Abstract
Importance
A recent randomized radiation dose escalation trial in unresectable stage III NSCLC showed a lower survival in the high-dose arm (74Gy vs. 60Gy) with concurrent chemotherapy. Quality of life (QOL), an important secondary endpoint, is presented here.
Objective
The primary QOL hypothesis predicted a clinically meaningful decline (CMD) in QOL via the Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) in the high-dose RT-arm at 3 months.
Design
RTOG 0617 was a randomized phase III study (conducted from Nov 2007 to Nov 2011) in stage III NSCLC using a 2×2 factorial design and stratified by histology, PET staging, performance status and radiation technique (3D-conformal RT [3DCRT] vs. intensity-modulated radiation [IMRT]).
Setting
185 institutions in the USA and Canada.
Participants
Of 424 eligible stage III NSCLC patients randomized, 360 (85%) consented to QOL, of whom 313 (88%) completed baseline QOL assessments.
Intervention for Clinical Trials
74Gy vs. 60Gy with concurrent and consolidation carboplatin/paclitaxel +/− cetuximab.
Main Outcomes and Measures
QOL was collected prospectively via FACT-Trial Outcome Index (FACT-TOI), equaling Physical-Well-Being (PWB) + Functional-Well-Being (FWB) + Lung Cancer Subscale (LCS). Data are presented at baseline & 3 and 12 months via minimal clinically meaningful changes of >=2 points for PWB, FWB or LCS or >=5 points for TOI.
Results
Patient demographics and baseline QOL scores were comparable between the 74Gy and 60Gy arms. Two-hundred-nineteen (72%) of living patients who completed QOL at baseline did so at 3 months and 137 (57%) of living patients did so at 12 months. Significantly more patients on 74Gy arm had clinically meaningful decline in FACT-LCS at 3 months than on the 60Gy arm (45% vs. 30%, p=0.02). At 12 months, fewer patients who received IMRT (vs 3DCRT) had clinically meaningful decline in FACT-LCS (21% vs 46%, p=0.003). Baseline FACT-TOI was associated with overall survival in multivariate analysis.
Conclusions and Relevance
Despite few differences in provider-reported toxicity between arms, QOL analysis demonstrated a clinically meaningful decline in QOL on the 74Gy arm at 3 months, confirming the primary QOL hypothesis. Baseline QOL was an independent prognostic factor for survival.
Study registered with ClinicalTrials.gov, number NCT00533949.
Keywords: Quality of life, patient-reported outcomes, non-small cell lung cancer, chemoradiation
Introduction
RTOG 0617 was an intergroup phase III trial which randomized patients with unresectable stage III non-small cell lung cancer (NSCLC) to one of four treatment arms in a 2 × 2 factorial design: 60 Gy (standard-dose RT) versus 74 Gy (high-dose RT) with concurrent and consolidation chemotherapy with or without cetuximab. This study asked a fundamental question as to whether or not RT dose escalation (and/or cetuximab) improves overall survival. The sobering answer was no, as the survival was lower on the high-dose RT arm and no different with the addition of cetuximab.1
The survival result of this randomized clinical trial (RCT) was not as hypothesized based on favorable phase II clinical trial data supporting the high-dose RT approach.2–4 While there were more grade 5 treatment related toxicities on the high-dose RT arm (8 vs. 3 patients), this difference was not significant. Based on the provider-reported toxicity scores, the only significant difference between the two arms was severe, albeit transient, esophagitis, which was higher on the 74Gy arm (21% vs. 7%, p<0.001).
Patient reported outcomes (PROs) are an important secondary endpoint of this study. Quality of life (QOL) was collected prospectively via a validated lung cancer instrument, the Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI)5,6, which has been associated with clinically meaningful changes in patients with lung cancer7. The primary QOL hypothesis predicted for a clinically meaningful decline (CMD) in the Lung Cancer Subscale (LCS) on the high-dose RT arm at 3 months. The prognostic value of QOL in predicting survival was also studied, as was the potential impact of radiation technique on QOL.
Materials & Methods
Study design and patients
The methodology for the RCT is described in detail in the clinical outcomes paper.1 Briefly, the study was designed as a 2×2 factorial design with RT dose as one factor and cetuximab as the other, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology, with a primary endpoint of overall survival. The study is registered with ClinicalTrials.gov, number NCT00533949. The institutional review board (IRB) of each participating institution reviewed and approved the study protocol. All patients were required to read and sign an IRB-approved informed consent document. Concurrent chemoradiation included weekly paclitaxel (45 mg/m2) & carboplatin (AUC=2), followed by 2 cycles of consolidation chemotherapy. In addition to the RT dose (60 Gy vs. 74 Gy) randomization, patients randomized to cetuximab received a 400 mg/m2 loading dose on Day 1 followed by weekly doses of 250 mg/m2. For the analysis, race was classified by patients (using options defined by the investigators).
