Article 1 1 Original research Non-Small Cell Lung Cancer
January 2017

John Varlotto
Paul Stephen Rava
Nitin Ohri
Joel S Greenberger firstname.lastname@example.com
Mark E Bernard
Department of Radiation Oncology
University of Pittsburgh Cancer Institute
PittsburghPAUSA

Scott M Glaser
Department of Radiation Oncology
University of Pittsburgh Cancer Institute
PittsburghPAUSA

Beant S Gill
Department of Radiation Oncology
University of Pittsburgh Cancer Institute
PittsburghPAUSA

Sushil Beriwal
Department of Radiation Oncology
University of Pittsburgh Cancer Institute
PittsburghPAUSA

Dwight E Heron
Department of Radiation Oncology
University of Pittsburgh Cancer Institute
PittsburghPAUSA

James D Luketich
Department of Thoracic Surgery
Medical Center
University of Pittsburgh
PittsburghPAUSA

David M Friedland
Division of Hematology/Oncology
Department of Medicine
Medical Center
University of Pittsburgh
PittsburghPAUSA

Mark A Socinski
Division of Hematology/Oncology
Department of Medicine
Medical Center
University of Pittsburgh
PittsburghPAUSA

Joel S Greenberger
Department of Radiation Oncology
University of Pittsburgh Cancer Institute
PittsburghPAUSA

University of Massachusetts Medical Center
USA

Albert Einstein College of Medicine
UMass Memorial Medical Center
USA, USA

Article 1 1 Original research Non-Small Cell Lung Cancer

Front. Oncol
71January 201710.3389/fonc.2017.00001Specialty section: This article was submitted to Radiation Oncology, Received: 05 April 2016 Accepted: 05 January 2017 Published: 23 January 2017Frontiers in Oncology | www.frontiersin.org Edited by: Reviewed by: *Correspondence: Citation: Bernard ME, Glaser SM, Gill BS, Beriwal S, Heron DE, Luketich JD, Friedland DM, Socinski MA and Greenberger JS (2017) Results of a Single Institution Experience with Dose-Escalated Chemoradiation for Locally Advanced Unresectablensclcdose escalationchemoradiationesophagitispneumonitis
Background:We determined factors associated with morbidity and outcomes of a series of non-small cell lung cancer (NSCLC) patients treated with dose-escalated chemoradiotherapy at the University of Pittsburgh Lung Cancer Program.Methods and materials:The records of 170 stage III NSCLC patients treated with definitive intent were retrospectively reviewed. All patients received four-dimensional CT simulation scan and had respiratory gating if tumor movement exceeded 5 mm. Overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated using log-rank and Cox regression analysis.The reviewer PR and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.

results: For the present series of patients, median follow-up was 36.6 months, median survival 27.4 months, and the 2-and 4-year OS was 56.0 and 30.7%, respectively. The 4-year LRC and FFDM were 43.9 and 40.7%, respectively. No benefit was associated with irradiation doses above 66 Gy in OS (p = 0.586), LRC (p = 0.440), or FFDM (p = 0.230). On univariate analysis, variables associated with worse survival included: clinical stage IIIB (p = 0.037), planning target volume (PTV) over 450 cc (p < 0.001), heart V30 over 40% (p = −0.048), and esophageal mean dose over 20% (p = 0.024), V5 (p = −0.015), and V60 (p = −0.011). On multivariable analysis, PTV above 450 cc (52.2 vs. 25.3 months, p < 0.001) and esophageal V60 >20% (43.8 vs. 21.3 months, p = −0.01) were associated with lower survival. Grade 2 or higher acute lung toxicity and esophagitis were detected in 9.5 and 59.7%, respectively of patients. Grade 2 or higher acute lung toxicity was reduced if lung V5 was ≤65 (7.4 vs. 23.8%, p = 0.03). Grade 2 or higher acute esophagitis was reduced if V60 ≤ 20% (62 vs. 81.3%, p = 0.018). The use of intensity-modulated radiation therapy was more frequent in stage IIIB compared to stage IIIA patients (56.5 vs. 39.5%, p = 0.048) and was associated with a higher lung V5 and V10.

conclusion: The outcomes of a program of dose-escalated chemoradiotherapy for unresectable stage IIIA and IIIB NSCLC patients were consistent with other studies and showed no benefit to radiation doses above 66 Gy. Furthermore, maintaining low esophageal V60 and lung V5 were associated with lower morbidity and mortality. The optimal chemoradiation therapy management of locally advanced non-small cell lung cancer (NSCLC) has been a subject of great interest (1). Even with current aggressive multi-modality treatment protocols, the clinical outcomes remain suboptimal (2). Previous clinical trials have established the superiority of concurrent chemoradiation using radiation doses between 60 and 66 Gy and revealed median survival times of 16-18 months (3)(4)(5). Dose-escalation protocols in Phase II clinical trials revealed the feasibility of radiation doses up to 74 Gy and suggested some increase in median survival to 26 months (6). Advances in radiation therapy techniques such as intensity-modulated radiation therapy (IMRT), three-dimensional conformal radiation therapy (3D-CRT), motion management, and attention to normal tissue dose parameters allowed dose escalation in some studies (7,8).

