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Journal of Clinical Oncology, Vol 26, No 24 (August 20), 2008: pp. 4001-4011 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.3312
Palliative Thoracic Radiotherapy for Lung Cancer: A Systematic Review
From the Cross Cancer Institute, Edmonton, Alberta; Odette Cancer Centre, Sunnybrook Health Sciences Centre; Princess Margaret Hospital, Toronto, Ontario, Canada; and the Blanchard Valley Regional Cancer Centre, Findlay, OH Corresponding author: Alysa Fairchild, MD, FRCPC, Department of Radiation Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2 Canada; e-mail: alysafai{at}cancerboard.ab.ca
Purpose The optimal dose of radiotherapy (RT) to palliate symptomatic advanced lung cancer is unclear. We systematically reviewed randomized controlled trials (RCTs) of palliative thoracic RT. Methods RCTs comparing two or more dose fractionation schedules were reviewed using the random-effects model of a freely available information management system. The relative risk and 95% CI for each outcome were presented in Forrest plots. Exploratory analysis comparing dose schedules after conversion to the time-adjusted biologically equivalent dose (BED) was performed to investigate for a dose-response relationship. Results A total of 13 RCTs involving 3,473 randomly assigned patients were identified. Outcomes included symptom palliation, overall survival, toxicity, and reirradiation rate. For symptom control in assessable patients, lower-dose (LD) RT was comparable with higher-dose (HD), except for the total symptom score (TSS): 65.4% of LD and 77.1% of HD patients had improved TSS (P = .003). Greater likelihood of symptom improvement was seen with schedules of 35 Gy10 versus lower BED. At 1 year after HD and LD RT, 26.5% versus 21.7% of patients were alive, respectively (P = .002). Sensitivity analysis suggests this survival improvement was seen with 35 Gy10 BED schedules compared with LDs. Physician-assessed dysphagia was significantly greater in the HD arm (20.5% v 14.9%; P = .01), and the likelihood of reirradiation was 1.2-fold higher after LD RT. Conclusion No significant differences were observed for specific symptom-control end points, although improvement in survival favored HD RT. Consideration of palliative thoracic RT of at least 35 Gy10 BED may therefore be warranted, but must be weighed against increased toxicity and greater time investment.
The majority of patients who present with locally advanced or metastatic lung cancer are treated with palliative intent,1 with the goals of relief of pain and other symptoms, and preservation of quality of life (QoL).2-3 Palliative-intent radiotherapy (RT) is effective for improvement of symptoms resulting from intrathoracic disease, such as hemoptysis, cough, chest pain, dyspnea, and airway obstruction,1,4-6 and in approximately one third of patients, improves global QoL.7 However, the optimal dose of RT needed to palliate symptoms of advanced lung cancer has not been well defined. Randomized controlled trials (RCTs) comparing different regimens for the amelioration of thoracic symptoms have reported contradictory results for symptom palliation.8-20 Even more controversial is what impact, if any, palliative RT has on survival. Results are again conflicting, with a few trials concluding that higher-dose (HD) radiation leads to prolonged survival,13,16,19 some finding equivalence,8-12,14,15,17,18 and one finding that HD RT worsened survival.20 Two trials reported equivalent QoL with HD,17-19 whereas two others concluded the opposite,13,16 with the remainder either not measuring QoL or not reporting results to date.8-12,14,15,19,20 A previous systematic review included trials published to 2001,21 and has been recently updated.22 The authors concluded that symptom improvement was equivalent regardless of RT dose and that any survival benefit would likely be modest and confined to patients with good performance status (PS). HD RT was associated with more acute adverse effects, although still generally mild, but neither reirradiation nor QoL end points were considered. Quantitative pooling was not performed because of heterogeneity of studies. Short fractionation has been recommended by many guidelines,1,5,21,23-25 although a number have cautioned against the use of single fractions for various reasons.1,21,23,26 Other position papers have not recommended a specific dose fractionation schedule.4,6,27,28 We systematically reviewed the RCTs of palliative thoracic RT for lung cancer to update the previous review and provide quantitative estimates of effect. The primary objective was to determine the RT schedule that maximized symptom palliation and survival and minimized the need for reirradiation and toxicity.
