8637 Cancer. Published by Elsevier Inc. This is an open access patients aged 70 years or older with LS-SCLC. However, article under the CC BY license (http://creativecommons. there is a lack of high-level evidence to guide treatment org/licenses/by/4.0/). in older patients as a result of their under- representation in clinical trials.17,18 Consequently, and also due to concerns regarding increased treatment- Keywords: SCLC; Limited stage; Radiotherapy; Elderly; related toxicity, or poorer tolerance of treatment- Chemotherapy related toxicity, older patients are less likely to receive standard of care treatment with the potential risk of under-treatment.19 Introduction In this analysis, we aimed to evaluate the outcomes of Lung cancer is a disease of the elderly with a older patients randomized to the CONVERT trial to median age of 71 years at diagnosis.1 Up to 13% of all inform treatment decisions in older patients in the era of lung cancer diagnoses are SCLC and of those 30% are modern chemoradiotherapy. defined as limited-stage disease (LS-SCLC) or stage I- III according to TNM classification.2-4 The prognosis of LS-SCLC is poor despite optimal treatment.2,3 The Materials and Methods current standard of care for fit patients with LS-SCLC Trial Design is thoracic radiotherapy delivered concurrently with Details of the trial design have been published previ- platinum doublet chemotherapy followed by prophy- ously.8 Briefly, the CONVERT trial was an international, lactic cranial irradiation (PCI) in patients without multicenter, phase III randomized controlled trial. The progressive disease.5 The optimal radiotherapy timing main eligibility criteria were: age 18 years of age or older; and schedule was investigated in the landmark Inter- Eastern Cooperative Oncology Group performance status group 0096 study which showed improved survival (PS) 0-1 (on a scale of 0 to 5, with 0 indicating no with twice-daily concurrent chemoradiotherapy (45 symptoms and higher numbers reflecting greater Gy/30 fractions over 3 weeks) compared to once-daily disability),20 patients with PS 2 due to disease-related treatment (45 Gy/25 fractions over 5 weeks) at the symptoms and not comorbidities; maximum of one of expense of higher rates of severe esophagitis.6 the following adverse biochemical factors: serum alkaline Following the Intergroup 0096 trial results in the phosphatase more than 1.5 times the upper limit of late 1990s, concerns regarding toxicity, the low dose normal, serum sodium less than the lower limit of normal, of radiotherapy used in the once-daily arm, and serum lactate dehydrogenase more than the upper limit logistical issues surrounding the delivery of twice-daily of normal. Patients were randomized to receive either radiotherapy resulted in its poor adoption in routine twice-daily radiotherapy (45 Gy/30 twice-daily fractions clinical practice.7 The CONVERT trial compared twice- over 19 days) or once-daily radiotherapy (66 Gy/33 daily daily to once-daily concurrent chemoradiotherapy in fractions over 45 days) concurrently with chemotherapy. the era of modern conformal radiotherapy in LS-SCLC.8 Radiotherapy commenced on day 22 of cycle 1. Three- The results showed no significant difference in sur- dimensional conformal radiotherapy was mandatory vival and toxicity between the two groups establishing and elective nodal irradiation was not permitted. twice-daily radiotherapy as the standard of care in Staging with positron-emission tomography – computed January 2019 Elderly Patients Treated in the CONVERT Trial 65 tomography and the use of intensity-modulated radio- treatment according to the Common Terminology therapy were permitted but not mandated. A radio- Criteria for Adverse Events [version 3.0])21; and therapy quality assurance program was set up, the details treatment compliance. OS and PFS were estimated of which have been reported previously.8 Chemotherapy using the Kaplan-Meier method and compared using consisted of 4 to 6 cycles of cisplatin and etoposide the log-rank test. Age groups were compared using every 3 weeks in both groups (etoposide 100 mg/m2 Pearson chi-squared and Fisher’s exact tests where intravenously on days 1–3 and cisplatin 75 mg/m2 appropriate and continuous variables were compared