NOT TO BE COPIED, DISSEMINATED OR REFERENCED...118 approved using an a-priori defined consensus-building methodology supported 119 by ASTRO approved tools for the grading of evidence

NOT TO BE COPIED, DISSEMINATED OR REFERENCED

1

Radical and adjuvant radiotherapy in locally advanced non-small cell lung cancer: 1 An American Society for Radiation Oncology (ASTRO) evidence-based clinical 2

practice guideline 3 4

George Rodrigues MD, PhD, FRCPCa,*, Hak Choy MDb, Jeffrey Bradley MDc, 5 Kenneth Rosenzweig MDd, Jeffrey Bogart MDe, Walter Curran Jr. MDf, Elizabeth 6 Gore MDg, Corey Langer MDh, Alexander Louie MDa, Stephen Lutz MDi, Mitchell 7 Machtay MDj, Varun Puri MDk, Maria Werner-Wasik MDl, Gregory M.M. Videtic 8

MD, CM, FRCPCm. 9 10 a. Department of Radiation Oncology, London Health Sciences Centre, 11 London, Ontario, Canada 12 b. Department of Radiation Oncology, University of Texas Southwestern, 13 Dallas, Texas 14 c. Department of Radiation Oncology, Washington University School of 15 Medicine, St Louis, Missouri 16 d. Department of Radiation Oncology, Mount Sinai School of Medicine, New 17 York, New York 18 e. Department of Radiation Oncology, State University of New York, 19 Syracuse, New York 20 f. Department of Radiation Oncology, Emory University School of Medicine, 21 Atlanta, Georgia 22 g. Department of Radiation Oncology, Medical College of Wisconsin, 23 Milwaukee, Wisconsin 24 h. Department of Medical Oncology, University of Pennsylvania, 25 Philadelphia, Pennsylvania 26 i. Department of Radiation Oncology, Blanchard Valley Regional Center, 27 Findlay, Ohio 28 j. Department of Radiation Oncology, UH Case Medical Center, Cleveland, 29 Ohio 30 k. Department of Surgery, Washington University School of Medicine, St. 31 Louis, Missouri 32 l. Department of Radiation Oncology, Thomas Jefferson University, 33 Philadelphia, Pennsylvania 34 m. Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio 35 36 * Corresponding author 37 38 A3-808 39 790 Commissioners Rd E 40 London, ON 41 Canada 42 N6A 4L6 43 [email protected] 44 45 Running Title: RT in NSCLC: ASTRO CPG 46


2

47

CONFLICT OF INTEREST STATEMENT 48

49

Before initiation of this guideline, all members of the Task Force were 50

required to complete disclosure statements. These statements are maintained at 51

ASTRO Headquarters in Fairfax, VA, and pertinent disclosures are published 52

within this report. The ASTRO Conflict of Interest Disclosure Statement seeks to 53

provide a broad disclosure of outside interests. Where a potential conflict is 54

detected, remedial measures to address any potential conflict are taken and will 55

be noted in the disclosure statement. The guideline chairs (GR and GV) in 56

concert with the ASTRO guidelines subcommittee reviewed these disclosures 57

and determined that they have no substantive impact upon the content of the 58

manuscript. 59

60

George Rodrigues, MD, PhD has received research funding from the 61

Ontario Institute of Cancer Research. Jeffrey Bradley, MD has received research 62

funding from Calypso Medical Inc. Jeffrey Bogart, MD has received travel 63

expense funding from Alliance Clinical Trials Cooperative Group. Hak Choy, MD 64

is on the advisory board for EMD and Bayer. In addition he has received 65

research funding from Celegene and has been a consultant for Eli Lilly. Walter 66

Curran Jr., MD has been a consultant for BMS. Corey Langer, MD has received 67

honoraria, been a consultant to, or served on the advisory board of BMS, Eli Lilly, 68

Genentech, Synta, and Abbott. Mitchell Machtay, MD served as a consultant to 69


3

Bristol Meyers Squibb, Eli Lilly, and Imclone. Maria Werner-Wasik, MD received 70

travel expense funding from Elekta Oncology. 71


4

ACKNOWLEDGEMENTS 72

73

The Guidelines Subcommittee of the Clinical Affairs and Quality 74

Committee of the American Society for Radiation Oncology prepared this 75

document. ASTRO guidelines present scientific, health, and safety information 76

and may to some extent reflect scientific or medical opinion. They are made 77

available to ASTRO members and to the public for educational and informational 78

purposes only. Any commercial use of any content in this guideline without the 79

prior written consent of ASTRO is strictly prohibited. 80

81

Adherence to this guideline will not ensure successful treatment in every 82

situation. Furthermore, this guideline should not be deemed inclusive of all proper 83

methods of care or exclusive of other methods of care reasonably directed to 84

obtaining the same results. The physician must make the ultimate judgment 85

regarding the propriety of any specific therapy in light of all the circumstances 86

presented by the individual patient. ASTRO assumes no liability for the 87

information, conclusions, and findings contained in its guidelines. In addition, this 88

guideline cannot be assumed to apply to the use of these interventions 89

performed in the context of clinical trials, given that clinical studies are designed 90

to evaluate or validate innovative approaches in a disease for which improved 91

staging and treatment are needed or are being explored. 92

93


5

This guideline was prepared on the basis of information available at the 94

time the Task Force was conducting its research and discussions on this topic. 95

There may be new developments that are not reflected in this guideline, and that 96

may, over time, be a basis for ASTRO to consider revisiting and updating the 97

guideline according to its policies. 98

99

The authors thank the following individuals who served as expert 100

reviewers of the manuscript: William Blackstock MD, Thomas Dilling MD, and 101

Inga Grills MD. The authors also thank ASTRO staff members George Velasco, 102

Chiemeka Chine, Caroline Patton, and Susan Keller for assistance with the 103

systematic literature review and for administrative support. 104


6

ABSTRACT 105

106

Purpose: To provide guidance to physicians and patients with regard to the use 107

of external beam radiation therapy (RT) in locally advanced non-small cell lung 108

cancer (LA NSCLC), based on available medical evidence complemented by 109

consensus-based expert opinion. 110

Methods and Materials: A Task Force authorized by the American Society for 111

Radiation Oncology (ASTRO) Board of Directors and Guidelines Subcommittee 112

conducted five systematic reviews on the following topics: (1) ideal radical RT 113

dose fractionation for radiotherapy alone; (2) ideal radical RT dose fractionation 114

for chemoradiation; (3) ideal timing of radical radiotherapy with systemic 115

chemotherapy; (4) indications for post-operative adjuvant RT; and (5) indications 116

for pre-operative neoadjuvant RT. Practice guideline recommendations were 117

approved using an a-priori defined consensus-building methodology supported 118

by ASTRO approved tools for the grading of evidence quality and the strength of 119

guideline recommendations. 120

Results: For patients managed by RT alone, a minimum dose of 60Gy of 121

radiotherapy is recommended. However, dose escalation beyond 60Gy in the 122

context of combined modality concurrent chemoradiation was not found to be 123

associated with any clinical benefits. In the context of combined modality 124

therapy, chemotherapy and radiation should ideally be given concurrently in 125

order to maximize survival, local control and disease response rate. For patients 126

who have undergone surgical resection, high-level evidence suggests that use of 127


7

postoperative radiotherapy does not influence survival but optimizes local control 128

for patients with N2 involvement, and its use in the setting of positive margins or 129

gross primary/nodal residual disease is recommended. No high-level evidence 130

exists for the routine use of pre-operative induction chemoradiotherapy; however, 131

modern surgical series and a post-hoc INT 0139 analysis suggest that a survival 132

benefit may exist if patients are properly selected and surgical techniques/post-133

operative care is optimized. 134

Conclusion: A consensus and evidence-based clinical practice guideline for the 135

radiotherapeutic management of LA NSCLC has been created addressing five 136

important questions. 137


8

INTRODUCTION 138

139

Lung cancer is the second most frequently diagnosed cancer in the United 140

States with approximately 80% of patients diagnosed with the non-small cell 141

pathological subtype. The burden of lung cancer is considerable in the United 142

States with an estimated 221,000 incident cases and approximately 157,000 143

deaths in 20111. According to SEER database statistics from 2002-2008, 22% of 144

patients have locally advanced disease with an associated five-year survival rate 145

of 25.1% (seer.cancer.gov). Therefore, approximately 50,000 patients will be 146

diagnosed with locally advanced (LA) non-small cell lung cancer (NSCLC) every 147

year and about 37,500 of these patients will die within five years of diagnosis. 148

149

LA NSCLC currently consist of a heterogeneous group of patients 150

including stage III patients with TanyN2-3M0, T4N0-1MO, and T3N1MO disease as per 151

the 7th edition of the American Joint Committee on Cancer 152

(www.cancerstaging.org). Stage II patients (T2b-T3N0 and T1-2N1) are sometimes 153

considered under the LA paradigm; however, these patients are more likely to 154

undergo surgical resection. Therefore, unresectable LA NSCLC is functionally 155

defined as consisting of stage II-III patients that cannot undergo a definitive 156

resection (either due to surgical resectability and/or medical operability factors). 157

Analogously, resectable LA NSCLC is practically defined as consisting of stage 158

II-III patients that can undergo a definitive resection after assessment to ensure 159


9

appropriate surgical resectability, adequate pulmonary reserve, and acceptable 160

medical operability risk. 161

162

In terms of unresectable disease, external-beam radiotherapy is routinely 163

utilized for the definitive treatment of unresectable LA NSCLC either as therapy 164

given concurrently or sequentially with systemic therapy or as primary curative 165

therapy without any other surgical or drug therapy (for patients that cannot 166

tolerate chemotherapeutic treatment)2. Given the central importance of 167

radiotherapy in the management of unresectable LA NSCLC combined with an 168

impressive track record of completed phase III randomized clinical trials informing 169

the management of this challenging patient population over the last 35 years 170

(Figure 1), a radiotherapy-focused practice guideline for unresectable LA NSCLC 171

is timely3. Additionally, the recent report of the dose-fractionation results of the 172

RTOG 0617 trial (60Gy vs. 74Gy) at the 2013 ASCO annual meeting makes a 173

guideline specifically addressing dose-fractionation in locally advanced non-small 174

cell lung cancer both timely and of interest to the radiation oncology 175

community4,5. 176

177

In terms of resectable disease, various randomized clinical trials and 178

meta-analyses have investigated the additional role of pre-operative 179

(neoadjuvant) and post-operative (adjuvant) therapies (e.g. radiotherapy and/or 180

chemotherapy) in improving clinical outcomes such as overall survival, local 181

control, and surgical resectability3. External-beam radiotherapy can be 182


10

considered for multimodality management of resectable LA NSCLC either as 183

therapy given prior to or after surgical resection; however, the indications for 184

employing such therapies are controversial6. Given the number of completed 185

phase III randomized clinical trials evaluating the management of resectable LA 186

NSCLC (Figure 1), a radiotherapy-focused practice guideline is needed to 187

summarize the available evidence for clinical practitioners. 188

189

Therefore, the purpose of this practice guideline is to provide guidance to 190

physicians and patients with regard to the use of curative-intent external-beam 191

radiotherapy for unresectable LA NSCLC as well as the neoadjuvant/adjuvant 192

treatment of resectable disease, based on available medical evidence 193

complemented by expert opinion. Other questions regarding the ideal utilization 194

and specific best practices of chemotherapeutic regimens or other radiotherapy 195

modalities such as stereotactic body radiation therapy are not a focus of this 196

guideline. Additionally, best practices regarding pretreatment imaging/staging, 197

treatment volumes and margins, motion management, and dosimetric 198

considerations will not be covered; however, the reader is referred to other 199

existing literature for guidance7,8,9,10,11. 200


11

METHODS AND MATERIALS 201

202

Process 203

204

The Guidelines Subcommittee of the ASTRO Clinical Affairs and Quality 205

Committee (CAQC) identified the use of external-beam radiation therapy (EBRT) 206

for the curative-intent (radical) treatment of LA NSCLC as a high-priority topic 207

needing an evidence-based practice guideline. Accordingly, a topic proposal 208

form (entitled: ASTRO clinical practice guideline on the role of radiotherapy in 209

locally advanced non-small cell lung cancer) was prepared by two ASTRO 210

members (George Rodrigues and Gregory Videtic) to initiate the official 211

consideration of this topic by ASTRO leadership. This form was submitted to the 212

ASTRO Board of Directors (BOD) and approved in October 2012. The ASTRO 213

BOD both authorized the creation of a practice guideline task force (TF) to study 214

issues related to EBRT in LA NSCLC and approved the TF membership (11 215

Radiation Oncologists, 1 Medical Oncologist, 1 Thoracic Surgeon, and 1 216

Radiation Oncology Resident) and external expert review panel (3 Radiation 217

Oncologists, see Acknowledgements). 218

219

Five specific key questions (KQ) were approved by the ASTRO BOD and 220

Guidelines Subcommittee specifically related to the ideal EBRT dose 221

fractionation for radical radiotherapy alone (key question 1), the ideal EBRT dose 222

fractionation (key question 2) and timing (key question 3) for radical 223


12

chemoradiotherapy in LA NSCLC, indications for post-operative (adjuvant) 224

radiotherapy for LA NSCLC (key question 4), and indications for pre-operative 225

(neoadjuvant) radiotherapy for LA NSCLC (key question 5). TF members were 226

divided into five subgroups (KQ1: AL, KR, GR; KQ2: J Bogart, J Bradley, GR; 227

KQ3: HC, WC, CL, GR; KQ4: GV, MM, SL, GR; KQ5: MW-W, EG, VP, GR) to 228

initially address the separate questions based on their areas of expertise. 229

Through a series of communications by conference calls and emails between 230

January 2013 and January 2014, the TF with ASTRO staff support completed the 231

systematic review, created evidence tables, evaluated the quality of evidence, 232

and formulated the clinical practice guidelines contained herein. 233

234

The initial draft of the manuscript was reviewed by three expert reviewers 235

nominated by the ASTRO lung resource panel (see Acknowledgements). 236

Subsequently, ASTRO legal counsel reviewed the guideline prior to a public 237

comment period (guideline on the ASTRO website from February 2014 to March 238

2014). Upon integration of external reviewer and public feedback into the 239

practice guideline document, the final document was submitted to the ASTRO 240

BOD for final review and approval in May 2014. Going forward, the ASTRO 241

Guidelines Subcommittee intends to monitor this guideline and initiate an update 242

when appropriate according to existing ASTRO policies. 243

244

Literature Search 245

246


13

A literature search strategy was developed around the five practice 247

guideline questions of EBRT dose fractionation for radical radiotherapy alone 248

without chemotherapy, EBRT dose fractionation for radical chemoradiation, 249

timing of radiation in relation to systemic chemotherapy, indications for adjuvant 250

radiotherapy, and indications for neoadjuvant radiotherapy. Inclusion criteria 251

keywords used to construct all five literature strategies for abstract/paper reviews 252

included: human, adult, LA NSCLC, and radiotherapy. Exclusion criteria 253

keywords common to all five questions/searches included: small cell lung cancer, 254

metastatic disease, non-curative or palliative intent, pre-clinical data, pediatric 255

populations, and carcinoid/mesothelioma or thymic tumors. Additional search 256

terms were used as needed (e.g. surgery for questions four and five). All search 257

strategies were performed on PubMed and restricted to English medical literature 258

only to assess for possible article inclusion during the January 1, 1966 to March 259

15, 2013 timeframe. In particular, identification of randomized controlled trials 260

(RCTs) or of other prospective non-randomized clinical trial or observational 261

studies (if RCTs were unavailable) was the focus of the literature search. 262

Reference lists associated with known published clinical practice guidelines, 263

consensus statements, meta-analyses, and systematic reviews were cross-264

referenced with search strategies to ensure a complete set of manuscripts and 265

abstracts for review by the TF. All potentially relevant abstracts were reviewed by 266

members of the TF for an assessment of practice guideline relevance prior to 267

data abstraction for creation of evidence tables. 268

269


14

All five guideline questions were converted into PICO format (Participants, 270

Interventions, Comparators, and Outcomes) to help support the construction of 271

literature searches and subsequent data abstraction (patient population 272

composition, treatment interventions, and outcomes). Based on the PICO 273

formatted questions summarized in Table 1, appropriate key words and MeSH 274

headings (Appendix 1) were used to search for papers relevant to the respective 275

guideline questions: (1) What is the ideal external-beam dose-fractionation for the 276

curative-intent treatment of locally advanced non-small cell lung cancer with 277

radiation therapy alone? (528 initial and 25 final articles); (2) What is the ideal 278

external-beam dose fractionation for the curative-intent treatment of locally 279

advanced non-small cell lung cancer with chemoradiotherapy? (42 initial and 6 280

final articles); and (3) What is the ideal timing of external-beam radiation therapy 281

in relation to systemic chemotherapy for the curative-intent treatment of locally-282

advanced non-small cell lung cancer? (42 initial and 15 final articles); (4) What 283

are the indications for adjuvant post-operative radiotherapy for the curative-intent 284

treatment of locally advanced non-small cell lung cancer? (528 initial and 11 final 285

articles); and (5) When is neoadjuvant radiotherapy prior to surgery indicated for 286

the curative-intent treatment of locally advanced non-small cell lung cancer? (528 287

initial and 17 final articles). An additional twenty-seven published clinical practice 288

guidelines documents, specifically relevant to one or more clinical practice 289

guideline key questions, were identified by the clinical guideline chair (GR). 290