Literature Search Strategy Two literature searches were conducted. The first was a search of PubMed (National Library of Medicine) between 1966 and 2007, using the text words "pulmonary or lung"; "metastasis or metastases"; "radiotherapy or radiation or irradiation"; "fraction"; "palliate or palliative or palliation"; with the following fields of interest: "clinical trial"; "controlled clinical trial"; "metaanalysis"; "practice guideline"; "RCT"; "review"; "phase I-IV trial"; "consensus conference"; "guideline"; "journal article"; "multicenter study"; "human". The second search used Medline (1966 to September 2007 week 1, including in-process and other nonindexed citations), Embase (1980 to 2007 week 36), and the Cochrane Central Register using MeSH headings ["explode radiotherapy", "explode palliative therapy", "therapy (optimized)", "clinical trial {publication type}"] and text words ("lung or bronchogenic"; "cancer or carcinoma"; "non small cell or NSCLC"; "radiotherapy", "irradiation or radiation"; and "palliat:"). There were no language restrictions for either search, but no eligible non-English studies were found. Eligible studies were also identified from reference lists of retrieved articles, review articles, and clinical practice guidelines. The selection of studies for inclusion was carried out independently by two authors (A.F. and K.H.). Each published report was assessed for quality using the validated Jadad scale,29 although scores were not used as weighting factors for analyses because of their homogeneity (five of 13 trials scored 2 of 5, and the remainder scored 3 of 5).
Inclusion and Exclusion Criteria
Analyses Data were abstracted independently by two authors (A.F. and K.H.) from text, tables, and figures of published reports. Estimation from figures was required for survival in six of 13 trials8,9,14,16,17,19 and for patient-assessed toxicity in two of 13 trials.10,20 Patients assessable for a specific symptom—those who reported the presence of a symptom at baseline—were tallied in presenting symptom palliation results because not all patients randomly assigned suffered from each symptom at study entry. For the calculation of survival, toxicity (dysphagia, pneumonitis, myelopathy) and reirradiation rate, results of randomized (intention-to-treat) comparisons are presented. For the four studies that did not report number of patients randomly assigned per arm,8,10,18-19 the total number of patients accrued was assumed to be equally divided between arms to provide the denominator for each.30 These studies were included in the intention-to-treat analysis despite their lack of true denominators because they represent a significant proportion of the total number of patients randomly assigned (1,235 of 3,473). For the two trials8,17 with three treatment arms, to avoid the potential bias of inclusion of the control arm twice, the intermediate dose arm was excluded, resulting in comparisons between the lowest and highest dose arms on the basis of biologically equivalent dose (BED) Gy10. If more than one time point for symptom assessment was reported, the one at or closest to 4 weeks after palliative RT was used. Responses to repeated irradiation for patients in five of 13 trials10,11,13,19,20 were necessarily included in reporting of symptom palliation rates because of the presumed overlap between the time of assessment of the symptom end point, and the median time to reirradiation. Duration of symptom control was reported in seven of 13 trials;9-11,14,18-20 onset of symptom relief was reported by two trials.8,19 QoL and radiographic response end points were not addressed because of the small number of trials reporting them and the heterogeneity of assessment instruments.
Statistical Methods
Sensitivity Analyses
 /β ratio = 10, T = overall treatment time, Tko (kickoff time for accelerated repopulation) = 7, A = 0.35 (as a measure of intrinsic radiosensitivity), Tp (effective doubling time) = 2.5 days, n = number of fractions, and d = dose per fraction. This approach does include the potential bias for multiple comparisons and should be considered hypothesis generating. However, it has the potential benefit of pooling clinically homogeneous trials together, and exploring whether the dose-response relationship is most likely to lie along the spectrum of doses tested to date.
Using an
Descriptive Results Thirteen randomized trials published since 1985 involving 3,473 randomly assigned patients were identified (Table 1). We excluded one trial included in the previous review because it contained a delayed RT arm.31 Five trials provided no information on specific symptom outcomes, including one trial that described the change of mean score instead of response rates, and so could not be included in quantitative analysis.9,12,16,18-19 Trial entry criteria are described in Appendix Table A1 (online only).
Of randomly assigned patients, 78% were male. Age of participants varied, as did its reporting: mean age was described in three trials (63 years; range, 60 to 67 years), median age in five trials (68 years; range, 65.8 to 70.4 years), and proportion either 60 years or older or 65 years or older reported in the remaining (56% and 70%, respectively). Despite PS entry requirements of some trials, PS of patients actually randomly assigned was variable and some patients did not meet stated criteria. For example, one trial required Karnofsky performance status of at least 60% but enrolled patients with Karnofsky performance status of 40% and 50%.8 A total of 95% of patients had NSCLC. Small-cell lung cancer (SCLC) patients were purposefully included by two of 13 trials,14,18 comprising an average 5% of patients accrued. For three trials, although histology for eligibility was based on local pathology report, central review determined that histology was in fact SCLC in a small proportion, and a further 3% could not be confirmed as NSCLC.13 The remaining trials did not report pathology review. One trial included an unspecified proportion of asymptomatic patients.8 Sundstrom et al17 included patients who were asymptomatic at the time of accrual but who had impending airway compromise, and stratified for the absence of symptoms in their analysis. Patients who declined radical treatment were included by one trial, comprising on average 7% of patients.16 Twenty-eight percent of patients had extrathoracic metastases at study entry (eight of 13 trials; range, 16% to 48%). Inclusion criteria were based on prognostic factors, such as performance status and/or weight loss, in four of 13 trials.16-19 Patients with bilateral or contralateral pulmonary disease and pleural effusion were allowed entry into some trials.