Health-related Quality of Life Measures
QOL was measured via the use of FACT-TOI (FACT-Trial Outcome Index), a validated component of the FACT-Lung (FACT-L) QOL instrument, which can be completed in <10 minutes and has been extensively used in lung cancer patients.5,6 FACT-TOI includes the Physical Well Being (PWB), the Functional Well Being (FWB), and the Lung Cancer Subscale (LCS). Importantly, FACT-TOI has been associated with clinically meaningful changes in lung cancer patients.7 The Lung Cancer Subscale (LCS) consists of nine items involving common lung cancer symptoms, such as shortness of breath, weight loss, coughing, and appetite. All items are rated on a five point Likert scale, from 0 (not at all) to 4 (very much). Cella et al.7 have reported minimal clinically meaningful changes of ≥ 2 points for PWB, FWB, LCS or ≥ 5 points for TOI, criteria used in this analysis.
The primary QOL hypothesis predicted a clinically meaningful decline (CMD) in Lung Cancer Subscale (LCS) in the high-dose radiation arm at 3 months. While radiation dose escalation was hypothesized to yield greater tumor cell kill, it may also increase the normal tissue toxicity, thereby leading to a decrease in QOL. QOL results presented here include the following timepoints: baseline (pretreatment), during the last week of chemoradiation, and at 3 and 12 months from the start of treatment. The patients were given the QOL instrument to be completed in the clinic at the specified time points. If the patient did not come into the clinic (and/or as requested), the questionnaire was mailed to the patient.
Statistical Considerations
All registered patients were offered the opportunity to prospectively participate in the QOL study. The differences in QOL scores (i.e. FACT-TOI and its subscales) between baseline and each follow-up evaluation were computed for each individual patient and then classified as a clinically meaningful change or not, based on the criteria defined by Cella, et al.7 QOL completion and reasons of non-compliance were reported. The impact of missing QOL measurements were systematically assessed by comparing if patients with and without QOL at each timepoint had similar distributions of treatment arms, pretreatment characteristics and overall survival, as well as using interaction tests to determine if the associations between treatment arms and pretreatment characteristics or treatment arms and overall survival differed between patients with and without QOL.
Descriptive statistics were presented for both categorical and continuous variables. Differences between study groups in pretreatment characteristics and QOL scores were assessed by using chi-square test or Fisher's exact test for categorical variables and t-tests or Wilcoxon rank sum tests.8 Effect sizes (ES) of QOL score changes between study groups were calculated based on Cohen’s d statistic.9 Differences between study groups in clinically meaningful decline (CMD) were assessed univariately using Cochran-Mantel-Haenszel statistics (stratified by cetuximab usage), and multivariately using logistic regression adjusting for important pre-treatment characteristics and dosimetric parameters.
The Kaplan-Meier method was used to estimate rates of overall survival (duration between randomization to death or to last follow up), and the log-rank test was used to compare these estimates between groups.10 Cox proportional hazards models were used to quantify the prognostic value of baseline QOL on overall survival after adjusting for RT level, cetuximab usage and potential prognostic factors. To address potential guarantee-time bias11, a conditional landmark analysis in conjunction with Cox proportional hazard models was used to evaluate the prognostic value of clinically meaningful decline (CMD) on conditional survival after adjusting for potential confounding variables. In this landmark analysis, patients whose last follow-up was prior to the landmark time (e.g., 3 months) were excluded from the analysis, and the change at the pre-specified landmark time (e.g., 3 months) was used a predictor for survival conditional on surviving the landmark time.12 A two-sided significance level of 0.05 was used throughout. Of note, the extent of QOL decline was analyzed based on predefined and independently validated clinically meaningful changes, already representing moderate effects.7 All analyses were performed with SAS software, version 9.2 (SAS Institute Inc., Cary, NC, USA, 2008).
Results
Between November 2007 and June 2011, the end of the RT-level randomization, the trial accrued 464 patients, of whom 424 were ultimately eligible for analysis. Figure 1 is a QOL Consolidated Standards of Reporting Trials (CONSORT) diagram detailing the level of QOL participation at each timepoint. Briefly, 360 (85%) consented to QOL, of whom 313 (87%) completed the baseline QOL form (FACT-TOI). Other than patient attrition (as expected), the main reason for missing data was institutional error (QOL form not given or collected on time).
