Key Points
Question
What is the 10-year survival rate for patients with unresectable stage III non–small-cell lung cancer who are administered curative chemoradiotherapy without experiencing adverse effects?
Findings
In this phase 3 randomized clinical trial of 440 patients who were assigned to 3 treatment groups, 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. Additional cases of late toxic effects (grade 3/4) were not observed since the initial report.
Meaning
This study contributes historical control data for comparing long-term outcomes of future clinical trials of chemoradiotherapy.
Abstract
Importance
Insufficient data are available regarding the long-term outcomes and cumulative incidences of toxic effects that are associated with chemoradiotherapy (CRT) for patients with stage III non–small-cell lung cancer.
Objective
To evaluate survival and late toxic effects 10 years after patients were treated with curative CRT.
Design, Setting, and Participants
This multicenter, phase 3 West Japan Thoracic Oncology Group (WJTOG) 0105 randomized clinical trial was conducted between September 2001 and September 2005 in Japan. Patients with histologically or cytologically confirmed non–small-cell lung cancer with unresectable stage III disease were assessed for eligibility. Additional data were analyzed from January 2018 to December 2019.
Interventions
A total of 440 eligible patients were randomly assigned to groups as follows: A (control), 4 cycles of mitomycin/vindesine/cisplatin plus thoracic radiotherapy (TRT) of 60 Gy; B, weekly irinotecan/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of irinotecan/carboplatin consolidation; or C, weekly paclitaxel/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of paclitaxel/carboplatin consolidation.
Main Outcomes and Measures
The primary outcome was 10-year survival probability after CRT. The secondary outcome was late toxic effects that occurred more than 90 days after initiating CRT.
Results
From September 2001 to September 2005, 440 patients (group A, n = 146 [33.2%; median (range) age, 63 (31-74) years; 18 women (12.3%)]; group B, n = 147 [33.4%; median (range) age, 63 (30-75) years; 22 women (15.0%)]; group C, n = 147 [33.4%; median (range) age, 63 (38-74) years; 19 women (12.9%)]) were enrolled. The median (range) follow-up was 11.9 (7.6-13.3) years. In groups A, B, and C, median (range) overall survival times were 20.5 (17.5-26.0), 19.8 (16.7-23.5), and 22.0 (18.7-26.2) months, respectively, and 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. There were no significant differences in overall survival among treatment groups. The 10-year progression-free survival probabilities were 8.5%, 6.5%, and 11.1% in groups A, B, and C, respectively. Grade 3 or 4 late toxic effect rates were 3.4% (heart, 0.7%; lung, 2.7%) in group A, and those only affecting the lung represented 3.4% and 4.1% in groups B and C, respectively. No other cases of late toxic effects (grades 3/4) were observed since the initial report.
Conclusion and Relevance
In this 10-year follow-up of a phase 3 randomized clinical trial, group C achieved similar efficacy and toxic effect profiles as group A 10 years after initiating treatment. These results serve as a historical control for the long-term comparisons of outcomes of future clinical trials of CRT.
Trial Registration
UMIN Clinical Trial Registry: UMIN000030811
This randomized clinical trial examines survival rates and late toxic effects 10 years after Japanese patients with stage III non–small-cell lung cancer were treated with curative chemoradiotherapy.
Introduction
The standard curative treatment strategy for selected patients with locally advanced non–small-cell lung cancer (NSCLC) is platinum-based chemotherapy with concurrent thoracic radiotherapy (TRT).1,2 The initial report of the West Japan Thoracic Oncology Group (WJTOG) 01053 trial establishes weekly carboplatin plus paclitaxel combined with TRT as the standard regimen among the 3 regimens because of its favorable toxic effect profile. Other studies found that concurrent chemoradiotherapy (CRT) with former-generation chemotherapy regimens achieved median survival of 16.1 to 30.0 months and 7-year overall survival (OS) rates ranging from 12.0% to 23.1%.4,5,6 However, limited data are available for patients who underwent concurrent CRT with third-generation chemotherapy who were followed up for more than 10 years.
