Conditions: Carcinoma, Non Small Cell Lung (NSCLC)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This is a prospective phase II study designed to evaluate an accelerated and adaptive RT approach for locally-advanced non-small cell lung cancer (NSCLC). All eligible subjects will have an interim PET-CT during radiation therapy to determine the metabolic complete response rate. Radiation therapy will be given in an accelerated fashion (2 Gy/fraction, 6 fractions/week) with concurrent chemotherapy. Interim responses will be assessed using PERCIST criteria.

Despite concurrent chemotherapy and radiation therapy, local/regional failure occurs in \~50% of patients with locally-advanced NSCLC. Clinical studies have demonstrated that accelerated fractionation (giving the same total dose in a shorter period of time) improves outcomes in several malignancies, including lung cancer. Administering higher than conventional doses of RT to all sites of original disease leads to inferior outcomes. Adapting the RT approach, giving a higher dose to slowly responding disease as assessed with interim PET has been shown to be feasible. PERCIST (Positron Emission Tomography Response Criteria in Solid Tumors) provides guidelines on how to report responses to therapy based on PET-CT. PET-CT response has been shown to be prognostic in a variety of clinical scenarios in lung cancer including after induction therapy. In one study, PET was performed after neoadjuvant chemoradiotherapy (40-50.4 Gy). Complete or partial metabolic response using PERCIST criteria was predictive of loco-regional, distant, and overall progression-free survival.

Detailed description:

Arms:
arm 1: Single arm, non randomized, open label study. Eligible subjects will receive standard of care Carboplatin IV once a week, Paclitaxel IV once a week given concurrently with daily hyperfractionated radiation therapy (RT). RT will be delivered as 6 fractions weekly.

Interventions: intervention 1: Carboplatin intervention 2: Paclitaxel intervention 3: Daily hyperfractionated radiation therapy
Intervention descriptions: intervention 1: Single arm non randomized open label study. Subjects will receive standard of care Carboplatin IV once a week. Chemotherapy is given concurrently with daily hyperfractioned radiation therapy. intervention 2: Single arm non randomized open label study. Subjects will receive standard of care Paclitaxel IV once a week. Chemotherapy is given concurrently with daily hyperfractioned radiation therapy. intervention 3: All subjects will receive 6 fractions(2Gy per fraction) of radiation therapy weekly. All subjects will complete an interim PET-CT after 48Gy-54Gy of RT . Subjects with a complete response on PET will complete RT at 60 Gy; subjects who have residual disease on interim PET and meet strict planning constraints eligibility will proceed to boost RT for a total RT dose of 72Gy. Interim PET-CT response will be measured using PERCIST criteria.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
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Phase II Study of Accelerated and Adaptive Radiation Therapy for 
Locally-Advanced NSCLC 
IRB# Pro00083154 
 
 
Principal Investigator 
 
Chris R. Kelsey, M.D. 
Associate Professor 
Department of Radiation Oncology 
Duke University Medical Center 
DUMC Box 3085 
Durham, NC 27710 
Tel: 919-668-5213 
Fax: 919-668-7345 
christopher.kelsey@duke.edu 
 
Sub- Investigators 
 
Joseph Salama, M.D. (Radiation Oncology) 
Tom Stinchcombe, M.D. (Medical Oncology) 
Xiaofei Wang, Ph.D. (Statistics) 
Junheng Gao  (Statistics) 
Olga James, M.D. (Nuclear Medicine) 
 
 
 
                                                
Clinical Trials.gov identifier: NCT03128008 
 
Protocol version date: 07August2018 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Phase II Study of Accelerated and Adaptive Radiation Therapy for 
Locally-Advanced NSCLC 
 
Schema 


 
 
 
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1.0 Background and Significance 
 
1.1 Rationale for Dose Intensification 
 
Historically, the conventional treatment for locally-advanced non-small cell lung cancer (NSCLC) was RT 
alone. RTOG 73-01 randomized 383 patients with NSCLC to 40 Gy (split course), or a continuous course of 40 
Gy, 50 Gy, or 60 Gy [1]. While local control was improved with 60 Gy, 5-year survival rate was only ~5% and 
did not differ between treatment arms. Due to improved intrathoracic control with 60 Gy, this became standard. 
However, local failure still occurred in most patients. In the 1980s-1990s, two approaches were taken to 
increase the effectiveness of conventional RT: adding chemotherapy to RT (first sequentially then concurrently) 
and intensifying the radiation therapy (dose escalation and/or altered fractionation).  
 
1.1.1 Chemotherapy with Conventional RT 
 
Several randomized studies compared RT alone (60 Gy) with cisplatin-based chemotherapy followed by RT 
[2-4]. These studies demonstrated a modest, but statistically significant, improvement in overall survival from 
~5% with RT alone to ~10% with sequential chemotherapy. Subsequent randomized studies compared 
sequential chemotherapy with concurrent chemotherapy and found the latter to be superior[5,6], with 5-year 
survival reaching 15-20% with concurrent chemotherapy and RT. Unfortunately, even with this approach, local 
failure occurs in ~50% or more of patients[7,8]. 
 
1.1.2 RT Dose Intensification without Chemotherapy (Table 1) 
 
The second approach attempting to improve local control and survival in locally-advanced NSCLC was 
intensifying the RT. Initial studies did not include chemotherapy. The largest randomized study was performed 
in the United Kingdom and evaluated continuous, hyperfractionated, accelerated radiotherapy (CHART)[9]. 
Patients with locally-advanced NSCLC were randomized to conventional RT (2 Gy qd to 60 Gy over 42 days) 
or CHART (1.5 Gy tid to 54 Gy in 12 consecutive days). CHART was associated with a 21% relative 
improvement in local control which translated to an improvement in survival (20% vs 13% at 3 years). 
However, the incidence of grade 3-4 esophagitis was also increased with accelerated treatment (19% vs 3%). 
This treatment approach has not been incorporated into broad practice for several reasons- lack of 
chemotherapy, logistical challenges of a tid schedule, and increased rates of esophagitis. Of note, two smaller 
studies, with different fractionation schedules, failed to demonstrate an advantage with RT intensification[4,10]. 
 
 
1.1.3 RT Dose Intensification with Chemotherapy (Table 1) 
 
As outlined above, chemotherapy improves survival in locally-advanced NSCLC when given with 
conventional RT. Several studies evaluated RT dose intensification combined with chemotherapy. A 
randomized study from the Eastern Cooperative Oncology Group (ECOG 2597) compared conventional 
radiation therapy (2 Gy qd to 64 Gy) with hyperfractionated accelerated RT (1.5 Gy tid to 57.6 Gy)[11]. All 
patients received sequential chemotherapy with carboplatin and paclitaxel. The study was closed early after 
enrolling 141 patients for multiple reasons: sequential instead of concurrent chemotherapy, logistical challenges 
of a tid fractionation schedule, and increased rates of esophagitis. Local control was not reported but survival at 
3 years was superior with accelerated RT (34% vs 14%), but this was not statistically significant (p=0.28). 
Grade 3-4 esophagitis was more common in the experimental arm (25% vs 16%). Two additional randomized 
studies, one using a hyperfractionated regimen[5] and the other using a split course of RT [12] (which may have 
decreased the effectiveness of RT), failed to demonstrate a survival advantage with RT dose-intensification. 
 
