Abstract
Introduction
The majority of lung cancer patients are elderly and poorly represented in randomized clinical trials. They are often undertreated due to concerns about their ability to tolerate aggressive treatment. We tested the hypothesis that elderly patients undergoing definitive lung radiation might tolerate treatment differently from younger patients.
Methods
125 patients who underwent definitive lung radiotherapy were identified from a prospective institutional database (UM cohort). Logistic regression modelling was performed to assess the impact of age on esophagitis grade ≥3 or ≥2 and pneumonitis grade ≥3 or ≥2, adjusting for esophageal and lung dose respectively, chemotherapy utilization, smoking status, and performance status. The analysis was validated in a large cohort of 691 patients from the Michigan Radiation Oncology Quality Consortium (MROQC) registry, an independent statewide prospective database.
Results
In the UM Cohort, multivariable regression models revealed a significant inverse correlation between age and rate of esophagitis for both toxicity levels, (adjusted odds ratio=0.93 for both models, 95% confidence intervals of (0.88,0.98) and (0.87,0.99)), with AUC of 0.747 and 0.721, respectively, demonstrating good fit. This same association was noted in the MROQC cohort. There was no significant association between age and pneumonitis.
Conclusions
There is a lower incidence of esophagitis with increasing age even after adjusting for use of chemotherapy. This is a novel finding in thoracic oncology. No age dependence was noted for pulmonary toxicity. The elderly are able to tolerate definitive thoracic radiation well and should be offered this option when clinically warranted.
Keywords: Elderly, Esophagitis, Lung Cancer, Radiation, Toxicity
1Introduction
Cancer is a disease of the elderly with over 60% of malignancies diagnosed in men and women over the age of 65.1, 2 As the elderly population continues to increase in the United States (US), the cancer burden will escalate as well. It is estimated that from 2010 to 2030, there will be a 45% increase in the overall cancer incidence, disproportionately accounted for by the elderly population.3 However, elderly patients are poorly represented in clinical trials that have defined the standard of care for cancer treatment. There is a significant gap in our understanding of the risks and benefits of managing elderly cancer patients with standard treatment regimens.
Lung cancer is the leading cause of cancer death for both men and women in the US.4 Over 65% of patients diagnosed with lung cancer are over the age of 65.5 Paradoxically, the average median age of patients on phase III randomized controlled trials for locally advanced non-small cell lung cancer (NSCLC) is 61 years,6 even though about half of the patients diagnosed with lung cancer in the US are over the age of 70.7, 8 This raises concern about how applicable these trials are to older patients and poses a challenge for the oncologists who are managing the care of these patients. A large SEER-Medicare analysis of patients older than age 66 with locally advanced NSCLC demonstrated that approximately one-third receive no treatment.9 Even elderly patients with good performance status and lack of comorbidities are less likely than younger patients to be offered aggressive treatments on the basis of age.10 Given the concern for decreasing functional reserve in older patients, providers question the elderly’s ability to tolerate standard cancer treatments.11 While the elderly are no different than younger patients in their willingness to accept aggressive treatment, they are less likely to sacrifice quality of life for incremental improvements in survival.12 However, there is a paucity of data to inform toxicity in the elderly population, perpetuating the phenomenon of ageism in cancer management.
Radiotherapy is a key component of the definitive treatment regimen for locally advanced non-small cell lung cancer. Esophagitis and radiation pneumonitis are potentially life-altering toxicities of thoracic radiation. There is limited data on the impact of age on incidence of these toxicities. We, therefore, analyzed the association between age and radiation-induced toxicities in patients enrolled on our institutional prospective lung cancer protocols. We then sought to validate our results in an independent cohort of patients treated on a large observational study as part of a statewide radiation oncology consortium. We hypothesized that increasing age may predict higher rates of radiation induced esophageal and pulmonary toxicity.