Figure 1.
RTOG 0617 CONSORT Diagram for QOL Assessments.
(QOL: Quality of life; Gy: Gray; n: Number of patients)
Table 1 shows the pretreatment characteristics for patients consenting to QOL by RT dose arm and RT technique. For both RT dose arms and techniques, approximately 60% of patients were male and 40% female. There were no significant differences between RT dose arms in demographics (including race) and there was equal use of cetuximab. Similarly, among patients who completed QOL at subsequent timepoints, there were no significant differences in any demographics or treatment factors between RT dose arms, except for more stage IIIB patients on the high-dose arm at the end of chemoradiation. There were no significant differences in treatment arms, pretreatment characteristics, or survival between patients with completed or missing QOL at baseline. Moreover, there were no significant differences in the associations between treatment arms and pretreatment characteristics, or treatment arms and survival between patients with or without QOL, suggesting that the data are missing at random.13 Table 2 shows the baseline Lung Cancer Subscale (LCS) and Functional Assessment of Cancer Therapy – Trial Outcome Index (FACT-TOI) scores and the changes over time at 3 and 12 months by radiation dose and technique. (These results at the end of chemoradiation are shown in eTable 1 and the Functional Well-Being [FWB] and Physical Well-Being [PWB] data are in eTable 2 in the Supplement). There were no significant differences in baseline QOL scores by RT dose or technique (Table 2).
Table 1.
Characteristics for Patients Consenting to QOL by Radiation Dose and Technique
| 60 Gy (n=186) |
74 Gy (n=174) |
3D-CRT (n=198) |
IMRT (n=162) |
Total (n=360) |
|
|---|---|---|---|---|---|
| RT Level | |||||
| Standard Dose:60 Gy | ----- | ----- | 104 (52.5%) | 82 (50.6%) | 186 (51.7%) |
| High Dose:74 Gy | ----- | ----- | 94 (47.5%) | 80 (49.4%) | 174 (48.3%) |
| RT Technique | |||||
| 3D-CRT | 104 (55.9%) | 94 (54.0%) | ----- | ----- | 198 (55.0%) |
| IMRT | 82 (44.1%) | 80 (46.0%) | ----- | ----- | 162 (45.0%) |
| Cetuximab | |||||
| Cetuximab | 85 (45.7%) | 81 (46.6%) | 91 (46.0%) | 75 (46.3%) | 166 (46.1%) |
| No cetuximab | 101 (54.3%) | 93 (53.4%) | 107 (54.0%) | 87 (53.7%) | 194 (53.9%) |
| Age (years) | |||||
| Median (Min-Max) | 64 (38–83) | 64 (41–83) | 64 (38–82) | 64 (38–83) | 64 (38–83) |
| Gender | |||||
| Male | 110 (59.1%) | 103 (59.2%) | 117 (59.1%) | 96 (59.3%) | 213 (59.2%) |
| Female | 76 (40.9%) | 71 (40.8%) | 81 (40.9%) | 66 (40.7%) | 147 (40.8%) |
| Race | |||||
| American Indian or Alaskan Native | 1 (0.5%) | 1 (0.6%) | 2 (1.0%) | 0 (0.0%) | 2 (0.6%) |
