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Long-Term Results of a Trial of Concurrent Chemotherapy and Escalating Doses of Radiation for Unresectable Non–Small Cell Lung Cancer: NCCTG N0028 (Alliance)
Journal of Thoracic Oncology, Volume 12, Issue 4, April 2017, Pages 697 - 703
Commentary by Tom Stinchcombe
The publication by Schild et al reports the long-term results of a phase I/II trial concurrent chemotherapy (carboplatin and paclitaxel weekly) with escalating dose of radiation in unresectable non-small cell lung cancer (NSCLC). The phase 2 portion of the trial was never completed. The maximum tolerated disease was 74 Gy in 37 fractions. Of the 25 patients enrolled 20 patients had stage III disease. The median survival and 5-year survival among patients with stage III NSCLC was 39.8 months and 15%, respectively. Grade 5 adverse events occurred in 4 of the 25 patients and included pneumonitis, infection/febrile neutropenia (2 patients), and gastrointestinal hemorrhage. Importantly, each radiation treatment plan was reviewed for quality of assurance before any therapy and any deviations from the guidelines were corrected before treatment was initiated. The patients treated on this trial had numerically lower radiation dose to heart than patients in the RTOG 0617 high dose arm. The careful quality assurance of radiation treatment planning may have contributed to the good outcomes observed on this trial. The use of high dose thoracic radiation therapy should not be done outside of a clinical trial, based on the results of RTOG 0617 which revealed an inferior survival with 74 Gy compared to the 60 Gy.
Oncogene addiction in non-small cell lung cancer: Focus on ROS1 inhibition
Francesco Facchinettia, Giulio Rossi, , Emilio Bria, , Jean-Charles Soria, Benjamin Besse, Roberta Minari, , Luc Friboulet, Marcello Tiseo
Cancer Treatment Reviews 55 (2017) 83–95
Crizotinib is approved in the United States and Europe for treatment of ROS1 rearranged non-small cell lung cancer. The detection of this rare oncogenic driver can be challenging with concerns about false positive and false negative test results. The two molecular approaches for diagnosis include in-situ testing (fluorescence in situ hybridization and immunohistochemistry) and extractive testing (real time PCR and next generation sequencing). Each of these methods has strengths and weaknesses which are reviewed in this publication. The European Board of pathologists recently proposed a clinical practice algorithm of IHC screening and further confirmation by ROS1 FISH assay in the IHC positive and cases where there is doubt about the accuracy of the results. There is a tendency to think of ALK and ROS1 interchangeably since both are sensitive to crizotinib, but there are important differences. For example of the second generation ALK inhibitor ceritinib is only slightly more active than crizotinib and alectinib is inactive. Similar to ALK acquired resistance mutations develop and the specific mutation (e.g. L1951R, S1968Y/F, L2026M, G2032R, and D2033N) may impact the activity of tyrosine kinase inhibitors. A number of clinical trials are enrolling treatment naïve, and patients who have previous received crizotinib.
This phase I/II trial was designed to determine the maximally tolerated dose of thoracic radiotherapy as part of a combined modality approach. This report includes the long-term outcomes of patients treated on this study. The phase II portion was never completed, as RTOG-0617 opened before it was concluded.
In this study, the maximally tolerated dose was defined as 74 Gy of radiation in 37 fractions. Twenty-five patients with unresectable NSCLC were treated with 2-Gy daily fractions and concurrent weekly carboplatin and paclitaxel. Of these patients, 20 had stage III disease and five had stage I or II disease.
Patients were followed until death or for a minimum of 5 years in the case of survivors. The median and 5-year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I or II disease, and 39.8 months and 15% in patients with stage III disease.
The median survival of the stage III patients was quite favorable. We believe that this may have been due to a robust central review program of radiotherapy plans before treatment, ensuring compliance with protocol guidelines along with very low exposure of the heart to radiotherapy. Further improvements in 5-year survival will likely require research on both systemic therapy and thoracic radiotherapy. Potential therapeutic modalities that may aid in these efforts include immunotherapy, targeted therapy, improved imaging, adaptive radiotherapy, simultaneous integrated boost techniques, novel dose fractionation regimens, and charged particle therapy.
Keywords: Chemoradiotherapy, Dose escalation, 3D radiotherapy, Unresectable non–small cell lung cancer.