Methods
Primary Study Population
As part of an Institutional Review Board approved study, patients undergoing definitive radiation for lung cancer with or without chemotherapy from 2004–2013 were identified from a prospective institutional database in which patients of all ages were eligible for inclusion (UM Cohort). Patients were excluded if they were treated with stereotactic body radiation therapy (SBRT) or if complete dose volume histograms (DVHs) were not available for review. Clinical records were reviewed to identify patient and tumor specific characteristics, including age, sex, smoking status, Karnofsky Performance Status (KPS), tumor histology, tumor stage, and utilization of chemotherapy. Treatment plans were individually reviewed to collect actual dose received by the esophagus and lungs. All cases in the database utilize modern photon dose calculations (Analytical Anisotropic Algorithm, Varian Medical Systems) and voxel-based biological corrections to equivalent dose in 2Gy fractions (EQD2), using the linear quadratic model (α/β=10Gy for esophagus and α/β=3Gy for lung), in order to account for variable dose per fraction prescriptions. All organs at risk were defined using the RTOG lung atlas.13 Esophageal dose was primarily defined by D2cc (the minimum dose to the most exposed 2cc of the esophagus), and lung dose by V20Gy (the volume of both lungs not involved with gross disease that received at least 20Gy), both of which have been previously correlated with toxicity. Secondary dosimetric parameters were generalized equivalent uniform dose (gEUD) with a=5 for esophagus (a single dose value that is a biologically equivalent representation of the dose distribution across the organ) and mean dose for lungs. As noted above, all dose values are in EQD2.
All patients had a toxicity evaluation by a radiation oncologist weekly during their radiation treatment. Follow-up schedules after completion of treatment varied, however, all patients were evaluated at least once in the first month after treatment, and every 3 months for the first 6 months. Physician-reported toxicity was collected at each of these visits and graded according to CTCAE v3.0 for esophagitis and pneumonitis. Maximum toxicity grade was used for this analysis.
Secondary Study Population
A second, independent cohort of patients with lung cancer was identified from the Michigan Radiation Oncology Quality Consortium registry (MROQC Cohort). MROQC is an alliance of 24 academic and community practice centers in the state of Michigan funded by Blue Cross Blue Shield of Michigan, through which clinical, treatment, and outcomes related data is prospectively collected for patients undergoing thoracic irradiation.14 Each participating site submits DVHs and DICOM-formatted files of actual treatment plans for each patient to MROQC. All patients undergoing definitive lung radiotherapy for stage I–III lung cancer were identified. SBRT patients and patients with incomplete DVHs were excluded. The same dose parameters for organs at risk identified in the derivative cohort were extracted from the MROQC database. EQD2 dose metrics were not available for this cohort so physical doses were used. MROQC eligibility is limited to conventionally fractionated patients and therefore physical doses were felt to be comparable. Physician-reported toxicity was retrieved from weekly on treatment visits during radiation and from follow-up visits.
Statistical Methodology
We fit a logistic regression separately to four outcomes (esophagitis or pulmonary toxicity; grade ≥2 or grade ≥3) with the goal of accurately quantifying and validating the age-toxicity association. In addition to age and dose, we adjusted for potential confounders: chemotherapy utilization, smoking status (never, former, current), and KPS. No variable selection was conducted. Descriptive summaries of the data (Figure 1 and Figure 2) suggested possible nonlinear age-toxicity and dose-toxicity relationships; however, after adjusting for other confounders, we did not find any non-linear associations that could be supported in a cross-validated framework. Both chemotherapy use and smoking status exhibited `sparse-data bias’, i.e. associations that were implausibly extreme due to a combination of a relatively small toxicity rate and a limited sample size. We adjusted for this bias by penalizing the likelihood with an expression equal to the log-density of a normal distribution with variance equal to 2, thereby shrinking the estimated associations of chemotherapy and smoking status with toxicity toward their null value (an odds ratio of 1).15
Figure 1.
Descriptive summary of the incidence of esophagitis in the UM Cohort
Figure 2.
Descriptive summary of the incidence of pneumonitis in the UM Cohort
Results
There were 179 patients extracted for the UM cohort. After exclusions (26 for SBRT and 28 for incomplete DVH data), 125 patients with lung cancer were included in our analysis. The median age in our institutional database was 66, with 34% of the patients older than 70. Data from 708 patients were extracted for the MROQC cohort. Seventeen of these patients were missing information for ≥1 of the clinical prognostic covariates, leaving 691 analyzable patients. Patient characteristics are detailed in Table 1.