intravenously on day 1 or cisplatin 25 mg/m2 intrave- using Mann-Whitney tests. The statistical analysis was nously on days 1–3 of the cycle). Each center elected to performed using Stata 13.1. prescribe 4 or 6 cycles for all their trial patients. Patients without evidence of progressive disease on computed tomography scan and with no clinical evidence of brain Results metastases were offered PCI no later than 6 weeks Patients following the last cycle of chemotherapy. There was no Between April 2008 and November 2013, 547 pa- upper age limit in the CONVERT trial. tients were randomized to the CONVERT trial. For the Patients were followed-up for 5 years after treat- purposes of the age-subgroup analysis, 57 patients (32 ment. All participants gave written informed consent to from the once-daily and 25 from the twice-daily treat- participate and the study was conducted according to ment arm, respectively) were excluded because they the Declaration of Helsinki and Good Clinical Practice did not receive protocol treatment; 46 did not receive Guidelines. The protocol was approved by the institu- any radiotherapy, 10 received sequential radiotherapy, tional review board or the research ethics committee at and 1 patient received palliative radiotherapy (Fig. 1). each study center. More older patients were excluded from this analysis compared to their younger counterparts (20% versus 9%, respectively). Outcomes and Statistical Analysis Of the 490 patients included in this analysis, 67 The outcomes of the age-subgroup analysis were (14%) were aged 70 years or older with a median age OS (defined as the time from randomization until of 73 years (range: 70–82 years). There were 21 pa- death from any cause); progression-free survival (PFS) tients aged 75 years or older and 4 patients aged 80 measured from randomization to the first date of any years or older. The median age of the younger group local or metastatic disease or, if missing, date of death; was 60 years (range: 29–70 years). Among the pa- acute toxicity (defined as toxicity occurring between tients 70 years or older, 29 (43%) and 38 (57%) were the start and up to 3 months after completion of randomized to the twice-daily and once-daily Figure 1. Patient allocation to age groups. 66 Christodoulou et al Journal of Thoracic Oncology Vol. 14 No. 1 Table 1. Patients’ Characteristics at Baseline per Age Group Table 1. Continued Age Group Age Group <70 (%) 70 (%) <70 (%) 70 (%) n ¼ 423 n ¼ 67 p Value n ¼ 423 n ¼ 67 p Value Age (years) Smoking historya Median (range) 60 (29–70) 73 (70–82) Never 5 (1) 0 (0) 0.003 Treatment Ex-smoker 257 (61) 55 (82) BD 220 (52) 29 (43) 0.180 Current 161 (38) 12 (18) OD 203 (48) 38 (57) GTV (mL) n ¼ 413 n ¼ 65 Sex Median (range) 81.6 (0.5-635.1) 93.4 (6.3-436.4) 0.390 Male 225 (53) 46 (69) 0.020 a Never smokers: adults who have never smoked a cigarette or who smoked Female 198 (47) 21 (31) fewer than 100 cigarettes in their entire lifetime; former smokers: adults ECOG PS who have smoked at least 100 cigarettes in their lifetime, but say they currently do not smoke; current smokers: adults who have smoked 100 0 198 (47) 29 (43) 0.840 cigarettes in their lifetime and currently smoke cigarettes every day (daily) 1 211 (50) 36 (54) or some days (nondaily). 2 14 (3) 2 (3) BD, twice daily; ECOG, Eastern Cooperative Oncology Group; GTV, gross MRC dyspnea score40 tumor volume; LDH, lactate dehydrogenase; LLN, lower limit of normal; 0 160 (38) 19 (28) 0.259 MRC, Medical Research Council; OD, once daily; PCI, prophylactic cranial irradiation; PET-CT, Positron-emission tomography–computed tomography; 1 142 (34) 29 (43) PS, performance status; UICC, Union for International Cancer Control; AJCC, 2 56 (13) 10 (15) American Joint Committee on Cancer; ULN, upper limit of normal. 