Radiation dose-escalation trials were evaluated for improved locoregional control (LRC) and overall survival (OS). A recent clinical Trial from the RTOG (RTOG 0617) for stage IIIA/B NSCLC (2) was initiated to randomize radiation dose groups to cohorts of 60 Gy compared to 74 Gy each with similar concurrent chemotherapy. The 74-Gy arm showed no benefit and was associated with a survival detriment. Both arms had the same LRC, distant metastasis rate and measured toxicity; however, further analysis showed that the use of IMRT was associated with better patient reported quality of life, and also that improved baseline pretreatment QOL was predictive of survival (9). Other parameters influencing survival included low heart dose, low esophageal morbidity, and smaller planning target volume (PTV). Although, it is important to note, the lack of pretreatment quality assurance from a central review has called the outcomes in question, especially when it comes to delineating normal structures such as the heart (10,11).

We now report the results of this single institution experience with definitive chemoradiation for stage IIIA and IIIB NSCLC and compare outcomes for patients treated with 3D-CRT compared to patients treated with IMRT.

MaTerials anD MeThODs

Patient Population

We carried out a retrospective study using the criteria established by the American Joint Committee on Cancer (AJCC) seventh edition for patients with Stage IIIA and IIIB NSCLC. All patients were treated with definitive intent over the interval 2001-2013. All patients were determined to be unresectable by either: multiple node positivity, contralateral or supraclavicular lymph nodes, or tumor invasion of adjacent organs.

Patient medical records were de-identified and analyzed with ethical approval by the University of Pittsburgh Institutional Review Board (IRB #PRO13020306). The review was done with compliance to our ethic standards. All patients received daily radiotherapy fractions using a megavoltage linear accelerator with photon energy above 6 MV, and either IMRT or 3D-CRT. Radiation therapy was delivered concurrently with dual agent chemotherapy. All patients received four-dimensional CT (4D-CT) scan to assess target motion at time of simulation. Respiratory gating was included in daily treatments if tumor movement during simulation was greater than 5 mm in any direction (12). staging The staging system for NSCLC changed during the years of the study, therefore, we used the AJCC seventh staging edition as a standard for all patients. Patients were staged using PET/CT of the chest, abdomen, and pelvis, brain MRI, mediastinal lymph node sampling, and biopsy of both primary cancer and multiple mediastinal lymph nodes.

Dosimetry Parameters

In general, the normal esophagus was defined as being from the cricopharyngeus muscle to the gastroesophageal junction and the lung volume including the bilateral lungs from the apex chest apex to the diaphragm while subtracting out the PTV. These were mostly already created using our treatment plan software and we also used paper charts to assist with determine dosimetry values. In general our goals were V20 for lung <30%, mean esophagus dose less than or equal to 35 Gy and cord dose less than or equal to 45 Gy. Heart dose varied based on tumor location. For IMRT we also added V5 <60% and V10 <40% constraints for lung. In our early experience, patients were treated with fixed-field IMRT and after expanded to both rapid arc and fixed-field IMRT. statistical analysis LRC, freedom from distant metastasis (FFDM), and OS were primary outcome measures, and were calculated using log-rank and Cox regression analysis from time of diagnosis. Locoregional control was defined as lack of progression of clinical disease, seen on follow-up imaging or biopsy of the radiation therapy treatment volume for primary and regional lymph nodes. Acute toxicity was evaluated using binomial regression and late toxicity evaluated using Cox regression, t-test, ANOVA, binomial regression, and linear regression analysis. Each outcome measurement was correlated to dosimetric variables. Multivariable analysis (MVA) was performed for each factor found to be significant on unvariant analysis (p ≤ 0.05). Statistical analysis was performed using IBM SPSS Statistics Version 23.

resUlTs

Patient Demographics

There were 597 patients with clinical stage IIIA or IIIB NSCLC in the UPCI database over the interval 2001 to 2013. Patients treated with palliative intent (n = 296) were excluded as were those receiving only surgical management (n = 28). Radiotherapy patients not treated with concurrent chemotherapy (n = 39) were excluded. The remaining cohort of 213 patients was evaluated. Forty-three patients were lost to follow-up defined as no follow-up from treatment. Median follow-up of the cohort of 170 patients was 22 months and is shown in Table 1. The Interquartile Range (IQR) was 8.9-39.6. Median follow-up was

Treatment and Dosimetric evaluation

All patients were treated with concurrent chemoradiation, median radiation dose was 72 Gy (IQR, 68-77). The treatment volume and doses had inhomogeneity corrections. IMRT was used in 27.1%. All patients received a 4D-CT simulation scan, and 13.5% required respiratory gating. Concurrent carboplatin and paclitaxel were the dual agents in 88.2% of patients.

Overall survival

Factors influencing Toxicity

In the present series, the median value of mean lung dose was 15.2 Gy (IQR, 13-18 Gy) and median lung V20 was 26% (IQR 21-31%). There was grade 2 or higher acute lung toxicity detected in 9.5% of patients. On univariate analysis, the use of 3D-CRT (p = 0.036) and V5 ≤ 65 (p = 0.036) were associated with a lower rate of pneumonitis. On multivariate analysis, lung V5 ≤ 65 was associated with a decreased acute grade 2 or higher lung toxicity (7.4 vs. 23.8%, p = 0.027). The incidence of 1-year and 2-year late grade 3+ pneumonitis was 1.2 and 2.1%, respectively. There were no detectable univariate factors that predicted for late grade 3 or higher pneumonitis.  The median value for the mean esophageal dose in the group was 28 Gy in the present study (IQR, 21-33 Gy). The median esophageal V60 was 16% (IQR, 3-27%). Acute grade 2 or higher esophagitis was detected 59.7% of patients. On univariate analysis, a lower radiation therapy dose as a continuous variable (p = −0.041) and esophageal V60 ≤ 20% (p = −0.027) were associated with lower rates of acute grade 2 or higher esophagitis. On multivariate analysis, esophageal V60 ≤ 20% was associated with a lower rate of acute grade 2 or higher esophagitis (62 vs. 81.3%, p = 0.018). We observed late 1-year and 2-year grade 3+ esophagitis in 4.5 and 6.5% of patients, respectively. There was no detectable univariate factor that predicted late grade 3 or higher esophagitis ( Table 3).