Table 1.
Patient Characteristics
| UM COHORT | MROQC COHORT | |||||
|---|---|---|---|---|---|---|
| Age <70 | Age ≥ 70 | Total | Age <70 | Age ≥ 70 | Total | |
| # of Patients | 82 | 43 | 125 | 389 | 302 | 691 |
| Median Age (Range) | 62 (40–70) | 77 (70–85) | 66 | 62 (39–70) | 77 (70–100) | 68 |
| Sex | ||||||
| Male | 60 (73%) | 35 (81%) | 95 (76%) | 217 (56%) | 160 (53%) | 377 (55%) |
| Female | 22 (27%) | 8 (19%) | 30 (24%) | 172 (44%) | 142 (47%) | 314 (45%) |
| KPS | ||||||
| ≥70 | 80 (98%) | 42 (98%) | 122 (98%) | – | – | – |
| <70 | 2 (2%) | 1 (2%) | 3 (2%) | – | – | – |
| Smoking Status | ||||||
| Current | 42 (51%) | 11 (26%) | 53 (42%) | 201 (52%) | 79 (26%) | 280 (41%) |
| Former | 35 (43%) | 26 (60%) | 61 (49%) | 178 (46%) | 201 (67%) | 379 (55%) |
| Never | 0 | 4 (9%) | 4 (3%) | 10 (3%) | 22 (7%) | 32 (5%) |
| Missing | 5 (6%) | 2 (5%) | 7 (6%) | 0 | 0 | 0 |
| Stage | ||||||
| I | 8 (10%) | 3 (7%) | 11 (9%) | 24 (6%) | 35 (12%) | 59 (9%) |
| II | 8 (10%) | 5 (12%) | 13 (10%) | 43 (11%) | 56 (19%) | 99 (14%) |
| III | 66 (80%) | 34 (79%) | 100 (80%) | 299 (77%) | 186 (62%) | 485 (70%) |
| Missing | 0 | 0 | 0 | 23 (6%) | 25 (8%) | 48 (7%) |
| Chemotherapy | ||||||
| Concurrent | 73 (89%) | 32 (74%) | 105 (84%) | 330 (85%) | 224 (74%) | 554 (80%) |
| Sequential | 0 | 0 | 0 | 33 (8%) | 32 (11%) | 65 (9.4%) |
| None | 9 (11%) | 11 (26%) | 20 (16%) | 26 (7%) | 46 (15%) | 72 (10%) |
| Median Elapsed Days During RT | 43 | 44 | 43 | 42 | 42 | 42 |
| Median Follow Up (mo) | 25.3 | 13.3 | 20.3 | 4.1 | 4.3 | 4.2 |
| Esophagitis | ||||||
| Grade ≥2 | 39 (47.6%) | 10 (23.3%) | 49 (39.2%) | 214 (55.0%) | 142 (47.0%) | 361 (52.2%) |
| Grade ≥3 | 13 (15.9%) | 1 (2.3%) | 14 (11.2%) | 8 (2.1%) | 5 (1.7%) | 13 (1.9%) |
| Pneumonitis | ||||||
| Grade ≥2 | 22 (26.8%) | 10 (23.3%) | 32 (26%) | N/A | N/A | N/A |
| Grade ≥ 3 | 7 (8.5) | 4 (9.3%) | 11 (9%) | N/A | N/A | N/A |
Esophagitis
Among the 125 patients in the UM cohort, 49 (39%) and 14 (11%) experienced Grade ≥2 and Grade 3 esophagitis, respectively. No grade 4 or 5 esophagitis was reported. Among the 82 patients of age <70, these rates were 48% and 16%; among the 43 patients age ≥70, these rates were 23% and 2%.
The multivariable regression models derived from the UM Cohort for Grade ≥2 and ≥3 are given in columns 1 and 3 of Table 2. In both models, there was a significant inverse correlation between age and incidence of esophagitis, with the odds of esophagitis reduced by a ratio of 0.92–0.93 for each additional year of age. The 95% confidence intervals (CIs) are similar: (0.87, 0.97) and (0.86, 0.99), respectively, for each model. Replacing D2cc with gEUD (a=5) and refitting these regression models yielded very similar results, with odds ratios (ORs) corresponding to age being approximately 0.92, and 95% CIs falling below 1.