Lung cancer is the most common cause of cancer deaths in the United States, resulting in an estimated 224,390 new cases diagnosed and 158,080 deaths in 2016.1 Most patients are not candidates for resection because they are not fit enough for surgery, have unresectable disease, or have metastases at the time of diagnosis. Today, the standard of care for patients with NSCLC who are not candidates for resection is stereotactic body radiation therapy for those with early disease and chemoradiotherapy for those with locally advanced disease.2 The chemotherapy and thoracic radiotherapy (TRT) are best administered concurrently in patients fit enough to withstand the rigors of combined modality therapy.3
Progress in the treatment of lung cancer has occurred over several years. In 1966, Wolf et al. reported on a phase III trial that randomized patients with localized advanced lung cancer to either TRT or a placebo.4 Total doses ranged from 40 to 50 Gy in daily doses of 1.5 to 2.0 Gy. The median survival of patients undergoing TRT was 142 days compared with 112 days (p = 0.05) for the patients who received placebo. This established the role of TRT for unresectable lung cancer. The Radiotherapy and Oncology Group (RTOG) (now NRG Oncology) performed a trial, RTOG 7301, that investigated various dose fractionation regimens. Patients with locally advanced NSCLC received TRT alone in 2-Gy daily fractions to total doses of 60 Gy, 50 Gy, or 40 Gy. A dose of 60 Gy was found to be better than 50 or 40 Gy in terms of local control.5 Since that time, 60 Gy in 30 fractions has been considered a standard regimen. After this report, randomized trials found that the addition of induction chemotherapy to TRT improved survival.6, 7, and 8 Later trials found that concurrent chemoradiotherapy was superior to sequential therapy.3 and 9
Questions remain as to what the optimal dose fractionation of TRT is when used as part of a combined approach. There is a widely held opinion that 60 Gy is inadequate to sterilize most large epithelial malignancies. This was based on classic tumor dose-response studies10 and a large trial that included biopsy specimens obtained after combined modality therapy.7
There were three phase I trials performed that sought to define the maximally tolerated dose (MTD) of TRT that could be administered concurrently with weekly paclitaxel and carboplatin. Two of the studies, RTOG 0117 and NCCTG N0028, established the MTD of TRT to be 74 Gy when given in 2-Gy daily fractions with concurrent paclitaxel and carboplatin.11, 12, and 13 The third trial included induction chemotherapy followed by concurrent chemoradiotherapy, with doses escalated from 60 to 74 Gy in 2-Gy daily fractions. They found no dose-limiting toxicity (DLT) within this dose range and thus did not define the MTD.14
The present analysis examines the long-term outcomes of patients treated as part of NCCTG N0028. After the phase I portion of the trial, accrual increased at that dose level as part of the phase II portion of the study. This accrual was curtailed as RTOG 0617/NCCTG 0628/CALGB 30609 was opened. It was a phase III trial that randomized patients to concurrent chemotherapy (paclitaxel and carboplatin) and either 60 Gy or 74 Gy of radiotherapy (RT) in 2-Gy daily fractions. A second randomization that included either cetuximab or no cetuximab was later added.
Material and Methods
Patients included in this trial had surgically or medically unresectable biopsy-proven NSCLC, an Eastern Cooperative Oncology Group performance status of 1 or less, weight loss of less than 10% in the prior 3 months, no prior treatment for the lung cancer, and adequate pulmonary and laboratory parameters. Required laboratory parameters included an absolute neutrophil count of at least 1500/mL, a platelet count of at least 100,000/mL, a total bilirubin level not exceeding 1.5 times the upper limit of normal, an aspartate transaminase level not exceeding three times the upper limit of normal, and a creatinine clearance of at least 40 mL/min. Adequate pulmonary function was defined as a forced expiratory volume in 1 second of at least 1 liter. Staging included a medical history and physical examination, a chest radiograph, a computed tomography scan, a chemistry panel, and a complete blood cell count. Patients with supraclavicular adenopathy or more than “minimum” pleural effusions were not eligible. This study was approved by each participating institutional review board, and all patients provided signed informed consent based on international standards. Of these 25 patients, 20 had stage III disease and five had stage I or II disease.
During TRT, concurrent chemotherapy was administered weekly and included intravenous carboplatin (area under the curve = 2) and paclitaxel (50 mg/m2). The patients did not receive planned chemotherapy after completing the TRT.