Methods
This multicenter, noninferiority phase 3 randomized clinical trial was conducted between September 2001 to September 2005 in Japan (Supplement 1). Concurrent TRT was administered to compare third-generation vs second-generation chemotherapy of patients with unresectable stage III NSCLC. The eligibility criteria were published.3 Patients provided written informed consent, and the ethics committees of the participating institutions approved this study. Patients were randomly assigned to stratified treatment groups as follows: sex, clinical stage, and institution (eFigure 1 in Supplement 2).
The original primary end point and sample size are shown in the eMethods Supplement 2. Survival curves and 5-year, 7-year, and 10-year survival probabilities were calculated using the Kaplan-Meier method. Late toxic effects were defined as adverse events occurring more than 90 days after TRT initiation. Late radiation-induced adverse effects were assessed according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring System (National Cancer Institute Common Terminology Criteria, version 2.0).7 All analyses were performed using SAS, version 9.4 (SAS Institute). All P values were reported as 2-sided, and P < .05 was considered to be statistically significant.
Results
Patients
Among the 456 patients, 153 (33.6%), 152 (33.3%), and 151 (33.1%) were allocated to groups A, B, and C, respectively. Additional data were retrospectively analyzed from January 2018 to December 2019. The safety and antitumor effects of treatments were eventually assessed using the data of 440 patients, and 109 of 456 patients (23.9%) were lost to follow-up mainly because of a lack of medical records (eFigure 2 in Supplement 2). Baseline patient characteristics were well balanced among the groups (Table 1), and patient characteristics that were handled as missing data were not significantly different from the overall patient characteristics (eTable 1 in Supplement 2).
Table 1. Patient Characteristics.
| Characteristics | Group, No. (%) | P value | ||
|---|---|---|---|---|
| A (n = 146) | B (n = 147) | C (n = 147) | ||
| Age, median (range), y | 63.0 (31-74) | 63.0 (30-75) | 63.0 (38-74) | .40 |
| ≥65 | 56 (38.4) | 66 (44.9) | 62 (42.2) | .52 |
| ≥70 | 27 (18.5) | 37 (25.2) | 31 (21.1) | .39 |
| Sex | ||||
| Men | 128 (87.7) | 125 (85.0) | 128 (87.1) | .82 |
| Women | 18 (12.3) | 22 (15.0) | 19 (12.9) | |
| Performance status | ||||
| 0 | 56 (38.4) | 66 (44.9) | 65 (44.2) | .45 |
| 1 | 90 (61.6) | 81 (55.1) | 81 (55.1) | |
| 2 | 0 | 0 | 1 (0.70) | |
| Smoking history | ||||
| Absence | 17 (11.6) | 15 (10.2) | 9 (6.1) | .23 |
| Presence | 129 (88.4) | 132 (89.8) | 138 (93.9) | |
| Weight loss during the 6-mo period | ||||
| <5% | 92 (63.0) | 100 (68.0) | 95 (64.6) | .70 |
| ≥5% | 28 (19.2) | 24 (16.3) | 29 (19.7) | |
| Unknown | 26 (17.8) | 23 (15.6) | 23 (15.6) | |
| Stage | ||||
| IIIA | 45 (30.8) | 49 (33.3) | 48 (32.7) | .90 |