3 36 (9) 2 (3) 4 3 (1) 1 (1) Weight loss in the two older patients with a PS of 2; one was random- last 6 months ized to the twice-daily treatment arm, and one to the No change 269 (64) 46 (69) 0.200 <5% 67 (16) 12 (18) once-daily arm. 5%–10% 43 (10) 1 (1) >10% 16 (4) 4 (6) Treatment Delivered Not known 28 (6) 4 (6) UICC/AJCC stage4 The majority of patients received 4 chemotherapy I-II 69 (16) 13 (20) 0.430 cycles (64% elderly versus 63% younger) with no sig- III 331 (78) 52 (78) nificant difference in those who received less than 4 Not known 23 (5) 2 (3) compared to 4 or more cycles in the two groups (p ¼ Serum alkaline phosphatase 0.24). A similar number of older compared to younger ULN  1.5 415 (98) 65 (97) 0.560 patients received 5 or 6 chemotherapy cycles (21% >ULN  1.5 8 (2) 2 (3) versus 26%, respectively, p ¼ 0.48). Radiotherapy Serum sodium compliance was worse in the elderly with significantly LLN 344 (81) 52 (78) 0.470 fewer patients receiving the optimal number of fractions ULN 102 (24) 14 (21) completed radiotherapy within the optimal treatment Not known 3 (1) 2 (3) time defined in the protocol (19 to 21 days in the twice- PCI daily and 45 to 47 days in the once-daily groups, No 42 (10) 7 (11) 0.870 respectively), but this did not reach statistical signifi- Yes 379 (90) 59 (89) cance (41 (61%) older versus 298 (71%) younger pa- PET-CT staging No 183 (43) 25 (37) 0.600 tients, respectively; p ¼ 0.153) (Table 2).8 Yes 239 (57) 42 (63) In the twice-daily radiotherapy arm, 19 of 29 older pa- Not known 1 (<1) 0 (0) tients (66%) completed chemotherapy compared to 23 of (continued) 38 older patients (61%) in the once-daily arm. A similar proportion of elderly patients received more than 30 frac- radiotherapy arms, respectively. Baseline characteris- tions of radiotherapy as per protocol in both treatment tics (Table 1) were well balanced apart from more arms: 22 (76%) and 27 patients (71%) in the twice-daily male patients (p ¼ 0.02) and ex-smokers (p ¼ 0.003) and once-daily radiotherapy arms, respectively (Table 2). in the elderly group. There were no statistically sig- Of the 21 patients older than 75 years, 11 did not nificant differences in PS or dyspnea score among the complete their planned chemotherapy and 4 did not two age groups (Table 1). Notably, there were only receive the intended radiotherapy. All 4 patients who January 2019 Elderly Patients Treated in the CONVERT Trial 67 Table 2. Radiotherapy Compliance per Age Group Dose (Gy) No. Fractions Overall Treatment Time (days) Arm (N) n (%) n (%) n (%) BD (249) <44 44-46 >46 <28 28-29 30 >30 <19 19 20-21 >21 <70 (220) 1 (0.4) 216 (98) 3 (1) 10 (5) 18 (8) 191 (87) 1 (0.4) 11 (5) 143 (65) 19 (9) 47 (21) 70 (29) 0 (0) 29 (100) 0 (0) 2 (7) 5 (17) 22 (76) 0 (0) 4 (14) 15 (52) 5 (17) 5 (17) OD (240) <60 60-62 64-68 <30 30-32 33 >33 <45 45 46-47 >47 <70 (202) 17 (8) 16 (8) 169 (84) 13 (6) 23 (11) 165 (82) 1 (0.5) 31 (15) 98 (49) 38 (19) 35 (17) 70 (38) 5 (13) 3 (8) 30 (79) 3 (8) 8 (21) 27 (71) 0 (0) 10 (26) 16 (42) 5 (13) 7 (18) BD, twice-daily; OD, once-daily. were 80 years or older completed radiotherapy; how- or distal disease progression was 18 months (95% CI: ever, only 1 completed their planned chemotherapy. 13–31) in the elderly and 16 months (95% CI: 14–19) in A similar proportion of patients in both groups the younger group (HR for PFS: 1.04, 95% CI: 0.76–1.41; received PCI: 59 (88%) versus 377 (89%) in the elderly p ¼ 0.81) (Fig. 2B). Two-year and OS rates were similar and younger groups, respectively, including two older independent of treatment arm in elderly patients: 30 patients older than 80 years. months (95% CI: 22–not reached) and 55% (95% CI: Thirty-seven of 57 patients who were excluded from 36–71), respectively, in the twice-daily group and 26 this analysis due to treatment protocol violations did not months (95% CI: 19–not reached) and 49% (95% CI: complete chemotherapy. Within the same group, only 2 31–64), respectively, in the once-daily group (HR for OS: of 10 patients who received sequential radiotherapy 0.97, 95% CI: 0.53–1.76; p ¼ 0.91) (Fig. 3). The median completed treatment. OS and PFS for the protocol violation group was 11 months (95% CI: 8–17) and 7 months (95% CI: 5–12) respectively. Survival With a median follow-up of 46 months; 2-year sur- vival was 53% (95% confidence interval [CI]: 41–64) in Acute Toxicity the elderly and 57% (95% CI: 52–61) in the younger Table 3 summarizes the rates of grade 3/4 acute group. Median survival was 29 months (95% CI: 21–39) toxicity. Older patients suffered from significantly more in the elderly and 30 months (95% CI: 26–35) in the neutropenia (84% versus 70%, p ¼ 0.02) and throm- younger group (hazard ratio [HR] for OS: 1.15, 95% CI: bocytopenia (28% versus 18%, p ¼ 0.05) compared to 0.84–1.59; p ¼ 0.38) (Fig. 2A). The median time to local their younger counterparts. However, this did not Figure 2. Kaplan-Meier curves for (A) overall survival and (B) progression-free survival for elderly (dashed red line) and younger (blue line) groups. Hazard ratios (HRs), 95% confidence intervals (Cis), p values, and number of patients at risk against yearly intervals are shown. 