Once the guideline chairs approved the relevant abstracts for each guideline 291

question; ASTRO staff and the guideline chair created master evidence tables 292


15

based on abstraction of patient population composition, treatment interventions, 293

and clinical outcomes (Supplementary Tables 1-5). Additional relevant papers 294

identified by TF members were also included in the master tables or as additional 295

material for justification for guideline statements. Once finalized and approved by 296

the TF, these tables formed the primary evidence base of the consensus-based 297

guideline recommendations contained within this document (see Process section 298

above). 299

300

Grading of Evidence, Recommendations, and Consensus Methodology 301

302

Practice guideline recommendations were approved using an a-priori 303

defined consensus-building methodology12, supported by ASTRO-approved tools 304

for the grading of evidence quality and the strength of guideline 305

recommendations. Where available, priority was given to higher quality evidence 306

to form clinical practice guideline recommendation statements in accordance with 307

the Institute of Medicine (IOM) standards. Guideline statements were developed 308

based on the body of evidence categorized by the American College of 309

Physicians (ACP) Strength of Evidence Rating13. The ACP’s ratings consist of 310

high quality evidence (HQE), moderate quality evidence (MQE), and low quality 311

evidence (LQE) to determine net benefits or risks (Appendix 2). Guideline 312

recommendation statements were developed and included evidence ratings 313

(where appropriate) which were initially created by the guideline chairs and later 314

approved by all committee members. The level of consensus on the guideline 315


16

recommendation statements among the panelists was evaluated through a 316

modified Delphi approach using a survey system coordinated by ASTRO staff to 317

all participating TF members. Panelists rated the agreement with each individual 318

recommendation pertaining to the key clinical questions on a five-point Likert 319

scale, ranging from strongly disagree to strongly agree (higher score corresponds 320

with stronger agreement). A pre-specified threshold of ≥ 75% of raters was 321

determined to indicate when consensus was achieved consistent with the 322

published literature12 and is summarized in Table 2. A final summary of clinical 323

guideline statements related to this project is listed in Appendix 3. 324


17

RESULTS 325

326

KQ1: What is the ideal external-beam dose-fractionation for the curative-327

intent treatment of locally advanced non-small cell lung cancer with 328

radiation therapy alone? 329

330

Guideline Statements 331

332

A. Radiotherapy alone has been shown to be superior to observation 333

strategies or chemotherapy alone for LA NSCLC in terms of overall 334

survival but at the cost of treatment-related side effects such as 335

esophagitis and pneumonitis (MQE). 336

337

B. Radiotherapy alone may be used as definitive radical treatment for 338

patients with LA NSCLC who are ineligible for combined modality therapy 339

(i.e. due to poor performance status, medical comorbidity, extensive 340

weight loss, and/or patient preferences) but with a tradeoff of survival for 341

improved treatment tolerability (HQE). 342

343

C. In the context of conventionally fractionated (1.80-2.15Gy) radiotherapy, a 344

minimum dose of 60Gy is recommended to optimize important clinical 345

outcomes such as local control (HQE). 346

347


18

D. Altered fractionation schedules that have been explored in the medical 348

literature include hyperfractionation (lower dose per fraction over the 349

standard treatment duration), accelerated fractionation (conventional 350

fraction size and same total dose, given in a shorter period of time), 351

accelerated hyperfractionation (combination of these two), and 352

hypofractionation (higher dose per fraction and fewer fractions). 353

354

E. Specific altered fractionation schemes that have been investigated in 355

various comparative effectiveness research investigations (including 356

randomized controlled trials) include 45Gy/15 fractions (hypofractionation), 357

69.6Gy/58 fractions BID (hyperfractionation), 54Gy/36 fractions TID over 358

12 consecutive days (CHART, accelerated hyperfractionation), and 359

60Gy/25 fractions BID (CHARTWEL, accelerated hyperfractionation). 360

361

Summary Tables 362

363

Table 3. Selected studies evaluating dose-escalation in the context of 364

conventionally fractionated radiotherapy in patients with locally 365

advanced NSCLC. 366

367

Table 4. Selected studies evaluating hypofractionated radiotherapy in patients 368

with locally advanced NSCLC. 369

370


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Table 5. Selected studies evaluating hyperfractionated +/- accelerated 371

radiotherapy in patients with locally advanced NSCLC. 372

373

Narrative 374

375

Radiotherapy versus No Treatment 376

377

There has been a paucity of randomized control trials evaluating the role 378

of modern radiotherapy versus no treatment in locally advanced NSCLC, 379

resulting in a greater reliance on other forms of comparative effectiveness 380

research to guide clinical practice. The initial RCT to define the role of 381

radiotherapy in LA NSCLC was coordinated by the Veterans Administration Lung 382

Group (VALG) and published in 196814. Eight hundred patients were randomized 383

to radiotherapy (target dose 40-50Gy), chemotherapy, and placebo. The trial 384

demonstrated an improvement in “long-term” survival in the radiotherapy arm 385

(18% one-year survival vs. 14% in the control group, p value not reported). The 386

authors concluded that radiotherapy was associated with a small improvement in 387

clinical outcome compared with other strategies. 388

389

Confirmation of this finding can be found in a recent analysis of the 390

Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare 391

records of 10,376 cases of elderly (greater than 65 years) unresected stage III 392

NSCLC between 1997 and 200715. Logistic regression was used to determine 393


20

propensity scores for radiotherapy treatment using pre-treatment 394

characteristics15. The study found that radiotherapy was associated with 395

improved overall survival (HR 0.76) at the cost of increased risk of hospitalization 396

for pneumonitis (OR 89), and esophagitis (OR 8). While the SEER registry does 397

not contain data related to specific dose and/or fractionation schedules, patients 398

were stratified by complexity of radiotherapy based on Medicare claims. 399

Recognizing the limitations of selection bias, the modest survival benefit 400

observed in this study was limited to patients treated with high complexity 401

regimens (e.g. multiple port three-dimensional therapy, arc therapy, intensity-402

modulated radiotherapy). 403

404

Dose in Conventionally Fractionated Radiotherapy 405

406

In the 1980s, the optimal dose and fractionation for standard fractionated 407

radiotherapy had yet to be defined. In a prospective trial, split course 408

radiotherapy 63Gy in 1.8Gy daily fractions divided into two blocks of 18 and 17 409

fractions separated by 10-14 days was compared to the standard of 59.4Gy in 410

1.8Gy daily fractions16. The theoretical advantages of split course radiotherapy 411

include: repair of normal cells leading to decreased toxicity, reoxygenation of 412

hypoxic tumor cells, and potential use of a shrinking field technique as tumor(s) 413

regress. The main disadvantage of split course radiotherapy is the possibility of 414

tumor regrowth during the break period potentially leading to inferior local control. 415

In this study, there was no observed statistical difference in survival between the 416


21

two arms. Split course radiotherapy was reported as having a modest benefit in 417

morbidity; however, these findings were not substantiated by the use of 418

standardized scales and physician-based morbidity assessments16. 419

420

The Radiation Therapy Oncology Group (RTOG) performed a phase III 421

randomized trial dose-escalation trial, RTOG 7301, using conventionally 422

fractionated radiotherapy comparing 40Gy (continuous or split course as two 423

separate study arms), 50Gy continuous course, and 60Gy continuous course 424

delivered in 2Gy per fraction17. In this landmark study, eligibility included 425

pathologically confirmed stage III NSCLC patients with a KPS greater than or 426

equal to 50. Three-year intrathoracic failure rates (defined by chest x-ray follow-427

up) of 52%, 42%, and 33% were reported for 40Gy, 50Gy, and 60Gy arms of the 428

study, respectively (demonstrating a dose-response relationship with local 429

control). While overall survival was not determined to be improved with 430

increased doses of radiotherapy in this study, further review of several RTOG 431

trials concluded that a dose-response relationship not only existed for local 432

control, but also for overall survival18. As a result of these studies, a minimum 433

dose of 60Gy in 2Gy fractions became a standard of care for LA NSCLC. 434

435

After the advent of three-dimensional conformal radiotherapy, other 436

investigators have explored dose escalation beyond 60Gy delivered in a 437

conventionally fractionated (1.80-2.15Gy per fraction) manner. RTOG 9311 was 438

a phase I-II trial evaluating dose-escalation for stage I–III patients with a KPS of 439


22

greater than or equal to 7019. Radiotherapy dosing schedules were stratified 440

based on lung V20 with Group 1 (V20 < 25% receiving progressively larger 441

doses ranging from 70.9Gy to 90.3Gy), Group 2 (V20 of 25–36% receiving 442

progressively larger doses ranging from 70.9Gy to 77.4Gy) and Group 3 (V20 > 443

37% which was closed due to poor accrual likely due to perceptions regarding 444

severe pneumonitis risk). Using fraction sizes of 2.15Gy, dose was safely 445

escalated to 83.8Gy (Group 1) and 77.4Gy (Group 2). 446

447

Investigators from the University of Michigan retrospectively reviewed data 448

from their institution on the safety of an individualized dose escalation scheme 449

that determined the prescription dose by calculation of the amount of normal lung 450

irradiated20. This resulted in a phase I study similar to RTOG 9311 in which 451

patients were treated between 63Gy and 103Gy in 2.1Gy fractions21. On 452

multivariate analysis, a 1% improvement in locoregional control was observed for 453

each additional Gray of radiotherapy delivered. Furthermore, patients receiving 454

greater than 74Gy were observed to have improved overall survival 455

characteristics compared to those patients receiving less than 69Gy. 456

457

Dose and Scheduling in Altered Fractionation Radiotherapy 458

459

In the 1990s, investigators from the VU Amsterdam retrospectively 460

reviewed their experience with hypofractionated LA NSCLC radiotherapy22. The 461

rationale for this approach was that in view of minimal differences in survival 462


23

between different fractionated schemes at the time, the center’s practice evolved 463

to fewer fractions. This was done to decrease inconvenience for patients, 464

particularly in those with poor general condition or those having to travel long 465

distances. The three regimens evaluated were 1) 40Gy split course given in 3 466

weeks (two courses of 20Gy in 4 or 5 fractions times separated by a 1 week 467

break); 2) 30-32Gy in 3 weeks (5-6Gy per fraction; 2 fractions per week); and 3) 468

24Gy in 3 fractions (8Gy per fraction; 1 fraction per week). Recognizing the 469

inherent selection bias of patient co-morbidity and performance status related to 470

the choice of fractionation, the 40Gy split course was associated with the best 471

survival (10.7 months vs. 7.6 months vs. 6.5 months for groups 1-3 respectively). 472

Given the uncommon rate of symptomatic pneumonitis and lack of severe 473

esophagitis associated with any of the regimens, the authors conclude that 474

hypofractionation was generally well tolerated irrespective of treatment schedule. 475

476

A more contemporaneous retrospective report from MD Anderson 477

evaluated institutional experience with hypofractionated radiotherapy (45Gy in 15 478

fractions over 3 weeks) as compared to conventionally fractionated standard (60-479

63Gy) or dose-escalated (>63Gy) radiotherapy23. Although patients in the 480

hypofractionated group were negatively selected (greater proportion of KPS 481

scores ≤ 70 and initial weight loss ≥ 5%); treatment-related side effects (radiation 482

dermatitis, nausea and vomiting, and weight loss) were all significantly less 483

compared to other dosing schedules. After adjusting for covariates, there were 484

no differences in any of the radiotherapy groups in terms of the patterns of local 485


24

or distant tumor control or overall survival. Recognizing the selection bias of 486

treatment based on patient demographics, the investigators contend that 487

hypofractionated regimens are a reasonable alternative to standard fractionation, 488

and should be prospectively evaluated using modern radiation technologies in 489

stage III LA NSCLC. 490

491

RTOG 8311 was designed as a phase I/II dose-escalation trial (assessing 492

60.0Gy, 64.8Gy, 69.6Gy, 74.4Gy and 79.2Gy) evaluating hyperfractionated 493

radiotherapy (1.2Gy BID) in stage II-IV NSCLC (with no metastases), KPS 494

greater or equal to 50, and minimal weight loss24. No significant differences in 495

acute or late normal tissues effect rates were found. In a subgroup analysis of 496

patients with good performance status and no weight loss, survival was improved 497

with the 69.6Gy dose schedule. 498

499

Given the findings of this study, the RTOG teamed with SWOG and ECOG 500

to launch a 3-arm phase III trial (Intergroup study) evaluating conventionally 501

fractionated radiotherapy to 60Gy, the aforementioned hyperfractioned 69.6 Gy 502

(treatments twice a day, at least 4-6 hours apart), and induction chemotherapy 503

followed by standard radiotherapy that had shown a survival improvement in the 504

landmark CALGB 8433 study25,26. In the former phase III trial, stringent exclusion 505

criteria were employed as only patients with less than 5% weight loss and KPS 506

greater than or equal to 70 were eligible. The final results of this intergroup study 507

indicate that those patients receiving chemotherapy prior to radiotherapy had 508


25

improved overall survival compared to the radiotherapy only arms. Although the 509

median survival of patients treated with hyperfractionated radiotherapy was 510

intermediate to those receiving combined therapy and standard radiotherapy 511

arms, this finding failed to reach statistical significance. 512

513

Similarly, the Medical Research Council (MRC) of Britain completed a 514

study of continuous hyperfractionated accelerated radiation therapy (CHART) 27. 515

It consisted of thrice-daily (TID) radiotherapy to a dose of 54Gy in 1.5Gy per 516

fraction, six-hour interfraction interval, delivered on 12 consecutive days. This 517

trial demonstrated a survival benefit of CHART over conventionally fractionated 518

standard radiotherapy, predominantly in squamous cell carcinoma patients. In a 519

retrospective subgroup analysis of RTOG 8808, patients with squamous cell 520

disease had a 5-year overall survival of 9% when treated with hyperfractionated 521

radiotherapy compared to 2% with conventionally fractionated standard 522

radiotherapy. These studies in aggregate hypothesize that hyperfractionated 523

radiotherapy may have maximum benefit in patients with tumors expressing 524

squamous histology. Nonetheless, given the resource intensive nature of 525

delivery of radiotherapy three times a day (including weekend days) in CHART, 526

the MRC also investigated a weekend-less hyperfractionated (CHARTWEL) 527

schedule of 60 Gy in 1.2 Gy twice-daily (BID) versus the TID approach28. In a 528

toxicity report of this study, the BID weekend-less approach was associated with 529

enhanced esophagitis and low-grade lung toxicity. However, the study 530

investigators concluded that these enhanced normal tissue reactions were not of 531


26

any clinical significance, and did not lead to any complications or more intensive 532

medical management. 533

534

More recently, accelerated hyperfractionated versus conventionally 535

fractionated radiotherapy in the context of 3D-conformal radiotherapy was 536

examined29. In this European co-operative study, patients were treated with 537

either 66 Gy in 2 Gy per fraction, or a CHARTWEL schedule of 60 Gy in 40 538

fractions over 2.5 weeks. Overall survival did not differ significantly between 539

these two regimens, and CHARTWEL was associated with higher rates of acute 540

dysphagia and radiological pneumonitis. Besides statistical chance, potential 541

reasons for the failure of benefit of CHARTWEL in this contemporaneous 542

population as compared to CHART in the MRC trial were 1) the use of 3D 543

conformal radiotherapy, 2) the use of a 10% higher dose in the standard arm, 544

and 3) a lower proportion of squamous histology patients in this trial. 545

546

To investigate both the effect of accelerated hyperfractionation and 547

combining radiotherapy with chemotherapy, an Australian multi-center trial 548

investigated the interaction of these two strategies via a randomized 2 x 2 549

factorial design30. In comparison to the default dose fractionation schedule of 60 550

Gy in 2 Gy per fraction daily; treatment time was either halved, combined with 551

carboplatin, or both. Hematologic toxicity was worse in patients receiving 552

chemotherapy, and acute esophagitis was worse in patients receiving altered 553

fractionation. There was no difference in survival in any of the 4 treatment arms. 554


27

555

As these and other randomized trials assessing hyperfractionated and/or 556

accelerated radiotherapy give conflicting results about the benefit of locoregional 557

control and overall survival, the Meta-Analysis of Radiotherapy in Lung Cancer 558

(MAR-LC) collaborative group decided to perform an individual patient data meta-559

analysis to more robustly determine treatment and toxicity effects31. The 560

investigators stratified trials into 4 categories: 1) very accelerated radiotherapy 561

(shortening the total duration of 50% or more compared with that of control arm); 562

2) moderately accelerated radiotherapy (shortening the total duration of more 563

than 15%, but less than 50% as compared with the control arm); 3) 564

hyperfractionated radiotherapy with identical total dose; and 4) hyperfractionated 565

radiotherapy with increased total dose. While there was no statistical evidence of 566

a benefit on progression free survival or locoregional failure with the use of 567

modified radiotherapy, overall survival improved from 15.9% to 19.7% at 3 years 568

and 8.3% to 10.8% at 5 years, respectively. This however, was at the cost of an 569

increased risk of acute severe esophageal toxicity from 9% to 19% (with the very 570

accelerated radiotherapy group being associated with the highest toxicity). From 571

a practical point of view, the authors dichotomized patients receiving a BED 572

greater than or equal to versus less than 55 Gy and found that absolute benefit in 573

overall survival with BED ≥55 Gy was 5.1% at 3 years and 3.4% at 5 years at a 574

cost of acute esophageal toxicity with an odds ratio of 2.9. It is important to note 575

that of the 12 trials included in the MAR-LC meta-analysis, half of these included 576

patients that were also treated with chemotherapy. Therefore, the degree to 577


28

which the use of systemic therapy contributed to the above stated conclusions is 578

difficult to discern, and thus the generalizability of effect and toxicity in a 579

radiotherapy alone treatment scheme remains contentious. 580


29

KQ2: What is the ideal external-beam dose fractionation for the curative-581

intent treatment of locally advanced non-small cell lung cancer with 582

chemoradiotherapy? 583

584


586

A. The standard thoracic radiotherapy dose-fractionation for patients treated 587

with concurrent chemotherapy, recently validated in a phase III RTOG trial 588

(RTOG 0617), is 60 Gy given in 2 Gy once daily fractions over 6 weeks 589

(HQE). 590

591

B. Dose escalation beyond 60 Gy with conventional fractionation has not 592

been proven to be associated with any clinical benefits including overall 593

survival (HQE). 594

595

C. Hyperfractionated radiotherapy regimens that do not result in acceleration 596

of the treatment course, even though the total nominal radiotherapy dose 597

may be modestly increased, do not appear to improve outcomes 598

compared with conventionally fractionated therapy (MQE). 599

600

D. The optimal thoracic radiotherapy regimen for patients receiving 601

sequential chemotherapy and radiotherapy is not known; however results 602

from the CHARTWEL and HART phase III studies suggest, but do not 603


30

prove, that increasing the biologic equivalent dose by using accelerated 604

hyperfractionated radiotherapy may be of benefit following induction 605

chemotherapy in locally advanced non-small cell lung cancer (MQE). 606

607

E. Although the impact of increasing the predicted biologic equivalent dose 608

via accelerated radiotherapy regimens is not clear, further study of 609

accelerated hypofractionated regimens is of interest to optimize the 610

therapeutic ratio of treatment, particularly in the context of advanced 611

imaging, radiotherapy planning, and treatment delivery. 612

613

Summary Tables 614

615

Table 6. Selected Phase III studies evaluating radiation schedules in the 616

context of concurrent or sequential chemotherapy in LA NSCLC 617

618

Narrative 619

620

Conventionally Fractionated Radiotherapy 621

622

The RTOG performed a series of radiation dose escalation trials leading 623

up to the 0617 phase III clinical trial. RTOG 9410 was a phase III randomized 624

trial comparing three arms; sequential chemotherapy followed by radiotherapy 625

(60 Gy), concurrent chemotherapy and daily radiotherapy (60 Gy), and 626


31

concurrent chemotherapy with BID radiotherapy (69.6 Gy)32. Patients on arms 1 627

and 2 received cisplatin (100mg/m2) and vinblastine (5mg/m2) on days 1 and 29. 628