Utilization and Outcomes of 3D-crT vs. iMrT

We compared factors that were associated with the radiation oncologist's choice of 3D-CRT vs. IMRT for radiotherapy management. We found no detectable difference by patient age (p = 0.095), gender (p = 0.072), race (p = 0.340), histology (p = 0.752), RT dose (p = 0.131), respiratory gating (p = 0.105), or PTV (p = 0.459). IMRT use was higher in IIIB patients than in IIIA patients (56.5 vs. 39.5%, p = 0.048). For IIIB compared to IIIA patients, IMRT was associated with a higher lung V5 (37 vs. 57%, p = 0.001) and V10 (30 vs. 43%, p = 0.002). Compared

DiscUssiOn

Despite advances in delivery techniques for radiation therapy, patients with locally advanced NSCLC have displayed suboptimal outcomes, and median survival remains between 15 and 26 months (2,13). Dose-escalation protocols for radiation therapy doses above 60 Gy showed a benefit, but also revealed increased toxicities (14). The addition of concurrent chemotherapy to 60 Gy radiation resulted in further improved survival (3)(4)(5). While some phase II studies showed the feasibility of doseescalated chemoradiation therapy with higher survival outcomes, the recent RTOG 0617 study did not confirm a benefit to the use of higher radiation dose (2,6). We compared the RTOG 0617 results with those of our single institution series at UPCI. The median survival for the present cohort of 170 evaluable NSCLC stage IIIA and IIIB patients was 27.4 months. This value is comparable to the median survival reported in the recent RTOG 0617 trial. In both studies, better staging with PET/CT leading to stage migration and improvements in treatment delivery and better supportive care may have accounted for the improvement in survival (2).

The median radiation dose delivered to patients in our single institution study was 72 Gy. We determined the value of dose escalation by comparing those patients treated to doses above 66 Gy with those receiving doses below 66 Gy. This cut-off value was based upon prior clinical trials comparing sequential to concurrent chemoradiation (3)(4)(5). Prior trials showed that concurrent, dual agent, platinum-based chemotherapy was more effective than use of sequential single drugs in chemoradiation protocols (3)(4)(5). We found no benefit for those patients treated above 66 Gy. We also found no benefit if the radiation dose was analyzed as a continuous variable. Therefore, we conclude that our data correlate with the results of RTOG 0617 showing no benefit to radiation dose escalation above 66 Gy.

The present analysis revealed that PTV volumes of NSCLC tumor above 450 cc were associated with a lower OS, LRC, and FFDM, again confirming the results presented in RTOG 0617 (2). Another clinical trial, which is a randomized phase II program, which evaluates adaptive planning in stage IIIA/B NSCLC patients for dose escalation, RTOG 1106, is ongoing. The control arm in this new study will receive 50 Gy, then continuing to 60 Gy after an interim PET/CT scan. The experimental arm will receive 46.2 Gy, then PET/CT scan evaluation, then use adaptive doseescalation ranges using the FDG-PET/CT scan up to a total dose of 80.4 Gy.

Our study revealed new information on toxicity of chemoradiotherapy of NSCLC. Acute grade 2 or higher lung toxicity in 9.5% patients was associated with a median lung V20 of 26 Gy. The data correlate well with a prior study showing that V20 values between 22 and 31 Gy led to an 8% pneumonitis rate (8). In this prior study (8), 42% of patients received chemotherapy (concurrent or sequential). In our study, the low rate of pneumonitis with high dose concurrent chemoradiation was likely attributable to 4D-CT simulation and the pre-screening of patients with tumor movement to include respiratory gating in their treatment program. Lower rates of lung toxicity were also detected in patients, where there was V5 ≤ 65%. A prior study (15), showed that V5 ≤ 42% did indeed correlate with a lower rate of acute pneumonitis for NSCLC patients treated with concurrent chemoradiation (15). A review of 220 esophageal cancer patients (16) also treated with radiation alone showed that V5 ≤ 60% correlated with lower rates of acute pneumonitis. We conclude that mean lung dose and lung V20 are the standard dosimetric parameters for predicting pneumonitis; however, we suggest that more attention should be given to the low dose volumes when treating patients with IMRT.

Esophagitis remains a serious complication of chemoradiotherapy of NSCLC. Esophageal grade 2 or higher toxicity rate was observed in 59.7% of our patients. This result was consistent with the combined grade 2 or higher esophagitis rate of the 74 Gy arm (43%) in the RTOG 0617 study (2). Keeping the esophageal V60 ≤ 20% correlated with lower frequency of detection of acute grade 2 or higher esophagitis. A retrospective analysis of another series of 109 NSCLC patients treated with concurrent chemoradiation showed the esophageal V60 correlated with higher rates of acute esophagitis (17). In yet another study, the threshold dose of 58 Gy predicted acute grade 3 or higher esophageal toxicity (18). Therefore, there is a consensus that the magnitude of the esophageal volume receiving more than 40-50 Gy correlates with the severity of acute esophagitis (19,20). Our results support efforts to ensure that as much of the esophagus as possible should be spared from the high-dose region. We will plan on incorporating our knowledge of the esophageal V60 this into our treatment planning for stage III patients treated with definitive chemoradiation.