68 Christodoulou et al Journal of Thoracic Oncology Vol. 14 No. 1 Table 4. Acute Grade 3/4 Toxicity in Patients 75 Years Old 75, n (%) Acute G3/4 Toxicity N ¼ 21 Neutropenia 16 (76) Neutropenic sepsis 1 (5) Infection 2 (10) Thrombocytopenia 6 (29) Radiation pneumonitis 1 (5) Esophagitis 5 (24) Vomiting 2 (10) or older developed significant toxicity: one patient experienced grade 3 esophagitis; one patient experi- enced grade 4 leucopenia and grade 3 urinary infection; one patient experienced grade 4 neutropenia, grade 2 pulmonary edema, and grade 3 cardiac ischemic infarc- tion; and one patient died from peripheral arterial ischemia, pancytopenia, and neutropenic sepsis. Grade 3/4 acute toxicity in elderly patients in the Figure 3. Kaplan-Meier curves for overall survival for elderly twice-daily radiotherapy group (n ¼ 29) and once-daily patients who received twice-daily (BD) (dashed red line) or radiotherapy group (n ¼ 38) was recorded as: radiation once-daily (OD) radiotherapy (blue line). Hazard ratios (HRs), 95% confidence intervals (Cis), p values and number of pneumonitis 0 (0%) versus 2 (5%), esophagitis 4 (14%) patients at risk against yearly intervals are shown. versus 9 (24%), neutropenic sepsis 3 (10%) versus 0 (0%), thrombocytopenia 10 (34%) versus 9 (23%), and vomiting 2 (7%) versus 0 (0%), respectively. translate into higher rates of neutropenic sepsis (4% There were eight treatment-related deaths, two in the versus 7%; p ¼ 0.07), hospitalization (duration of elderly and six in the younger group (3% versus 1.4%, inpatient stay in days, median [range]; 0 [0–42] versus p ¼ 0.67). In the elderly group, one patient died from 0 [0–50]; p ¼ 0.21), and transfusion of red blood cells neutropenic sepsis and one from dementia attributed to (43% versus 34%; p ¼ 0.14) or of platelets (9% versus PCI. In the younger group, causes of death included 6%; p ¼ 0.39) in the elderly and younger groups, neutropenic sepsis in two patients, radiation pneumo- respectively. The rates of grade 3/4 radiation esophagitis nitis in two patients, sepsis in one patient, and bronchial (19% versus 20%; p ¼ 0.870) and grade 3/4 pneumo- pneumonia in one patient. There were seven cardiovas- nitis (3% versus 2%; p ¼ 0.31) were similar in the cular deaths in the younger group and none in the elderly and younger groups, respectively. elderly group. In the group older than 75 years (n ¼ 21), acute In the protocol violation group (n ¼ 57), none of the grade 3/4 radiation pneumonitis was reported in one patients developed grade 3/4 radiation pneumonitis or patient (5%), grade 3/4 esophagitis in five patients esophagitis. Twenty-one patients (37%) developed acute (24%), grade 3/4 neutropenic sepsis in one patient grade 3/4 neutropenia, five patients (9%) grade 3/4 (5%), and grade 3/4 vomiting in two patients (10%) as infection, three patients (5%) grade 3/4 neutropenic shown in Table 4. All four patients aged 80 years of age sepsis, three patients (5%) grade 3/4 thrombocytopenia, and two patients (4%) grade 3/4 vomiting. Table 3. Acute Grade 3/4 Toxicity per Age Group <70, n (%) 70, n (%) Discussion Acute Grade 3/4 Toxicity N ¼ 423 N ¼ 67 p Value In this study, we report the results of the age- subgroup analysis of the CONVERT trial, the largest Neutropenia 293 (70) 56 (84) 0.020 Neutropenic sepsis 29 (7) 3 (4) 0.070 chemoradiotherapy randomized trial to date in LS-SCLC. Infection 49 (12) 9 (13) 0.670 The results showed comparable survival and toxicity Thrombocytopenia 77 (18) 19 (28) 0.050 between older and younger patients who participated in Radiation pneumonitis 6 (2) 2 (3) 0.310 the trial. We defined older patients as those aged Esophagitis 85 (20) 13 (19) 0.870 70 years or more as this cutoff has been commonly used Vomiting 22 (5) 2 (3) 0.070 as the age limit for entry into lung cancer clinical trials. January 2019 Elderly Patients