| IIIB | 101 (69.2) | 98 (66.7) | 99 (67.3) | |
| T status | ||||
| T0 | 1 (0.70) | 0 | 0 | .27 |
| T1 | 13 (8.90) | 22 (15.0) | 17.0 (11.6) | |
| T2 | 36 (24.7) | 38 (25.9) | 26.0 (17.7) | |
| T3 | 24 (16.4) | 16 (10.9) | 27.0 (18.4) | |
| T4 | 72 (49.3) | 71 (48.3) | 77.0 (52.4) | |
| N status | ||||
| N0 | 11 (7.5) | 13 (8.8) | 9 (6.1) | .63 |
| N1 | 8 (5.5) | 5 (3.4) | 7 (4.8) | |
| N2 | 94 (64.4) | 86 (58.5) | 99 (67.3) | |
| N3 | 33 (22.6) | 43 (29.3) | 32 (21.9) | |
| Histology | ||||
| Adenocarcinoma | 58 (39.7) | 69 (46.9) | 48 (47.2) | .45 |
| Squamous cell carcinoma | 88 (60.3) | 78 (53.1) | 99 (57.8) | |
Efficacy
The median (range) follow-up time of the surviving patients was 11.9 (7.6-13.3) years. The updated median OS rates were 20.5 months (95% CI, 17.5–26.0), 19.8 months (95% CI, 16.7–23.5), and 22.0 months (95% CI, 18.7–26.2) in groups A, B, and C, respectively (Figure, A). Consistent with the initial report, there was no significant difference in OS among the 3 groups (group A vs B: hazard ratio [HR], 1.18; 95% CI, 0.92-1.51; P = .19; group A vs C: HR, 1.01; 95% CI, 0.79-1.30; P = .94; group B vs C: HR, 0.85; 95% CI, 0.67-1.90; P = .21). In groups A, B, and C, the 5-year survival probabilities were 20.8%, 16.0%, and 18.3%, respectively; the 7-year survival probability was 14.8%, 13.9%, and 16.3%, respectively; and the 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. Median progression-free survival (PFS) rates were 8.3 months (95% CI, 7.4–9.7), 7.9 months (95% CI, 6.9–8.5), and 9.5 months (95% CI, 7.8–10.5) in groups A, B, and C, respectively (Figure, B). In groups A, B, and C, the 5-year PFS probabilities were 10.2%, 10.8%, and 12.3%, respectively; the 7-year PFS probability was 10.2%, 7.9%, and 12.3%, respectively; and the 10-year PFS probabilities were 8.5%, 5.9%, and 11.1%, respectively. The cumulative rates of recurrence by relapse site, type of poststudy treatment, and cause of death are shown in eFigure 3 and eTables 2 and 3 in Supplement 2. The status of epidermal growth factor receptor sequence variants was unknown, although 65 patients (14.7%) received an epidermal growth factor receptor tyrosine kinase inhibitor.
Figure. Comparison of Overall Survival (OS) and Progression-Free Survival (PFS) Among the 3 Randomly Assigned Groups.
The P value represents superiority, not noninferiority. NA indicates not applicable.
Safety
Late radiation toxic effects are listed in Table 2. The proportions of grade 3 or 4 late toxic effects were 3.5% (lung, 2.8%; heart, 0.7%; n = 146), 3.4% (lung, 3.4%; n = 147), and 4.7% (lung, 4.7%; n = 147) in groups A, B, and C, respectively. Ten patients (6.9%) in group A, 12 (8.2%) in group B, and 11 (7.4%) in the CRT group experienced a grade 2 or higher lung toxic effects. No additional cases of grade 3 or 4 late toxic effects were recorded since the initial report.
Table 2. Late Radiotherapy Morbidity.