| Asian | 3 (1.6%) | 5 (2.9%) | 3 (1.5%) | 5 (3.1%) | 8 (2.2%) |
| Black or African American | 16 (8.6%) | 17 (9.8%) | 19 (9.6%) | 14 (8.6%) | 33 (9.2%) |
| Native Hawaiian or Other Pacific Islander | 1 (0.5%) | 0 (0.0%) | 1 (0.5%) | 0 (0.0%) | 1 (0.3%) |
| White | 164 (88.2%) | 150 (86.2%) | 171 (86.4%) | 143 (88.3%) | 314 (87.2%) |
| Unknown | 1 (0.5%) | 1 (0.6%) | 2 (1.0%) | 0 (0.0%) | |
| Zubrod PS | |||||
| 0 | 114 (61.3%) | 109 (62.6%) | 123 (62.1%) | 100 (61.7%) | 223 (61.9%) |
| 1 | 72 (38.7%) | 65 (37.4%) | 75 (37.9%) | 62 (38.3%) | 137 (38.1%) |
| PET Staging | |||||
| No | 18 (9.7%) | 20 (11.5%) | 25 (12.6%) | 13 (8.0%) | 38 (10.6%) |
| Yes | 168 (90.3%) | 154 (88.5%) | 173 (87.4%) | 149 (92.0%) | 322 (89.4%) |
| Histology | |||||
| Squamous cell | 81 (43.5%) | 82 (47.1%) | 96 (48.5%) | 67 (41.4%) | 163 (45.3%) |
| Adenocarcinoma | 73 (39.2%) | 59 (33.9%) | 69 (34.8%) | 63 (38.9%) | 132 (36.7%) |
| Large cell | 3 (1.6%) | 6 (3.4%) | 6 (3.0%) | 3 (1.9%) | 9 (2.5%) |
| NOS | 29 (15.6%) | 27 (15.5%) | 27 (13.6%) | 29 (17.9%) | 56 (15.6%) |
| AJCC Stage | |||||
| IIIA/N2 | 123 (66.1%) | 108 (62.1%) | 137 (69.2%)* | 94 (58.0%)* | 231 (64.2%) |
| IIIB/N3 | 63 (33.9%) | 66 (37.9%) | 61 (30.8%) | 68 (42.0%) | 129 (35.8%) |
| Volume PTV (cc) | (n=155) | (n=149) | (n=174) | (n=130) | |
| Median (Min-Max) | 447.3 (99.0–1851.2) | 467.5 (100.6–1836.4) | 409.2* (99.0–1836.4) | 508.3* (103.3–1851.2) | 454.8 (99.0 – 1851.2) |
| Educational Level | (n=168) | (n=162) | (n=186) | (n=144) | |
| < High School | 25 (14.9%) | 21 (13.0%) | 29 (15.6%) | 17 (11.8%) | 46 (13.9%) |
| High School | 77 (45.8%) | 65 (40.1%) | 77 (41.4%) | 65 (45.1%) | 142 (43.0%) |
| > High School | 66 (39.3%) | 76 (46.9%) | 80 (43.0%) | 62 (43.1%) | 142 (43.0%) |
| Marital Status | (n=180) | (n=170) | (n=191) | (n=159) | |
| Married/Partnered | 118 (65.6%) | 117 (68.8%) | 123 (64.4%) | 112 (70.4%) | 235 (67.1%) |
| Single/Widowed/Divorced | 62 (34.4%) | 53 (31.2%) | 68 (35.6%) | 47 (29.6%) | 115 (32.9%) |
QOL: Quality of life; Gy: Gray; 3D-CRT: Three-dimensional conformal radiation therapy; IMRT: Intensity-modulated radiation therapy; RT: radiation therapy; Min-Max: Minimum-Maximum; PET: Positron Emission Tomography; NOS: Not Otherwise Specified; AJCC: American Joint Committee on Cancer; PTV: Planning target volume; cc: cubic centimeter
< high school = 8th grade or less and 9–11th grade;
> high school = Vocational/Technical School, Associate degree/Some college, Bachelor's degree, Advanced degree
the differences between 3D-CRT and IMRT for these factors (AJCC stage and PTV volume) were significantly different (p<=0.03), but all other comparisons were not significantly different (p>0.1).
Table 2.