Treated in the CONVERT Trial 69 Trial data to inform treatment decisions in this pa- very little data to guide the management of octogenar- tient group are limited and more than 10 years old. A ians with LS-SCLC. Most of the evidence comes from phase II trial of concurrent accelerated hyper- small retrospective series evaluating outcomes in pa- fractionated radiotherapy (1.5 Gy/fraction twice daily to tients with both limited- and extensive-stage disease, a total dose of 45 Gy) and carboplatin/etoposide often treated with chemotherapy alone and with limited chemotherapy showed a median survival of 15 months, toxicity outcomes.33-35 Because of the small number of 5-year survival of 13%, and tolerable toxicity in 72 fit octogenarians in the CONVERT trial, we cannot draw any patients with LS-SCLC aged 70 years or more.22 Analysis firm conclusions on the appropriate management of of the Surveillance, Epidemiology and End Results – these patients; however, given the high rates of observed Medicare data from 565 patients who were older than toxicity in this analysis, this should be further investi- 65 years between 1992 and 2007 showed similar sur- gated in larger studies. vival with the use of concurrent chemoradiotherapy with In this analysis, chemotherapy compliance was not cisplatin/etoposide compared to carboplatin/etoposide different in the two age groups, even in patients who (median survival 13.8% versus 13.7%, respectively).23 received more than 4 cycles of chemotherapy. Fewer Apart from the CONVERT trial, the only other age- older patients completed the optimal number of radio- group analysis from a randomized controlled trial therapy fractions; however, radiotherapy compliance investigating concurrent chemoradiotherapy in LS-SCLC was greater than 70% in the elderly with low rates of (Intergroup 0096) showed similar survival outcomes radiation pneumonitis and esophagitis, indicating that between age groups. However, worse hematological radiotherapy, even when administered in a twice-daily toxicity and treatment-related mortality was reported in schedule, is well tolerated by older patients. In the patients older than the age of 70 years compared to their Intergroup 0096 study, more older patients failed to younger counterparts.24 complete 4 cycles of chemotherapy compared to their In CONVERT, hematological toxicity was higher in the younger counterparts, although radiotherapy compli- elderly but there was no increased risk of neutropenic ance was not reported. There were more older patients sepsis or hospitalization. In contrast to the Intergroup with a PS of 2 (10%) in the Intergroup 0096 study 0096 trial, fatal toxicity was similar in the two age compared to CONVERT (3%), which could have groups of the CONVERT trial, probably reflecting contributed to the lower treatment compliance. In the reduced rates of toxicity with the use of advanced CONVERT trial, the two patients in the elderly group radiotherapy techniques. However, the small group of with a PS of 2 (aged 76 and 73 years, respectively) patients aged 80 years or older in the trial experienced completed treatment as per protocol, suggesting that severe toxicity including one treatment-related death treatment completion could be feasible in less fit pa- reported as dementia from PCI. In a meta-analysis of tients, although the small number of patients prevents 2140 patients with SCLC, Pignon et al.25 showed any meaningful conclusions. More older compared to improved survival outcomes with chemoradiotherapy younger patients were excluded from the analysis (concurrent, sequential, or alternating) compared to because they did not receive protocol treatment. This chemotherapy alone in patients younger than 70 years, could be due to a number of reasons, including more but this was not shown in older patients (relative risk of aggressive disease and concerns regarding increased death: 1.07, 95% CI: 0.70–1.64). Although the benefit of treatment-related complications in the elderly who PCI to OS and intracranial recurrence is well established generally have a higher comorbidity burden. in SCLC, data on the efficacy and safety of PCI in elderly Our results are particularly relevant as robust evi- patients with LS-SCLC are lacking.26,27 Early studies dence