Patients on arm 3 received cisplatin (50mg/m2) on days 1, 8, 29, and 36 and oral 629

etoposide (50mg) given twice daily for 10 weeks. The radiotherapy was delivered 630

using two-dimensional techniques prevalent during that era. The primary 631

objective of the trial was to determine if concurrent chemoradiotherapy improved 632

overall survival compared to sequential chemotherapy followed by radiotherapy. 633

A secondary primary objective was to determine if a higher dose of radiotherapy 634

(Arm 3, 69.6 Gy) given twice daily was superior to single daily fraction 635

radiotherapy (Arms 1 and 2, 60 Gy). The median overall survival times were 14.6, 636

17, and 15.6 months for the sequential, concurrent and concurrent 637

hyperfractionated arms, respectively. The five-year survivals were 10%, 16%, 638

and 13%, respectively, significantly favoring the concurrent once-daily arm. 639

Concurrent chemotherapy led to significantly higher ≥ grade 3 non-hematological 640

toxicity when compared to sequential therapy (particularly for the 641

hyperfractionated radiation arm). There was no observed advantage to the 642

hyperfractionation approach. 643

644

With the onset of three-dimensional conformal radiation therapy (3DCRT) 645

techniques, the RTOG initiated a dose escalation trial (RTOG 9311) for patients 646

with medically inoperable or unresectable stages I-III NSCLC33. This was the 647

first multi-institutional trial testing 3DCRT for NSCLC (see KQ1 as well). Most 648

patients received radiotherapy alone; however sequential chemotherapy followed 649


32

by radiotherapy was allowed. The planning target volume included the gross 650

tumor volume (primary tumor and involved nodes) plus a margin of 1cm or 651

greater. Elective nodal regions were not included in the planning target volume. 652

Patients were stratified into radiation dose levels depending on the value of 653

normal lung tissue receiving doses of 20 Gy or greater (V20). Patients with a V20 654

< 25% received 70.9 Gy/33 fractions, 77.4 Gy/36 fractions, 83.8 Gy in 39 655

fractions and 90.3 Gy/42 fractions, successively. Patients with a V20 of 25-36% 656

received 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with 657

a V20 37% (Group 3) closed early secondary to poor accrual and the 658

perception of excessive risk for the development of radiation pneumonitis. The 659

estimated rate of grade 3 or worse late lung and esophageal toxicity for patients 660

with V20 < 25% treated to 90.3 Gy was 13% and 6%, respectively. For V20 661

values between 25-36% treated to doses of 77.4 Gy, the pneumonitis rate was 662

15%. Dose-escalated radiotherapy was generally well tolerated, except in the 663

90.3 Gy group. Two of 31 patients treated to this dose died of radiation-related 664

late toxicities; one of fatal hemoptysis and one from a tracheoesophageal fistula 665

that developed within the esophagus following stent placement for a benign 666

stricture (autopsy performed). The involved portion of the esophagus received 667

the full prescription dose in this patient. Perhaps the most important information 668

to come from this trial was that the 90.3 Gy dose of radiation alone was deemed 669

too toxic. 670

671


33

Near the completion of RTOG 9311, the initial results of RTOG 9410 were 672

reported, showing that concurrent chemotherapy was needed in the next trial. 673

Therefore, the RTOG launched a trial, L-0117, escalating radiotherapy dose with 674

3DCRT in the setting of concurrent paclitaxel and carboplatin chemotherapy to 675

establish the maximum tolerated dose (MTD) associated with the treatment 676

combination34,35. The trial was initially designed to dose escalate by increasing 677

the fraction size and decreasing the overall treatment time. Doses of 90.3 Gy on 678

9311 took over nine weeks to deliver. So, this trial was initiated at a dose level of 679

75.25 Gy in 2.15 Gy fractions with a plan to continue escalating through 80.5 Gy 680

in 2.3 Gy fractions, 79.5 Gy in 2.65 Gy fractions, and 75 Gy in 3 Gy fractions. 681

However, excessive toxicity was encountered at the 75.25 Gy dose level 682

resulting in one death and two others with grade 3 pneumonitis. The trial was re-683

designed by de-escalating the total dose to 74 Gy delivered in 2 Gy fractions in 684

the setting of the same concurrent chemotherapy. Phase II reported 55 patients 685

completing a dose of 74 Gy and a median follow up period of 19.3 months, the 686

median overall survival was 25.4 months for all patients, and 21.6 months for 687

those with stage III disease. 688

689

During the time interval around RTOG 0117, additional groups were 690

prospectively escalating radiotherapy dose in conventional fractions within the 691

setting of concurrent weekly paclitaxel and carboplatin. The North Central 692

Cancer Treatment Group (NCCTG), the University of North Carolina, and the 693

Cancer and Leukemia Group B (CALGB) collectively accrued 13 patients to the 694


34

NCCTG 0028 phase I trial. Patients were treated with 3DCRT without elective 695

nodal irradiation to doses of 70, 74, and 78 Gy36. No dose-limiting toxicities 696

(DLTs) were reported for the three patients who received 70 Gy. One DLT 697

occurred in the six patients treated to 74 Gy. Two DLTs occurred in the four 698

patients treated to 78 Gy. There were a total of 3 DLTs observed, grade 3 699

pneumonitis (n= 2) and 1 grade 4 pneumonitis. Similar to the findings of RTOG 700

0117, the MTD of this intergroup trial was determined to be 74 Gy. With a median 701

follow-up of 28 months, the median survival time was observed to be 37 months. 702

703

North Carolina investigators reported the results of four sequential 704

prospective phase I/II studies to assess the safety and feasibility of high-dose 705

(74-90 Gy) 3DCRT in the setting of concurrent chemotherapy37. This group 706

delivered 2 cycles of induction carboplatin and paclitaxel followed by dose-707

escalated radiotherapy with weekly carboplatin and paclitaxel using successively 708

more intensive radiotherapy doses of 60 Gy, 66 Gy, 70 Gy, and 74 Gy. One 709

hundred twelve patients were accrued, with a median follow-up of 4.9 years for 710

surviving patients. The median survival for all study patients was 24 months 711

(range 18-31 months). The one-, three-, and five-year overall survival rates were 712

69% (60-77%), 36% (27-45%), and 24% (16-33%), respectively. 713

714

The CALGB reported results of a 2-arm phase II trial (CALGB 30105) 715

treating stage III patients with chemoradiotherapy with both arms using 74 Gy38. 716

Patients received either induction carboplatin (AUC 6) and paclitaxel (225mg/m2) 717


35

followed by concurrent weekly carboplatin (AUC 2) and paclitaxel (45mg/m2) 718

during radiotherapy or induction carboplatin (AUC 5) and gemcitabine 719

(1000mg/m2) followed by concurrent gemcitabine twice weekly (35mg/m2) during 720

radiotherapy. The trial enrolled 69 patients and was reported with a median 721

follow up of 16.4 months. Median survival times were 24.2 months for the 722

carboplatin/paclitaxel arm and 17 months for the carboplatin/gemcitabine arms, 723

respectively. The gemcitabine arm was closed early due to 13% grade 5 724

pulmonary events. 725

726

A prospective radiation dose-escalation study has also been reported from 727

Japan. Sekine et al. from the National Cancer Center Hospital in Tokyo reported 728

a phase I study employing escalated doses of radiotherapy in patients with stage 729

III NSCLC alongside concurrent cisplatin and vinorelbine in 4-week cycles39. 730

Successive radiation doses assessed in this study were 66 Gy, 72 Gy, and 78 731

Gy. Stringent normal tissue dose constraints were applied, keeping the lung V20 732

≤ 30%, and excluding patients with excessive dose to lung and esophagus. The 733

median, 3-year, and 4-year overall survival rates were 41.9 months, 72.3% and 734

49.2%, respectively. 735

736

RTOG 0617 was a phase III randomized intergroup effort with two 737

objectives; a) to determine if chemoradiation using 74 Gy led to superior overall 738

survival compared to 60 Gy and b) to determine if the addition of post-739

radiotherapy cetuximab, an antibody to EGFR, improved overall survival. This 740


36

was a four-arm trial using a 2x2 factorial design. Patients received weekly 741

carboplatin and paclitaxel as the backbone of chemoradiotherapy. Patients with 742

stage IIIA NSCLC were enrolled, regardless of histology or EGFR status. Both 743

primary objectives have been presented40 and have demonstrated that 74 Gy is 744

not superior to standard 60 Gy of radiotherapy. Additionally, 74 Gy may be 745

associated with worse overall survival compared to 60 Gy. Median and overall 746

survival rates at 18 months are 28.7 months and 66.9% versus 19.5 months and 747

53.9%, for the 60 Gy and 74 Gy arms, respectively (p=0.0007, one-sided). 748

Progression free survival (PFS) and local tumor control also appeared to be 749

inferior with higher doses. Additionally, there was an increased rate of severe 750

esophagitis on the 74 Gy arm. Fatal toxicity was observed in 2 patients on the 60 751

Gy arm and 10 patients on the 74 Gy arm. The addition of cetuximab had no 752

effect on overall survival compared to chemoradiation alone. Data analysis of 753

both endpoints is continuing at this time. Nevertheless, the results of this large 754

scale trial have called into question the approach of conventionally fractionated 755

dose escalation for stage III NSCLC. Limitations of the RTOG 0617 study 756

include: the fact that it is currently available in abstract form only, concerns 757

regarding PTV and lung/cardiac dosimetry, and concerns regarding margin 758

selection in the 74 Gy arm. 759

760

Hyperfractionated Radiotherapy 761

762


37

Using twice-daily radiotherapy over the same time interval as conventional 763

radiotherapy (i.e. 6 weeks) is defined as hyperfractionated radiotherapy. The 764

principal behind hyperfractionation is to increase the tumoricidal total dose while 765

allowing normal tissue repair using smaller fraction sizes (1.1-1.2 Gy per 766

fraction). Multiple trials have used hyperfractionated radiotherapy in combination 767

with concurrent chemotherapy. RTOG 9204 was a randomized phase II 768

comparison of standard dose (with conventional fractionation) versus 769

hyperfractionation41. The standard arm used induction chemotherapy 770

(vinblastine and cisplatin days 1 and 29) followed by concurrent chemoradiation 771

(cisplatin days 50, 71, and 92). Standard radiotherapy was given in 1.8 Gy 772

fractions (2.0 Gy in the boost volume) to a dose of 63 Gy. The hyperfractionation 773

arm used cisplatin and oral etoposide (days 1 and 29). The radiation prescription 774

was 1.2 Gy BID to a total dose of 69.6 Gy. The hyperfractionation arm was found 775

to be associated with a significantly longer time to in-field progression (30% vs 776

49% at 4 years). The median and overall survival rates were similar between 777

both approaches. 778

779

As stated above, RTOG 9410 used concurrent chemotherapy and 780

hyperfractionated radiotherapy to 69.6 Gy in Arm 3, compared to sequential 781

chemotherapy followed by once-daily radiotherapy and concurrent chemotherapy 782

with once-daily radiotherapy40. The median survival and five-year survival rates 783

in the hyperfractionated arm was 15.6 months and 13%, respectively. These 784

were numerically inferior to the concurrent chemotherapy with once-daily 785


38

radiotherapy arm (median survival 17 months and five-year survival 16%), though 786

the trial was not specifically designed to compare these two arms to each other. 787

Additionally, the acute grade 3-5 non-hematologic toxicity was greater in the BID 788

hyperfractionation arm, including a 45% ≥ acute grade 3 esophagitis rate. When 789

reported, the results of this trial effectively ceased further investigations of 790

hyperfractionated radiation with concurrent chemotherapy in NSCLC within the 791

RTOG. 792

793

In the interest of completeness, RTOG 9801 was a randomized quality-of-794

life study that tested the effects of the cytoprotectant amifostine in the setting of 795

concurrent chemoradiation (with hyperfractionation) for stage III NSCLC42,43. The 796

chemoradiation regimen was induction paclitaxel and carboplatin (days 1 and 22) 797

followed by weekly carboplatin and paclitaxel during twice-daily radiation to 69.6 798

Gy. This study failed to reach its primary endpoint of reducing ≥ acute grade 3 799

esophagitis rates with the study drug. The 5-year overall survival rate was 17% in 800

both arms. 801

802

Hyperfractionated Accelerated 803

804

Accelerating the time to complete a radiotherapy course, while maintaining 805

a similar nominal cumulative dose in comparison to conventional fractionation, 806

results in an increase in predicted biologic equivalent dose. Some experimental 807

and clinical experience suggest that accelerating the radiotherapy course may 808


39

lead to improved tumor control, perhaps by allowing less opportunity for tumor 809

repopulation during treatment. 810

811

As described in the prior section addressing KQ1, the CHART trial is one 812

of few studies demonstrating that changing the way that radiotherapy is 813

administered may result in improved overall survival, regardless of the site of 814

disease44. However, this trial was performed prior to systemic chemotherapy 815

being recognized as part of standard therapy for stage III non-small cell lung 816

cancer. Continuous hyperfractionated radiotherapy regimens have not been 817

extensively studied with concurrent chemotherapy, likely due to concerns 818

regarding potential toxic effects of therapy, particularly severe dysphagia. On the 819

other hand, CHART regimens have been studied in the context of sequential 820

therapy. 821

822

The CHARTWEL trial randomized patients with localized NSCLC to 823

receive either conventionally fractionated radiotherapy to a dose of 66 Gy in daily 824

2 Gy fractions, or accelerated radiotherapy to a dose of 60 Gy in 1.5 Gy fractions 825

delivered TID45. This study allowed, but did not mandate, neoadjuvant 826

chemotherapy. While there was not a significant overall survival benefit with 827

accelerated radiotherapy, there was a trend towards improved local control with 828

increasing T or N stage and after neoadjuvant chemotherapy (although 829

chemotherapy was only administered to approximately 50 patients in each 830


40

cohort). Acute dysphagia was more common with accelerated radiotherapy 831

without any observed difference in clinical pulmonary toxicity. 832

833

The HART trial, conducted by the Eastern Cooperative Oncology Group, 834

randomized patients with stage III NSCLC to receive either hyperfractionated 835

accelerated radiotherapy, 57.6 Gy in 15 days including 12 treatment days, or 836

conventionally fractionated radiotherapy, 64 Gy in 2 Gy daily fractions46. This 837

trial closed early due to slow accrual with a total of 119 patients randomized after 838

two cycles of paclitaxel and carboplatin chemotherapy. Median survival was 20.3 839

months with accelerated radiotherapy and 14.9 months with standard 840

radiotherapy, though the difference was not statistically significant. Three-year 841

survival was 34% with accelerated radiotherapy compared with 14% with 842

standard radiotherapy. As expected, acute esophagitis was increased with 843

accelerated radiotherapy, although a higher rate of pulmonary toxicity was 844

observed in the standard arm. These trials suggest potential benefit of using 845

accelerated hyperfractionated radiotherapy in patients with stage III non-small 846

cell lung cancer that received sequential rather than concurrent treatment. 847

848

Twice-daily accelerated radiotherapy has been studied with concurrent 849

chemotherapy, although some trials have included a planned radiotherapy 850

treatment interruption in the twice-daily arm. A phase III Australian multicenter 851

trial assessed the impact of reducing treatment time to deliver 60 Gy thoracic 852

radiotherapy from 6 weeks to 3 weeks47. Radiotherapy was given in 2 Gy 853


41

fractions, either twice daily or once daily, with or without concurrent single agent 854

carboplatin chemotherapy (70mg/m2 on days 1-5 of radiotherapy). There were 855

no significant differences amongst treatment arms, although the trial was 856

relatively underpowered with approximately 50 patients per cohort. Moreover, it 857

was observed that patients treated with standard radiotherapy received more 858

chemotherapy than the accelerated arm. Significantly greater treatment related 859

esophagitis was observed with accelerated radiotherapy. 860

861

Trials conducted by the North Central Cancer Treatment Group (NCCTG) 862

used a regimen of 1.5 Gy twice-daily radiotherapy to a total dose of 60 Gy with a 863

2 week planned break. NCCTG 902451 studied the split course 60 Gy regimen 864

with combination cisplatin and etoposide chemotherapy in comparison to 865

standard radiotherapy48. While only 99 eligible patients were entered on this 866

three-arm phase 3 study, there was a suggestion of benefit with split course 867

hyperfractionated radiotherapy with regard to local recurrence and survival. A 868

subsequent phase 3 study, NCCTG 942452, randomized patients to receive 869

either split course twice-daily radiotherapy or standard radiotherapy to 60 Gy 870

concurrent with cisplatin and etoposide chemotherapy49. No significant 871

difference was found in overall survival, 2-year survival or local failure between 872

the treatment arms. A Swedish phase II randomized trial assessed a twice-daily 873

accelerated regimen giving a dose of 64.6 Gy in 1.7 Gy fractions against 874

conventional radiotherapy with either daily or weekly paclitaxel chemotherapy50. 875