The TRT included daily doses of 2 Gy on weekdays to an initial dose of 70 Gy (dose level 1). The total dose was escalated in 4-Gy increments until the MTD was determined by utilizing a “cohorts of three” study design for the phase I portion. The clinical target volume was based on computed tomography findings and included the primary tumor plus adenopathy (any lymph node >1 cm in short diameter). The planning target volume (PTV) included the clinical target volume plus respiratory motion. The TRT was delivered by using three-dimensional treatment planning with fields that included 1.5-cm margins between the PTV and the block edge, ensuring adequate disease coverage. Multiple fields were used without elective nodal RT to adjacent, clinically negative nodes.
The dose was prescribed to an isodose curve that encompassed at least 95% of the PTV. No more than 20% of the PTV received more than 110% of the prescribed dose. No more than 1% of the PTV received less than 93% of the prescribed dose. No more than 1% or 1 cm2 of the tissue outside the PTV received more than 110% of the prescription dose. Treatment was delivered with 6- or 10-MV x-ray beams. Tissue inhomogeneity corrections were not used. The following dose-volume limitations were required: none of the spinal cord received more than 48 Gy, no more than 40% of the total lung volume received more than 20 Gy, the entire circumference of the esophagus did not receive more than 60 Gy, the brachial plexus did not receive more than 60 Gy, one-third of the heart did not receive more than 60 Gy, two-thirds of the heart could not receive more than 50 Gy, and the entire heart did not receive more than 40 Gy. Every effort was made to avoid the overlap of all treatment fields on skin or subcutaneous tissues.
A radiation oncologist (S.E.S.) and a physicist (Geoffrey Ibbott, PhD, M.D. Anderson Cancer Center, Houston, Texas) reviewed each plan for quality assurance before any therapy. Any deviations from the guidelines were corrected before treatment. Three-dimensional treatment planning was used; most plans included a five-field or six-field approach.
The MTD was defined as the highest dose at which no more than one patient out of six had DLT, with the next higher dose resulting in no more than two of six patients having DLT. The DLT was defined as grade 3 or greater esophagitis or pneumonitis or grade 4 or greater radiation dermatitis, hematologic toxicity (for 5 or more days or with fever), dyspnea, or other nonhematologic toxicity. Adverse events (AEs) were graded by using the Common Toxicity Criteria Version 2.0. Any patient failing to complete therapy (defined as RT and chemotherapy) for any reason other than toxicity attributable to study treatment was considered not evaluable and was replaced. Dose escalation was performed after patients in a cohort were observed for a minimum of 1 month after the completion of RT.
A total of 25 evaluable patients were treated on this trial from July 2002 to January 2008. Included were seven women and 18 men with ages ranging from 48 to 83 years (median 71 years). Clinical stages included I or II (five patients) and III (20 patients). See Table 1 for the baseline characteristics of the patients treated on this trial.
Patient Characteristics (N = 25)
|Median age (range), y||71 (48–83)|
|Race, n (%)|
|American Indian or Alaska Native||1 (4.0%)|
|Sex, n (%)|
|Performance score, n (%)|
|Weight loss, n (%)|
|Smoking status, n (%)|
|Never smoked||2 (8.0%)|
|Former smoker||15 (60.0%)|
|Current smoker||8 (32.0%)|
|Stage, n (%)|
|Histologic type, n (%)|
|NSCLC (not otherwise specified)||8 (34.0%)|
|Squamous cell||8 (32.0%)|
|Large cell neuroendocrine||1 (4.0%)|
The phase I portion of the trial followed a cohorts of three study design. The first three patients were treated at dose level 1(70 Gy in 35 fractions), with none having a DLT. The second cohort of three patients received 74 Gy in 37 fractions with no DLTs. Three patients were then treated at the third dose level (78 Gy in 39 fractions). In one of the first three evaluable patients receiving 78 Gy, a DLT developed during the observation period. One more patient was treated to 78 Gy and had a DLT. Then, three more patients were treated at the second dose level, 74 Gy. One of the six patients treated at dose level 2 had a DLT, and the phase I portion of the trial was closed.13 Of the 15 patients, 13 evaluable patients received protocol treatment. Twelve more patients were treated at the MTD of 74 Gy. Accrual stopped when RTOG 0617 opened. Therefore, a total of three patients received 70 Gy, 18 patients received 74 Gy, and four patients received 78 Gy.
Patients were followed until death or, in the case of survivors, for a minimum of 5 years after registration. All data were censored at 5 years for those alive longer than 5 years. Progression-free survival (PFS) and survival data were analyzed. Median and 5-year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I/II disease, and 39.8 months and 15% in patients with stage III disease (Fig. 1A and B). PFS values are shown in Figure 1C and D. The 95% confidence intervals for both survival and PFS are shown in Figure 1B and D.