to guide treatment decisions in elderly LS-SCLC report age (older than 60 years) as a factor associated patients is lacking. The large retrospective analysis by with increased risk for acute and chronic neurotoxicity Corso et al.16 is the only other recent study that inves- following PCI, the concurrent administration of chemo- tigated outcomes of older patients (aged 70 years or therapy with PCI, and a PCI dose greater than 30 Gy.28-30 older) with LS-SCLC following chemoradiotherapy A retrospective analysis of 1926 elderly (aged 70 years showing a survival benefit of chemoradiotherapy or older) LS-SCLC patients using the Surveillance, compared to chemotherapy alone (OS 15.6 months Epidemiology and End Results database showed that the versus 9.3 months, respectively, p < 0.001).16 However, survival benefit of PCI is maintained for patients older this population-based study did not report on toxicity. than 70 years, although no toxicity data were pre- This analysis is associated with a number of limitations sented.31 A more recent analysis of a cohort of 151 pa- that restrict the generalizability of the results to elderly tients aged 70 years or older who were treated with PCI patients treated in routine clinical practice. Firstly, at the MD Anderson Center showed no survival advan- despite the absence of an upper age limit in the trial, tage in patients with tumors 5 cm or larger.32 There are only a small group of patients (14%) were older than the 70 Christodoulou et al Journal of Thoracic Oncology Vol. 14 No. 1 age of 70 years. Secondly, all patients except two in the design. None of the funders had any role in the collec- elderly cohort had a PS of 0-1. These criteria only apply tion, analysis and interpretation of data, in the writing of to a small proportion of elderly patients with LS-SCLC, the report, and in the decision to submit the article for which highlights the need for adequately powered, publication. The authors thank the National Cancer elderly-specific clinical trials or for population-based Research Institute Radiotherapy Trials Quality Assur- studies which may be more representative of the pa- ance team (Nicki Groom and Elena Wilson) for their tients seen in the routine setting. Thirdly, due to the support, the Manchester Clinical Trials Unit and all the small numbers of patients who are 75 years or older and investigators at the participating sites, and Sally Falk for 80 years or older, preventing any meaningful statistical editorial assistance. comparisons, we only provide summary statistics for treatment compliance and toxicity; therefore, the results References should be interpreted with caution. 1. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in More recently, there has been interest in investi- elderly patients: an analysis of the surveillance, epide- gating physiological or functional parameters rather miology, and end results database. J Clin Oncol. than chronological age in treatment decisions. However, 2007;25:5570–5577. 2. Khakwani A, Rich AL, Tata LJ, et al. Small-cell lung there is still a lack of consensus on the definition of cancer in England: trends in survival and chemotherapy “elderly” patients. 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The NSCLC based on the CGA showed no difference in sur- IASLC Lung Cancer Staging Project: proposals regarding vival. However, patients experienced significantly less the relevance of TNM in the pathologic staging of small toxicity of any grade in the CGA arm.37 Disappointingly, cell lung cancer in the forthcoming (seventh) edition of prescreening methods for frailty that could differentiate the TNM classification for lung cancer. J Thorac Oncol. 2009;4:1049–1059. fit patients able to receive standard of care treatment 5. Rudin CM, Ismaila N, Hann CL, et al. Treatment of from those who would benefit from a CGA to personalize small-cell lung cancer: American Society of Clinical treatment have failed to show efficacy.38 Further Oncology endorsement of the American College of research is required to evaluate the utility of these tools Chest Physicians guideline. J Clin Oncol. 2015;33:4106– in clinical practice.39 4111. In conclusion, concurrent chemoradiotherapy with 6. 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