Although a planned treatment break of one week was included, overall treatment 876


42

time was reduced resulting in a higher predicted biologic equivalent dose 877

compared with conventional radiotherapy. In this trial, all patients received 2 878

cycles of induction paclitaxel and carboplatin chemotherapy, and a third cycle of 879

concurrent paclitaxel and carboplatin was given with the start of accelerated 880

radiotherapy. Overall outcomes were encouraging, with 24% 5-year survival, but 881

there were no clear differences in either survival or quality of life between 882

accelerated and conventional radiotherapy. 883

884

Hypofractionated Accelerated Radiotherapy 885

886

Classical teaching in radiobiology suggests that delivery of larger doses 887

per fraction is associated with an increased risk of severe late toxic effects. 888

Nevertheless, even prior to the availability of recent advances in treatment 889

planning and delivery, hypofractionation was studied in select patients with LA 890

NSCLC. Prospective trials from Europe have assessed hypofractionated 891

radiotherapy in the context of both sequential and concurrent therapy. A regimen 892

of 66 Gy in 2.75 Gy fractions was demonstrated to be feasible concurrent with 893

daily cisplatin in a phase I EORTC trial51. A subsequent phase III trial, EORTC 894

08972, randomized patients to receive this regimen 66 Gy in 2.75 Gy fractions 895

with concurrent cisplatin or sequential to 2 cycles of cisplatin and gemcitabine 896

chemotherapy52. The trial closed prematurely due to slow accrual greatly limiting 897

the power of the study. Median survival was approximately 16 months on both 898

treatment arms, with 3-year survival of 34% and 22% for the concurrent and 899


43

sequential arms, respectively. Acute esophageal toxicity was increased with 900

concurrent therapy, though late toxicity was deemed acceptable in both arms, 901

suggesting feasibility of the hypofractionated regimen. 902

903

A randomized phase II trial (n=126) from the United Kingdom (SOCCAR) 904

employed hypofractionated radiotherapy to a lower dose, 55 Gy in 2.75 Gy 905

fractions, with either concurrent or sequential chemotherapy53. Doublet 906

chemotherapy with cisplatin and vinorelbine was given in both arms, and median 907

survival was 27.4 months in the concurrent arm and 18.6 months in the 908

sequential chemotherapy arm. Local relapse was observed in 10% of patients 909

treated with concurrent therapy and 22% of patients in the sequential arm. 910

Toxicity appeared acceptable in both arms. The same authors reported their 911

retrospective experience treating NSCLC, including 90 patients with stage III 912

disease, with concurrent chemotherapy and hypofractionated radiotherapy, 913

demonstrating that severe esophageal toxicity necessitating dilatation was 914

observed in 8 patients. A single arm phase II trial from the Korean Radiation 915

Oncology Group (0301) tested a regimen of 60 Gy in 2.4 Gy fractions (to the 916

gross target volume) concurrent with weekly paclitaxel and carboplatin 917

chemotherapy, and outcomes were encouraging with a median overall survival of 918

28.1 months54. Two patients died from hemorrhage during therapy and severe 919

late pulmonary and esophageal toxicity were observed in 4 of 49 patients and 3 920

of 49 patients, respectively. 921

922


44

The above trials suggest encouraging outcomes may be achieved with 923

hypofractionated radiotherapy and concurrent chemotherapy, even with modest 924

nominal total doses of radiotherapy, but randomized comparisons with 925

conventionally fractionated radiotherapy have not been performed. The relative 926

impact of chemotherapy intensity or radiotherapy dose intensity (and total dose) 927

is difficult to discern from available data. As noted previously, a relatively small 928

increase in dose per fraction to 2.15 Gy was not found to be feasible in a phase 929

I/II RTOG trial targeting a relatively high total dose of 75.25 Gy concurrent with 930

carboplatin and paclitaxel chemotherapy33. On the other hand, relatively small 931

prospective studies from China have demonstrated the feasibility of delivering 932

high nominal radiotherapy doses, ranging from 68 Gy to 78 Gy in 2.5 Gy to 3 Gy 933

fractions, sequentially after chemotherapy55,56. Nevertheless, the median survival 934

on these studies appears similar to sequential chemotherapy and radiotherapy 935

studies using lower total doses of hypofractionated radiotherapy including the 936

SOCCAR trial and EORTC 08972. Phase III trials directly testing the value of 937

hypofractionated radiotherapy, in comparison to conventional or accelerated 938

hyperfractionated radiotherapy, in the context of sequential therapy have not 939

been conducted. 940

941

Active prospective cooperative group studies are assessing high dose per 942

fraction radiotherapy, as part of concurrent therapy for stage IIII NSCLC, in the 943

context of advanced technology. A phase I trial from the CALGB is designed to 944

test the maximum dose per fraction that can be given when the nominal total 945


45

dose is held constant at 60 Gy and concurrent plus adjuvant paclitaxel and 946

carboplatin chemotherapy is given. The current cohort is being treated at 2.73 Gy 947

per fraction for 22 fractions. RTOG 1106 is a randomized phase II trial of 948

individualized adaptive radiotherapy using during-treatment FDG-PET/CT in LA 949

NSCLC. Doses as high as 85 Gy in 30 fractions will be delivered on this study. 950

951


46

KQ3: What is the ideal timing of external-beam radiation therapy in relation 952

to systemic chemotherapy for the curative-intent treatment of locally 953

advanced non-small cell lung cancer? 954

955


957

A. There is phase III evidence demonstrating improved overall survival, local 958

control, and response rate associated with concurrent chemoradiation 959

when compared against sequential chemotherapy followed by radiation 960

(HQE). 961

962

B. There is no proven role for the routine use of induction chemotherapy prior 963

to chemoradiotherapy; although, this treatment paradigm can be 964

considered for the management of bulky tumors to allow for radical 965

planning after chemotherapy response (MQE). 966

967

C. There are no phase III data specifically supporting the role for 968

consolidation chemotherapy after chemoradiotherapy for the improvement 969

of overall survival; however, this treatment is still routinely given to 970

manage potential micrometastatic disease particularly if full systemic 971

chemotherapy doses were not delivered during radiotherapy (MQE). 972

973


47

D. For patients that cannot tolerate concurrent chemoradiotherapy, 974

sequential chemotherapy followed by radical radiation has been shown to 975

be associated with an overall survival benefit when compared to 976

radiotherapy alone (HQE). 977

978

E. The ideal concurrent chemotherapy regimen has not been determined; 979

however, the two most common regimens (cisplatin/etoposide and 980

carboplatin/paclitaxel) are the subject of a completed phase III clinical trial 981

(NCT01494558) 982

983

Summary Tables 984

985

Table 7. Selected multicenter phase III randomized controlled trials comparing 986

concurrent with sequential chemoradiotherapy. 987

988

Table 8. Selected phase II trials comparing induction or consolidation 989

chemotherapy with concurrent chemoradiotherapy 990

991

Narrative 992

993

Until the 1980s, radiotherapy alone had been the standard of care for 994

locally advanced NSCLC despite dismal survival data associated with this 995

approach57,58,59,60. During the early 1990s, results of multiple randomized phase 996


48

III studies shifted the standard toward concurrent chemoradiotherapy in an effort 997

to treat both locoregional and micrometastatic disease in patients with LA 998

NSCLC. Initially, sequential therapy (chemotherapy followed by radiotherapy) 999

was used to avoid overlapping toxicities and clinical trials established the efficacy 1000

of this sequence compared to radiotherapy alone. Then, other follow-up studies 1001

compared sequential to concurrent chemoradiotherapy and demonstrated a 1002

benefit for the concurrent approach. 1003

1004

Sequential Therapy 1005

1006

The Cancer and Leukemia Group B (CALGB) trial 8433, which 1007

randomized patients to conventional radiotherapy (60 Gy in 30 fractions) or two 1008

cycles of cisplatin and vinblastine followed by conventional radiotherapy, 1009

demonstrated an improvement in median survival to 13.7 months (compared to 1010

9.6 months for conventional radiotherapy alone) and 5-year overall survival of 1011

17% (compared to 6%)61. These results were confirmed in an Intergroup trial, 1012

which randomized patients to conventional radiotherapy (60 Gy in 30 fractions), 1013

hyperfractionated radiotherapy (69.6 Gy in 58 fractions of 1.2 Gy BID), or 1014

chemotherapy (vinblastine and cisplatin) followed by conventional RT62. The 1015

median survival was significantly improved in the sequential arm compared to 1016

either radiotherapy arms (13.2 vs. 11.4 and 12 months). The 2-year overall 1017

survival rates were 32% vs. 19% and 24% respectively. Additionally, two-meta 1018

analyses confirmed that one- and two-year survival rates were improved with a 1019


49

sequential approach63,64. Collectively, these trials defined sequential 1020

chemoradiation as a standard of care for an aggressive approach in the 1021

treatment of unresectable LA NSCLC prior to trials assessing concurrent 1022

chemoradiotherapy. 1023

1024

Concurrent Chemoradiotherapy 1025

1026

In order to try to improve clinical outcomes such as local-regional tumor 1027

control and overall survival, concurrent administration of chemotherapy and 1028

radiotherapy was studied in multiple clinical trials. This approach was thought to 1029

have a better potential for improvements in clinical outcomes because it would 1030

provide earlier treatment of micrometastatic disease and exploit the synergistic 1031

effect of chemotherapy and radiotherapy, while also delivering the treatment in 1032

the shortest time. The superiority of concurrent chemoradiotherapy compared 1033

with sequential therapy has been demonstrated in two large, multicenter phase III 1034

trials. 1035

1036

RTOG 9410 was a 3-arm trial in which patients received either induction 1037

cisplatin and vinblastine followed by conventional radiotherapy alone, cisplatin 1038

and vinblastine concurrently with conventional radiotherapy, or cisplatin and 1039

etoposide concurrently with hyperfractionated BID radiotherapy to a dose of 69.6 1040

Gy65. The clinical outcomes were significantly improved in the concurrent arm 1041

compared to the sequential arm with regards to median survival (17.0 vs. 14.6 1042


50

months), 4-year overall survival (17% vs 12%) and local control (66% vs 59%). 1043

Acute grade 3 or higher nonhematologic toxicity was increased in the concurrent 1044

arm (48% vs 30%), but the observed rates of late toxicity were similar. 1045

1046

These results were confirmed by the West Japan Lung Cancer Group in 1047

which patients were assigned to either concurrent chemotherapy (two cycles of 1048

cisplatin, mitomycin and vindesine) plus split course radiotherapy (2 courses of 1049

28 Gy in 2 Gy fractions, separated by 10 days) or two cycles of the same 1050

chemotherapy regimen followed by radiotherapy alone (56 Gy in 28 fractions with 1051

no break)66. Results favored the concurrent arm in regards to response rate 1052

(84% vs 66%), median survival (17 vs. 13 months), and 5-year overall survival 1053

(16% vs 9%). 1054

1055

The optimal chemotherapy regimen for use in conjunction with concurrent 1056

thoracic radiotherapy is not known due to a paucity of randomized trials 1057

comparing different chemotherapy regimens in the LA NSCLC setting. The two 1058

chemotherapy regimens that have been most commonly used are the 1059

combination of cisplatin and etoposide67 and the weekly carboplatin and 1060

paclitaxel68 regimens. In a recent Japanese study, concurrent carboplatin and 1061

paclitaxel had the lowest rates of grade 3-4 neutropenia and equal outcomes 1062

(median survival of 22 months) compared to those receiving mitomycin, 1063

vindesine and cisplatin or irinotecan and cisplatin69. Some argue, however, that 1064

cisplatin-based regimens may lead to improved outcomes over carboplatin-based 1065


51

regimens70. Results of a recently completed phase III study comparing these two 1066

regimens are eagerly anticipated (NCT01494558). More recently, the use of 1067

pemetrexed plus cisplatin is more prevalent in patients with nonsquamous 1068

NSCLC71,72. With modern staging techniques, improved supportive care, and 1069

diminshed prevalence of squamous cell histology, patients with LA NSCLC who 1070

undergo combined modality therapy obtain median survival rates ranging from 21 1071

to 26 months in current trials73. 1072

1073

Induction Chemotherapy Followed by Chemoradiotherapy 1074

1075

The use of induction chemotherapy prior to concurrent chemoradiotherapy 1076

was associated with increased toxicity, but no survival advantage, no reduction in 1077

distant metastasis or decrease in locoregional progression. These findings were 1078

observed in at least one phase III (CALGB 39081)68 study and one randomized 1079

phase II (LAMP)74 study that used primarily a carboplatin/paclitaxel regimen. In 1080

the CALGB 39081 phase III study, patients received two cycles of induction 1081

therapy with carboplatin and paclitaxel followed by chemoradiotherapy versus 1082

immediate concurrent chemoradiotherapy alone for LA NSCLC68. There was no 1083

statistically significant difference in the median survival (14 vs. 12 months), or 2-1084

year overall survival (29% and 31%). Radiation-related toxicities were not 1085

significantly different between the two arms. Due in part to this study, induction 1086

chemotherapy is not routinely employed in the treatment of LA NSCLC. 1087

However, in certain instances, induction chemotherapy prior to definitive therapy 1088


52

should be considered if the gross disease cannot be safely encompassed in a 1089

radiotherapy portal without leading to unacceptably high risk of radiation-1090

associated side effects (i.e. pneumonitis and/or esophagitis). In such cases, a 1091

trial of induction chemotherapy can be used and subsequent definitive therapy 1092

can be utilized if an adequate response to the induction therapy is obtained.75 1093

1094

Consolidation Therapy 1095

1096

The exact role of consolidation chemotherapy after chemoradiotherapy 1097

remains uncertain. Initial promising results of the phase II SWOG S9504 1098

(median survival of 26 months)76 supported the proposition that consolidation 1099

chemotherapy might improve survival in LA NSCLC. This was further addressed 1100

in the phase III Hoosier Oncology Group trial, which randomized patients to 1101

concurrent chemoradiotherapy with cisplatin and etoposide followed by three 1102

cycles of docetaxel consolidation or observation67. The trial was stopped early 1103

based upon a planned interim analysis that met the predefined rule for futility. 1104

There was no difference in the median survival of patients receiving consolidation 1105

therapy (21.2 months) versus the observation arm (23.3 months). Similarly, there 1106

was no difference in progression free survival with or without consolidation 1107

therapy (10.8 vs. 10.3 months). There were higher rates of treatment-related 1108

toxicities in the docetaxel arm, including death (5.5% vs. 0%). An additional 1109

phase III trial using consolidation cisplatin/vinorelbine or observation after 1110

concurrent chemoradiation with the same chemotherapy regimen did not 1111


53

demonstrate improved progression free or overall survival77. Based on these 1112

results, when cisplatin-containing regimens are used during concurrent therapy, 1113

there appears to be no conclusive role for consolidation therapy. 1114

1115

However, some argue that if the standard for stage IV disease is to 1116

administer four to six cycles of chemotherapy, how are only two cycles of 1117

chemotherapy given with concurrent radiotherapy sufficient to treat 1118

micrometastatic disease? Due to this consideration, the use of consolidation 1119

therapy following concurrent chemoradiation is routinely used in clinical practice 1120

in order to optimize the treatment of micrometastatic disease. When weekly 1121

radiosensitizing low-dose carboplatin and paclitaxel are administered 1122

concurrently with thoracic radiotherapy, consolidation therapy with full systemic 1123

doses is often given to address concern for systemic disease. Several studies 1124

have demonstrated improved survival outcomes for this approach74,78. Based on 1125

the recent phase III Intergroup trial (RTOG 0617), two cycles of consolidation 1126

carboplatin and paclitaxel is routinely employed when a concurrent 1127

carboplatin/paclitaxel regimen is utilized79. 1128


54

KQ4: What are the indications for adjuvant post-operative radiotherapy for 1129

the curative-intent treatment of locally advanced non-small cell lung 1130

cancer? 1131

1132


1134

A. Phase III studies and meta-analyses of postoperative radiotherapy 1135

(PORT) in completed resected (R0) LA NSCLC with N2 disease suggest 1136

that its addition to surgery does not improve overall survival but may 1137

improve local control when compared to observation strategies (MQE). 1138

1139

B. Phase III studies and meta-analyses of PORT in completely resected (R0) 1140

LA NSCLC with N0-1 disease demonstrate inferior survival when 1141

compared to observation strategies (MQE). 1142

1143

C. Since level 1 evidence supports the administration of adjuvant 1144

chemotherapy for completely resected (R0) LA NSCLC based on 1145

improvements in overall survival compared to patients on observation, any 1146

PORT therapy should be delivered sequentially after chemotherapy in 1147

order not to interfere with standard of care chemotherapy (LQE). 1148

1149

1150


55

D. For patients receiving adjuvant PORT for R0 disease, conventionally 1151

fractionated doses in the range of 50 Gy to 54 Gy (in 1.8-2.0 Gy/day) 1152

should be utilized (LQE). 1153

1154

E. Patients with microscopic residual (R1) primary disease (i.e., positive 1155

margin) and/or microscopic (i.e., extra-capsular extension) nodal disease 1156

may be appropriate candidates for PORT (ideally given concurrently with 1157

chemotherapy) with conventionally fractionated doses in the range of 54 1158

Gy to 60 Gy (in 1.8-2.0 Gy/day fraction size) in order to improve local 1159

control (LQE). 1160

1161

F. Patients with high-risk features after resection (gross residual primary 1162

and/or macroscopic (R2) nodal disease) of LA NSCLC may be appropriate 1163

candidates for PORT (ideally given concurrently with chemotherapy) with 1164

conventionally fractionated doses of at least 60 Gy (in 1.8-2.0 Gy/day 1165

fraction size) in order to improve local control (LQE). 1166

1167

Summary Table 1168

1169

Table 9. Selected publications assessing post-operative radiotherapy 1170

after surgical resection in non-small cell lung cancer. 1171

1172

Narrative 1173


56

1174

LA NSCLC is a historic term that can be broadly defined as including lung 1175

tumors that have spread beyond the primary site to metastases. By the criteria of 1176

the AJCC TNM staging manual, LA NSCLC tumors are generally classified as 1177

“stage III” based on their corresponding tumor (T) and mediastinal nodal (N) 1178

features80. In general, treatment of LA NSCLC has been controversial given that 1179