The RTOG 0617 study showed that the use of IMRT did improve the QOL in NSCLC patients and reduced rates of grade 3 pneumonitis. In addition, there was an increased likelihood of completing adjuvant chemotherapy (2,9). We found that IMRT use was greater for IIIB patients, likely due to the requirement for coverage of supraclavicular and contralateral mediastinal disease, while achieving acceptable V20 volumes (mean, 30%) and attempting to still reduce lung toxicity. IMRT treatment plans decreased the esophageal V60 volume and the maximum heart dose. There was a trend for IMRT treatment plans to decrease the heart V30 volume, a parameter associated with survival outcomes on univariate analysis, but not multivariate analysis. A lowered heart V30 was also associated with improved survival outcomes in the RTOG 0617 study (2).

There was no statistically significant increase in survival for IIIA or IIIB patients treated with IMRT vs. 3D-CRT, although median survival times were different. In a secondary analysis of the data in RTOG 0617, the high-dose arm was associated with a lower patient reported QOL at 3 months, and baseline pretreatment QOL was predictive of survival (9). IMRT use was associated with a less deterioration of QOL compared to patients receiving 3D-CRT. We were unable to associate use of IMRT with a possible survival benefit, although a trend in this direction was apparent. A larger study with a more balanced distribution between uses of IMRT compared to 3D-RT may result in a statistically significant difference.

Patients treated with IMRT did not show a decreased rate of acute esophagitis or pneumonitis. This result may have been attributable to a higher usage of IMRT for patients with IIIB disease, and the need for larger treatment volumes. Two retrospective reviews of NSCLC patients showed decreased rates of pneumonitis with use of IMRT when compared to 3D-CRT for NSCLC (7,21). Radiation therapy planning comparing 3D-CRT to IMRT showed that IMRT also lead to a 50% relative reduction in predicted esophageal complications (22).

We analyzed our data using Kaplan-Meier plots, and this method revealed separation of the LRC and FFDM curves from OS (Figure 1). The data suggest that patients in our cohort may have died from causes other than local or distant recurrence of NSCLC. Since patients with aerodigestive cancers have a 3-5% yearly risk of a second aerodigestive primary cancer, we recommend that radiation oncologists ensure that long-term follow-up visits include screening for second cancers.

There were limitations to our retrospective analysis of NSCLC patients, including: (1) single institution retrospective review, (2) lack of a prospective randomized trial, and (3) limited follow-up interval. These factors might have led to both overestimating the primary outcomes and underestimating late toxicity. We also have a limited number of patients, and thus, our reports should be compared with other single institution reports and randomized control trials. We are additionally limited since we did not have electronic records for most of our patients and, therefore, may lead unreported events. Last, our dosimetry data are based on treating physicians who may have used different treatment considerations. We have overcome this issue by implementation of clinical pathways to guide our physicians and to have a more uniform criterion for care.

In a retrospective review of stage IIIA/B, NSCLC patients at UPCI larger PTV volumes and esophageal V60 > 20% were associated with poorer survival. Acute grade 2 or higher lung toxicity was lower in the V5 ≤ 65% group and acute grade 2 plus esophagitis was lower in the V60 ≤ 20% group. We recommend that patients with unresectable stage IIIA and IIIB NSCLC, who require radiotherapy be treated to doses not exceeding 66 Gy.

aUThOr cOnTriBUTiOns MB performed the retrospective review of the data analyzed in the manuscript and performed the majority of the statistics and was responsible for drafting and editing the manuscript. SG assisted with statistics and drafting of the manuscript. BG assisted in drafting the manuscript, statistical analysis, and literature review. SB oversaw drafting of the manuscript and edits and outlined the message and topic. DH assisted in drafting the manuscript and providing edits. JL provided edits concerning surgical outcomes. DF and MS reviewed the manuscript for medical oncology. JG led the team and edited the manuscript.

Keywords: nsclc, dose escalation, chemoradiation, esophagitis, pneumonitis Radiation Dose Escalation in Lung Cancer Frontiers in Oncology | www.frontiersin.org January 2017 | Volume 7 | Article 1 inTrODUcTiOn

FigUre 1 |
1comparison of the overall survival (Os), locoregional control (lrc), and freedom from distant metastasis (FFDM) for stage iiia/B non-small cell lung cancer. The median survival was 25.9 months for the entire cohort. Both local recurrence and distant metastasis remained a major factor decreasing survival.