(A) Overall survival of the entire cohort censored at 5 years. (B) Overall survival by stage. (C) Progression-free survival of the entire cohort. (D) Progression-free survival by stage. KM Est, Kaplan-Meier estimate; CI, confidence interval; NA, not available.
Dosimetry information for the lung and heart exposures were collected and can be found in Table 2. Toxicity (AEs) was evaluated by using the Common Toxicity Criteria for Adverse Events, version 2, and is summarized in Tables 3 and 4. Overall, grade 3, 4, and 5 AEs occurred in 60%, 4%, and 16% of patients, respectively. The distribution of hematologic and nonhematologic AEs is shown in Table 3, and specific systems affected by these AEs are shown in Table 4. Grade 5 toxicity occurred in four of 25 patients (16%) and included pneumonitis, infection/febrile neutropenia (two patients), and gastrointestinal hemorrhage.
TRT Heart and Lung Dosimetry
(N = 25)
(N = 105)
|V20: % of lung volume receiving ≥20 Gy|
|V5: % of lung volume receiving ≥5 Gy|
|Mean lung dose, Gy|
|Heart V30: % of heart volume receiving 30 Gy|
|Heart V50: % of heart volume receiving 50 Gy|
|Heart V60: % of heart volume receiving 60 Gy|
TRT, thoracic radiotherapy; NA, not available.
Summary of Maximum Adverse Events (Regardless of Attribution)
|Type of Adverse Event||n||(%)|
|Grade 1 event||(0.0%)|
|Grade 2 event||5||(20.0%)|
|Grade 3 event||15||(60.0%)|
|Grade 4 event||1||(4.0%)|
|Grade 5 event||4||(16.0%)|
|Grade 1 event||3||(12.0%)|
|Grade 2 event||11||(44.0%)|
|Grade 3 event||9||(36.0%)|
|Grade 4 event||1||(4.0%)|
|Grade 5 event||(0.0%)|
|Grade 1 event||(0.0%)|
|Grade 2 event||8||(32.0%)|
|Grade 3 event||13||(52.0%)|
|Grade 4 event||(0.0%)|
|Grade 5 event||4||(16.0%)|
Note: Numbers reported for each grade represent the numbers of patients for whom the given grade of adverse event was the maximum experienced.
Detailed Analysis of Adverse Events
|Type||Grade of Adverse Event|
|1 (Mild)||2 (Moderate)||3 (Severe)||4 (Life Threatening)||5 (Lethal)|
Note: Maximum grade per patient per body system regardless of attribution. Number of evaluable patients: 25.
Patterns of failure were also studied and are found in Table 5. Nineteen patients had progression, and of these patients, three had no specific sites recorded. Isolated local failure alone occurred in four of 25 patients (16%) (three in-field failures and one out-of-field failure), distant failure alone occurred in 11 patients (44%), and both local and distant failure occurred in one patient (4%).
Patterns of Failure (n = 19)
|Sites of Progression||n (%)|
|Distant alone||11 (44%)|
|Distant + locally regional (in-field)||1 (4%)|
|Local regional (in-field)||3 (12%)|
|Local regional (out of field)||1 (4%)|
|Information lacking on sites of failure||3 (12%)|
|Total distanta||12 (48%)|
|Total local-regional||5 (20%)|
a adrenal, brain, liver, lung, spine, or soft tissue
This is the only phase 1 study for unresectable NSCLC that has included concurrent carboplatin, paclitaxel, and escalating doses in daily doses of 2 Gy alone. RTOG 0017 contained a phase 1 portion that included various daily doses, although it too arrived at the MTD being 74 Gy in 37 fractions. The median survival was 39.8 months in stage III patients in the current study and 21.6 months in the phase II portion of the RTOG 0117.11 The median survival was 52.9 months in stage I or II patients in the current study. These studies and others led to the phase III randomized trial RTOG 0617/NCCTG 0628/CALGB 30609.15 As in NCCTG 0028 and RTOG 0117, concurrent carboplatin and paclitaxel were administered with 74 Gy or 60 Gy of radiation in 2-Gy daily fractions, which resulted in median survival times of 20.3 and 28.7 months, respectively. Thus, from the aforementioned data one can conclude that RTOG 0117 and RTOG 0617 found that concurrent chemotherapy plus high-dose conventionally fractionated TRT (74 Gy) resulted in virtually identical median survival times in locally advanced NSCLC of 21.6 and 20.3 months. Thus, the investigators’ expectations were met from this perspective. The surprising finding was that the patients in the low-dose arm receiving only 60 Gy achieved a favorable median survival of 28.7 months. However, this should not have been a complete surprise as there was evidence published that patients treated with concurrent doublet chemotherapy and conventional doses of involved field RT did have similarly favorable median survival.16 and 17 It appears that involved field TRT appears to increase survival by lessening the toxicity resulting from irradiating greater volumes of lung, esophagus, and heart than when one electively irradiates clinically negative lymph nodes in the chest. One lesson was that high-dose TRT (74 Gy) may also be decreasing survival compared with lower-dose TRT (60 Gy), related to excessive heart exposure.15