“stage III” consists of heterogeneous disease subgroups (by prognosis) 1180

generated by the various combinations of these possible primary tumor and 1181

mediastinal nodal characteristics81. For fit (medically operable) patients whose 1182

primary tumors are associated with a limited mediastinal lymph node burden (i.e., 1183

N2 only) and deemed potentially resectable, surgery has often been offered as 1184

the major approach to definitive cancer treatment81. However in this highly 1185

selected group of patients, there is still a recognized high risk for both local and 1186

distant failure after surgery, as demonstrated by modest overall survival and local 1187

control rates81. Surgical resections are referred to as either R0 (complete), R1 1188

(microscopically positive resection margin), or R2 (macroscopic residual tumor). 1189

1190

Adjuvant chemotherapy (CT) and radiotherapy have been extensively 1191

evaluated over the past decades in order to determine the potential additive 1192

impact to important clinical outcomes. Currently, adjuvant CT has become the 1193

standard-of-care for patients with completely resected stage II and III NSCLC, 1194

after the results from multiple randomized trials, later validated by meta-analyses, 1195

demonstrated that addition of platinum-based CT after resection of LA NSCLC 1196


57

leads to absolute overall survival improvements at 5 years of between 5% and 1197

15%82,83,84,85,86,87,88,89. 1198

1199

The role of postoperative radiotherapy (PORT) for resected lung cancer 1200

has been investigated in prospective trials as early as the 1960s, with the first 1201

randomized controlled trial of PORT of relevance to current practice published in 1202

1980. Results from these trials, in which PORT was administered across a range 1203

of resected lung cancer stages (I-III), had suggested local control benefits to the 1204

addition of PORT but overall survival outcomes were 1205

inconclusive90,91,92,93,94,95,96,97,98. In order to clarify the role of PORT in resected 1206

lung cancer, the Meta-analysis Group of the British Medical Research Council 1207

(MRC) Clinical Trials Unit (CTU) established the PORT Meta-analysis Trialists 1208

Group C to study the role of PORT by undertaking a meta-analysis of individual 1209

patient data from the published randomized trials. Results of this MRC meta-1210

analysis were first published in 199899 and suggested an overall survival 1211

detriment to the addition of PORT for all stages of resected NSCLC. In 2004, 1212

data were updated based on the addition of a new trial and published in 2005100. 1213

In 2008, the meta-analysis was updated again to include data from another new 1214

trial90 and the results were reported online in 2010 as part of the Cochrane 1215

collaboration101, but with no change in conclusions from their initial publication. In 1216

summary, the last review has reported on 2343 patients from 11 trials and noted 1217

a significant adverse effect of PORT on survival with a hazard ratio of 1.18 (18% 1218

relative increase in the risk of death). The authors further noted that this 1219


58

detrimental effect is most pronounced for patients with stage I/II [N0-N1 nodal 1220

disease]. For stage III [N2] patients (i.e. LA NSCLC) there is no clear evidence of 1221

an adverse effect on survival, but there is a benefit with respect to local control 1222

[local recurrence rate 41% (observation arm) versus 26% (PORT arm)]. 1223

1224

Mindful of this updated conclusion on the effect of PORT in resected LA 1225

NSCLC (i.e., neither survival improvement or detriment; local control 1226

improvement), it is important to note that almost all the studies of resected LA 1227

NSCLC included in the meta-analysis were conducted prior to standard 1228

administration of adjuvant CT. There are currently 2 additional phase III studies 1229

to reference but that were not included in the most recent MRC meta-1230

analysis102,103. They further support the conclusions of the most recent MRC 1231

PORT updated meta-analysis. The first is a Polish study of PORT in resected 1232

stage III NSCLC whose data was not available to the MRC researchers and 1233

showed no survival improvement but a local control benefit to PORT102. The 1234

second is a study which did not meet its accrual goal but whose partial results 1235

were published in 2007103. In this trial, all patients had received adjuvant CT prior 1236

to being randomized to PORT or observation. There were no differences 1237

between the observation and the PORT arms with respect to overall or failure-1238

free survival. Table 7 provides a summary list of selected studies of interest to 1239

PORT in resected LA NSCLC. In individual studies where results were reported 1240

for blended stage groupings, stage III specific patient numbers and outcomes 1241

were abstracted, as feasible. 1242


59

1243

Overall, the studies are heterogeneous in keeping with the timeline over 1244

which they were conducted and over a range of variables recorded, including but 1245

not limited to: the clinical means for assessing, staging and determining patient 1246

eligibility for trials, the quality and type of surgery conducted, the pathologic 1247

stages of the patients treated, and the selection/assessment/reporting of 1248

outcomes. From a specific radiotherapy perspective, this meta-analysis has been 1249

extensively critiqued since its relevance to modern radiotherapy is 1250

questioned104,105. PORT doses (total dose and fractionation) were reported to be 1251

variable between studies. Two-dimensional planning of radiotherapy dose 1252

delivery was routine and there was no computed tomography–based treatment 1253

planning (three-dimensional planning) in the majority of trials. In the majority of 1254

studies, radiotherapy fields were typically large given the limits of radiography for 1255

target definition and usually included the entire mediastinum, occasionally the 1256

supraclavicular region or the contralateral hilum. In addition, a variety of different 1257

dose fractionation schedules were investigated. Concerns have been expressed 1258

over the use of Co-60 units in many studies in that this may have contributed to 1259

potential morbidity, but this opinion is not universally seen as an indicator of 1260

morbid or suboptimal therapy104. 1261

1262

With respect to potential benefits of PORT in resected LA NSCLC, results 1263

from contemporary retrospective studies and subset analyses of recent 1264

randomized trials including adjuvant CT suggest possible survival improvements 1265


60

with PORT but must be interpreted with caution given the nature of the studies. 1266

These critiques notwithstanding, the MRC meta-analysis clearly indicates 1267

potential risk in PORT administration but its finding of improved local control for 1268

N2 disease supports further clarification on the role of PORT in a modern phase 1269

III trial with surgical controls, administration of adjuvant CT and utilization of 1270

modern radiotherapy planning techniques. The Lung Adjuvant Radiotherapy Trial 1271

(Lung ART) is an ongoing randomized controlled trial being conducted by the 1272

European Organization for Research and Treatment of Cancer (EORTC)105. It is 1273

enrolling patients with completely resected NSCLC with proven N2 involvement 1274

and after standard of care postoperative CT randomizing them to mediastinal 1275

PORT (54 Gy in 1.8 Gy-2 Gy fractions) planned using three-dimensional planning 1276

radiotherapy techniques with a primary endpoint of disease-free survival. A 1277

recent meta-analysis confirms that this research question is appropriate given the 1278

association of both local control and overall survival with modern postoperative 1279

radiation techniques106. 1280

1281

Additionally, the use of pre-operative positron emission tomography (PET) 1282

scans to aid treatment planning theoretically improves both lymph node targeting 1283

and decreases doses to adjacent normal structures when compared to 1284

techniques employed in previously published trials. Until completion of the Lung 1285

ART trial, it is not unreasonable for physicians to discuss the potential local 1286

control benefits afforded by PORT in selected patients even in the absence of 1287

overall survival benefits (as demonstrated by the MRC meta-analysis), while 1288


61

discussing the recognized potential toxicities and morbidity of PORT and the 1289

influence that adjuvant CT may have on the delivery and safety of PORT. 1290

1291

The differentiation of adjuvant PORT for resected disease from post-1292

operative radiotherapy for positive margin disease, extra-capsular nodal 1293

extension or gross residual primary or nodal disease (R1-microscopic disease or 1294

R2-macroscopic disease) is important. Notwithstanding the absence of 1295

randomized evidence, in these high-risk R1 and R2 situations, treatment with 1296

PORT is an established indication, due to the high local/regional relapse 1297

associated with these patients. In this setting PORT is routinely administered 1298

concurrently with post-operative CT to ensure the earliest administration of local 1299

therapy. PORT doses in clinical practice for R1 disease are typically 54 Gy to 60 1300

Gy and at least 60 Gy in R2 disease (in 1.8-2.0 Gy daily fractions)107. 1301


62

KQ5: When is neoadjuvant radiotherapy prior to surgery indicated for the 1302

curative-intent treatment of locally advanced non-small cell lung cancer? 1303

1304


1306

A. There is no level I evidence recommending the use of induction 1307

radiotherapy (or chemoradiotherapy) followed by surgery for patients with 1308

resectable stage III NSCLC (HQE). 1309

1310

B. In those patients who are selected for trimodality approach, preoperatively 1311

planned lobectomy (as opposed to pneumonectomy), based on best 1312

surgical judgment, is preferable, since it was associated with 1313

survival benefit in the exploratory post-hoc INT 0139 analysis (MQE). 1314

1315

C. No definitive statement can be made about best patient selection criteria 1316

for the trimodality therapy, although no weight loss, female gender, and 1317

one (vs. more) involved nodal stations were associated with improved 1318

outcome in INT 0139 (MQE). 1319

1320

D. The ideal preoperative radiotherapy dose is currently not known; however, 1321

a minimum of 45 Gy should be delivered consistent with the INT 0139 trial 1322

(LQE). 1323

1324


63

E. Preoperative conventionally fractionated doses up to 60 Gy are reported to 1325

be associated with higher mediastinal clearance rates, although no 1326

significant correlation with improved survival has been demonstrated 1327

(LQE). 1328

1329

Summary Table 1330

1331

Table 10. Mediastinal pCR (N2 nodal clearance) rates by type of induction 1332

therapy. 1333

1334

Narrative 1335

1336

Surgical resection is the standard of care for patients with stage I-II 1337

NSCLC, achieving survival rates of 50-75% at 5 years, with the majority of 1338

patients dying as a result of distant metastases. Survival of patients with stage 1339

IIIA NSCLC treated solely with surgery varies widely depending on patient 1340

selection. Five year survival rate is estimated at 34% for those with single station 1341

and minimal mediastinal (N2) lymph node involvement (defined as normal size 1342

lymph nodes on a computerized chest tomography with microscopic only nodal 1343

metastases), compared to 3-11% for those with either two or more nodal stations 1344

involved and/or abnormal size lymph nodes108. Yet there remains a persistent 1345

interest in the scientific community not to abandon surgery altogether in stage III 1346

NSCLC which is mostly due to the suboptimal local control of the primary lung 1347


64

tumors achievable with thoracic radiotherapy or chemoradiotherapy. Additionally, 1348

surgery provides the most definitive mediastinal staging and leads to upstaging in 1349

more than 10% of patients. The proponents of surgery as part of management of 1350

stage III NSCLC have mounted trials comparing the trimodality 1351

(chemoradiotherapy followed by surgery) or bimodality (CT alone, followed by 1352

surgery) to the definitive standard of care thoracic RT with concurrent CT. 1353

1354

The Intergroup (INT) 0139 Phase III randomized clinical trial109, comparing 1355

trimodality therapy to the definitive concurrent chemoradiotherapy, demonstrated 1356

no survival advantage to the trimodality arm (median survival, 23.6 months vs. 1357

22.2 months in the surgical vs. definitive chemoradiotherapy arms), with 1358

improved progression-free survival of 12.8 vs. 10.5 months. The study enrolled 1359

396 eligible medically operable good performance status patients with T1-3N2M0 1360

NSCLC, without any limitation on mediastinal nodal size. Three quarters of all 1361

patients had a single mediastinal station involved and 20% had two involved 1362

stations. Chemotherapy in both arms consisted of cisplatin and etoposide and 1363

the RT doses were 45 Gy and 61 Gy conventionally fractionated (1.8 Gy/fraction) 1364

in the preoperative vs. definitive chemoradiotherapy arms, respectively. In the 1365

surgical arm, non-progressing patients underwent thoracotomy. Overall, 88% of 1366

all patients were eligible for thoracotomy and 71% had a complete surgical 1367

excision; 5.5%, incomplete resection, and only 4.5% had no resection (total of 1368

81% actually undergoing thoracotomy). Among those requiring pneumonectomy, 1369


65

perioperative mortality was 26%; 50% for those who had a complex right 1370

pneumonectomy. 1371

1372

Despite the lack of survival difference between arms, other clinical trials 1373

were conducted or are ongoing110,111,112,113,114. The enthusiasm for these trials 1374

can be justified by the belief that it was the excessive and unexpected patient 1375

mortality from pneumonectomy patients in the INT 0139 study that diluted the 1376

potential survival advantage in the surgical arm. This hypothesis is supported by 1377

the exploratory unplanned analysis of the INT 0139 data, demonstrating that 1378

patients who underwent lobectomy after induction chemoradiotherapy, 1379

experienced an improved survival when compared to patients matched (by 1380

performance status, age, sex and T stage) from the definitive chemoradiotherapy 1381

arm (median survival of 34 months vs. 22 months and 5 year survival rates of 1382

36% vs. 18%, respectively)109. In this analysis, patient survival in this surgical 1383

arm was not hindered by the observed low lobectomy-related mortality of 1%. 1384

Such survival is notable in the multi-institutional setting, pre-PET era and with 2-1385

dimensional RT. In comparison, the best median reported so far in the 1386

cooperative group setting for patients with stage IIIA/B NSCLC (60 Gy arm of the 1387

RTOG 0617)115 is 28.7 months, with 2% treatment-related mortality. In the 1388

RTOG 0617 trial, 90% of patients were staged with PET and all received modern 1389

3-dimensional RT or intensity-modulated RT (IMRT). A direct comparison of 1390

survival between the INT 0139 and RTOG 0617 is obviously flawed, since 1391


66

patients in INT 0139 represented per definition a more favorable, resectable 1392

stage IIIA only population (presumably with an overall lower disease burden). 1393

1394

The difficulties with pneumonectomy in INT 0139 led to a perception 1395

among many that patients with stage III NSCLC who are otherwise trimodality 1396

candidates, should not be offered surgery if pneumonectomy would be required, 1397

and should be treated with chemoradiotherapy. The high post-pneumonectomy 1398

mortality in INT 0139 is an outlier when compared to other published surgical 1399

series, where mortality ranging between 3% to 17% has been 1400

reported116,117,118,119. Several reasons may explain this difference: INT 0139 was 1401

a multi-institutional cooperative group trial which enrolled patients over a 7 year 1402

span (1994-2001), by necessity allowing surgeons and institutions with different 1403

levels of expertise. There was no requirement to cover the bronchial stump with 1404

vascularized tissue flap (in order to minimize the risk of bronchopleural fistula, 1405

BPF) and no protocol-specified guidance was provided on postoperative fluid 1406

management. However, these potential explanations have not been subjected to 1407

prospective randomized investigation in order to test their validity. 1408

1409

In a large series of 350 patients undergoing surgery after induction 1410

chemoradiotherapy 45 Gy twice-daily116, lack of stump reinforcement and poor 1411

performance status were the only significant factors for the occurrence of BPF in 1412

a multivariate analysis. Mortality rate after pneumonectomy was 7.2% (12% on 1413

the right side and 2.9% on the left), and it was 3.8% after lobectomy. Main 1414


67

causes of death were pneumonia and Adult Respiratory Distress Syndrome 1415

(ARDS). BPF occurred after pneumonectomy in 8% of patients (6.4% on the 1416

right and 1.6% on the left) and after lobectomy, in 1.9%, with an overall 1417

postoperative morbidity rate of 44%. 1418

1419

In a similar report of 176 pneumonectomies after induction CT or 1420

chemoradiotherapy118, the authors concluded that “the need for pneumonectomy 1421

for complete resection alone should not be a reason to exclude patients from a 1422

potentially curative procedure if done in an experienced center”, and quote an 1423

overall survival rate of 38% at 5 years. An analysis of the Society of Thoracic 1424

Surgeons General Thoracic Surgical Database of 525 patients with lung cancer 1425

undergoing resection after CT (n=153), chemoradiotherapy (349) or radiotherapy 1426

(23)120, of whom 203 had stage IIIA lung cancer was performed. This 1427

investigation presented propensity-adjusted rates that detected no difference in 1428

discharge mortality, prolonged length of stay, or a composite of major morbidity 1429

for patients receiving induction therapy. It is important to note that induction 1430

therapy patients had a 3-fold rate of BPF and more infections, laryngeal nerve 1431

injury and blood transfusions than those treated with surgery alone. As surgical 1432

perceptions shift from denying a pneumonectomy after chemoradiotherapy to 1433

considering it a safe and standard procedure, a need for accepted operative 1434

patient management guidelines becomes more relevant. 1435

1436


68

Patient selection is crucial, taking into account performance status, as well 1437

as pulmonary and cardiovascular function tests. In addition to the individual 1438

surgical and anesthesia expertise, high-volume centers have reported better 1439

results121. A mandatory coverage of the bronchial stump, keeping patients “dry” 1440

both during the surgical procedure, as well in the postoperative period, seems to 1441

limit the incidence of ARDS. One group of investigators122 recommends 1442

delivering no greater than 1 L of fluids during surgery, avoiding high oxygen 1443

concentrations and severely limiting postoperative fluid administration, 1444

maintaining a considerable negative fluid balance. 1445

1446

One surgical alternative to pneumonectomy for central tumors is sleeve 1447

lobectomy, a procedure in which only the involved lobe with part of the mainstem 1448

bronchus is removed and the remaining lobe is reimplanted on the mainstem 1449

bronchus, preserving lung tissue. Sleeve lobectomy might have been 1450

underutilized following induction therapy for fear of postoperative complications. 1451