Multiple phase I/II studies [13,14] have demonstrated that 74 Gy is the maximally-tolerated dose when 
given with conventionally fractionated (2 Gy qd) with concurrent chemotherapy. These studies provided the 
basis for the Intergroup randomized study comparing 60 Gy and 74 Gy with concurrent chemotherapy with 


 
 
 
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carboplatin and paclitaxel on a weekly schedule, and after completion of chemoradiotherapy, two cycles of 
systemic dose carboplatin and paclitaxel were given (referred to as consolidation therapy). This study 
randomized patients to conventional dose RT (2 Gy qd to 60 Gy) or high-dose RT (2 Gy qd to 74 Gy). The 
high-dose arm was discontinued early after an interim analysis demonstrated futility. Median survival was 28.7 
months for the conventional dose arm versus 20.3 months for the high-dose arm (p=0.004). This study suggests 
that dose intensification is not successful when the full dose of radiation therapy is delivered to the entire initial 
treatment volume. Of note, a secondary randomization to concurrent and adjuvant cetuximab demonstrated no 
benefit. 
 
Table 1 
Randomized Studies Evaluating Altered Fractionation in NSCLC 
Study 
n 
Treatment 
Survival 
Grade  
3-4 Esophagitis 
Radiation therapy alone 
Sause[4] 
310 
RT  (60 Gy, 2 Gy qd) 
RT  (69.6 Gy,1.2 Gy bid) 
5% 
6% (5 years) 
NS 
Ball[10] 
99 
RT  (60 Gy, 2 Gy qd) 
RT  (60 Gy, 2 Gy bid) 
10% 
13% (5 years) 
12% 
32% 
Saunders[9] 563 
RT  (60 Gy, 2 Gy qd) 
RT  (54 Gy, 1.5 Gy tid) 
13% 
20% (3 years, p<0.01) 
3% 
19% 
Radiation therapy and chemotherapy 
Belani[15] 
119 
CT→RT (64 Gy, 2 Gy qd) 
CT→RT (57.6 Gy, 1.5 Gy tida) 
14% 
34% (3 years, p=0.28) 
16% 
25% 
Schild[12] 
234 
CT-RT (60 Gy, 2 Gy qd) 
CT-RT (60 Gy, 1.5 Gy bidb) 
37% 
40% (2 years) 
20% 
18% 
Curran[5] 
397 
CT-RT (60 Gy, 2 Gy qd) 
CT-RT (69.6 Gy, 1.2 Gy bid) 
21% 
17% (4 years) 
NS 
Bradley[16] 424 
CT-RT (60 Gy, 2 Gy qd) 
CT-RT (74 Gy, 2 Gy qd) 
28.7 months  
20.3 
months 
(median, 
p=0.004) 
7% 
15% 
NS- not stated; a2nd daily fraction 1.8 Gy; bsplit course, which will decrease rates of esophagitis but also decrease local tumor control. 
Belani- carboplatin and paclitaxel 
Schild- cisplatin and etoposide 
Curran- cisplatin and vinblastine 
Bradley- carboplatin and paclitaxel 
 
 
1.1.4 Summary of Rationale for Dose Intensification 
 
Based on RTOG 0617, the current standard of care for locally-advanced NSCLC is concurrent 
chemotherapy with conventional RT (60-66 Gy). Administering higher doses to all sites of disease appears to be 
counterproductive. However, despite concurrent chemotherapy and radiation therapy, local failure is common, 
occurring in ~50%[7,8] or more[2] of patients.  
A recent meta-analysis demonstrated a statistically significant improvement in survival with accelerated 
radiation therapy[17]. We recently completed a phase I study that demonstrated that the dose of RT could be 
safely escalated to 74 Gy using accelerated RT (6 fractions/week) and concurrent chemotherapy[18]. Another 
prospective study at our institution demonstrated that adapting the RT using interim PET is feasible[19]. In this 
study, all patients received a standard dose of RT (60 Gy) to all sites of original disease. A PET was performed 
at 50 Gy. If dosimetric constraints could be met, and the patient was tolerating treatment well without high-


 
 
 
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grade toxicity, a boost dose of 10 Gy (total dose- 70 Gy) was given to residual FDG-avid disease apparent at 50 
Gy on the interim PET. The metabolic complete response rate at 50 Gy was 8%. 
 
For this phase II study, we plan to investigate a strategy of accelerated and adaptive RT. Patients with 
locally-advanced NSCLC will receive RT (6 fractions/week), to a total dose of 60 Gy. Patients will undergo a 
PET at 50 Gy. In the absence of high-grade toxicity, and if strict normal tissue dosimetric constraints can be 
met, then a 12 Gy boost will be administered to residual FDG-avid disease to a total dose of 72 Gy. All patients 
will receive concurrent weekly carboplatin and paclitaxel. 
 
1.1.5 Rationale for Carboplatin and Paclitaxel 
 
Carboplatin and paclitaxel is a widely accepted platinum-doublet chemotherapy regimen that has been 
studied extensively in the setting of concurrent radiation therapy for locally-advanced non-small cell lung 
cancer. It is listed as an appropriate chemotherapy regimen when given with concurrent RT by the NCCN and 
was the chemotherapy backbone for the recently reported RTOG 0617 regimen[16].  Older trials have employed 
combination chemotherapy with cisplatin and etoposide, cisplatin and vinblastine, and mitomycin, vindesine, 
and cisplatin (MVP). Due to concerns about the toxicities and tolerability of the cisplatin-based chemotherapy 
several trials have investigated more recently developed chemotherapy combinations.  
 