FACT-LCS and FACT-TOI Scores Over Time by Radiation Dose and Technique
| Baseline | Change at 3 Months | Change at 12 Months | ||||
|---|---|---|---|---|---|---|
| Treatment Arm | 60 Gy | 74 Gy | 60 Gy | 74 Gy | 60 Gy | 74 Gy |
| LCS | (n=161) | (n=152) | (n=108) | (n=111) | (n=70) | (n=67) |
| Mean (Std Dev) | 18.7 (5.1) | 19.5 (4.9) | 0.5 (5.8) | −1.7 (5.9) | −0.4 (5.0) | −0.2 (5.1) |
| Median (Min-Max) | 19.0 (3.0–28.0) | 20.0 (3.0–28.0) | 0.0 (−14.0–17.0) | −2.0 (−15.0–15.0) | 0.0 (−11.0–15.0) | −1.0 (−13.0 – 12.0) |
| Effect Size | ----- | −0.381 | 0.035 | |||
| p-value* | 0.22 | 0.02 | 0.94 | |||
| No Decline | ----- | ----- | 75 (70.1%) | 60 (55.0%) | 45 (65.2%) | 41 (61.2%) |
| Decline | ----- | ----- | 32 (29.9%) | 49 (45.0%) | 24 (34.8%) | 26 (38.8%) |
| p-value* | ----- | 0.02 | 0.62 | |||
| TOI | (n=161) | (n=152) | (n=105) | (n=108) | (n=69) | (n=67) |
| Mean (Std Dev) | 60.8 (13.4) | 61.4 (13.7) | −6.7 (16.0) | −9.8 (15.6) | −3.7 (13.3) | −4.9 (14.2) |
| Median (Min-Max) | 62.0 (25.6–83.0) | 63.0 (23.0–84.0) | −8.6 (−47.0–38.0) | −8.4 (−47.0–20.0) | −3.0 (−30.2–28.0) | −5.3 (−50.0–26.0) |
| Effect Size | ----- | −0.198 | −0.090 | |||
| p-value* | 0.69 | 0.39 | 0.79 | |||
| No Decline | ----- | ----- | 46 (43.8%) | 46 (42.6%) | 36 (52.2%) | 33 (49.3%) |
| Decline | ----- | ----- | 59 (56.2%) | 62 (57.4%) | 33 (47.8%) | 34 (50.7%) |
| p-value* | ----- | 0.89 | 0.72 | |||
| RT Technology | 3D-CRT | IMRT | 3D-CRT | IMRT | 3D-CRT | IMRT |
| LCS | (n=179) | (n=134) | (n=129) | (n=87) | (n=84) | (n=52) |
| Mean (Std Dev) | 19.1 (5.0) | 19.0 (5.0) | −1.1 (6.1) | 0.2 (5.6) | −1.0 (5.0) | 0.8 (4.9) |
| Median (Min-Max) | 20.0 (3.0–28.0) | 19.0 (3.0–28.0) | −2.0 (−14.0–15.0) | 0.0 (−15.0–17.0) | −2.0 (−11.0–12.0) | 1.0 (−13.0–15.0) |
| Effect Size | ----- | 0.214 | 0.366 | |||
| p-value* | 0.85 | 0.04 | 0.02 | |||
| No Decline | ----- | ----- | 74 (57.4%) | 61 (70.1%) | 45 (53.6%) | 41 (78.8%) |
| Decline | ----- | ----- | 55 (42.6%) | 26 (29.9%) | 39 (46.4%) | 11 (21.2%) |
| p-value* | ----- | 0.05 | 0.003 | |||
| TOI | (n=179) | (n=134) | (n=127) | (n=86) | (n=84) | (n=52) |
| Mean (Std Dev) | 61.3 (13.7) | 60.9 (13.3) | −9.0 (15.6) | −7.2 (16.2) | −6.0 (13.0) | −1.5 (14.6) |
| Median (Min-Max) | 62.0 (23.0–83.0) | 63.0 (31.0–84.0) | −8.6 (−47.0–31.0) | −8.3 (−45.0–38.0) | −7.8 (−34.0–28.0) | −2.0 (−50.0–28.0) |
| Effect Size | ----- | 0.114 | 0.336 | |||
| p-value* | 0.70 | 0.45 | 0.02 | |||
| No Decline | ----- | ----- | 54 (42.5%) | 38 (44.2%) | 36 (42.9%) | 33 (63.5%) |
| Decline | ----- | ----- | 73 (57.5%) | 48 (55.8%) | 48 (57.1%) | 19 (36.5%) |
| p-value* | ----- | 0.82 | 0.01 | |||
FACT: Functional Assessment of Cancer Therapy; LCS: Lung Cancer Subscale; TOI: Trial Outcome Index; Chemo/RT: Chemoradiotherapy; Gy: Gray; Std.Dev: Standard deviation; Min-Max: Minimum-Maximum; RT: radiation therapy
Limited to patients with baseline and relevant follow-up FACT forms.
Change is calculated by subtracting baseline from follow-up. A positive change indicates an improvement, and a negative change indicates a decrease in function.
Effect sizes between groups were calculated as the difference in mean score changes divided by the pooled standard deviation of the score changes.
p-value for continuous data is from a t-test; p-value from categorical data is from a chi-square test; all p-values are two-sided.