Radiotherapy
Symptom Palliation
Baseline symptoms were assessed by validated questionnaire in two of 13 trials (Lung Cancer Symptom Scale16 and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Lung Cancer17) and by modification of a validated questionnaire in another two (Rotterdam symptom checklist13,19). The remainder used various methods to describe symptoms, most commonly categoric scales (eg, none, mild, moderate, severe) recorded at the time of direct physician questioning or completion of a symptom diary. Hemoptysis. Five trials reported proportions of patients who had a complete resolution of hemoptysis after RT, encompassing 247 patients in the HD arms and 244 patients in the LD arms (Fig 1). Proportions of patients with complete response were 73.7% and 68.9%, respectively (P = .19); 80.2% of patients (nine trials; 316 of 394) in the lower-dose (LD) arms and 81.2% (323 of 398) in the HD arms had any degree of improvement (complete response plus partial response) in hemoptysis (P = .91; Fig 1).
Cough. Five trials reported proportions of patients who had a complete resolution of cough after RT, comprising 123 patients in the HD arms and 151 in the LD arms (Fig 2). Proportions of patients with complete response were 27.9% and 32.1%, respectively (P = .41), with a pooled RR of 1.08 (95% CI, 0.90 to 1.28). 53.5% of 832 patients (nine trials) receiving lower RT doses and 48.2% of 782 patients receiving HD reported improvement in cough after RT, with a pooled RR of 1.10 (95% CI, 1.00 to 1.21). Although the P value was borderline significant at .04, because the lower boundary of the 95% CI included 1.0, there is considered to be no statistical difference between dose regimens (Fig 2).
Chest pain. Five trials reported 264 patients in the LD arms and 275 patients in the HD arms who were assessable for complete resolution of chest pain. Among the total, 51.9% (LD arms) and 57.5% (HD arms) of patients had complete response (P = .43; Fig 3). There was significant heterogeneity (P = .03). A total of 64.8% of 474 in the LD arms and 63.8% of 484 patients in the HD arms of eight trials reported that their chest pain improved after RT (P = .94; Fig 3).
Overall symptom burden. Four trials reported a total symptom score instead of each symptom separately, representing 330 patients in the LD arms and 315 patients in the HD arms (Fig 4). Resepctively, 10.0% (33 of 330) and 16.2% (51 of 315) of patients had complete response, with a pooled odds ratio (OR) of 0.58 (P = .15). A total of 55.5% (LD) and 60.9% (HD) of patients in four trials improved to some degree (P = .003). A greater likelihood of symptomatic improvement was seen with schedules of 35 Gy10 BED, such as 30 Gy in 10 daily fractions, versus those of lower BED (Fig 4B to 4C).
Onset and Duration of Symptom Control In two trials, patients receiving LD RT had more rapid onset of symptom relief than did those receiving HD.13,19 However, another trial found no difference.8 Duration of palliation was reported by seven trials.9-11,14,17,19,20 Teo et al9 reported a nonsignificant increase in duration of palliation by 1.5 weeks with HD schedules. Improvement appeared to last at least 50% of the remaining survival time, with no difference between arms in the Medical Research Council (MRC) 91 and MRC92 trials;10-11 in the Rees et al trial,14 though, the only symptom that improved in more than 50% of patients for at least 8 weeks was hemoptysis. The palliative effect lasted throughout the planned follow-up period (4 months) in another trial.17 Palliation was reached in week 5 for LD patients versus week 7 in HD patients, and duration was significantly longer in the HD arms, persisting until week 22 (P < .001).19 Duration was more difficult to interpret in the Senkus-Konefka et al trial20 because it consisted of the number of assessments, not necessarily consecutive, in which improvement was reported.