A  three-arm phase III perform by West Japan Thoracic Oncology Group trial (WTJOG) investigated the 
combination of weekly carboplatin (AUC=2) and paclitaxel (40 mg/m2) concurrent with thoracic radiation 
therapy (TRT)  followed by systemic dose carboplatin (AUC=5) and paclitaxel (200 mg/m2) or carboplatin  
(AUC=2) and irinotecan (20 mg/m2) concurrent with RT followed by systemic dose carboplatin (AUC=5) and 
irinotecan (50 mg/m2 on days 1,8) compared to the standard therapy of mitomycin, vinblastine and cisplatin 
(MVP) concurrent with RT followed by two cycles of MVP[20]. The median survival observed in the MVP arm 
and carboplatin and paclitaxel arms were 20.5 and 22 months, respectively. The 5-year OS rate in MVP and 
carboplatin and paclitaxel arms were 17.5% and 19.8%, respectively. The incidence of grade 3 or 4 neutropenia, 
febrile neutropenia, and gastrointestinal disorders observed on the MVP were statistically significantly higher 
than the incidence observed on the carboplatin and paclitaxel arm. The number of patients who received 0,1, or 
2 cycles of systemic dose chemotherapy in the carboplatin and paclitaxel arm was 30.6%, 19.7%, and 49.7%, 
respectively; significantly more patients in the carboplatin and paclitaxel arm received two courses of the 
systemic therapy (p=0.002). The conclusion of the trial was that the combination of carboplatin and paclitaxel 
had a more favorable toxicity profile and should be considered a standard regimen in the management of locally 
advanced NSCLC.  
 
A three arm, non-comparative randomized phase II trial investigated the optimal sequencing of carboplatin and 
paclitaxel with daily thoracic radiation therapy to 63 Gy/7 weeks/34 fractions.32 Patients were randomized to 
two cycles of induction carboplatin (AUC=6)  and paclitaxel (200 mg/m2) followed by TRT alone (arm 1), two 
cycles of induction carboplatin (AUC=6) and paclitaxel (200 mg/m2) followed by concurrent carboplatin 
(AUC=2) and paclitaxel (45 mg/m2) with TRT (arm 2), or concurrent carboplatin (AUC=2) and paclitaxel (45 
mg/m2) with TRT followed by systemic dose carboplatin (AUC=2) and paclitaxel (200 mg/m2) (arm 3)[11].  
The median overall survival observed in arms 1, 2, and 3 was 13.0, 12.7 and 16.3 months, respectively. The rate 
of grade 3 and 4 esophagitis observed in arms 1, 2, and 3 was 3%, 19%, and 28%, respectively (p<0.001); the 
higher rate of esophagitis in the concurrent chemoradiotherapy. Of the patients enrolled in arm 3, 25% did not 
receive systemic chemotherapy, 8% received a single cycle, and 67% received two cycles. The conclusion of 
the authors was the weekly concurrent carboplatin and paclitaxel followed by the consolidation carboplatin and 
paclitaxel was associated with the best outcome.  
 


 
 
 
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The combination of these trials led to the adoption of carboplatin and paclitaxel weekly with concurrent TRT 
followed by consolidation carboplatin and paclitaxel for two cycles as the chemotherapy platform for the ROG 
0617 phase III trial previously discussed. Patients received weekly carboplatin (area under curve (AUC) of 2)  
and paclitaxel 45 mg/m2 weekly during concurrent TRT, and followed by two cycles of carboplatin (AUC of 6) 
and paclitaxel (200 mg/m2) every 3 weeks for 2 cycles. In the patients assigned to the 60 Gy and 74 Gy arms 
concurrent chemotherapy was delivered per protocol in 88% and 85% of patients, respectively, and with 
acceptable variation in additional 6% of patients of both arms. Consolidation chemotherapy was delivered per 
protocol in the 60 Gy and 74 Gy arms in 70% and 64% of patients, respectively, and with acceptable variation 
in 5% of patients. Finally, a VA study showed no difference in clinical outcomes, with less toxicity, when 
carboplatin and paclitaxel are utilized instead of cisplatin and etoposide[21]. 
 
Since weekly administration of carboplatin and paclitaxel was given concurrently with thoracic irradiation in 
above studies, we chose to administer these agents in the same fashion for this phase II trial. 
 
1.1.6 Rational for Primary Endpoint 
 
 
PERCIST (Positron Emission Tomography Response Criteria in Solid Tumors) provides guidelines on how 
to report responses to therapy based on PET-CT[22,23]. PET-CT response has been shown to be prognostic in a 
variety of clinical scenarios in lung cancer including after induction therapy[24]. In one study, PET was 
performed after neoadjuvant chemoradiotherapy (40-50.4 Gy). Complete or partial metabolic response using 
PERCIST criteria was predictive of loco-regional, distant, and overall progression-free survival[25]. The 
complete metabolic response rate was 2%; the partial metabolic response rate was 45%. Interim PET-CT 
response may provide a more rapid assessment of the efficacy of therapy than conventional clinical endpoints 
such as progression-free or overall survival. 
 
2.0 Purpose 
 
Despite concurrent chemotherapy and radiation therapy, local/regional failure occurs in ~50% of patients 
with locally-advanced NSCLC. Clinical studies have demonstrated that accelerated fractionation (giving the 
same total dose in a shorter period of time) improves outcomes in several malignancies, including lung 
cancer[17]. Administering higher than conventional doses of RT to all sites of original disease leads to inferior 
outcomes[16]. Adapting the RT approach, giving a higher dose to slowly responding disease as assessed with 
interim PET has been shown to be feasible[19]. This is a prospective phase II study designed to study an 
accelerated and adaptive RT approach for locally-advanced NSCLC.  
 
2.0 Objectives 
2.1 Primary Objective 
To determine the metabolic complete response rate, assessed using interim PET-CT, in an accelerated fashion 
(2 Gy/fraction, 6 fractions/week) with concurrent chemotherapy. 
Hypothesis- The metabolic complete response rate, assessed using interim PET-CT between 48Gy and 
54Gy, will increase from 8% to 20% with RT dose acceleration (6 fractions/week). 
2.2 Secondary Objectives 
2.2.1 To determine how many patients will be eligible for an RT boost after assessment with an interim PET-CT 
between 48Gy and 54Gy, delivered in an accelerated fashion (6 fractions/week) with concurrent chemotherapy. 


 
 
 
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2.2.2 To evaluate clinical outcomes including overall survival, progression-free survival, and local control with 
an accelerated and adaptive RT approach. 
2.2.3 To correlate clinical outcomes (survival, progression-free survival, local control) with interim PET-CT 
responses using PERCIST criteria. 
 