However, it seems that sleeve lobectomy appears to be safe after induction 1452

chemoradiotherapy123,124. 1453

1454

Multiple studies109,110,114 have demonstrated that patients who achieve 1455

mediastinal sterilization or nodal pathologic complete response (pCR, i.e. down 1456

staging of preoperative N2 lymph nodes into N0 or N1) achieve longer survival 1457

than those with persistent N2 disease following either CT alone (median survival 1458

time 57 months for post-CT N0/N1 status vs. 16 months for N2 status)114 or 1459


69

concurrent chemoradiotherapy (MST 37 months for post chemoradiotherapy N0 1460

status vs. 26 months for persistent N1-N3)109. 1461

1462

A definitive relationship between pCR rates and survival is not always 1463

evident, but achieving nodal pCR is a strong predictor of survival and may be a 1464

surrogate marker for eradication of distant chemotherapy-sensitive 1465

micrometastases. These patients may be the best candidates for additional 1466

postoperative chemotherapy109. Therefore, maximizing the rate of pCR seems a 1467

priority when designing preoperative regimens. It is not clear whether choosing 1468

the type of platinum doublet chemotherapy used (cisplatin- vs. carboplatin-based) 1469

impacts on outcome. 1470

1471

Historically, the RT doses used in the preoperative setting were limited to 1472

45-50 Gy, mostly due to safety concerns. With advent of modern RT 1473

techniques, such as 3DCRT/IMRT and IGRT, dose escalation of daily standard 1474

fractionated preoperative RT becomes a potentially attractive approach to 1475

improve mediastinal pCR rates. Several single institution studies reported 1476

acceptable safety and efficacy of using definitive RT doses of 59-60 Gy with 1477

concurrent chemotherapy, with nodal pCR rates (defined as conversion from N2 1478

to N0/N1) of 34-88%122,123,124. These results seem to compare favorably with the 1479

pCR rates reported after RT doses of 45-50 Gy; however, both patient selection 1480

and appropriate presurgical restaging are important factors to consider prior to 1481

the implementation of such therapy. 1482


70

1483

The RTOG conducted a phase II 0229 study110, in which 57 eligible stage 1484

III NSCLC patients with pathologically proven N2 or N3 nodes received 61.2 Gy 1485

concurrently with weekly carboplatin and paclitaxel chemotherapy, followed by 1486

surgery within 8 weeks from chemoradiotherapy completion and further 1487

consolidation chemotherapy. The projected primary endpoint of the study was 1488

mediastinal pCR of 70%. Out of 57 eligible patients, 56 completed induction 1489

therapy and proceded to surgery, with 65% (37/57) undergoing resection (76% 1490

R0 and 24%, R1). The mediastinal pCR was documented in 63% (27/43) of 1491

patients who underwent nodal re-evaluation. Median survival for those with 1492

mediastinal pCR was not reached, and was 33 months for those with residual 1493

nodal disease. 1494

1495

The RTOG 0229 results confirm a high rate of nodal tumor clearance 1496

following high-dose preoperative RT, demonstrating at the same time real life 1497

challenges of conducting a complex trimodality trial in a multi-institutional setting. 1498

Despite careful initial patient selection, 5/56 patients eligible for resection were 1499

found unresectable; 5 were medically inoperable; 2 had distant progression and 1500

6/19 with persistent N2 disease did not undergo resection based on the decision 1501

of the surgeon. The controversy of whether patients not achieving nodal 1502

clearance should undergo surgery remains unresolved, although data from INT 1503

0139 indicates that the median survival time for patients with persistent N2 1504


71

disease who did not have surgical resection in 0139 was 7.9 months vs. 26.4 1505

months for those with the residual N1-N3 status who did have surgery109. 1506

1507

One alternative approach is to abort surgery in those patients with either 1508

persistent N3 nodes or multiple N2 stations involvement and to proceed with 1509

surgery in those with a single persistently involved station124. Preoperative 1510

pathologic investigation of mediastinal nodes after chemotherapy or 1511

chemoradiotherapy is not routinely employed due to the concern of mediastinal 1512

fibrosis. However, in skilled hands125, successful re-do mediastinoscopy after 1513

previous CT and/or chemoradiotherapy was possible in >80% of patients in 1514

retrieving nodal tissue. 1515

1516

Another controversial issue relates to the most optimal type of induction 1517

therapy: CT alone or chemoradiotherapy. Overall, mediastinal sterilization 1518

seems more likely after induction chemoradiotherapy (radiotherapy dose 45 Gy) 1519

than following CT alone110,112,114,126,127,128,129,130,131. The RTOG and SWOG have 1520

mounted a phase III randomized trial (RTOG 0412/SWOG 0333), attempting to 1521

answer this question, with survival as the primary endpoint. Patients with PET-1522

staged pathologically confirmed stage IIIA (N2) NSCLC were randomized to 1523

either induction CT alone (cisplatin and docetaxel), or to the induction 1524

chemoradiotherapy (same CT with 50.4 Gy 3D RT delivered concurrently), with 1525

surgery and maintenance docetaxel to follow. Only 18 patients out of a planned 1526


72

574 were enrolled and the study closed due to poor accrual, likely due to weak 1527

levels of physician and patient equipoise. 1528

1529

Two studies132,133 examined the same issue but exist in the abstract form 1530

only. A recent Swiss Group for Clinical Research (SAKK) phase III randomized 1531

study134 randomized 219 patients with pathologically confirmed resectable stage 1532

IIIA NSCLC to receive induction CT (cisplatin and docetaxel) vs. the same CT, 1533

then accelerated concomitant boost RT (44 Gy in 22 fractions over 3 weeks), 1534

followed by surgery in both arms. The observed resectability rate was high (81 1535

vs. 82%) and there was no difference in local failure rates (22 vs. 24%) or event-1536

free survival, the primary study endpoint (12.8 vs. 11.8 months) in the CT-then-1537

RT arm vs. the induction CT alone arm, respectively. Although median survival 1538

times in this abstract were one of the best reported for the preoperative studies, 1539

no concurrent chemoradiotherapy arm was used in comparison to CT alone. 1540

1541

A unique opportunity to compare postoperative morbidity and mortality 1542

following different induction therapies (CT vs. chemoradiotherapy) in a 1543

randomized setting is offered by the German Lung Cancer Cooperative Group 1544

(GLCCG) phase III trial [Q5:5] in patients with stages IIIA and IIIB (67% of all 1545

patients) NSCLC younger than 70 years, in which 524 eligible patients were 1546

randomized to the experimental arm (three cycles of cisplatin and etoposide, 1547

followed by RT, 1.5 Gy twice daily to 45 Gy with concurrent carboplatin and 1548

vindesine, followed by surgical resection), or the control arm (three cycles of 1549


73

cisplatin and etoposide, followed by surgery and postoperative RT, 54 Gy in 1.8 1550

Gy fractions). There was no significant difference between arms with regard to 1551

surgical mortality (9% vs. 5%); BPF incidence (3.8% vs. 2.1%); bleeding (1.5% 1552

vs. 0.7%) or pneumonia. Outcome measures were not different either: 1553

resectability rate (73% vs. 69%); R0 resection rate (53% vs. 56%); median 1554

survival time (19.2 vs. 19.7 months), although nodal pCR was higher in the 1555

experimental arm. Overall, this largest phase III trial of preoperative therapy was 1556

admirably successful in its accrual and conduct, but was not able to answer the 1557

question whether induction CT is superior to induction chemoradiotherapy, since 1558

postoperative RT was used in the control arm, effectively comparing the 1559

preoperative RT approach to the postoperative RT. Additionally, low overall 1560

resectability rate of 54.5%, related to the inclusion of marginally resectable or 1561

even unresectable patients, made the study results difficult to interpret. 1562

1563

Even though level I evidence is lacking on the choice of best induction 1564

therapy before surgery for patients with stage IIIA (N2) NSCLC, the majority of 1565

such patients in the US receive chemoradiotherapy rather than CT alone (80% 1566

vs. 20%, respectively)120. Of interest, only half of all patients with known stage 1567

IIIA NSCLC receive any induction therapy before surgery120. New areas of 1568

investigation in the preoperative induction approach to stage IIIA NSCLC include 1569

the addition of biologic targeted agents (panitumomab in the ongoing RTOG 1570

0839 phase II randomized trial). 1571


74

CONCLUSION 1572

1573

A consensus and evidence-based clinical practice guideline for the 1574

radiotherapeutic management of LA NSCLC has been created addressing five 1575

questions including: dose fractionation of radiotherapy alone, dose fractionation 1576

with concurrent chemoradiation, timing of radiotherapy with chemotherapy, 1577

indications of post-operative radiotherapy, and indications of pre-operative 1578

radiotherapy. Specific guideline statements were graded in terms of evidence 1579

quality and were subjected to a consensus building methodology requiring 1580

greater than 75% agreement to be adopted. 1581

1582

High quality evidence was observed in several areas. In terms of 1583

radiotherapy alone management, a minimum dose of 60 Gy of conventionally 1584

fractionated radiotherapy is recommended. However, dose escalation beyond 60 1585

Gy (conventionally fractionated) in the context of combined modality concurrent 1586

chemoradiation was not found to be associated with any improvement in clinical 1587

benefits. In the context of combined modality therapy, chemotherapy and 1588

radiation should ideally be given concurrently in order to maximize survival, local 1589

control and disease response rate. For patients who have undergone surgical 1590

resection, no high-level evidence exists for the routine use of post-operative 1591

radiotherapy; however, it can be utilized to optimize local control in situations with 1592

positive margins, gross primary/nodal residual disease, or N2 (mediastinal) 1593

involvement. No high-level evidence exists for the routine use of pre-operative 1594


75

induction chemoradiotherapy; however, modern surgical series and a post-hoc 1595

analysis of the INT 0139 trial suggest that a survival benefit may exist if patients 1596

are properly selected and surgical techniques/post-operative care is optimized. 1597


76

FIGURE CAPTIONS 1598

1599

Figure 1. Timeline of Landmark Radiotherapy Clinical Investigations in Locally 1600

Advanced Non-small Cell Lung Cancer 1601


77

REFERENCES 1602

1603

1. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact 1604

of eliminating socioeconomic and racial disparities on premature cancer 1605

deaths. CA Cancer J Clin 2011;61:212-36. 1606

1607

2. McCloskey P, Balduyck B, Van Schil PE, et al. Radical treatment of non-1608

small cell lung cancer during the last 5 years. Eur J Cancer 1609

2013;49:1555-64. 1610

1611

3. Ramnath N, Dilling TJ, Harris LJ, et al. Treatment of stage III non-small 1612

cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: 1613

American College of Chest Physicians evidence-based clinical practice 1614

guidelines. Chest 2013;143:e314S-40S. 1615

1616

4. Bradley JD, Paulus R, Komaki R, et al. A randomized phase III 1617

comparison of standard-dose (60 Gy) versus high-dose (74 Gy) 1618

conformal chemoradiotherapy with or without cetuximab for stage III non-1619

small cell lung cancer: Results on radiation dose in RTOG 0617. J Clin 1620

Oncol 2013;31:abstr 7501. 1621

1622

5. Cox JD. Are the results of RTOG 0617 mysterious? Int J Radiat Oncol 1623

Biol Phys 2012;82:1042-4. 1624


78

1625

6. Santos ES, Castrellon A, Blaya M, et al. Controversies in the 1626

management of stage IIIA non-small-cell lung cancer. Expert Rev 1627

Anticancer Ther 2008;8:1913-29. 1628

1629

7. Belderbos JS, Kepka L, Spring Kong FM, et al. Report from the 1630

International Atomic Energy Agency (IAEA) consultants' meeting on 1631

elective nodal irradiation in lung cancer: non-small-Cell lung cancer 1632

(NSCLC). Int J Radiat Oncol Biol Phys 2008;72:335-42. 1633

1634

8. Rosenzweig KE, Sura S, Jackson A, et al. Involved-field radiation therapy 1635

for inoperable non-small cell lung cancer. J Clin Oncol 2007;25:5557-61. 1636

1637

9. Yuan S, Sun X, Li M, et al. A randomized study of involved-field 1638

irradiation versus elective nodal irradiation in combination with concurrent 1639

chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J 1640

Clin Oncol 2007;30:239-44. 1641

1642

10. Emami B, Mirkovic N, Scott C, et al. The impact of regional nodal 1643

radiotherapy (dose/volume) on regional progression and survival in 1644

unresectable non-small cell lung cancer: an analysis of RTOG data. Lung 1645

Cancer 2003;41:207-14. 1646

1647


79

11. Senan S, Burgers S, Samson MJ, et al. Can elective nodal irradiation be 1648

omitted in stage III non-small-cell lung cancer? Analysis of recurrences in 1649

a phase II study of induction chemotherapy and involved-field 1650

radiotherapy. Int J Radiat Oncol Biol Phys 2002;54(4):999-1006. 1651

1652

12. Loblaw DA, Prestrud AA, Somerfield MR, et al. American Society of 1653

Clinical Oncology Clinical Practice Guidelines: formal systematic review-1654

based consensus methodology. J Clin Oncol 2012;30:3136-40. 1655

1656

13. Qaseem A, Snow V, Owens DK, et al. The development of clinical 1657

practice guidelines and guidance statements of the American College of 1658

Physicians: summary of methods. Ann Intern Med 2010;153:194-9. 1659

1660

14. Roswit B, Patno ME, Rapp R, et al. The survival of patients with 1661

inoperable lung cancer: a large-scale randomized study of radiation 1662

therapy versus placebo. Radiology 1968;90:688-97. 1663

1664

15. Sigel K, Lurslurchachai L, Bonomi M, et al. Effectiveness of radiation 1665

therapy alone for elderly patients with unresected stage III non-small cell 1666

lung cancer. Lung Cancer 2013 Sep 4. doi:pii: S0169-5002(13)00268-7. 1667

10.1016/j.lungcan.2013.06.011. 1668

1669


80

16. Routh IA, Hickman B, Khansur T. Report of a prospective trial - Split-1670

course versus conventional radiotherapy in the treatment of non-small 1671

cell lung cancer. Rad Med 1995;13:115-9. 1672

1673

17. Perez CA, Stanley K, Grundy G, et al. Impact of Irradiation Technique 1674

and Tumor Extent in Tumor Control and Survival of Patients with 1675

Unresectable Non-Oat Cell Carcinoma of the Lung: Report by the 1676

Radiation Therapy Oncology Group. Cancer 1982;15;50:1091-9. 1677

1678

18. Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on 1679

survival in carcinoma of the lung treated with irradiation. Int J Radiat 1680

Oncol Biol Phys 1986;12: 539-47. 1681

1682

19. Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of 1683

RTOG 9311: a phase I-II dose-escalation study using three-dimensional 1684

conformal radiotherapy in patients with inoperable non-small-cell lung 1685

carcinoma. Int J Radiat Oncol Biol Phys 2005;61:318-28. 1686

1687

20. Hazuka MB, Turrisi AT 3rd, Lutz ST, et al. High-dose thoracic irradiation 1688

incorporating beam's eye view display in non-small cell lung cancer: a 1689

retrospective multivariate analysis. Int J Radiat Oncol Biol Phys 1690

1993;27:273-84. 1691

1692


81

21. Kong FM, Ten Haken RK, Schipper MJ, et al. High-dose radiation 1693

improved local tumor control and overall survival in patients with 1694

inoperable/unresectable non-small-cell lung cancer: long-term results of 1695

a radiation dose escalation study. Int J Radiat Oncol Biol Phys 1696

2005;63:324-33. 1697

1698

22. Slotman BJ, Njo KH, de Jonge A, et al. Hypofractionated radiation 1699

therapy in unresectable stage III non-small cell lung cancer. Cancer 1700

1993;72:1885-93. 1701

1702

23. Amini A, Lin SH, Wei C, et al. Accelerated hypofractionated radiation 1703

therapy compared to conventionally fractionated radiation therapy for the 1704

treatment of inoperable non-small cell. Radiat Oncol 2012;7:33. 1705

1706

24. Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of 1707

hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 1708

Gy: possible survival benefit with greater than or equal to 69.6 Gy in 1709

favorable patients with Radiation Therapy Oncology Group stage III non-1710

small-cell lung carcinoma: report of Radiation Therapy Oncology Group 1711

83-11. J Clin Oncol 1990;8:1543-55. 1712

1713


82

25. Sause W, Kolesar P, Taylor IV S, et al. Final results of phase III trial in 1714

regionally advanced unresectable non-small cell lung cancer. Chest 1715

2000;117:358-64. 1716

1717

26. Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III 1718

non-small-cell lung cancer: seven-year follow-up of cancer and leukemia 1719

group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210-5. 1720

1721

27. Saunders M, Dische S, Barrett A, et al. Continuous, hyperfractionated, 1722

accelerated radiotherapy (CHART) versus conventional radiotherapy in 1723

non-small cell lung cancer: mature data from the randomised multicentre 1724

trial. Radiother Oncol 1999;52:137-48. 1725

1726

28. Saunders MI, Rojas A, Lyn BE, et al. Experience with dose escalation 1727

using CHARTWEL (continuous hyperfractionated accelerated 1728

radiotherapy weekend less) in non-small-cell lung cancer. Br J Cancer 1729

1998;78:1323-8. 1730

1731

29. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized 1732

phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-1733

accelerated versus conventionally fractionated radiotherapy in non-small 1734

cell lung cancer (NSCLC); Radiother Oncol 2011;100:76-85. 1735

1736


83

30. Ball D, Bishop J, Smith J, et al. A randomised phase III study of 1737

accelerated or standard fraction radiotherapy with or without concurrent 1738

carboplatin in inoperable non-small cell lung cancer: final report of an 1739

Australian multi-centre trial. Radiother Oncol 1999;52:129-36. 1740

1741

31. Mauguen A, Le Péchoux C, Saunders MI, et al. Hyperfractionated or 1742

Accelerated Radiotherapy in Lung Cancer: An Individual Patient Data 1743

Meta-Analysis. J Clin Oncol 2012;30:2788-97. 1744

1745

32. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent 1746

chemoradiation for stage III non-small cell lung cancer: randomized 1747

phase III trial RTOG 9410. J Natl Cancer Inst 2011;103:1452-60. 1748

1749

33. Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of 1750

RTOG 9311: a phase I-II dose-escalation study using three-dimensional 1751

conformal radiotherapy in patients with inoperable non-small-cell lung 1752

carcinoma. Int J Radiat Oncol Biol Phys 2005;61:318-28. 1753

1754

34. Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase II 1755

component of a phase I/II dose intensification study using three-1756

dimensional conformal radiation therapy and concurrent chemotherapy 1757

for patients with inoperable non-small-cell lung cancer: RTOG 0117. J 1758

Clin Oncol 2010;28:2475-80. 1759


84

1760

35. Bradley JD, Moughan J, Graham MV, et al. A phase I/II radiation dose 1761

escalation study with concurrent chemotherapy for patients with 1762

inoperable stages I to III non-small-cell lung cancer: phase I results of 1763

RTOG 0117. Int J Radiat Oncol Biol Phys 2010;77:367-72. 1764

1765

36. Schild SE, McGinnis WL, Graham D, et al. Results of a Phase I trial 1766

of concurrent chemotherapy and escalating doses of radiation for 1767

unresectable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 1768

2006;65:1106-11. 1769

1770

37. Stinchcombe TE, Lee CB, Moore DT, et al. Long-term follow-up of a 1771

phase I/II trial of dose escalating three-dimensional conformal thoracic 1772

radiation therapy with induction and concurrent carboplatin and paclitaxel 1773

in unresectable stage IIIA/B non-small cell lung cancer. J Thorac Oncol 1774

2008;3:1279-85. 1775

1776

38. Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase 1777

II trial of induction chemotherapy followed by concurrent chemotherapy 1778

and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III 1779

non-small-cell lung cancer: CALGB 30105. J Clin Oncol 2008;26:2457-63. 1780

1781


85

39. Sekine I, Sumi M, Ito Y, et al. Phase I study of concurrent high-dose 1782

three-dimensional conformal radiotherapy with chemotherapy using 1783

cisplatin and vinorelbine for unresectable stage III non-small-cell lung 1784

cancer. Int J Radiat Oncol Biol Phys 2012;82:953-9. 1785

1786





Oncol 2013;31:abstr 7501. 1791

1792

41. Komaki R, Seiferheld W, Ettinger D, et al. Randomized phase II 1793

chemotherapy and radiotherapy trial for patients with locally advanced 1794

inoperable non-small-cell lung cancer: long-term follow-up of RTOG 92-1795

04. Int J Radiat Oncol Biol Phys 2002;53:548-57. 1796

1797

42. Movsas B, Scott C, Langer C, et al. Randomized trial of amifostine in 1798

locally advanced non-small-cell lung cancer patients receiving 1799

chemotherapy and hyperfractionated radiation: radiation therapy 1800

oncology group trial 98-01. J Clin Oncol 2005;23:2145-54. 1801

1802

43. Lawrence YR, Paulus R, Langer C, et al. The addition of amifostine to 1803

carboplatin and paclitaxel based chemoradiation in locally advanced non-1804


86

small cell lung cancer: long-term follow-up of Radiation Therapy 1805

Oncology Group (RTOG) randomized trial 9801. Lung Cancer 1806

2013;80:298-305. 1807

44. Saunders M, Dische S, Barrett A, et al. Continuous, hyperfractionated, 1808

accelerated radiotherapy (CHART) versus conventional radiotherapy in 1809

non-small cell lung cancer: mature data from the randomised multicentre 1810

trial. CHART Steering committee. Radiother Oncol 1999;52:137-48. 1811

1812

45. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized 1813

phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-1814

accelerated versus conventionally fractionated radiotherapy in non-small 1815

cell lung cancer (NSCLC). Radiother Oncol 2011;100:76-85. 1816

1817

46. Belani CP, Wang W, Johnson DH, et al. Phase III study of the Eastern 1818

Cooperative Oncology Group (ECOG 2597): induction chemotherapy 1819

followed by either standard thoracic radiotherapy or hyperfractionated 1820

accelerated radiotherapy for patients with unresectable stage IIIA and B 1821

non-small-cell lung cancer. J Clin Oncol 2005;23:3760-7. 1822

1823

47. Ball D, Bishop J, Smith J, et al. A randomised phase III study of 1824

accelerated or standard fraction radiotherapy with or without concurrent 1825

carboplatin in inoperable non-small cell lung cancer: final report of an 1826

Australian multi-centre trial. Radiother Oncol 1999;52:129-36. 1827


87

1828

48. Bonner JA, McGinnis WL, Stella PJ, et al. The possible advantage of 1829

hyperfractionated thoracic radiotherapy in the treatment of locally 1830

advanced nonsmall cell lung carcinoma: results of a North Central 1831

Cancer Treatment Group Phase III Study. Cancer 1998;82:1037-48. 1832

1833

49. Schild SE, Stella PJ, Geyer SM, et al. The outcome of combined-1834

modality therapy for stage III non-small-cell lung cancer in the elderly. J 1835

Clin Oncol 2003;21:3201-6. 1836

1837

50. Nyman J, Friesland S, Hallqvist A, et al. How to improve loco-regional 1838

control in stages IIIa-b NSCLC? Results of a three-armed randomized 1839

trial from the Swedish Lung Cancer Study Group. Lung Cancer 1840

2009;65:62-7. 1841

1842

51. Uitterhoeve AL, Belderbos JS, Koolen MG, et al. Toxicity of high-dose 1843

radiotherapy combined with daily cisplatin in non-small cell lung cancer: 1844

results of the EORTC 08912 phase I/II study. European Organization for 1845

Research and Treatment of Cancer. Eur J Cancer 2000;36:592-600. 1846

1847

52. Belderbos J, Uitterhoeve L, van Zandwijk N, et al. Randomised trial of 1848

sequential versus concurrent chemo-radiotherapy in patients with 1849


88

inoperable non-small cell lung cancer (EORTC 08972-22973). Eur J 1850

Cancer 2007;43:114-21. 1851

1852

53. Maguire J, O'Rourke N, McNememin R, et al. SOCCAR: Internationally 1853

resonant results from a randomizsed trial based on UK clinical practise. 1854

Thorax 2012;67:abstr A47. 1855

1856

54. Cho KH, Ahn SJ, Pyo HR, et al. A Phase II study of synchronous three-1857

dimensional conformal boost to the gross tumor volume for patients with 1858

unresectable stage III non-small-cell lung cancer: results of Korean 1859

Radiation Oncology Group 0301 study. Int J Radiat Oncol Biol Phys 1860

2009;74:1397-404. 1861

1862

55. Zhu ZF, Fan M, Wu KL, et al. A phase II trial of accelerated 1863

hypofractionated three-dimensional conformal radiation therapy in locally 1864

advanced non-small cell lung cancer. Radiother Oncol 2011;98:304-8. 1865

1866

56. Wu KL, Jiang GL, Liao Y, et al. Three-dimensional conformal radiation 1867

therapy for non-small-cell lung cancer: a phase I/II dose escalation 1868

clinical trial. Int J Radiat Oncol Biol Phys 2003;57:1336-44. 1869

1870

57. Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the 1871

patterns of failure in patients with unresectable non-oat cell carcinoma of 1872


89

the lung treated with definitive radiotherapy. Report by the Radiation 1873

Therapy Oncology Group. Cancer 1987;59:1874-1881. 1874

1875

58. Petrovich Z, Stanley K, Cox JD, et al. Radiotherapy in the management 1876

of locally advanced lung cancer of all cell types: Final report of 1877

randomized trial. Cancer 1981;48:1335-1340. 1878

1879

59. Roswit B, Patno ME, Rapp R, et al. The survival of patients with 1880

inoperable lung cancer: A large-scale randomized study of radiation 1881

therapy versus placebo. Radiology 1968;90:688-697. 1882

1883

60. Payne DG. Non-small-cell lung cancer: Should unresectable stage III 1884

patients routinely receive high-dose radiation therapy? J Clin Oncol 1885

1988;6:552-558. 1886

1887

61. Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III 1888

non-small-cell lung cancer: seven-year follow-up of cancer and leukemia 1889

group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210-5. 1890

1891

62. Sause W, Kolesar P, Taylor S, et al. Final results of phase III trial in 1892

regionally advanced unresectable non-small cell lung cancer - Radiation 1893

Therapy Oncology Group, Eastern Cooperative Oncology Group, and 1894

Southwest Oncology Group. Chest 2000;117:358-64. 1895


90

1896

63. Chemotherapy for non-small cell lung cancer. Non-small Cell Lung 1897

Cancer Collaborative Group. Cochrane Database Syst Rev 1898

2000:CD002139. 1899

1900

64. Okawara G, Mackay JA, Evans WK, et al. Management of unresected 1901

stage III non-small cell lung cancer: a systematic review. J Thor Oncol 1902

2006;1:377-93. 1903

1904

65. Curran WJ, Jr., Paulus R, Langer CJ, et al. Sequential vs Concurrent 1905

Chemoradiation for stage III Non-Small Cell Lung Cancer: Randomized 1906

Phase III Trial RTOG 9410. J Natl Cancer Inst 2011;103:1452-60. 1907

1908

66. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent 1909

versus sequential thoracic radiotherapy in combination with mitomycin, 1910

vindesine, and cisplatin in unresectable stage III non-small-cell lung 1911

cancer. J Clin Oncol 1999;17:2692-9. 1912

1913

67. Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III Study of Cisplatin, 1914

Etoposide, and Concurrent Chest Radiation With or Without 1915

Consolidation Docetaxel in Patients With Inoperable stage III Non-Small-1916

Cell Lung Cancer: The Hoosier Oncology Group and US Oncology. J 1917

Clin Oncol 2008;26:5755-60. 1918


91

1919

68. Vokes EE, Herndon JE, II, Kelley MJ, et al. Induction chemotherapy 1920

followed by chemoradiotherapy compared with chemoradiotherapy alone 1921

for regionally advanced unresectable stage III non-small-cell lung cancer: 1922

Cancer and Leukemia Group B. J Clin Oncol 2007;25:1698-704. 1923

1924

69. Yamamoto N, Nakagawa K, Nishimura Y, et al. Phase III study 1925

comparing second- and third-generation regimens with concurrent 1926

thoracic radiotherapy in patients with unresectable stage III non-small-1927

cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J 1928

Clin Oncol 2010;28:3739-45. 1929

1930

70. Wang L, Wu S, Ou G, et al. Randomized phase II study of concurrent 1931

cisplatin/etoposide or paclitaxel/carboplatin and thoracic radiotherapy in 1932

patients with stage III non-small cell lung cancer. Lung Cancer 1933

2012;77:89-96. 1934

1935

71. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed 1936

plus best supportive care versus placebo plus best supportive care for 1937

non-small-cell lung cancer: a randomised, double-blind, phase 3 study. 1938

Lancet 2009;374:1432-40. 1939

1940


92

72. Scagliotti G, Hanna N, Fossella F, et al. The Differential Efficacy of 1941

Pemetrexed According to NSCLC Histology: A Review of Two Phase III 1942

Studies. Oncologist 2009;14:253-63. 1943

1944

73. Salama JK, Vokes EE. New radiotherapy and chemoradiotherapy 1945

approaches for non-small-cell lung cancer. J Clin Oncol 2013;31:1029-1946

38. 1947

1948

74. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy 1949

regimens of paclitaxel and carboplatin for locally advanced non-small-cell 1950

lung cancer: A randomized phase II locally advanced multi-modality 1951

protocol. J Clin Oncol 2005;23:5883-91. 1952

75. Ettinger DS, Akerley W, Borghaei H, et al. National Comprehensive 1953

Cancer Network. Non-small cell lung cancer, version 2.2013. J Natl 1954

Compr Canc Netw 2013; 11(6): 645-53. 1955

76. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after 1956

concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: 1957

phase II Southwest Oncology Group Study S9504. J Clin Oncol 1958

2003;21:2004-10. 1959

1960

77. Huber RM, Engel-Riedel W, Kollmeier J, et al. GILT phase III study: 1961

Concomitant radiotherapy (RT) with Oral Vinorelbine (NVBo) plus 1962


93

Cisplatin (P) followed by consolidation (C) with NVBo+P plus BSC or 1963

BSC alone in stage (st) III NSCLC. Onkologie 2012;35:167-8. 1964

1965

78. Colin P, Jovenin N, Ganem G, et al. Effect of paclitaxel-carboplatin (PC) 1966

consolidation chemotherapy after weekly PC concurrent chemo-1967

radiotherapy (CCR) for patients with locally advanced non-small cell lung 1968

cancer (LA NSCLC): 3-year definitive results of the B001-phase III 1969

GERCOR-study. J Clin Oncol 2006;24:7112. 1970

1971





Oncol 2013;31:abstr 7501. 1976

1977

80. Thorax. In: AJCC cancer staging handbook. Eds. Edge SB et al. 7th 1978

edition, Springer. 2010. Pp. 297-330. 1979

1980

81. Ramnath N, Dilling TJ, Harris LJ, et al. Treatment of stage III non-small 1981

cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: 1982

American College of Chest Physicians evidence-based clinical practice 1983

guidelines. Chest 2013;143:e314S-40S12. 1984

1985


94

82. Arriagada R, Auperin A, Burdett S, et al. Adjuvant chemotherapy, with or 1986

without postoperative radiotherapy, in operable non-small-cell lung 1987

cancer: two meta-analyses of individual patient data. Lancet 1988

2010;375:1267-1277. 1989

1990

83. Butts CA, Ding K, Seymour L, et al. Randomized phase III trial of 1991

vinorelbine plus cisplatin compared with observation in completely 1992

resected stage IB and II non-small-cell lung cancer: updated survival 1993

analysis of JBR-10. J Clin Oncol 2010;28:29-34. 1994

1995

84. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus 1996

cisplatin versus observation in patients with completely resected stage 1997

IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International 1998

Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 1999

2006;7:719-727. 2000

2001

85. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant 2002

chemotherapy in patients with completely resected non-small-cell lung 2003

cancer. N Engl J Med 2004;350:351-360. 2004

2005

86. Le Chevalier T, Dunant A, Arriagada R, et al. Long-term results of the 2006

International Adjuvant Lung Cancer Trial (IALT) evaluating adjuvant 2007


95

cisplatin-based chemotherapy in resected non-small cell lung cancer 2008

(NSCLC). J Clin Oncol 2008;26:abstr 7507. 2009

2010

87. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin 2011

evaluation: a pooled analysis by the LACE Collaborative Group. J Clin 2012

Oncol 2008;26:3552-3559. 2013

2014

88. Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant 2015

chemotherapy for completely resected stage I, II, or IIIA non-small-cell 2016

Lung cancer. J Natl Cancer Inst 2003;95:1453-1461. 2017

2018

89. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. 2019

observation in resected non-small-cell lung cancer. N Engl J Med 2005; 2020

352:2589-2597. 2021

2022

90. Park JH. Postoperative adjuvant therapy for stage IIIA non-small cell lung 2023

cancer. J Thorac Oncol 2007;2:S651. 2024

2025

91. Feng QF, Wang M, Wang LJ, et al. A study of postoperative radiotherapy 2026

in patients with non-small-cell lung cancer: a randomized trial. Int J 2027

Radiat Oncol Biol Phys 2000;47:925-929. 2028

2029


96

92. Dautzenberg B, Arriagada R, Chammard AB, et al. A controlled study of 2030

postoperative radiotherapy for patients with completely resected 2031

nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des 2032

Cancers Bronchiques. Cancer 1999;86:265-273. 2033

2034

93. Mayer R, Smolle-Juettner FM, Szolar D, et al. Postoperative radiotherapy 2035

in radically resected non-small cell lung cancer. Chest 1997;112:954-2036

959. 2037

2038

94. Stephens RJ, Girling DJ, Bleehen NM, et al. The role of post-operative 2039

radiotherapy in non-small-cell lung cancer: a multicentre randomised trial 2040

in patients with pathologically staged T1-2, N1-2, M0 disease. Medical 2041

Research Council Lung Cancer Working Party. Br J Cancer 2042

1996;74:632-639. 2043

2044

95. Debevec M, Bitenc M, Vidmar S, et al. Postoperative radiotherapy for 2045

radically resected N2 non-small-cell lung cancer (NSCLC): randomised 2046

clinical study 1988-1992. Lung Cancer 1996;14:99-107. 2047

2048

96. The Lung Cancer Study Group. Effects of postoperative mediastinal 2049

radiation on completely resected stage II and stage III epidermoid cancer 2050

of the lung. The Lung Cancer Study Group. N Engl J Med 2051

1986;315:1377-1381. 2052


97

2053

97. Van Houtte P, Rocmans P, Smets P, et al. Postoperative radiation 2054

therapy in lung caner: a controlled trial after resection of curative design. 2055