Survival
Toxicity Dysphagia. Among randomly assigned patients, 84.2% (range, 48% to 100%) were assessable for physician-assessed dysphagia versus 79.0% for patient-assessed dysphagia (range, 51% to 100%). Toxicity in the form of dysphagia secondary to esophagitis was the only adverse effect reported by four or more trials. However, the actual form in which it was reported differed widely, in terms of physician- or patient self-assessment, timing, and method (Appendix Table A3, online only). Physician-assessed dysphagia was significantly greater in the HD arm, at 20.5% (167 of 815) versus 14.9% (123 of 824) in the LD arm (P = .01; Fig 7A). A lower incidence of dysphagia was reported after 30 Gy10 BED versus higher BED schedules (Fig 7B). Pooling of patient self-assessment data was not valid (Fig 7A).
Myelopathy. This late adverse effect of RT was reported by 10 trials, of which three had confirmed cases. Point estimates were each less than 0.5% and not significantly different (0.3% incidence for the HD arms v 0.08% for the LD arms). The pooled OR was 0.39 and the 95% CI was 0.08 to 2.01 (Appendix Fig A1, online only). Pneumonitis. Pneumonitis affected 3.6% of patients randomly assigned to HD RT versus 1.8% of those assigned to LD (P = .68). Individual OR ranged from 0.06 to 1.80 with a pooled OR of 0.66 (95% CI, 0.10 to 4.56); however, test for heterogeneity was not significant (Appendix Fig A2, online only).
Reirradiation Rate
This meta-analysis is, to our knowledge, the first to report the results of quantitative pooling of RCTs comparing different dose fractionation schedules of palliative thoracic radiotherapy for locally advanced lung cancer. We confirmed the conclusions of the previous systematic review in terms of the equivalence of palliation of specific symptoms, but report that patients have a statistically lower total symptom score after HDs of palliative thoracic RT. In addition, we report a 4.8% absolute increase in overall survival at 1 year, favoring dose schedules of 35 Gy10 BED, at the expense of significantly increased esophagitis. Athough there is a greater incidence of chest reirradiation after LD RT, this is not statistically significant. Although the use of palliative chemotherapy for NSCLC is increasing, RT alone can provide more timely palliation of thoracic symptoms without the morbidity of chemotherapy, and may be the primary or only treatment option for poor-PS patients, or patients who have declined or progressed despite systemic therapy. It is interesting to note that HDs of thoracic RT resulted in a survival benefit in this patient population, a significant proportion of whom either have or will eventually develop extrathoracic metastases. Perhaps improvement in PS subsequent to symptom palliation allowed patients to receive systemic therapy for which they would not otherwise have been candidates. Improvement in PS may also lead to increased ambulation, resulting in less deconditioning, and decreased risks of immobilization such as pneumonia or venous thromboembolism.32 Finally, greater control of intrathoracic disease may minimize some of the greatest mortality risks associated with locally advanced lung cancer, such as postobstructive pneumonia, tracheoesophageal fistula, or massive hemoptysis. This result is unlikely to be caused by selection bias because all included studies randomly assigned eligible patients between treatment arms. We recognize that there is significant clinical heterogeneity across the dose ranges that were compared across the trials. Pooling across trials is reasonable to provide the answer to the question, "Does a difference in response exist when HD RT is compared with LD RT?" A quantitative analysis of the relative effect can increase the power of detecting such a difference, with the important qualifying statement that the pooled estimate and event rates cannot be generalizable to any particular dose range. Sensitivity analysis based on BED should be considered exploratory because there are a limited number of studies per dose category. Trials included are heterogeneous in terms of both inclusion criteria and end point assessment. Descriptions of the eligible patient population varied from vague ("advanced inoperable"8), to quite stringent in terms of specific disease- or patient-characteristics.15,17,19 Although most trials required a minimum estimated life span, some groups of patients ultimately were not as fit as initially thought, with 25% of patients accrued in one trial dying within 3 months.14 In terms of controlling for prognostic factors besides age and performance status, only four of 13 trials documented 10% or greater weight loss at entry, which varied from approximately one third17 to three quarters of patients,16,18-19 and in one trial was imbalanced between arms.15 It is well-known that physicians tend to underestimate patients’ symptom burden.33 However, relying on patient self-assessment, although the gold standard, risks large amounts of missing data. For example, the MRC91 and MRC92 trials required patients to complete symptom diary daily for 6 months; between 21% and 27% of patients provided no data at all.10-11 The pretreatment patient symptom questionnaire was completed in only 82% of patients in another trial.15 Differences in timing and method of palliation assessment, symptom definitions, the instrument used (and whether it is validated), and