| Toxic effects | Study group | Grade, No. (%) | ||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| Esophagus | A | 2 (1.4) | 0 | 0 | 0 | 0 |
| B | 1 (0.7) | 0 | 0 | 0 | 0 | |
| C | 0 | 1 (0.7) | 0 | 0 | 0 | |
| Heart | A | 0 | 0 | 1 (0.7) | 0 | 0 |
| B | 0 | 0 | 0 | 0 | 0 | |
| C | 0 | 0 | 0 | 0 | 0 | |
| Lung | A | 36 (24.7) | 6 (4.1) | 2 (1.4) | 2 (1.4) | 0 |
| B | 33 (22.4) | 7 (4.8) | 4 (2.7) | 1 (0.7) | 0 | |
| C | 36 (24.5) | 4 (2.7) | 3 (2.0) | 3 (2.0) | 1 (0.7) | |
| Skin | A | 2 (1.4) | 0 | 0 | 0 | 0 |
| B | 2 (1.4) | 0 | 0 | 0 | 0 | |
| C | 2 (1.4) | 0 | 0 | 0 | 0 | |
| Spine | A | 1 (0.7) | 0 | 0 | 0 | 0 |
| B | 1 (0.7) | 0 | 0 | 0 | 0 | |
| C | 1 (0.7) | 0 | 0 | 0 | 0 | |
Discussion
To our knowledge, this was the first multicenter phase 3 study to demonstrate the 10-year survival and cumulative incidences of toxic effects associated with concurrent CRT with third-generation chemotherapy for unresectable stage III NSCLC. According to the results of the PACIFIC trial of durvalumab, a monoclonal antibody against programmed cell death 1 ligand 1, consolidation after CRT became the standard of care for unresectable stage III NSCLC.8 In the updated survival data of the PACIFIC trial, the 36-month OS rates for durvalumab and placebo were 83.1% and 43.5%, respectively.9 In this study, 36-month OS rates were approximately 25% to 35% in each group, which were worse than that of the placebo group in the PACIFIC trial. This may be explained by the PACIFIC trial’s exclusion of patients who experienced disease progression or who had poor performance status and died within 42 days after radiation therapy terminated.
In contrast, the latest data (NRG Oncoclogy RTOG 0617) for long-term outcomes of CRT without durvalumab show that the standard dose (60 Gy) with concurrent chemotherapy should remain the standard of care and that the highest 5-year OS rate is 32.1% for stage III NSCLC.10 The most important difference in our study is the radiation technique. The RTOG 0617 trial used radiation therapy with intensity-modulated radiation therapy or 3-dimensional conformal external beam radiation therapy, which are becoming the current standard of radiotherapy.11 Intensity-modulated radiation therapy improves the coverage of tumors and enhances the therapeutic ratio by avoiding adjacent organs at risk and achieves favorable outcomes compared with historical controls.12 Furthermore, RTOG 0617 used positron emission tomography (PET) staging of approximately 90% of enrolled patients. Positron emission tomography was not available during our study, and staging was performed using computed tomography and magnetic resonance imaging. Patients with micrometastases that could be detected only by PET were allowed to enroll.
The overall proportions of late grade 2 or higher lung toxic effects were similar, and the incidences of grades 3 and 4 esophageal and cardiac toxic effects were relatively low in each group. In RTOG 0617, the percentages of heart volumes receiving 5 or more Gy and 30 or more Gy were 50.4% and 20.0% in the standard dose groups, respectively. Grade 3 or higher heart toxic effects were experienced by 31 patients (6.4%). In this case, reduced heart toxic effects may be explained by most patients adhering to the required total dose that was delivered to the entire whole heart, which should be less than 45 Gy, whereas the dose to half the heart volume should be less than 50 Gy. Furthermore, we strictly excluded patients with a history of heart disease.
Limitations
The study’s most substantial limitation is that the standard of care changed with the approval of the PACIFIC regimen. Furthermore, intensity-modulated radiation therapy and PET staging were not available at all institutions when our study began, its retrospective nature limits the interpretations of toxic effect assessments, and 23.9% of patients were lost to follow-up.
Conclusions
In a 10-year follow-up of CRT, the efficacies and toxic effects of groups A, B, and C were similar. The results of this study serve as a historical control for long-term outcomes of future clinical trials of CRT for unresectable stage III NSCLC.
Trial protocol
eMethods. Statistical analysis in the original report
eFigure 1. Study design
eFigure 2. CONSORT diagram
eFigure 3. Cumulative rates or recurrence by relapse site
eTable 1. Patients' characteristics handled as missing data
eTable 2. Post-treatment after progression
eTable 3. Cause of death
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eMethods. Statistical analysis in the original report
eFigure 1. Study design
eFigure 2. CONSORT diagram
eFigure 3. Cumulative rates or recurrence by relapse site
eTable 1. Patients' characteristics handled as missing data
eTable 2. Post-treatment after progression
eTable 3. Cause of death
Data sharing statement