TaBle 1 |
1Baseline characteristics for entire cohort (n = 170).Patient variables
results

age
Median and range (years)
67 (38-91)

gender
Male
111 (65.3%)
Female
59 (34.7%)

race
Caucasian
137 (80.6%)
African-American
33 (19.4%)
NOS/other

histology
Adenocarcinoma
77 (45.3%)
Squamous cell
54 (31.8%)
Large cell
10 (5.9%)
Mixed
2 (1.2%)
NSCLC/NOS
27 (15.9%)

stage
T4N0
10 (5.9%)
T3N1
3 (1.8%)
T4N1
3 (1.8%)
T0N2
8 (4.7%)
T1N2
21 (12.4%)
T2N2
36 (21.2%)
T3N2
16 (9.4%)
T4N2
20 (11.8%)
T0N3
8 (4.7%)
T1N3
11 (6.5%)
T2N3
17 (10%)
T3N3
7 (4.1%)
T4N3
10 (5.9%)

stage
IIIA
97 (57.1%)
IIIB
73 (42.9%)

chemotherapy
Carboplatin paclitaxel
150 (88.2%)
Cisplatin and etoposide
5 (2.9%)
Carboplatin and protein-bound paclitaxel
1 (0.6%)
Cisplatin and gemcitabine
1 (0.6%)
Carboplatin and pemetrexed
2 (1.2%)
Carboplatin and etoposide
5 (2.9%)
Carboplatin and docetaxel
3 (1.8%)
Cisplatin and docetaxel
3 (1.8%)

Volumes
Median GTV (cc)
84 (4-586)
Median PTV (cc)
338 (43-1303)

Technique
3D-RT
119 (70%)
IMRT
46 (27.1%)
N/A
5 (2.9%)

simulation
No gating
127 (74.7%)
Gating
23 (13.5%)
N/A
20 (11.8%)

Dose (gy)
Median and range
72 (54-84)

Dose ranges (gy)
54-66
41 (24.1%)
67-70
32 (18.8%)
71-74
51 (30%)
75-80
45 (26.5%)
81-84
1 (0.6%)

GTV, gross tumor volume; NA, not available; NSCLC, non-small cell lung cancer; NOS,
not otherwise specified; 3D-CRT, three-dimensional conformal radiation therapy; IMRT,
intensity-modulated radiation therapy; PTV, planning target volume.

3

Bernard et al.
Radiation Dose Escalation in Lung Cancer

Frontiers in Oncology | www.frontiersin.org
January 2017 | Volume 7 | Article 1

36.6 months (IQR, 26.6-63.7) for the subset of patients still
living.

Esophageal volumes of V60 that were over 20% were also associated with reduced survival (V60 ≤ 20 vs. >20; 43.8 vs. 21.3 months, p = 0.01). Radiation dose above 66 Gy was not associated with improved OS (p = 0.586). Statistical analysis is shown inTable 2.The 2-and 4-year LRC for the entire group was 54.4 and 43.9%, respectively. On univariate analysis, large PTV was associated with a reduced LRC [≤450 vs. >450 cc, HR = 1.86; 95% confidence interval (CI) (1.03-3.36), p = 0.039]. Radiation dose above 66 Gy was not associated with increased LRC (p = 0.440).The percentage of 2-and 4-year FFDM was 54.4 and 40.7%, respectively, for the entire group. On univariate analysis, higher radiation therapy doses (p = 0.041) and PTV > 450 cc (p = 0.004) were each associated with reduced FFDM. On multivariate analysis, PTV above 450 cc [≤450 vs. >450 cc, HR = 2.median survival of the entire group was 27.4 months. There
was a 2-and 4-year OS of 56.0 and 30.7%, respectively. On
univariate analysis decreased survival was detected in the subset
of patients with: (1) stage IIIB (p = 0.037), (2) PTV > 450 cc
(p < 0.001), (3) heart V30 > 40% (p = 0.048), (4) esophageal
mean dose of >20% (p = 0.024), (5) esophageal V5 > 60%
(p = 0.015), and (6) esophageal V60 > 20% (p = 0.011). On
multivariate analysis decreased survival was detected in patients
with a large PTV (≥450 vs. <450 cc; 52.2 vs. 25.3 months,
p < 0.001). locoregional control

Freedom from Distant Metastasis

15, 95%
CI (1.27-3.62), p = 0.004] was associated with reduced FFDM. A
radiation dose above 66 Gy was not associated with an improved
FFDM (p = 0.230).

TaBle 3 |
3Univariate and multivariable analysis (MVa) for acute toxicity.acute grade 2+ lung
toxicity

acute 2+ esophagitis

3D-crT vs. iMrT
hr = 3.181 (1.079-9.384),
p = 0.036

p = 0.086

rT dose
p = 0.626
hr = 1.060, 95%
confidence interval (ci)
(1.002-1.120, p = 0.041)
PTV
p = 0.720
p = 0.951

lung
Mean
p = 0.893
-
V5 ≤ 65
hr = 3.884, 95% ci
(1.096-13.767), p = 0.036

-

V10
p = 0.377
-
V20
p = 0.345
-
V30
p = 0.895
-

esophagus
Max
-
0.743
Mean
-
0.077
V5
-
0.208
V60 ≤ 20
-
hr = 2.2697, 95% ci
(1.115-6.340), p = 0.027

MVa
V5 ≤ 65
7.4 vs. 23.8%, p = 0.027
-
Esophageal V60 ≤ 20
62 vs. 81.3%, p = 0.018

3D-CRT, three-dimensional conformal radiation therapy; IMRT, intensity-modulated
radiation therapy; PTV, planning target volume, RT, radiation therapy.

TaBle 2
2| Univariate and multivariable analysis (MVa) for overall survival (Os), lrc, and freedom from distant metastasis (FFDM).