At the end of concurrent chemoradiation, 173 of the 313 patients with baseline QOL (55.3%) completed QOL with similar completion rates on the 60 Gy and 74 Gy arms (57.1% vs 53.2%, p=0.57). The decline in Lung Cancer Subscale (LCS) at the end of chemoradiation trended to be higher in the 74 Gy arm (32.6% vs. 45.7% p=0.08, ES= −0.31). Compared to the end of chemoradiation, more patients (219 or 70% of those with baseline QOL) completed QOL at 3 months after baseline (the primary QOL timepoint) and 9 patients (2.9%) died prior to this assessment. The proportion of completed forms at 3 months was also similar between RT dose arms (67.1% vs. 73.0%, p=0.31). The proportion of patients who reported a clinically meaningful decline (CMD) in the Lung Cancer Subscale (LCS) for the 74 Gy arm was significantly higher at 3 months than for the 60 Gy arm (29.9% vs. 45.0%, p=0.02), corresponding to a moderate effect size (ES) of 0.38 (Table 2 and Figure 2). At 12 months after baseline, 73 patients (23.3%) of the 313 who completed the baseline QOL were not alive; 137 patients (43.8%) completed QOL, corresponding to a completion rate of 57.1% among living patients. The proportion of completed forms at 12 months was again similar between the radiation (RT) dose arms (p=0.21). The decline in QOL at 12 months between the RT dose arms was similar for FACT-TOI (Trial Outcome Index), as well as all the subscales. These results continued to hold in multivariate analysis (MVA) after adjusting for potential confounding variables, including cetuximab usage, RT dosimetric factors, treatment parameters, and baseline characteristics.
Figure 2.
Percent of FACT-LCS Decline.
(FACT: Functional Assessment of Cancer Therapy; LCS: Lung Cancer Subscale; Gy: Gray; 3D-CRT: Three-dimensional conformal radiation therapy; IMRT: Intensity-modulated radiation therapy)
Within an exploratory analysis (see eTable 3 and eTable 4 in the Supplement), several dosimetric factors appeared to be significantly associated with clinically meaningful declines in QOL in both univariate and multivariate logistic regression models as follows: Lung V20 (% lung receiving >20 Gy) was associated with clinically meaningful decline (CMD) in Physical Well-Being (PWB), Functional Well-Being (FWB) and Trial Outcome Index (TOI) at end of chemoradiation; Esophagus V60 (% esophagus receiving >60 Gy) and planning target volume (PTV) were associated with clinically meaningful declines (CMD) in Physical Well-Being (PWB) and Trial Outcome Index (TOI) at 3 months. Heart V5 (% heart receiving >5 Gy) was associated with clinically meaningful decline (CMD) in Functional Well Being (FWB) at 12 months. The variations in radiation doses (between IMRT and 3D-CRT) for the lung, esophagus and heart were not significantly different among patients completing the QOL forms at baseline (see eTable 4 in the Supplement) or any subsequent timepoint. Of note, conditional survival of patients with early clinically meaningful decline (CMD) in the Lung Cancer Subscale (LCS) at the end of chemoradiation was nonsignificantly lower than those without, with 18-month survival rates 53.7% vs. 70.6%, respectively (log-rank p=0.27).
Intensity modulated RT (IMRT) was utilized in 44.1% and 46.0% of patients with baseline QOL in the 60 Gy and 74 Gy arms (p=0.72, Table 1), respectively. Of note, this study was stratified, but not randomized, by radiation technology (IMRT vs. 3-dimensional conformal RT, 3DCRT). Overall there were no significant differences in patient demographics or treatment factors between IMRT vs. 3DCRT (Table 1), with the exception that significantly more higher stage patients (43% vs. 31% stage IIIB, p=0.04) and larger planning target volumes (PTVs) (median 509 vs. 409 cc, p<0.001) were treated using IMRT (vs. 3DCRT). When analyzing results by radiation technique (Table 2 and Figure 2), patients who received IMRT had significantly less clinically meaningful decline (CMD) in the Lung Cancer Subscale (LCS) (21.2%) at 12 months compared to those treated with 3DCRT (46.4%), p=0.003, ES=0.37. Similar results at 12 months were found utilizing the FACT-TOI, Trial Outcome Index [TOI] (57% vs. 36%, p=0.01, ES=0.34). Radiation technique remained significantly associated with clinically meaningful declines (CMD) in the Lung Cancer Subscale (LCS) (OR=0.29 [0.13–0.69], p=0.005) and TOI (OR=0.42 [0.20–0.90], p=0.03) at 12 months in multivariate logistic regression models.
Beyond RT dose level, baseline QOL (PWB, FWB and FACT-TOI) was also significantly associated with survival separately in univariate and multivariate Cox regression models. Table 3 presents a multivariate Cox proportional hazard analysis between baseline FACT-TOI (Trial Outcome Index) (continuous) and survival, with adjustment for cetuximab usage, planning target volume (PTV), and heart V5 (% heart receiving >5 Gy). Every 10 points higher on the FACT-TOI (Trial Outcome Index) at baseline (for a given patient compared to another) corresponded to a 10% decreased risk of death (HR=0.901, p=0.046). Other significant variables on multivariate analysis (MVA) included planning target volume (PTV) and heart V5.