NCCTG N0028 achieved very high median survival of 39.8 months in stage III patients. This may be due in part to the fact that the patients treated on NCCTG N0028 had very small heart exposures, with median V40 and V50 values of less than 1% and a median V60 value of 0%. Additionally, all plans were double-checked for protocol compliance before therapy, which may have aided in protocol compliance and outcome. Also interesting was the 5-year survival rate of 15% in stage III patients in NCCTG N0028; the patterns of failure data found on Table 5 suggest that that distant failure continues to be the dominant pattern of failure. Thus, improving systemic therapy with new strategies will be critical to decreasing mortality further. In spite of relatively high median survival results, grade 5 toxicity resulting in death was also high, occurring in four of 25 patients (16%).
Investigators continue to experiment with methods to potentially enhance the survival of patients with NSCLC who receive TRT. Progress was made with induction chemotherapy followed by TRT.18 Then, concurrent combined modality therapy was determined to be superior to sequential therapy.3 and 9 Recent RT advances include the use of involved field TRT, which has improved survival, and intensity-modulated RT, which has decreased pneumonitis.16, 17, and 19 Both hyperfractionation and hypofractionation have led to favorable survival outcomes as well.20 and 21 RTOG is currently investigating TRT dose intensification with adaptive photon therapy and improving the dose distribution with proton therapy. The Alliance has been investigating targeted therapy and immunotherapy with TRT.
This study helped establish the MTD for TRT when administered in conventional 2-Gy daily fractions with concurrent carboplatin and paclitaxel. It was referenced in RTOG 0617/NCCTG 0628/CALGB 30609 as aiding in the selection of the high-dose program. Although the survival in the high-dose arm of that trial was inferior to that in the standard (60-Gy) arm, the present study resulted in a very high median survival for patients with stage III NSCLC. This could be because it was small and the result of chance or possibly due to having seasoned investigators checking all plans before therapy. Additionally, the patients in this trial did have very low RT doses to the heart, which may have enhanced patient survival. In any case, we continue to explore various TRT options to improve patient outcome. Improvements in care for patients with unresectable NSCLC will require improving both systemic therapy and TRT.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under the award numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology) and by the following U.S. Public Health Service grants: P30CA015083, CA025224, U10CA035101, U10CA035103, U10CA035415, U10CA037404, U10CA037417, U10CA060276, and U10CA180790. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The following institutions participated in this study: Iowa-Wide Oncology Research Coalition National Community Oncology Research Program, Des Moines, Iowa (Robert Behrens, UG1CA189816); Mayo Clinic Lead Academic Participant, Rochester, Minnesota (Steven Alberts, U10CA180790); Missouri Valley Cancer Consortium, Omaha, Nebraska (Gamini Soori); and Sanford National Cancer Institute Community Oncology Research Program of the North Central Plains, Sioux Falls, South Dakota (Preston Steen, UG1CA189825).
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a Department of Radiation Oncology, Mayo Clinic, Scottsdale, Arizona
b Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota
c Division of Medical Oncology, Phoenix, Arizona
d Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa
e Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
f Carolinas Medical Center/Levine Cancer Institute-University, Charlotte, North Carolina
g Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
h Division of Pulmonary Medicine, Mayo Clinic, Rochester, Minnesota
i Denver Jewish Respiratory Hospital, Denver, Colorado
∗ Corresponding author. Address for correspondence: Steven E. Schild, MD, Department of Radiation Oncology, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ, 85259.
Disclosure: The authors declare no conflict of interest.
© 2017 International Association for the Study of Lung Cancer, Published by Elsevier B.V.