Table 2.
Multivariable odds ratios (with 95% confidence intervals) for esophagitis
| UM Cohort ≥ Grade 2 |
MROQC Cohort ≥ Grade 2 |
UM Cohort ≥ Grade 3 |
MROQC Cohort ≥ Grade 3 |
|
|---|---|---|---|---|
|
Age (per Year) |
0.92 (0.87, 0.97) | 0.98 (0.96, 0.99) | 0.93 (0.86, 0.99) | 0.97 (0.92, 1.03) |
|
Dose (per Gray) |
1.07 (1.03, 1.12) | 1.06 (1.04, 1.07) | 1.12 (1.03, 1.25) | 1.04 (0.99, 1.11) |
|
Concurrent Chemo (vs No Chemo) |
2.58 (0.52, 30.1) | 2.19 (1.23, 3.99) | 1.98 (0.18, 94.0) | 1.03 (0.22, 6.94) |
|
Sequential Chemo (vs No Chemo) |
No Patients | 1.70 (0.81, 3.63) | No Patients | 0.85 (0.08, 6.93) |
|
Smoking (Current vs Never) |
1.86 (0.28, 21.9) | 0.63 (0.28, 1.40) | 1.07 (0.11, 14.3) | 0.58 (0.10, 4.27) |
|
Smoking (Former vs Never) |
2.60 (0.42, 30.1) | 0.97 (0.44, 2.13) | 1.57 (0.18, 21.2) | 0.69 (0.13, 5.01) |
|
KPS (per Point) |
1.00 (0.95, 1.05) | Data Not Available | 1.01 (0.94, 1.08) | Data Not Available |
Using D2cc, Figure 3 plots the model-estimated probabilities of Grade 3 esophagitis by age for seven different dose values. These dose values represent equally spaced percentiles of the esophageal doses received by the 125 patients, spanning from 16Gy (5th percentile) to 75Gy (95th percentile). At age 50, the probability of Grade ≥3 esophagitis ranges from about 0.1% at 16Gy to 49% at 75Gy. In contrast, by age 70, these probabilities fall to <0.1% at 16Gy and 17% at 75Gy. Thus, at very low and very high dose levels, the estimated relative risk of esophageal toxicity for a 70-year old patient is one-third of what is estimated for a 50-year old.
Figure 3.
Predicted risk of Grade ≥3 Esophagitis at seven different D2cc doses as a function of age for a hypothetical patient who is assumed to be a never smoker with a KPS of 85, who is receiving concurrent chemotherapy.
The Grade ≥2 and ≥3 esophagitis models for the UM cohort were cross-validated to assess model fit. The cohort was randomly partitioned into 10 subcohorts in a blocked fashion, meaning the patients experiencing esophagitis were distributed as uniformly as possible. We sequentially refit the model against all combinations of 9 subcohorts, calculating the discrimination in the held-out subcohort. The average cross-validated discrimination, or the area under the ROC curve (AUC), was 0.782 and 0.774, respectively, for Grade ≥2 and ≥3. Interpreting these numbers, for a random pair of patients, one with esophagitis and one without, our model correctly identifies the patient with esophagitis as having greater risk with a probability of 77%. The median cross-validated predicted probability of Grade ≥2 esophagitis was 58% and 32%, respectively, for patients who did and did not have Grade ≥2 esophagitis. For the Grade ≥3 model, these same probabilities were 23% and 6%.
Among the 691 patients in the MROQC cohort with complete information, the number of patients with Grades ≥2 and ≥3 esophagitis was 356(52%) and 13(1.9%), respectively. One patient experienced grade 4 esophagitis, and no patients experienced grade 5 esophagitis. Among the 389 patients age <70, the rates of Grades ≥2 and ≥3 esophagitis were 55% and 2.1%; among the 302 patients age ≥70, these rates were 47% and 1.7%. The apparent inverse association between age and esophagitis was confirmed in the MROQC cohort after accounting for potential confounders, albeit to a lesser extent than in the UM Cohort: with an odds ratio of 0.97–0.98 per year. The 95% CIs were (0.96, 0.99) and (0.92, 1.03), respectively, for Grades ≥2 and ≥3 esophagitis (Table 2).