Table 3.
Multivariate Cox Model of Overall Survival
| Covariate | Comparison | Dead/Total RL |
Dead/Total Group 2 |
HR (95% CI) | p-value* |
|---|---|---|---|---|---|
| Radiation Level | High Dose vs. Standard Dose (RL) | 97/155 | 106/147 | 1.42 (1.07, 1.87) | 0.01 |
| Cetuximab Assignment | No Cetuximab vs. Cetuximab (RL) | 90/133 | 133/169 | 0.90 (0.68, 1.19) | 0.44 |
| PTV | Continuous | 203/302 | 1.001 (1.000, 1.001) | 0.04 | |
| Heart V5 | Continuous | 203/302 | 1.007 (1.002, 1.012) | 0.01 | |
| FACT-TOI | Continuous | 203/302 | 0.901 (0.813, 0.998) | 0.046 |
RL: Reference level; HR: Hazard ratio; CI: Confidence interval; PTV: Planning target volume; Heart V5: volume of heart receiving ≥ 5Gy; FACT: Functional Assessment of Cancer Therapy; TOI: Trial Outcome Index
Two-sided p-value
Underlying multivariate model developed in the primary endpoint analysis.
Baseline FACT measure was divided by 10 prior to modeling.
Discussion
Despite few differences in provider-reported toxicities between RT-dose arms, the patient reported outcomes (PROs) clearly demonstrated a clinically meaningful decline (CMD) in quality of life (QOL) on the high-dose radiation arm at 3 months, confirming the primary QOL hypothesis. Prior studies have demonstrated a “disconnect” between the patient and provider-based perspective, which often underestimates the level of symptom burden.14,15 The only clinically relevant provider-based toxicity found to be significantly different between RT-dose arms was severe esophagitis. Yet, whereas the rate of severe esophagitis at 3 months on the high-dose arm was only 21%, >50% of patients reported a clinically meaningful decline (CMD) in FACT-TOI (Trial Outcome Index) at 3 months. Interestingly, in the RTOG 0617 clinical outcomes paper1, the significant factors associated with survival on multivariate analysis were RT-dose level, planning target volume (PTV), heart dose, and severe esophagitis. When incorporating QOL into the model, baseline QOL (FACT-TOI), rather than esophagitis, was significantly associated with survival, in addition to RT-dose level, PTV and heart dose (Table 3). Prior studies have shown that QOL is significantly associated with survival in lung cancer and other cancers.16,17 In this study, every 10 points higher in the QOL (FACT-TOI) score at baseline (for a given patient compared to another) corresponded to a 10% decreased risk of death. Similarly, in another locally advanced NSCLC randomized trial, a 10-point higher baseline global QOL score corresponded to a decrease in the hazard of death by 10%.16 This clinically relevant finding suggests that QOL may be considered as a stratification factor in future locally advanced NSCLC trials.
This analysis raises a question as to whether the early decline in QOL on the high-dose radiation arm may be associated with the survival decrement in this study. Of note, patients with a clinically meaningful decline (CMD) in Lung Cancer Subscale (LCS) early on (at the completion of chemoradiation) were found to have a nonsignificantly lower 18-month survival (54%) compared to those without clinically meaningful decline (CMD) in LCS (71%). In another trial, a decline in Lung Cancer Subscale (LCS) was significantly associated with lower survival in lung cancer.18 Other important factors to consider include tumor volume and heart dose. Tumor volume is a well-known negative prognostic factor for survival.19 Heart dose also appears to be another factor that may partly explain the decline in overall survival and poorer QOL in the high-dose arm. From a dosimetric perspective, lung V20 (% of lung receiving >20 Gy) and esophagus V60 (% of esophagus receiving >60 Gy) correlated with clinically meaningful declines (CMD) in QOL at early timepoints (within 3 months), possibly due to the acute radiation effects of inflammation in these organs. Only heart V5 (% of heart receiving > 5 Gy) significantly correlated with clinically meaningful decline (CMD) with longer follow-up (at 12 months), suggesting that chronic radiation cardiac effects may be clinically relevant and deserve further study. Thus far, no single covariate explains the large survival gap between the two RT-dose arms, suggesting that the answer to this complex issue is likely multi-factorial.