the completeness of follow-up are likely responsible for the large differences in reported esophagitis. Moreover, in trials where both physicians and patients assessed the same adverse effect, this was not necessarily at comparable times or with comparable instruments.17 Additionally, some trials recorded dysphagia as an adverse effect only when it occurred in patients who did not report it at baseline, to increase likelihood that it was in fact a result of treatment. The differences between physician- and patient-assessed esophagitis (Fig 7) are interesting as a visual demonstration of both the underlying heterogeneity of the trial designs and the suggestion that the incidence of patient-reported dysphagia is greater than two-fold that of the physician reports. Adding to the inherent subjectivity of measuring symptom burden is the absence of a current standard questionnaire or methodology to accomplish this, as evidenced by the studies reviewed. Perhaps the time has come for a consensus statement on palliative radiotherapy end points and their measurement in the treatment of intrathoracic tumor, similar to the recent effort in the realm of bone metastases.34 Other difficulties in end point assessment surround potential bias introduced by using any late event as an end point, and complexity of interpretation of reirradiation rate. To be assessable for either, patients must live long enough, continue to be followed, and have a PS that allows rereferral to a radiation oncologist for assessment. Nonspecialist caregivers may not recognize late effects that occur months to years after RT. Because reirradiation was not a prespecified end point in any trial, its use and reporting were at the discretion of the treating physician, without guidance as to appropriate timing, dose, or patient population. This systematic review provides further evidence of equivalency of specific symptom palliation outcomes, but describes statistically significantly improved total symptom score and overall survival with HDs of palliative thoracic RT compared with LDs. Consideration of RT schedules of at least 35 Gy10 BED may therefore be warranted in certain clinical scenarios, provided that patients are informed of the trade-off between the potential advantages (survival benefit, decreased likelihood of reirradiation to the thorax) and disadvantages (higher incidence of esophagitis, greater time investment) of each schedule. Alternatively, patients with intrathoracic symptoms and a short expected survival may achieve a high rate of symptom relief with minimal toxicity and inconvenience with a short course of palliative thoracic radiotherapy.
The author(s) indicated no potential conflicts of interest.
Conception and design: Alysa Fairchild, Kristin Harris, Elizabeth Barnes, Rebecca Wong, Stephen Lutz, Andrea Bezjak, Patrick Cheung, Edward Chow Administrative support: Alysa Fairchild, Kristin Harris, Elizabeth Barnes, Edward Chow Collection and assembly of data: Alysa Fairchild, Kristin Harris, Elizabeth Barnes, Rebecca Wong, Andrea Bezjak, Edward Chow Data analysis and interpretation: Alysa Fairchild, Kristin Harris, Elizabeth Barnes, Rebecca Wong, Stephen Lutz, Andrea Bezjak, Patrick Cheung, Edward Chow Manuscript writing: Alysa Fairchild, Kristin Harris, Elizabeth Barnes, Rebecca Wong, Stephen Lutz, Andrea Bezjak, Patrick Cheung, Edward Chow Final approval of manuscript: Alysa Fairchild, Kristin Harris, Elizabeth Barnes, Rebecca Wong, Stephen Lutz, Andrea Bezjak, Patrick Cheung, Edward Chow
Presented in part at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 28–November 1, 2007, Los Angeles, CA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Nestle U, Nieder C, Walter K, et al: A palliative accelerated irradiation regimen for advanced non-small-cell lung cancer vs conventionally fractionated 60Gy: Results of a randomized equivalence study. Int J Radiat Oncol Biol Phys 48:95-103, 2000[CrossRef][Medline] 16. Bezjak A, Dixon P, Brundage M, et al: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC. 15). Int J Radiat Oncol Biol Phys 54:719-728, 2002[CrossRef][Medline] 17. Sundstrøm S, Bremnes R, Aasebo U, et al: Hypofractionated palliative radiotherapy (17Gy per two fractions) in advanced non–small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: A national phase III trial. J Clin Oncol 22:801-810, 2004 18. Erridge SC, Gaze MN, Price A, et al: Symptom control and quality of life in people with lung cancer: A randomized trial of two palliative radiotherapy fractionation schedules. 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Jadad AR, Moore RA, Carroll D, et al: Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 17:1-12, 1996[CrossRef][Medline] 30. Wu JSY, Wong R, Johnston M, et al: Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 55:594-605, 2003[CrossRef][Medline] 31. Reinfuss M, Glinski B, Kowalska T, et al: Radiotherapy for stage III, inoperable, asymptomatic small cell lung cancer: Final results of a prospective randomized study (240 patients) [in French]. Cancer Radiother 3:475-479, 1999[Medline] 32. Townsend PW, Rosenthal HG, Smalley SR, et al: Impact of postoperative radiation therapy and other perioperative factors on outcome after orthopedic stabilization of impending or pathologic fractures due to metastatic disease. J Clin Oncol 12:2345-2350, 1994 33. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