Radiation Pneumonitis
There was less evidence for an age-lung toxicity association. The rate of pneumonitis in the UM Cohort was 32/125(25%) and 11/125(9%), respectively, for Grades ≥2 and ≥3. No patients experienced grade 4 pneumonitis, and 2 patients experienced grade 5 pneumonitis. Among the 83 patients age <70, the rates of Grades ≥2 and ≥3 pneumonitis were 27% and 8%; among the 46 patients age ≥70, these rates were nearly the same: 22% and 9%.
The multivariable regression models are given in Table 3. There was no meaningful association between age and pneumonitis detected: OR=0.99 for Grade ≥2 and OR=1.02 for Grade ≥3. The CIs are nearly symmetric about 1 with a width of approximately 0.10. Replacing V20Gy with mean lung dose did not change our conclusions. Given there was no association between pneumonitis and age, we did not seek to confirm this ‘lack of significance’ in the MROQC cohort.
Table 3.
Multivariable odds ratios (with 95% confidence intervals) for pulmonary toxicity
| UM Cohort ≥ Grade 2 | UM Cohort ≥ Grade 3 | |
|---|---|---|
| Age (per Year) | 0.99 (0.94, 1.04) | 1.02 (0.95, 1.11) |
| Dose (per Gray) | 1.11 (1.04, 1.20) | 1.10 (1.00, 1.22) |
| Chemo (vs No) | 0.53 (0.14, 2.16) | 0.31 (0.05, 1.69) |
| Smoking (Current vs Never) | 2.89 (0.43, 34.5) | 1.57 (0.18, 20.3) |
| Smoking (Former vs Never) | 3.40 (0.55, 39.1) | 1.99 (0.27, 24.6) |
| KPS (per Point) | 1.03 (0.98, 1.09) | 1.01 (0.94, 1.09) |
Discussion
Our study demonstrates a significantly decreased incidence of radiation esophagitis in elderly patients. This finding remained significant even after adjusting for esophageal dose, concurrent chemotherapy, history of smoking, and performance status. In patients who are never smokers with good performance status, who receive high doses of radiation to the esophagus with concurrent chemotherapy, the probability of esophagitis for a 70 year old is approximately one-third that of an identical 50 year old patient. This relationship between age and esophagitis was initially demonstrated in a prospective cohort from our institution and then validated in a large prospective state-wide registry suggesting generalizability to a broader population. The overall rate of grade ≥3 esophagitis in the present study is 11% in the UM cohort, which is comparable to prospective randomized trials.16 The overall rate of esophagitis is low in the MROQC cohort and may represent variations in toxicity reporting and grading among physicians. This lack of events could explain the attenuated trend in the MROQC database. In our analysis, there was no apparent correlation between radiation pneumonitis and age, which is consistent with prior studies.17 Within this lack of correlation, it is still important to note that age did not appear to increase one’s risk of pneumonitis.
To our knowledge, the inverse correlation between age and esophagitis is a novel finding in thoracic oncology.17–21 Pignon et al previously studied the effect of age on toxicity in patients undergoing thoracic radiation in a meta-analysis of six randomized trials.17 Their study overall showed no significant age-dependent distribution of acute or late toxicities. There was a trend towards increased late esophagitis in the elderly; however, this was attributed to a subset of patients who had undergone hypofractionated radiotherapy. Furthermore, the studies included in this meta-analysis used older radiation techniques. Our study is the first to evaluate the effect of age on toxicity related to thoracic radiotherapy in the context of dosimetric parameters in the modern treatment planning era, recognizing that dose itself is a significant confounder.