The main limitation of this analysis, which affects many QOL studies, is the issue of missing data.20,21 In this study, approximately 70% of patients completed QOL at 3 months and 57% of living patients completed QOL at 12 months. While these QOL completion rates are reasonable for a locally advanced lung cancer trial22,23, it raises the possibility that there could be non-random factors underlying the missing QOL. Although matched at baseline, patients who were sicker or with poorer quality of life during the study period (or who died at earlier endpoints) could disproportionately have not completed the QOL tools. In this study, however, there were no significant differences in the associations between treatment arms and pretreatment characteristics, or treatment arms and survival between patients with or without QOL. Moreover, among patients who completed QOL, there were essentially no significant differences in demographics or treatment factors (including use of cetuximab) between arms at any QOL timepoint. Other than patient attrition (as expected in a lung cancer trial), the main reason for missing data was institutional error (such as the QOL form not being administered or collected on time). To reduce missing QOL data, RTOG has tested an electronic web-based strategy.24 This novel approach almost eliminated institutional error as the cause of missing data by using real time email reminders. A strength of this QOL analysis is that the results were not simply based on differences that were statistically significant, but more importantly, upon changes that were clinically meaningful using a validated QOL instrument. The results emphasize the importance of having a predefined clinically meaningful change upon which to interpret QOL findings.
As QOL provides data directly from the patient perspective, it provides an opportunity to explore potential strategies that might not have otherwise been appreciated. While RTOG 0617 was stratified, but not randomized, to compare intensity modulated RT (IMRT) vs. 3D conformal RT (3DCRT), less clinically meaningful decline (CMD) in the Lung Cancer Subscale (LCS) at 1 year was associated with the use of IMRT (p=0.003), despite the fact that IMRT was used to treat patients with higher stages and larger volumes. Retrospective studies have previously suggested dosimetric and/or clinical benefits of IMRT (over 3DCRT) in stage III NSCLC.25–27 IMRT facilitates integrated RT dose painting to tumor regions while minimizing dose to surrounding normal tissues when performed carefully with motion control and image-guided RT, as in this study. As previously reported1, overall, the use of IMRT versus 3D-CRT did not impact on survival in this study and a detailed analysis of this issue will be published separately. To our knowledge, RTOG 0617 is the largest prospective study incorporating QOL as an endpoint in patients treated with modern techniques of IMRT or 3DCRT for stage III NSCLC.
In conclusion, the QOL analysis of RTOG 0617 demonstrates that baseline QOL was significantly associated with survival on multivariate analysis. This analysis suggests that improved RT treatment techniques may enhance the therapeutic window for patients with lung cancer. Finally, despite few differences in provider reported toxicity between RT-dose arms, the patient reported outcomes (PROs) demonstrated significantly worse QOL in the high-dose arm at 3 months, confirming the primary QOL hypothesis.
Supplementary Material
Acknowledgements
All authors of this research paper have directly participated in the planning or analysis of the study, and have read and approved the final version submitted.
This project was supported by grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA180803 from the National Cancer Institute (NCI) and Bristol-Myers Squibb. The manuscript’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Benjamin Movsas, M.D.
Varian, Inc. – Grant: Research support to department for projects not related to this study.
Philips, Inc. – Grant: Research support to department for projects not related to this study.
Raymond B. Wynn, M.D.
RTOG – Grant: Institutional grants during the conduct of this study.
Rebecca Paulus, B.S.
National Cancer Institute – Grant #s: U10CA21661, U10CA37422.
Bristol-Myers Squibb (BMS) – Grant funds received for general study support; BMS did not have the right nor were they permitted to influence the design or conduct of the study; the collection, management, analysis and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Dr. Chen Hu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
We thank the patients who volunteered to take part in this quality of life study; caregivers of the study participants; and RTOG Data Management Center for their help in answering questions regarding the study.
Footnotes
The following authors have reported no potential conflicts of interest:
Chen Hu, PhD; Jeffrey Sloan, PhD, HSR; Jeffrey Bradley, MD; Ritsuko Komaki, MD; Gregory Masters, MD; Vivek Kavadi, MD; Samir Narayan, MD; Jeff Michalski, MD; Douglas W. Johnson, MD; Christopher Koprowski, MD; Walker J. Curran, Jr. MD; Yolanda I. Garces, MD; Rakesh Gaur, MD; John Schallenkamp, MD; Daphna Y. Gelblum, MD; Robert M. MacRae, MD; Hak Choy, MD.
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