3.0 Patient Recruitment 
This will be a prospective study with all eligible patients offered enrollment prior to their radiation treatment. 
The subject population (with no gender or minority restrictions) will include adult patients meeting the 
eligibility criteria.  Inclusion of women and minorities will be encouraged. Lung cancer is a diseases of adults-  
patients under 18 will be excluded from this study. All patients must sign an IRB approved informed consent 
prior to enrollment 
 
4.0 Eligibility Criteria 
Conditions for Patient Eligibility 
1. Histologic/cytologic documentation of non-small cell lung cancer (NSCLC) 
2. Unresectable stage II-III disease, per AJCC 8th edition 
3. Zubrod/ECOG performance status 0-1 
4. Weight loss < 10% in preceding 3 months prior to diagnosis 
5. Adequate organ function defined as the following 
1. Absolute neutrophil count of ≥ 1,500 and platelet count ≥ 100,000  
2. Cockcroft calculated creatinine clearance of ≥ 45 ml/min or 1.5 x the upper limit of normal (ULN) 
3. A total bilirubin ≤ 1.5 ULN, aspartate aminotransferase (AST) ≤ 2.0 x ULN 
6. ≥ 18 years of age. 
7. Negative pregnancy test in women of child-bearing potential 
8. Signed study-specific informed consent. 
9. No prior chemotherapy or radiotherapy for NSCLC  
10. No prior mediastinal or thoracic radiation  
 
Conditions for Patient Ineligibility 
1. Prior thoracic irradiation. 
2. Medical contraindications to thoracic irradiation. 
3. Pre-existing sensory neuropathy of grade ≥ 2 
4. Pleural effusion: when pleural fluid is visible on both CT scan and on a chest x-ray, a pleuracentesis is  
required to confirm that the pleural fluid is cytologically negative. Patients with effusions that are minimal 
(i.e. not visible on chest x-ray) or that are too small to safely tap are eligible 
5. Patients with contralateral hilar involvement 
 
 
 
 
 


 
 
 
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5.0 Pretreatment Evaluation 
1. A complete history and physical to include recent weight loss and performance status 
2. Laboratory studies will include a complete blood count (CBC) with differential, complete metabolic 
panel, and pregnancy test in women of child-bearing potential 
3. Baseline staging exams within 8 weeks of signing written consent: 
a. PET-CT (skull-base to mid-thigh) 
b. Brain MRI with contrast (preferred) or head CT scan with and without contrast  
 
6.0 Registration Procedures 
Only radiation oncologists listed as Key Personnel for this study by the Duke University Health System 
(DUHS) IRB and who have completed the DUHS required ethics training may enroll patients on this study. The 
patient’s primary medical oncologist will be apprised of the patient’s intent to participate on study. Following 
verification of eligibility the patient will be assigned a sequential study ID number.  
 
7.0 Protocol Treatment 
 
7.1 Radiation Therapy  
 
Radiation therapy is to be initiated concurrently with the first cycle of chemotherapy. All radiation planning and 
treatment procedures are standard of care. 
 
Equipment 
All patients will be treated using either three-dimensional or intensity modulated (including volumetric 
modulated arc therapy- VMAT) techniques with a linear accelerator using photon energies of 6, 10, and/or 15 
MV.  
 
Treatment Planning 
 Treatment planning procedures are standard of care. A custom immobilization device will be designed for each 
patient. Intravenous and oral contrast are recommended but not mandated. A CT-Sim procedure will be 
performed with respiratory management on all patients.  At the discretion of the treating physician, patients may 
be treated with breath hold techniques if this is deemed appropriate.   
 
Target Volume 
The gross tumor volume (GTV) will include the primary tumor (GTV-Lung) as well as PET positive lymph 
nodes in regional lymph nodes (GTV-LNs). These volumes will be adjusted to account for motion observed on 
the 4D CT dataset. The GTV-Lung will be expanded by 5 mm to account for possible microscopic extension 
beyond the visible primary tumor mass. The GTV-LNs will be expanded by 3 mm to allow for microscopic 
extracapsular extension. The expanded lung and lymph node volumes will be combined to create a clinical 
target volume (CTV). The CTV will be expanded by 3-5 mm to create a planning target volume (PTV) to 
account for daily set-up uncertainty and motion that may not have been accounted for in the 4D CT scan. The 
PTV will be the final target for radiation treatment planning.  
 
Treatment Planning Technique 
Patients can undergo three-dimensional or intensity-modulated radiation therapy (including VMAT). An 
original plan to 60 Gy will be designed. 
 
The following dose constraints are recommended per standard of care: 


 
 
 
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1. Lung V20 (volume of lung receiving 20 Gy or more) ≤ 35% 
2. Spinal cord Dmax (maximum point dose) < 50 Gy 
3. Heart V30 (volume of heart receiving 30 Gy or more) ≤ 50% 
4. Esophagus V60 (volume of esophagus receiving 60 Gy or more) ≤ 20% 
5. Brachial plexus Dmax ≤ 64 Gy 
 
RT Treatment 
 
Patients will be set up daily using daily kV imaging +/- cone-beam CT. Typically, radiation will be given 
with 6 weekly fractions (with two fractions administered once a week, preferably on Fridays, separated by 6 
hours). Patients may begin radiation therapy on a day other than Monday. In such cases, they will receive daily 
radiation treatments and will receive two fractions on one day of that week (preferably Fridays).  
During weeks that have holidays, the number of fractions delivered will be at the discretion of the treating 
radiation oncologist. Any missed treatment(s) during a holiday will be added at the end of radiation.  
It will not be considered a protocol deviation if a patient receives less than 6 fractions during a holiday week or 
during the first week of radiation therapy. 
 
Treatment Interruptions during RT 
Treatment breaks due to radiation-induced esophagitis will be given at the discretion of the radiation 
oncologist. Other (less common) reasons for a treatment break will be: 
 
1. Febrile neutropenia (ANC ≤ 500). RT will be resumed once the ANC is >800 and the patient has been 
afebrile for at least 24 hours. 
2. Grade 3 thrombocytopenia associated with bleeding or grade 4 thrombocytopenia (platelets < 20,000). RT 
will be resumed once the platelets are > 20,000. 
3. Non-hematologic grade 3-4 toxicity if felt by treating radiation oncologist that a break is necessary (i.e. 
significant skin reaction). 
 
7.2 Chemotherapy 
Primarily standard of care concurrent and consolidation chemotherapy is administered using carboplatin and 
paclitaxel. However, any chemotherapy regimens per the National Comprehensive Cancer Network (NCCN) 
version 2.2018 issued on December 19, 2017 for non-small cell lung cancer will be acceptable for the 
concurrent and consolidation phase, at the discretion of the treating physician. Premedication, adjustments to 
dosing schedules, discontinuation of chemotherapy, and/or dose modifications, and/or alternative systematic 
therapy will be determined by the treating medical oncologist per clinical assessment. General guidelines for 
concurrent and consolidation chemotherapy are included in the protocol. 
 
Concurrent Chemotherapy: 
Concurrent chemoradiotherapy: given weekly during the duration of thoracic radiation to include boost week. 
 