Os
locoregional control
FFDM

Age ≤60
p = 0.373
HR = 0.614 (0.368-1.024), p = 0.062
p = 0.261
Gender
p = 0.166
p = 0.408
p = 0.686
Race
p = 0.742
p = 0.540
p = 0.926
Histology
p = 0.155
p = 0.904
p = 0.562
IIIA vs. IIIB
hr = 1.465; 95% confidence interval (ci)
(1.024-2.096), p = 0.037

p = 0.467
hr = 0.598, 95% ci
(0.374-0.956), p = 0.032
RT dose (continuous)
p = 0.761
p = 0.706
0.511
≤66 vs. >66 Gy
p = 0.586
p = 0.440
p = 0.230
3D vs. IMRT
p = 0.427
p = 0.991
0.964
PTV450cc
hr = 2.305, 95% ci (1.478-3.596), p < 0.001
hr = 1.860; 95% ci (1.031-3.356),
p = 0.039

hr = 2.149, 95% ci
(1.274-3.624), p = 0.004

lung
Mean
p = 0.402
-
-
V5
p = 0.584
-
-
V10
p = 0.519
-
-
V20
p = 0.474
-
-
V30
p = 0.186
-
-

heart
Maximum
p = 0.242
-
-
Mean
p = 0.091
-
-
V30 ≤ 40
hr = 1.836, 95% ci (1.005-3.353), p = 0.048
-
-

esophageal
Max
p = 0.408
-
-
Mean ≤ 20
hr = 2.146, 95% ci (1.105-4.167), p = 0.024
-
-
V5 ≤ 60
hr = 1.017, 95% ci (1.003-1.030), p = 0.015
-
-
V60 ≤ 20
hr = 1.758, 95% ci (1.135-2.721), p = 0.011
-
-

MVa
PTV450cc
52.2 vs. 25.3 months, p < 0.001
hr = 1.860; 95% ci (1.031-3.356),
p = 0.039

hr = 2.149, 95% ci
(1.274-3.624), p = 0.004
Esophageal V60 ≤ 20
43.8 vs. 21.3 months, p = 0.01
-
-

3D-CRT, three-dimensional conformal radiation therapy; IMRT, intensity-modulated radiation therapy; PTV, planning target volume; RT, radiation therapy.

TaBle 4 |
4Dosimetric outcomes for 3D-crT vs. intensity-modulated radiation therapy (iMrT) in iiia and iiiB non-small cell lung cancer patients.Mean
p-Value

clinical iiia

lung
Mean
3D
15
0.491
IMRT
16
V5
3D
37
0.001
IMRT
57
V10
3D
30
0.002
IMRT
43
V20
3D
23
0.195
IMRT
26
V30
3D
19
0.758
IMRT
19

heart
Maximum
3D
56
0.068
IMRT
68
Mean
3D
12
0.430
IMRT
14
V30
3D
15
0.716
IMRT
17

esophagus
Max
3D
69
0.049
IMRT
74
Mean
3D
25
0.528
IMRT
27
V5
3D
57
0.288
IMRT
61
V60
3D
14
0.785
IMRT
15

clinical iiiB

lung
Mean
3D
17
0.774
IMRT
17
V5
3D
45
0.009
IMRT
59
V10
3D
33
0.004
IMRT
45
V20
3D
28
0.413
IMRT
30
V30
3D
23
0.240
IMRT
21

heart
Maximum
3D
71
0.026
IMRT
53
Mean
3D
17
0.133
IMRT
12
V30
3D
24
0.054
IMRT
13

esophagus
Max
3D
74
0.452
IMRT
72
Mean
3D
34
0.739
IMRT
33
V5
3D
66
0.087

5

Bernard et al.
Radiation Dose Escalation in Lung Cancer

Frontiers in Oncology | www.frontiersin.org
January 2017 | Volume 7 | Article 1

to patients treated with 3D-CRT, there was a lower esophageal
mean dose for IMRT patients (69 vs. 74%, p = 0.049) (Table 4).
The median survival for IIIB patients treated with IMRT was

higher than those treated with 3D-CRT, but the data did not
reach statistical significance (19.0 vs. 26.1 months, p = 0.429).
IMRT use was also associated with improved survival for IIIA
patients, but did not reach statistical significance (28.7 vs.
42.3 months, p = 0.418).

acKnOWleDgMenTsThe authors would like to acknowledge Karlotta Ashby and Karen Holeva for ensuring ethical compliance and providing them with the ability to conduct this retrospective review.FUnDingThis study was funded by the Department of Radiation Oncology of UPCI.reFerences
Definitive radiation therapy in locally-advanced non-small cell lung cancer: executive summary of an American society for radiation oncology (ASTRO) evidence-based clinical practice guideline. G Rodrigues, H Choy, J Bradley, K E Rosenzweig, J Bogart, W J Curran, Jr, 10.1016/j.prro.2015.02.012Pract Radiat Oncol. 53Rodrigues G, Choy H, Bradley J, Rosenzweig KE, Bogart J, Curran WJ Jr, et al. Definitive radiation therapy in locally-advanced non-small cell lung cancer: executive summary of an American society for radiation oncology (ASTRO) evidence-based clinical practice guideline. Pract Radiat Oncol (2015) 5(3):141-8. doi:10.1016/j.prro.2015.02.012

Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomized, two-by-two factorial p. J D Bradley, R Paulus, R Komaki, G Masters, G Blumenschein, S Schild, 10.1016/S1470-2045(14)71207-0Lancet Oncol. 162Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomized, two-by-two factorial p. Lancet Oncol (2015) 16(2):187-99. doi:10.1016/S1470-2045(14)71207-0

Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. W J Curran, R Paulus, C J Langer, R Komaki, J S Lee, S Hauser, 10.1093/jnci/djr325J Natl Cancer Inst. 103Curran WJ, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: ran- domized phase III trial RTOG 9410. J Natl Cancer Inst (2011) 103(19):1452-60. doi:10.1093/jnci/djr325

Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally-advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 study. P Fournel, G Robinet, P Thomas, P J Souquet, H Léna, A Vergnenégre, 10.1200/JCO.2005.03.070J Clin Oncol. 2325Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally-advanced non-small-cell lung can- cer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 study. J Clin Oncol (2005) 23(25):5910-7. doi:10.1200/JCO.2005.03.070

Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally-advanced non-small cell lung cancer: a randomized study. P Zatloukal, L Petruzelka, M Zemanova, L Havel, F Janku, L Judas, 10.1016/j.lungcan.2004.03.004Lung Cancer. 461Zatloukal P, Petruzelka L, Zemanova M, Havel L, Janku F, Judas L, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorel- bine in locally-advanced non-small cell lung cancer: a randomized study. Lung Cancer (2004) 46(1):87-98. doi:10.1016/j.lungcan.2004.03.004

Dose-escalating conformal thoracic radiation therapy with induction and concurrent carboplatin/paclitaxel in unresectable stage IIIA/B nonsmall cell lung carcinoma: a modified phase I/II trial. S R Patel, J Jenkins, N Papadopolous, L Havel, F Janku, L Judas, 10.1002/1097-0142(20010901)92:5<1213:AID-CNCR1440>3.0.CO;2-0Cancer. 925Patel SR, Jenkins J, Papadopolous N, Havel L, Janku F, Judas L, et al. Dose-escalating conformal thoracic radiation therapy with induction and concurrent carboplatin/paclitaxel in unresectable stage IIIA/B non- small cell lung carcinoma: a modified phase I/II trial. Cancer (2001) 92(5):1213-23. doi:10.1002/1097-0142(20010901)92:5<1213:AID-CN-

Influence of technologic advances on outcomes in patients with unresectable, locally-advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Z X Liao, R R Komaki, H D Thames, H H Liu, S L Tucker, R Mohan, 10.1016/j.ijrobp.2009.02.032doi:10.1016/ j.ijrobp.2009.02.032Int J Radiat Oncol Biol Phys. 3Liao ZX, Komaki RR, Thames HD, Liu HH, Tucker SL, Mohan R, et al. Influence of technologic advances on outcomes in patients with unresectable, locally-advanced non-small-cell lung cancer receiving concomitant chemo- radiotherapy. Int J Radiat Oncol Biol Phys (2010) 76(3):775-81. doi:10.1016/ j.ijrobp.2009.02.032

Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). M V Graham, J A Purdy, B Emami, W Harms, W Bosch, M A Lockett, 10.1016/S0360-3016(99)00183-2Int J Radiat Oncol Biol Phys. 452Graham MV, Purdy JA, Emami B, Harms W, Bosch W, Lockett MA, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys (1999) 45(2):323-9. doi:10.1016/S0360-3016(99)00183-2

Quality of life analysis of a radiation dose-escalation study of patients with non-small-cell lung cancer: a secondary analysis of the radiation therapy oncology group 0617 randomized clinical trial. B Movsas, C Hu, J Sloan, J Bradley, R Komaki, G Masters, 10.1001/jamaoncol.2015.3969doi:10.1001/ jamaoncol.2015.3969JAMA Oncol. 23Movsas B, Hu C, Sloan J, Bradley J, Komaki R, Masters G, et al. Quality of life analysis of a radiation dose-escalation study of patients with non-small-cell lung cancer: a secondary analysis of the radiation therapy oncology group 0617 randomized clinical trial. JAMA Oncol (2016) 2(3):359-67. doi:10.1001/ jamaoncol.2015.3969

Variation of cardiac contours using different heart definitions for NSCLC patients enrolled on RTOG 0617. Y Gong, E M Gore, V Bar-Ad, M Wheatley, F Kong, J Yu, 10.1016/j.ijrobp.2014.05.2150doi:10.1016/ j.ijrobp.2014.05.2150Int J Radiat Oncol Biol Phys. 901739Gong Y, Gore EM, Bar-Ad V, Wheatley M, Kong F, Yu J, et al. Variation of cardiac contours using different heart definitions for NSCLC patients enrolled on RTOG 0617. Int J Radiat Oncol Biol Phys (2014) 90(1):s739. doi:10.1016/ j.ijrobp.2014.05.2150

Imaging and data acquisition in clinical trials for radiation therapy. T J Fitzgerald, M Bishop-Jodoin, D S Followill, J Galvin, M V Knopp, J M Michalski, FitzGerald TJ, Bishop-Jodoin M, Followill DS, Galvin J, Knopp MV, Michalski JM, et al. Imaging and data acquisition in clinical trials for radiation therapy.