The main strength of our investigation is the large number of patients with prospectively collected toxicity data, as well as detailed dosimetric data for organs at risk available for correlation. For esophageal toxicity, we chose to look at D2cc as several series have shown maximum doses to the esophagus to predict grade 3 esophagitis.22–25 Furthermore, using maximum dose reduces the impact of variations in esophageal contours. While esophageal contours were standardized in the UM cohort, there are likely variations in the MROQC database. We also chose to look at gEUD which allows us to represent a heterogeneous dose distribution across a structure in terms of a single biologically equivalent dose value. We selected an “a” value of 5 for our gEUD calculation to give some weight to the maximum dose to respect the serial nature of the esophagus while incorporating volumetric dose. The ability to adjust for esophageal dose eliminates confounding factors related to tumor location, stage, and variations in treatment planning. We acknowledge that there are limitations to this study. The UM database is comprised of patients enrolled on institutional clinical protocols. Despite having no age limitations, physician assessment may bias which patients are offered enrollment. The majority of patients in the UM cohort had a KPS of 70 or greater which may reflect a tendency to select fit patients for treatment. However, this was consistent in both younger and elderly patients. Given that our model was validated in a large independent cohort, undetected confounding factors are likely distributed homogenously. We recognize that chemotherapy is a significant contributor to esophagitis. In the UM cohort, the majority of patients received concurrent chemotherapy. Furthermore, after adjusting for chemotherapy utilization, age remained a significant independent predictor of esophagitis. Further validation of these findings in a cohort in which all patients received full dose chemotherapy and radiation may be warranted. Regardless, our data suggests that high doses of radiation with judicious use of chemotherapy is well tolerated in the elderly.
The mechanism behind decreased esophagitis in the elderly is not understood. We considered the possibility of decreased reporting in the elderly. However, there are objective surrogates for grade 3 esophagitis, including weight loss. Patients were weighed weekly which we anticipate would identify patients with severely altered swallowing. We also analyzed median number of elapsed days during the treatment course to determine if there was a tendency for older patients to take more treatment breaks or otherwise have a prolonged treatment course. However, we saw no differences between the patients older than and younger than 70. Esophagus-specific physiologic changes that would account for decreased effect from radiation were not found in our review of the literature.26 There is, however, a body of evidence to suggest that there is decreased visceral pain sensation with advancing age. Lasch et al used intraesophageal balloon distension to demonstrate significantly decreased esophageal pain sensation in healthy individuals older than 65 compared to a younger population.27 Johnson et al performed a population-based study of nearly 12,000 patients who were enrolled in clinical trials designed to assess the effectiveness of proton pump inhibitors in the setting of erosive esophagitis. All patients reported their symptoms of heartburn at baseline and underwent an endoscopy to evaluate the status of esophagitis prior to any therapeutic interventions. Johnson found that patients over age 70 had the greatest incidence of severe esophagitis yet were the least likely to report symptoms of severe heartburn.28 These findings would suggest that older age is not necessarily protective of radiation-induced esophagitis but rather that esophagitis is not readily detected in the elderly. Future study is required to understand the mechanism behind the decreased incidence of esophagitis in the elderly and the implications of this in their management.
Pattern of care studies suggest that the elderly are being undertreated for various malignancies including lung cancer, independent of other variables including performance status.29, 30 Our study undermines this practice and supports standard definitive treatment for the elderly with good performance status.
Acknowledgments
We thank the Michigan Radiation Oncology Quality Consortium for their collaboration. MROQC is supported by Blue Cross Blue Shield of Michigan and the Blue Care Network as part of the BCBSM Value Partnerships program.
Philip Boonstra has funding from CTI biopharmaceuticals. Matthew Schipper has a consulting role for Armune Bioscience and Hygieia Sciences. Martha Matuszak has funding from Varian and NIH. Feng-Ming Kong has funding and honoraria from Varian. Randall Ten Haken received travel support from Varian. Gregory Kalemkerian has funding from OncoMed, Pfizer, Astex Pharmaceuticals, GlaxoSmithKline, and Millennium.
Funding: This work was supported in part by NIH grant P01-CA059827 and R01 CA142840.
Footnotes
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Conflicts of Interest: All other authors have no disclosures.
Abbreviations: DVH = Dose-volume histogram, gEUD = generalized equivalent uniform dose, GTV = Gross tumor volume, Gy = Gray, MROQC= Michigan Radiation Oncology Quality Consortium, US = United States
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