Treatment administration 
Agent 
Dose 
Infusion time 
Days 
Paclitaxel 
45 mg/m2 
1 hour 
Weekly  
Carboplatin 
AUC=2 
30 minutes 
Weekly 
  
 
 
 
AUC= area under curve 
 


 
 
 
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Consolidation Chemotherapy: 
Consolidation chemotherapy: beginning ~4 weeks after completion of concurrent chemoradiotherapy. 
Treatment administration 
 
Agent 
Dose 
Infusion time 
Days 
Paclitaxel  
200 mg/m2 
3 hours 
1 
Carboplatin  
AUC=6 
30-60  minutes 
1 
7.2.1 Concurrent and Consolidation Chemotherapy Guidelines 
1. Ototoxicity: For grade ≥ 3 toxicity discontinue carboplatin permanently 
2. Hypersensitivity reactions: For grade 3 reactions, in subsequent cycles use double dose steroids 
pretreatment and decrease infusion rate for the first 1/3 of the infusion. For last 2/3 of infusion, double the rate 
of the infusion. For documented grade 4 hypersensitivity reactions to paclitaxel discontinue paclitaxel 
3. Cardiotoxicity: If patient develops chest pain, hypotension, or arrhythmia other than asymptomatic 
bradycardia, the paclitaxel infusion should be stopped and patients should not receive further paclitaxel. For 
asymptomatic sinus bradycardia, the infusion does not need to be stopped and patient should be observed 
carefully for development of symptoms of bradycardia. 
4. Hepatic dysfunction  
 
AST                   Bilirubin  
           Paclitaxel  
< 2.0 ULN and < 1.5 mg/dl 
100% 
2.0-5.0 X ULN and < 1.5 mg/dl 
50% 
> 5.0 X ULN or ≥ 1.5 mg/dl 
0% 
 
Check labs weekly and if labs return to normal (AST< 2.0 x ULN and bilirubin < 1.5 mg/dl) within 3 weeks, 
reinstitute paclitaxel at 100% of dose. If AST > 5.0 x ULN or bilirubin > 1.5 mg/dl after 3 weeks, consider 
discontinuing chemotherapy.  
 
7.2.2 Concurrent Chemotherapy Guidelines 
Concurrent chemoradiotherapy: given weekly during the duration of thoracic radiation. 
 
Treatment administration 
Agent 
Dose 
Infusion time 
Days 
Paclitaxel a 
45 mg/m2 
1 hour 
Weekly  
Carboplatin b 
AUC=2 
30 minutes 
Weekly 
AUC= area under curve 
 
a Premedications for Paclitaxel 
1. Dexamethasone 20 mg PO on the evening prior to and morning of paclitaxel or 20 mg IV 30 minutes 
prior to paclitaxel administration. 
2. Diphenhydramine 50 mg IV (or equivalent) 30 minutes prior to paclitaxel administration. 
3. Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or famotidine 20 mg) 30 minutes prior to 
paclitaxel. 
b Carboplatin should be infused following the administration paclitaxel 
 
The Calvert formula (Dose = AUC X [CrCl + 25]) will be used to calculate the carboplatin dose. Carboplatin 
dose calculated using the Calvert equation, and using the baseline creatinine obtained prior to  day 1of CRT. 
The patient’s glomerular filtration rate as creatinine clearance (CrCl) in mL/min will be estimated using the 


 
 
 
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Cockcraft-Gault formula, and the maximum CrCl that will be used in the calculation of carboplatin dose is a 
CrCl=125. 
 
Cockcroft-Gault formula: 
 
For males:  Creatinine clearance (mL/min) = (140 – age) x weight in kilograms 
                                                                                       72 x serum creatinine in mg/dl 
 
For females: use same formula but multiply by 0.85 for creatinine clearance. 
 
Dose Modifications during Concurrent Therapy 
 
Dose levels during concurrent therapy 
Agent  
Starting dose  
Dose level -1 
Paclitaxel 
45 mg/m2 
Not applicable 
Carboplatin  
AUC=2 
Not applicable 
 
There will be no dose modifications for paclitaxel and carboplatin during concurrent chemotherapy 
 
Guidelines for holding Paclitaxel/Carboplatin for Hematologic Toxicity 
 
Toxicity 
NCI CTCAE Grade 
(CTCAE v 4.0) 
Paclitaxel Dose At Start of 
Subsequent 
treatment 
of 
Therapya 
Carboplatin Dose at 
Start of Subsequent 
Therapya 
Neutropenia 
 
1 (1500-1999/mm3) 
 
Maintain dose level 
Maintain dose level 
2 (1000-1499/mm3) 
Maintain dose level 
Maintain dose level 
3 (500-999/mm3) 
Hold therapyb 
Hold therapyb 
4 (<500/mm3) 
Hold therapyb 
Hold therapyb 
Neutropenic fever 
Hold therapyb 
Hold therapyb 
Thrombocytopenia 
 
1 (<LLN-75,000/mm3) 
Maintain dose level 
Maintain dose level 
2 (50,000-74,999/mm3) 
Hold therapyb 
Hold therapyb 
3 (25,000-49,999/mm3) 
Hold therapyb 
Hold therapyb 
4 (<25,000/mm3) 
Hold therapyb 
Hold therapyb 
Other Hematologic toxicities There will be no dose modifications for changes in leukopenia or 
lymphopenia.  
a Dose levels are listed above 


 
 
 
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b Repeat lab work weekly and resume chemotherapy based on this table. 
 
Doses that are missed during weekly schedule concurrent with radiation will not be made up  
If paclitaxel and/or carboplatin doses must be withheld for greater than two consecutive weeks,  
the drug(s) may be held permanently for the duration of concurrent therapy. 
 
 
Parameters for holding Paclitaxel/Carboplatin therapy for Non-Hematologic Toxicity 
during concurrent Therapy 
 
Worst Toxicity 
NCI CTCAE Grade 
(CTCAE v 4.0) a,b 
Paclitaxel Dose At Start  
of Subsequent Cycles of 
Therapyb 
Carboplatin Dose At Start  
of Subsequent Cycles of 
Therapyc 
Neuropathyc 
 
≤ Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Hold therapy until 
Grade ≤ 1; restart at full dose 
Maintain dose level 
Grade 3 
Discontinue therapy 
Maintain dose level 
Other 
Non-Hematologic 
toxicities  
 
≥ Grade 3 
Hold treatment until 
≤ Grade 2 
Hold treatment until 
≤ Grade 2 
 
a. For ≤ CTCAE Grade 2 non-hematologic toxicity not described above, excluding neuropathy, maintain dose 
level of all study.  For neuropathy, follow the guidelines listed above. 
b. Paclitaxel for Neuropathy :If paclitaxel doses must be withheld for greater than two consecutive weeks, the 
drug will be held permanently for the duration of concurrent therapy 
 
c. Carboplatin Dose Modifications for Renal Toxicity : A > 10% change in the serum creatinine, based on 
weekly calculated creatinine clearance, will warrant a recalculation of the carboplatin dose 
 
7.2.3 Consolidation Chemotherapy Guidelines 
Consolidation chemotherapy and/or immunotherapy will be at the discretion of the treating medical oncologist 
based on clinical assessment. The consolidation phase will begin 4 weeks after completion of radiotherapy 
(Cycles 5 and 6; Cycle = 21 days).  If the patient is unable to begin chemotherapy at the 4-week time point 
following radiotherapy, the chemotherapy may be delayed up to an additional 4-weeks. Patients will be required 
to have an ANC≥ 1,500/mm3 or platelet count > 100,000 mm3. 
 