. 10.1016/j.ijrobp.2015.10.028Int J Radiat Oncol Biol Phys. 942Int J Radiat Oncol Biol Phys (2016) 94(2):404-11. doi:10.1016/j.ijrobp.2015. 10.028

The management of respiratory motion in radiation oncology report of AAPM task group 76. P J Keall, G S Mageras, J M Balter, R S Emery, K M Forster, S B Jiang, 10.1118/1.2349696doi:10.1118/ 1.2349696Med Phys. 33Keall PJ, Mageras GS, Balter JM, Emery RS, Forster KM, Jiang SB, et al. The management of respiratory motion in radiation oncology report of AAPM task group 76. Med Phys (2006) 33:3874-900. doi:10.1118/ 1.2349696

Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest oncology group phase II study, SWOG 9019. K S Albain, J J Crowley, A T Turrisi, D R Gandara, W B Farrar, J I Clark, 10.1200/JCO.2002.03.055doi:10.1200/ JCO.2002.03.055J Clin Oncol. 2016Albain KS, Crowley JJ, Turrisi AT, Gandara DR, Farrar WB, Clark JI, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest oncology group phase II study, SWOG 9019. J Clin Oncol (2002) 20(16):3454-60. doi:10.1200/ JCO.2002.03.055

A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of lnoperable non-oat-cell carcinoma of the lung: RTOG 7301. C A Perez, K Stanley, P Rubin, D R Gandara, W B Farrar, J I Clark, 10.1002/1097-0142(19800601)45:11<2744:AID-CNCR2820451108>3.0.CO;2-UCancer. 451111<2744:AID-CNCR2820451108>3.0.CO;2-UPerez CA, Stanley K, Rubin P, Gandara DR, Farrar WB, Clark JI, et al. A prospective randomized study of various irradiation doses and fraction- ation schedules in the treatment of lnoperable non-oat-cell carcinoma of the lung: RTOG 7301. Cancer (1980) 45(11):2744-53. doi:10.1002/1097- 0142(19800601)45:11<2744:AID-CNCR2820451108>3.0.CO;2-U

Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). S Wang, Z Liao, X Wei, H H Liu, S L Tucker, C S Hu, 10.1016/j.ijrobp.2006.07.1337doi:10.1016/ j.ijrobp.2006.07.1337Int J Radiat Oncol Biol Phys. 665Wang S, Liao Z, Wei X, Liu HH, Tucker SL, Hu CS, et al. Analysis of clin- ical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). Int J Radiat Oncol Biol Phys (2006) 66(5):1399-407. doi:10.1016/ j.ijrobp.2006.07.1337

. W B Shen, S C Zhu, H M Gao, Y M Li, Z K Liu, J Li, Low dose volume histogram analysis of the lungs in prediction of acute radiation pneumonitis in patients with esophageal cancer treated with three-dimensional conformal radiotherapyShen WB, Zhu SC, Gao HM, Li YM, Liu ZK, Li J, et al. [Low dose volume histogram analysis of the lungs in prediction of acute radiation pneumonitis in patients with esophageal cancer treated with three-dimensional conformal radiotherapy].

. 10.3760/cma.j.issn.0253-3766.2013.01.010doi:10.3760/ cma.j.issn.0253-3766.2013.01.010Zhonghua Zhong Liu Za Zhi. 351Zhonghua Zhong Liu Za Zhi (2013) 35(1):45-9. doi:10.3760/ cma.j.issn.0253-3766.2013.01.010

Esophagus in-field: a new predictor for esophagitis. H B Caglar, M Othus, A M Allen, 10.1016/j.radonc.2010.07.024Radiother Oncol. 1Caglar HB, Othus M, Allen AM. Esophagus in-field: a new predictor for esophagitis. Radiother Oncol (2010) 97(1):48-53. doi:10.1016/j.radonc.2010. 07.024

Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy. A K Singh, M A Lockett, J D Bradley, 10.1016/S0360-3016(02)03937-8Int J Radiat Oncol. 552Singh AK, Lockett MA, Bradley JD. Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol (2003) 55(2):337-41. doi:10.1016/S0360-3016(02)03937-8

Radiation therapy for locally-advanced lung cancer. M E Bernard, D A Clump, R Lalonde, S Beriwal, 10.3978/j.issn.2218-676X.2015.08.03doi:10.3978/ j.issn.2218-676X.2015.08.03Transl Cancer Res. 44Bernard ME, Clump DA, Lalonde R, Beriwal S. Radiation therapy for local- ly-advanced lung cancer. Transl Cancer Res (2015) 4(4):356-71. doi:10.3978/ j.issn.2218-676X.2015.08.03

Radiation dose-volume effects in the esophagus. M Werner-Wasik, E Yorke, J Deasy, J Nam, L B Marks, 10.1016/j.ijrobp.2009.05.070Int J Radiat Oncol Biol Phys. 3SupplWerner-Wasik M, Yorke E, Deasy J, Nam J, Marks LB. Radiation dose-volume effects in the esophagus. Int J Radiat Oncol Biol Phys (2010) 76(3 Suppl):86-93. doi:10.1016/j.ijrobp.2009.05.070

Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. S S Yom, Z Liao, H H Liu, S L Tucker, C S Hu, X Wei, 10.1016/j.ijrobp.2006.12.031doi:10.1016/ j.ijrobp.2006.12.031Int J Radiat Oncol Biol Phys. 681Yom SS, Liao Z, Liu HH, Tucker SL, Hu CS, Wei X, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys (2007) 68(1):94-102. doi:10.1016/ j.ijrobp.2006.12.031

Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. I S Grills, D Yan, A A Martinez, F A Vicini, J W Wong, L L Kestin, 10.1016/S0360-3016(03)01359-2Int J Radiat Oncol Biol Phys. 573Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL. Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys (2003) 57(3):875-90. doi:10.1016/S0360-3016(03) 01359-2

Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Conflict of Interest Statement: The authors declare that the research was con- ducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.