Treatment administration 
 
Agent 
Dose 
Infusion time 
Days 
Paclitaxel a 
200 mg/m2 
3 hours 
1 
Carboplatin b 
AUC=6 
30-60  minutes 
1 
 
Premedications for Paclitaxel 


 
 
 
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1. Dexamethasone 20 mg PO on the evening prior to and morning of paclitaxel or 20 mg IV 30 minutes 
prior to paclitaxel administration. 
2. Diphenhydramine 50 mg IV (or equivalent) 30 minutes prior to paclitaxel administration. 
3. Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or famotidine 20 mg) 30 minutes prior to 
paclitaxel. 
4. Anti-emetic therapy should be given at the discretion of the treating physician. 
 
b The Calvert formula (Dose = AUC X [CrCl + 25]) will be used to calculate the carboplatin dose. Carboplatin 
dose calculated using the Calvert equation, and using the creatinine on day 1 of each cycle in order to adjust for 
any potential change in renal function. Patient’s glomerular filtration rate as creatinine clearance (CrCl) in 
mL/min will be estimated using the Cockcraft-Gault formula, and the maximum CrCl that will be used in the 
calculation of carboplatin dose is a CrCl=125. 
Cockcroft-Gault formula: 
For males:  Creatinine clearance (mL/min) = (140 – age) x weight in kilograms 
72  serum creatinine in mg/dl 
 
  For females: Use same formula but multiply by 0.85 for creatinine clearance 
Dose Modifications During Consolidation Therapy 
 
Dose levels for paclitaxel and carboplatin during consolidation chemotherapy 
Agent 
Starting dose 
Dose level -1 
Paclitaxel 
200 mg/m2 
150 mg/m2 
Carboplatin 
AUC=6 
AUC=4.5 
 
 
Paclitaxel/Carboplatin Dose Modifications for Hematologic Toxicity 
 
Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0) 
Paclitaxel Dose at  
Start of Subsequent  
Cycles of Therapya,c 
Carboplatin Dose at 
Start of Subsequent 
Cycles of Therapya,c 
Neutropenia 
 
1 (1500-1999/mm3) 
Maintain dose level 
Maintain dose level 
2 (1000-1499/mm3) 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 
week.  If not recover in 1  week, 
decrease by 1 dose level when ≥ 
1,500 mm3 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 week.  
If not recovered in 1 weee, 
decrease by 1 dose level when ≥ 
1,500 mm3 
3 (500-999/mm3) 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 
week.  If not recovered in 1 
week, decrease by 1 dose level 
when ≥ 1,500 mm3 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 week.  
If not recovered in 1 week, 
decrease by 1 dose level when ≥ 
1,500 mm3 


 
 
 
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4 (<500/mm3) 
Hold therapyb and decrease by 1 
dose level when ≥ 1,500 mm3 
Hold therapyb and decrease by 1 
dose level when ≥ 1,500 mm3 
Thrombocytopenia 
 
1 (≥ 75,000/mm3) 
Maintain dose level 
Maintain dose level 
2 (50,000-74,999/mm3) 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 week.  
If not recovered in 1 week, 
decrease by 1 dose level when ≥ 
75,000 mm3 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 
week.  If not recovered in 1 
week, decrease by 1 dose level 
when ≥ 75,000 mm3 
3 (25,000-49,999/mm3) 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 week.  
If not recovered in week, decrease 
by 1 dose level when ≥ 75,000 
mm3 
Hold therapyb.  Maintain dose 
level if fully recovered in 1 
week.  If not recovered in 1 
week, decrease by 1 dose level 
when ≥ 75,000 mm3 
4 (<25,000/mm3) 
Hold therapyb and decrease by 1 
dose level when ≥ 75,000 mm3 
Hold therapyb and decrease by 1 
dose level when ≥ 75,000 mm3 
Other Hematologic 
toxicities 
There will be no dose modifications for changes in leukopenia or 
lymphopenia. 
 
a Dose levels are relative to the worst toxicities in the previous cycle.  For consolidation therapy, dose 
reductions of paclitaxel and carboplatin below the -1 dose level will not be allowed. 
bRepeat lab work weekly and resume chemotherapy based on this table. 
cDose delays greater than 2 weeks will warrant discontinuation of chemotherapy for the consolidation cycles. 
 
Paclitaxel/Carboplatin Dose Modifications for Non-Hematologic Toxicity During Consolidation Therapy 
 
Worst Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0) a 
Paclitaxel Dose At Start of 
Subsequent 
Cycles 
of 
Therapyb 
Carboplatin Dose At Start of 
Subsequent Cycles of Therapyb 
Neuropathy 
 
≤ Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Hold treatment until Grade ≤ 1; 
restart at full dose 
Maintain dose level 
Grade 3 
Discontinue therapy 
Maintain dose level 
Other non-hematologic 
toxicities  
 
 
Grade 3 
Hold treatment until 
≤ Grade 2 
Hold treatment until 
≤ Grade 2 
a. For ≤ CTCAE Grade 2 non-hematologic toxicity not described above, excluding neuropathy, maintain dose 
level of all study drugs.  For neuropathy, follow the guidelines above. 
b. Dose level are relative to the worst toxicities in previous cycle 
  


 
 
 
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Paclitaxel Dose Modifications for Neuropathy: if paclitaxel doses must be withheld for greater than two 
consecutive weeks, the drug will be held permanently for the duration of the consolidation therapy. 
 
7.3 Interim PET-CT 
Patients will undergo an interim PET-CT after 4 weeks of radiation therapy between 48Gy and 54 Gy. The 
interim PET-CT may be delayed up to 60 Gy. Patients can have diabetes but their blood sugar must be <200 
mg/dL at the time of interim PET-CT simulation. If the PET-CT cannot be completed due to hyperglycemia or 
other issues, the patient will complete radiation therapy to a dose of 60 Gy with no boost. The PET-CT will be 
obtained based on institutional standards. In general, patients will be administered 8-15mCi (exact activity 
prescribed based on patient weight) of 18F-FDG through IV injection and rested before PET-CT scanning. The 
PET imaging will be started approximately 60 minutes after FDG injection with acquisition time of 3.5 minutes 
per bed position. The iterative algorithm incorporating point spread function (PSF) and time of flight (TOF) will 
be used for PET-CT image reconstruction. In conjunction with the PET, the patient will undergo a CT-Sim 
treatment planning scan for re-planning. 
 
 
 
The planning PET-CT will be exported to our treatment planning software. The treating radiation oncologist 
will contour all sites of residual FDG-avid disease (defined as disease with FDG uptake > background uptake in 
the liver assessed using visual analysis supplemented with semi-quantitative values such as SUVmax) that 
corresponds with areas of original involvement. These volumes will be reviewed with a nuclear medicine 
physician and/or radiologist to assess response and confirm residual FDG-avid disease. Patients who achieve a 
complete metabolic response, defined as complete resolution of FDG uptake, with FDG uptake less than the 
mean standardized uptake value of the liver corrected for lean body mass, and indistinguishable from that of the 
surrounding background, will not be eligible for a boost. A boost plan will be designed using the same 
expansion criteria as previously outlined. Patients will be eligible for a boost (2 Gy qd to 12 Gy, 6 
fractions/week, total dose 72 Gy) if all of the following are met: 
 
Eligibility for Boost 
Dosimetric criteria (composite of initial and boost plans) 
1. Lung V20 ≤ 35% 
2. Spinal cord Dmax <50Gy 
3. Esophageal V60 ≤ 20% 
4. Heart V30 ≤ 50% 
5. Brachial plexus Dmax ≤ 64 Gy 
 
Clinical criteria 
1. No evidence of local, regional, or distant progression on interim PET-CT 
2. No grade 3-4 non-hematologic toxicity related to radiation therapy after completing 60 Gy 
If dose-volume histogram (DVH) metrics to an organ exceeds any of these criteria based on the initial plan, but 
the boost plan does not contribute any further dose to that organ, then the patient is still eligible for a boost. 
7.4 Treatment Assessments 
Patients will be assessed on a weekly basis as part of routine clinical care by the radiation oncologist and 
treatment-related toxicities will be prospectively recorded. Patients will also be evaluated routinely by the 
medical oncologist per the standard of care. As necessary patients will be seen more often. 
Blood work will be obtained weekly during treatment at the discretion of the treating medical oncologist. 


 
 
 
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8.0 Confidentiality and Protection of Research Subjects 
All study-related materials will be stored electronically on password-protected computers within locked offices. 
Paper study-related forms will similarly be stored in locked offices. All personnel involved in the conduct and 
analysis of data from the study will have ethics training in the protection of research subjects. The research data 
security plan (RDSP) will be reviewed and approved by the appropriate IT security personnel. 
 
9.0 Protocol Management and Data Collection  
This study will be conducted in accordance with Good Clinical Practice guidelines and Duke University School 
of Medicine policies. Data will be entered on the study specific e-forms in a password protected REDCap 
database.  
9.1 Adverse Events: 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study therapy and which 
does not necessarily have a causal relationship with this treatment.  For this protocol, the definition of AE 
also includes worsening of any pre-existing medical condition.  An AE can therefore be any unfavorable 
and unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of radiation therapy, whether or not related to use of the radiation 
therapy. Abnormal laboratory values that require therapy, adjustment in prior therapy, or are grade 2 and 
higher will be considered an adverse event and will be captured. All AEs at the start of concurrent 
chemoradiation therapy (CRT) through 30 days post CRT will be captured in the adverse events case report. 
AEs will be assessed according to the CTCAE version 4.0.  If CTCAE grading does not exist for an AE, the 
severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal (5). 
Attribution of AEs will be indicated as follows: 
− Definite:  The AE is clearly related to the study therapy 
− Probably:  The AE is likely related to the study therapy 
− Possible:  The AE may be related to the study therapy 
− Unlikely:  The AE is doubtfully related to the study therapy 
− Unrelated:  The AE is clearly NOT related to the study therapy 
10.0 Risk/Benefit Assessment 
Patients with locally-advanced NSCLC are at high risk of relapse and death. Long-term (4-5 years) survival is 
~15-20% in patients with good performance status without significant weight loss. Local failure after 
concurrent chemotherapy and radiation therapy occurs in ~50% of patients. Thus, increasing the intensity of RT 
is rational and may improve clinical outcomes for these patients.  
 
Risks of Radiation to the Lung:  
The expected acute side effects of RT to the lung include fatigue, skin erythema, esophagitis, low blood counts, 
alopecia in the radiation field that may not grow back, cough, chest discomfort, and potentially pneumonitis. 
The risk of grade 3-4 esophagitis with conventional therapy occurs in 15-25% of patients.  
 
Less likely but serious side effects of RT to the lung include difficulty breathing, shortness of breath, irritation 
and/or damage to the heart, irregular or rapid heartbeat, heart failure, irritation and/or damage to the spinal cord, 


 
 
 
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narrowing of the esophagus, and death. It is possible that the risk of severe esophagitis (requiring treatment 
breaks, feeding tubes, hospitalization, etc.) will be greater with accelerated treatment, especially if a radiation 
boost dose is administered. We will attempt to avoid this by utilizing IMRT as appropriate, particularly if the 
esophageal V60 > 17%, which can better spare normal tissues from the high dose component of treatment. 
Further, a boost will only be pursued if strict dosimetric constraints can be met and the patient is not having 
high-grade toxicity at the end of standard therapy. 
 
Also, it is possible that the use of an accelerated RT schedule and or a boost (which can potentially increase the 
volume of lung exposed to RT) will increase the risk of lung injury, acute pneumonitis in particular. The 
patients will be monitored weekly during RT and regularly after treatment to evaluate these toxicities. Finally, it 
is possible that a higher radiation dose could lead to excess mortality, as evidenced in RTOG 0617[16]. As local 
failure remains a dominant pattern of disease recurrence, which occurs in the majority of patients with stage III 
NSCLC, interest remains in pursuing selective boosts using much smaller RT fields that should be associated 
with far less toxicity that giving a full escalated dose to all sites of original involvement. 
 
Risk of Chemotherapy  
Common side effects associated with carboplatin/paclitaxel include alopecia, thrombocytopenia, neutropenia, 
anemia, anorexia, nausea and vomiting, fatigue, arthalgias, and myalgias. Less common but potentially serious 
side effects include nephrotoxicity, hypersensitivity reaction, peripheral neuropathy, sensory peripheral 
neuropathy, dermatitis, mucositis, dysgeusia, and hearing loss and/or ringing in the ears. 
 
Risks of the Interim PET-CT  
The interim PET-CT requires the use of diagnostic radiation. This research will give a study patient the 
equivalent of about twelve extra years' worth of this natural radiation, which is far less than the therapeutic 
radiation they will receive for their malignancy. Everyone receives a small amount of unavoidable radiation 
each year. Some of this radiation comes from space (e.g., being a passenger on airline flights), some arises from 
naturally-occurring radioactive forms (e.g., radon) in the soil, water, and building materials. The increased risk 
of a radiation-induced cancer from the interim PET-CT is deemed to be very low. 
 
All initial staging modalities requiring by this study (laboratory work, PET-CT, MRI) are standard modalities to 
evaluate the extent of disease. Radiation therapy and chemotherapy are standard for patients with locally-
advanced NSCLC. The use of IMRT is an accepted method of planning and delivering radiation therapy. As 
such, all treatment-related expenses will be charged to the patient and/or their insurance carrier. The cost of the 
interim PET-CT will be borne by the Department of Radiation Oncology.  
 
11.0 Statistical Considerations 
The primary objective of the study is to determine the metabolic complete response rate, assessed using interim 
PET-CT, in an accelerated fashion (2 Gy/fraction, 6 fractions/week) with concurrent chemotherapy. Secondary 
objective are (1) to determine how many patients will be eligible for an RT boost using an interim PET-CT scan 
at 48Gy to 54 Gy of RT, delivered in an accelerated fashion (6 fractions/week) with concurrent chemotherapy; 
(2) to evaluate clinical outcomes including overall survival, progression-free survival, and local control with an 
accelerated and adaptive RT approach; and (3) to correlate clinical outcomes (survival, progression-free 
survival, local control) with interim PET-CT responses using PERCIST criteria. 
Sample size justification 
The sample size of this single arm phase II trial is determined such that we have adequate power to detect an 
increase of the metabolic complete response rate (MCRR) from 8% to 20% among patients who receive 


 
 
 
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accelerated and adaptive radiation therapy and concurrent chemotherapy in locally advanced NSCLC. We 
observed an 8% metabolic complete response rate in our prior feasibility study[19]. In other words, if the true 
MCR rate is 20% or greater, this approach would be worthy of further investigation. On the other hand, if the 
true MCR rate is 8% or less, there is an interest in concluding that the combined chemoradiotherapy is not 
worthy of further investigation. The hypothesis is:  
H0: p ≤ 0.08 versus H1: p ≥ 0.20 
where p is the true MCR rate after the combined chemoradiotherapy. 
We will use Simon’s 2-stage design to evaluate the MCR of the experimental therapy [26] The 2-stage design 
allow a futility test after stage I patients have been evaluated for MCR rate. The specific design described below 
is also the design that yields the smallest maximum sample size under the null hypothesis (minmax) among all 
designs satisfying type I error of 0.10 and type II error of 0.15. 
Specifically, the first stage of the trial will enroll 32 patients. If there are 2 or fewer patients who responds 
(complete response) among the 32 patients, the trial will be terminated; otherwise, the trial will move forward to 
enroll additional 15 patients. If 6 or fewer patients among the total of 47 patients who responds, the 
experimental therapy will be concluded as not worthy of further investigation; otherwise it will be concluded 
that the experimental therapy has sufficient activity worthy of further investigation. The above design has 
expected sample size 39.2 under the null hypothesis. The early stopping probability at stage I is 0.5226. The 
actual type I and type II errors are 0.0772 and 0.1480, respectively.  
Given expected attrition rate of 8% due to early withdrawal before completing the treatments or ineligibility, we 
will enroll 51 patients to this study in order to observe 47 evaluable patients. 
Accrual rate and accrual duration 
The phase II trial will register a total 51 patients. We expect approximately 1 locally advanced patients who 
meet the eligibility criteria will be enrolled per month. It will take approximately 51 months to reach the target 
accrual. Follow up of at least 24 months will be required for all patients for progression free survival and overall 
survival.  
Statistical analysis methods: 
For the cohort of the patient who meet eligibility criteria and receive radiotherapy with concurrent 
chemotherapy, the metabolic complete response (MCR) rate, as assessed using interim PET-CT, will be 
estimated using the UMVUE method [27] and its exact 80% confidence interval and the p-value will be 
calculated [28]. 
The proportion of the patients who are eligible for an RT boost after completing a standard dose of RT (60 Gy), 
delivered in an accelerated fashion (6 fractions/week) with concurrent chemotherapy, will be estimated as well 
as its confidence interval.  
The overall survival (OS and progression-free survival (PFS) for the treated patients will be characterized by 
Kalan-Meier estimator. The medial OS and median PFs will be estimated as well as their 95% confidence 
intervals. The local control rate for the treated patients will be estimated as well as its 95% confidence intervals. 
The correlation between outcomes (survival, progression-free survival, local control) with interim PET-CT 
responses per PERCIST criteria by univariate analysis and multivariate analysis. For survival endpoints, the 
univariate analysis will be log-rank test and the multivariate analysis will be Cox proportional hazard model in 
which baseline prognostic factors will be adjusted.  
The type of adverse events, the frequency of each type and its grade will be summarized 


 
 
 
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Page 22 of 22 
Amended Version: 7 August 2018                                                CONFIDENTIAL 
 
 
Appendix A: Boost Eligibility Worksheet 
 
Phase II Study of Accelerated and Adaptive Radiation Therapy  
for Locally-Advanced NSCLC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
By signing below, the investigator acknowledges that s/he participated in the treatment plan and concurs with 
the documentation above for radiation boost as outlined by the Pro00083154 study protocol. 
 
____________________________________________  
 
 
Printed Name of Examiner  
 
 
 
 
 
  
____________________________________________  
 
 
 
 
______________ 
Signature of Examiner  
 
 
 
 
 
 
   
 
 
 
 
 
 
Date 
 
 
 
 
Patient Name: 
MRN: 
Study ID: 
Interim PET date: 
Investigator: 
Eligibility for Boost: Patients cannot be considered eligible for boost radiation 
therapy for this study unless all of the following dosimetric and clinical constraints 
are met. 
 
Interim PET-CT 
(Clinical criteria 
based on interim 
PET) 
 
 
Residual Disease evident? 
Yes        No 
Local progression? 
Yes        No 
Distant progression? 
Yes        No 
Regional progression? 
Yes        No 
Clinical Criteria 
Grade 3-4 non-hematologic toxicities 
 
Yes        No 
Dosimetric 
Criteria 
 
 
 
  
 
Lung V20 ≤ 35% 
Yes        No 
Spinal Cord Dmax < 50 Gy 
Yes        No 
Esophageal V60  ≤ 20% 
Yes        No 
Heart V30 ≤ 50% 
Yes        No 
Brachial plexus Dmax ≤ 64Gy 
Yes        No 
  
 
 
Based on the 
following criteria 
(circle one) 
 
Eligible                                Ineligible 
(proceed to 72Gy)                   (proceed to 60 Gy)