Int J Radiat Oncol Biol Phys 1980;6:983-986. 2056

2057

98. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-2058

small-cell lung cancer: systematic review and Meta-analysis of individual 2059

patient data from nine randomised controlled trials. Lancet 2060

1998;352:257–63. 2061

2062

99. Burdett S, Stewart L, on behalf of the PORT Meta-analysis Trialist 2063

Group. Postoperative radiotherapy in non-small cell lung cancer: update 2064

of an individual patient data metaanalysis. Lung Cancer 2005;47:81–83. 2065

2066

100. Postoperative radiotherapy for non-small cell lung cancer. PORT Meta-2067

analysis Trialists Group. Editorial Group: Cochrane Lung Cancer Group 2068

Published Online: 20 JAN 2010. Accessed August 20, 2013; http://0-2069

onlinelibrary.wiley.com.library.ccf.org/doi/10.1002/14651858.CD002142.2070

pub2/abstract 2071

2072

101. Walasek T, Kowalska T, Reinfuss M, et al. The effectiveness of 2073

postoperative external beam radiotherapy for incompletely resected non-2074

small cell lung cancer. Pneumonol Alergol Pol 2003;71:488-495. 2075


98

2076

102. Perry MC, Kohman LJ, Bonner JA, et al. A phase III study of surgical 2077

resection and paclitaxel/carboplatin chemotherapy with or without 2078

adjuvant radiation therapy for resected stage III non-small-cell lung 2079

cancer: Cancer and Leukemia Group B 9734. Clin Lung Cancer 2080

2007;8:268-272. 2081

2082

103. Saynak M, Higginson DS, Morris DE et al. Current Status of 2083

Postoperative Radiation for Non–Small-Cell Lung Cancer. Semin Radiat 2084

Oncol 20:192-200. 2085

2086

104. Le Pechoux C. Role of Postoperative Radiotherapy in Resected Non-2087

Small Cell Lung Cancer: A Reassessment Based on New Data. 2088

Oncologist 2011;16:672–681. 2089

2090

105. http://groups.eortc.be/radio/2205508053.htm, accessed August 20, 2013. 2091

2092

106. Billiet C, Decaluwé H, Peeters S, et al. Modern post-operative 2093

radiotherapy for stage III non-small cell lung cancer may improve local 2094

control and survival: A meta-analysis. Radiother Oncol 2013 Oct 4. 2095

doi:pii: S0167-8140(13)00396-4.10.1016/j.radonc.2013.08.011. 2096

2097


99

107. Decker RH, Wilson LD. Postoperative radiation therapy for non-small cell 2098

lung cancer. Semin Thorac Cardiovasc Surg 2008;20:184-7. 2099

2100

108. Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with 2101

resected N2 non-small-cell lung cancer: evidence for a subclassification 2102

and implications. J Clin Oncol 2000;18:2981-9. 2103

2104

109. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus 2105

chemotherapy with or without surgical resection for stage III non-small-2106

cell lung cancer: a phase III randomised controlled trial. Lancet 2107

2009;374:379-86. 2108

2109

110. Suntharalingam M, Paulus R, Edelman MJ, et al. Radiation therapy 2110

oncology group protocol 02-29: a phase II trial of neoadjuvant therapy 2111

with concurrent chemotherapy and full-dose radiation therapy followed by 2112

surgical resection and consolidative therapy for locally advanced non-2113

small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 2012; 2114

84:456-63. 2115

2116

111. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study2117

=0839. Accessed August 29, 2013. 2118

2119


100

112. Thomas M, Rübe C, HoffkneChT P, et al. German Lung Cancer 2120

Cooperative Group. Effect of preoperative chemoradiation in addition to 2121

preoperative chemotherapy: a randomised trial in stage III non-small-cell 2122

lung cancer. Lancet Oncol 2008; 9:636-48 2123

2124

113. Friedel G, Budach W, Dippon J, et al. Phase II trial of a trimodality 2125

regimen for stage III non-small cell lung cancer using chemotherapy as 2126

induction treatment with concurrent hyperfractionated chemoradiation 2127

with carboplatin and paclitaxel followed by subsequent resection: A 2128

single center study. J Clin Oncol 2010;28:942-948. 2129

2130

114. Betticher DC, Hsu Schmitz H, Totsch M et al. Mediastinal Lymph Node 2131

Clearance After Docetaxel-Cisplatin Neoadjuvant Chemotherapy Is 2132

Prognostic of Survival in Patients With stage IIIA pN2 Non-Small-Cell 2133

Lung Cancer: A Multicenter Phase II Trial. J Clin Oncol 2003;21:1752-2134

1759. 2135

2136

115. Bradley R, Paulus K, Komaki R, et al. A randomized phase III 2137




Oncol 2013;31:abstr 7501. 2141

2142


101

116. Stamatis G, Djuric D, Eberhardt W, et al. Postoperative morbidity and 2143

mortality after induction chemoradiotherapy for locally advanced lung 2144

cancer: an analysis of 350 operated patients. Europ J Cardiothor 2145

Surgery 2002;22:292-297. 2146

2147

117. Steger V, Spengler W, Hetzel J, et al. Pneumonectomy: calculable or 2148

non-tolerable risk factor in trimodal therapy for stage III non-small cell 2149

lung cancer? Europ J Cardiothor Surgery 2011;41:880-885. 2150

2151

118. Weder W, Collaud S, Eberhardt W, et al. Pneumonectomy is a valuable 2152

treatment option after neoadjuvant therapy for stage III non-small cell 2153

lung cancer. J Thoracic Cardiovascul Surgery 2010;139:1424-30. 2154

2155

119. Pisters KM, Vallières E, Crowley JJ, et al. Surgery with or without 2156

preoperative paclitaxel and carboplatin in early-stage non-small-cell lung 2157

cancer: Southwest Oncology Group Trial S9900, an intergroup, 2158

randomized, phase III trial. J Clin Oncol 2010;28:1843-9 2159

2160

120. Evans NR III, Li S, Wright CD, et al. The impact of induction therapy on 2161

on morbidity and operative mortality after resection of primary lung 2162

cancer. Gener Thoracic Surgery 2010;139:991-6. 2163

2164


102

121. Birkmeyer JD, Stukel TA, Siewers AE, et al. Surgeon volume and 2165

operative mortality in the United States. N Engl J Med 2003;27:2117-27. 2166

122. Sonett JR, Suntharalingam M, Edelman M, et al. Pulmonary resection 2167

after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy 2168

in non-small cell lung cancer. Ann Thoracic Surg 2004;78:1200-1205. 2169

2170

123. Daly BDT, Fernando H, Ketchedjian A, et al. Pneumonectomy after high-2171

dose radiation and concurrent chemotherapy for nonsmall cell lung 2172

cancer. Ann Thorac Surg 2006;82:227-3. 2173

2174

124. Cerfolio RJ, Bryant AS, Jones VL, et al. Pulmonary resection after 2175

concurrent chemotherapy and high dose (60 Gy) radiation for non-small 2176

cell lung cancer is safe and may provide increased survival. Europ J 2177

Cardiothor Surgery 2009;35:718-723. 2178

2179

125. Louie BE, Kapur S, Farivar AS, et al. Safety and utility of 2180

mediastinoscopy in non-small cell lung cancer in a complex 2181

mediastinum. Ann Thorac Surg 2011;92:278-283. 2182

2183

126. Pass HI, Pogrebniak HW, Steinberg SM, et al. Randomized trial of 2184

neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 2185

1992;53:992-8. 2186

2187


103

127. O’Brien ME, Splinter T, Smit EF, et al. Carboplatin and paclitaxel as an 2188

induction regimen for patients with biopsy-proven stage IIIA N2 non-small 2189

cell lung cancer. An EORTC phase II study (EORTC 08958). Eur J 2190

Cancer 2003;39:1416-22. 2191

2192

128. VanZandwijk N, Smit EF, Kramer GWP, et al. Gemcitabine and cisplatin 2193

as induction regimen for patients with biopsy-proven stage IIIA N2 non-2194

small cell lung cancer: A phase II study of the European Organization for 2195

Research and Treatment of Cancer Lung Cancer Cooperative Group. J 2196

Clin Oncol 2000;18:2658-2664. 2197

2198

129. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent Cisplatin/Etoposide 2199

Plus Chest Radiotherapy Followed by Surgery for Stages IIIA (N2) and 2200

IIIB Non-Small-Cell Lung Cancer: Mature Results of Southwest Oncology 2201

Group Phase II Study 8805. J Clin Oncol 1995;13:1880-1892. 2202

2203

130. Choi NC, Carey RW, Daly W, et al. Potential impact on survival of 2204

improved tumor downstaging and resection rate by preoperative twice 2205

daily radiation and concurrent chemotherapy in Stage IIIA non-small cell 2206

lung cancer. J Clin Oncol 1997;15:712-7222. 2207

2208

131. Eberhardt W, Wilke H, Stamatis G, et al. Preoperative chemotherapy 2209

followed by concurrent chemoradiation therapy based on 2210


104

hyperfractionated accelerated radiotherapy and definitive surgery in 2211

locally advanced non-small-cell lung cancer: Mature results of a phase II 2212

trial. J Clin Oncol 1998;16:622-634 2213

2214

132. Fleck J, Carmargo J, Godoy D, et al. Chemoradiotherapy alone versus 2215

chemotherapy alone as a neoadjuvant treatment for stage II non-small 2216

cell lung cancer: Preliminary report of a phase III randomized trial. Proc 2217

Am Soc Clin Oncol 1993:abstr 1108. 2218

2219

133. Sauvaget J, Rebischung J, Vannetzel J. Phase III study of neo-adjuvant 2220

MVP versus MVP plus chemoradiotherapy in stage III NSCLC. Proc Am 2221

Soc Clin Oncol 2000;19:abstr 1935. 2222

2223

134. Pless M, Stupp R, Ris H-B, et al. Neoadjuvant chemotherapy with or 2224

without preoperative irradiation in stage IIIA/N2 non-small cell lung 2225

cancer: A randomized phase III trial by the Swiss Group for Clinical 2226

Cancer Research (SAKK trial 16/00). J Clin Onc 2013;31:abstr 7503. 2227


105

Figure 1.2228

2229


106

2230

Table 1. Patient, Interventions, Comparators, and Outcomes (PICO) Formatted Guideline Questions

Question Participants Interventions Comparators Outcomes

Question 1 What is the ideal external-beam dose-

fractionation for the curative-intent treatment of

locally-advanced non-small cell lung cancer

with radiation therapy alone?

Patients with curative-

intent non-resectable

locally-advanced non-

small cell lung cancer

treated with radiation

alone

Higher biological

equivalent dose

radical external-

beam schedule(s)

Lower biological

equivalent dose

external-beam

schedule(s)

Overall survival and

local control.

Regional and distant

failure rates.

Treatment toxicity

(pneumonitis,

esophagitis),

Compliance rates

(proportion of patients

completing prescribed

radiation therapy),

Hospitalization rates,

HRQoL (general,

pulmonary, and

gastrointestinal).

Question 2 What is the ideal external-beam dose

fractionation for the curative-intent

treatment of locally-advanced non-small cell

lung cancer with chemoradiotherapy?





treated with

chemoradiotherapy

Higher biological

equivalent dose

radical external-

beam schedule(s)

Lower biological

equivalent dose

external-beam

schedule(s)

Question 3 What is the ideal timing of external-beam

radiation therapy in relation to systemic

chemotherapy for the curative-intent treatment

of locally-advanced non-small cell lung cancer?





treated with

chemoradiotherapy

Immediate

concurrent

chemoradiotherapy

Sequential

chemotherapy followed

by radiation therapy (or

chemoradiotherapy


107

Question 4 What are the indications for adjuvant post-

operative radiotherapy for the curative-intent


lung cancer?


intent post-resection



Adjuvant

radiotherapy (with

or without

chemotherapy)

No adjuvant

radiotherapy

Overall survival and

local control.


failure rates.

Treatment toxicity

(pneumonitis,

esophagitis).

Question 5 When is neoadjuvant radiotherapy prior to

surgery indicated for the curative-intent


lung cancer?


intent potentially

resectable or resectable

locally-advanced

non-small cell lung cancer

Neo-adjuvant

radiotherapy (with

or without

chemotherapy)

No radiotherapy Overall survival and

surgical resectability.


failure rates.

Treatment toxicity

(pneumonitis,

esophagitis).


108

Table 2. Grading of Evidence, Recommendations and Consensus Methodology

Guideline Recommendation

Strength

of

Evidence

Strength of

Recommendation

Percent (%)

Agreement

KQ1. What is the ideal external-beam dose-fractionation for the curative-intent treatment of locally-advanced non-small cell lung cancer with radiation therapy

alone?

Statement A. Radiotherapy alone has been shown to be superior to observation strategies or chemotherapy

alone for LA NSCLC in terms of overall survival but at the cost of treatment-related side effects such as

esophagitis and pneumonitis.

MQE Strong 86%

Statement B. Radiotherapy alone may be used as definitive radical treatment for patients with LA NSCLC

who are ineligible for combined modality therapy (i.e. due to poor performance status, medical comorbidity,

extensive weight loss, and/or patient preferences) but with a tradeoff of survival for improved treatment

tolerability.

HQE Strong 100%

Statement C. In the context of conventionally fractionated (1.80-2.15 Gy) radiotherapy, a minimum dose of

60 Gy is recommended to optimize important clinical outcomes such as local control. HQE Strong 100%

Statement D. Altered fractionation schedules that have been explored in the medical literature include

hyperfractionation (lower dose per fraction over the standard treatment duration), accelerated fractionation

(conventional fraction size and same total dose, given in a shorter period of time), accelerated

hyperfractionation (combination of these two), and hypofractionation (higher dose per fraction and fewer

fractions).

n/a Strong 100%

Statement E. Specific altered fractionation schemes that have been investigated in various comparative

effectiveness research investigations (including randomized controlled trials) include 45 Gy/15 fractions

(hypofractionation), 69.6 Gy/58 fractions BID (hyperfractionation), 54 Gy/36 fractions TID over 12

consecutive days (CHART, accelerated hyperfractionation), and 60 Gy/25 fractions BID (CHARTWEL,

accelerated hyperfractionation).

n/a Strong 100%

KQ2. What is the ideal external-beam dose fractionation for the curative-intent treatment of locally-advanced non-small cell lung cancer with chemoradiotherapy?

Statement A. The standard thoracic radiotherapy dose-fractionation for patients treated with concurrent

chemotherapy, recently validated in a phase III RTOG trial (RTOG 0617), is 60 Gy given in 2 Gy once daily

fractions over 6 weeks.

HQE Strong 93%

Statement B. Dose escalation beyond 60 Gy with conventional fractionation has not been proven to be

associated with any clinical benefits including overall survival (HQE). HQE Strong 86%


109

Statement C. Hyperfractionated radiotherapy regimens that do not result in acceleration of the treatment

course, even though the total nominal radiotherapy dose may be modestly increased, do not appear to

improve outcomes compared with conventionally fractionated therapy.

MQE Strong 93%

Statement D. The optimal thoracic radiotherapy regimen for patients receiving sequential chemotherapy and

radiotherapy is not known; however results from the CHARTWEL and HART phase III studies suggest, but

do not prove, that increasing the biologic equivalent dose by using accelerated hyperfractionated

radiotherapy may be of benefit following induction chemotherapy in locally advanced non-small cell lung

cancer.

MQE Strong 86%

Statement E. Although the impact of increasing the predicted biologic equivalent dose via accelerated

radiotherapy regimens is not clear, further study of accelerated hypofractionated regimens is of interest to

optimize the therapeutic ratio of treatment, particularly in the context of advanced imaging, radiotherapy

planning, and treatment delivery.

n/a Strong 100%

KQ3. What is the ideal timing of external-beam radiation therapy in relation to systemic chemotherapy for the curative-intent treatment of locally-advanced non-

small cell lung cancer?

Statement A. There is phase III evidence demonstrating improved overall survival, local control, and

response rate associated with concurrent chemoradiation when compared against sequential chemotherapy

followed by radiation.

HQE Strong 100%

Statement B. There is no proven role for the routine use of induction chemotherapy prior to

chemoradiotherapy; although, this treatment paradigm can be considered for the management of bulky

tumors to allow for radical planning after chemotherapy response.

MQE Strong 93%

Statement C. There are no phase III data specifically supporting the role for consolidation chemotherapy

after chemoradiotherapy for the improvement of overall survival; however, this treatment is still routinely

given to manage potential micrometastatic disease particularly if full systemic chemotherapy doses were not

delivered during radiotherapy.

MQE Strong 93%

Statement D. For patients that cannot tolerate concurrent chemoradiotherapy, sequential chemotherapy

followed by radical radiation has been shown to be associated with an overall survival benefit when

compared to radiotherapy alone.

HQE Strong 86%

Statement E. The ideal concurrent chemotherapy regimen has not been determined; however, the two most

common regimens (cisplatin/etoposide and carboplatin/paclitaxel) are the subject of a completed phase III

clinical trial (NCT01494558).

n/a Strong 100%

KQ4. What are the indications for adjuvant post-operative radiotherapy for the curative-intent treatment of locally-advanced non-small cell lung cancer?


110

Statement A. Phase III studies and meta-analyses of postoperative radiotherapy (PORT) in completed

resected (R0) LA NSCLC with N2 disease suggest that its addition to surgery does not improve overall

survival but may improve local control when compared to observation strategies.

MQE Strong 93%

Statement B. Phase III studies and meta-analyses of PORT in completely resected (R0) LA NSCLC withN0-

1 disease demonstrate inferior survival when compared to observation strategies. MQE Strong 100%

Statement C. Since level 1 evidence supports the administration of adjuvant chemotherapy for completely

resected (R0) LA NSCLC based on improvements in overall survival compared to patients on observation,

any PORT therapy should be delivered sequentially after chemotherapy in order not to interfere with

standard of care chemotherapy.

LQE Strong 93%

Statement D. For patients receiving adjuvant PORT for R0 disease, conventionally fractionated doses in the

range of 50 Gy to 54 Gy (in 1.8-2.0 Gy/day) should be utilized. LQE Strong 100%

Statement E. Patients with microscopic residual (R1) primary disease (i.e., positive margin) and/or

microscopic (i.e., extra-capsular extension) nodal disease may be appropriate candidates for PORT (ideally

given concurrently with chemotherapy) with conventionally fractionated doses in the range of 54 Gy to 60

Gy (in 1.8-2.0 Gy/day fraction size) in order to improve local control (LQE).

LQE Strong 93%

Statement F. Patients with high-risk features after resection (gross residual primary and/or macroscopic (R2)

nodal disease) of LA NSCLC may be appropriate candidates for PORT (ideally given concurrently with

chemotherapy) with conventionally fractionated doses of at least 60 Gy (in 1.8-2.0 Gy/day fraction size) in

order to improve local control (LQE).

LQE Strong 93%

KQ5. When is neoadjuvant radiotherapy prior to surgery indicated for the curative-intent treatment of locally-advanced non-small cell lung cancer?

Statement A. There is no level I evidence recommending the use of induction radiotherapy (or

chemoradiotherapy) followed by surgery for patients with resectable stage III NSCLC. HQE Strong 93%

Statement B. In those patients who are selected for trimodality approach, preoperatively planned lobectomy

(as opposed to pneumonectomy), based on best surgical judgment, is preferable, since it was associated with

survival benefit in the exploratory post-hoc INT 0139 analysis.

MQE Strong 93%

Statement C. No definitive statement can be made about best patient selection criteria for the trimodality

therapy, although no weight loss, female gender, and one (vs. more) involved nodal stations were associated

with improved outcome in INT 0139.

MQE Strong 93%

Statement D. The ideal preoperative radiotherapy dose is currently not known; however, a minimum of 45

Gy should be delivered consistent with the INT 0139 trial. LQE Strong 93%

Statement E. Preoperative conventionally fractionated doses of 60 Gy or greater were associated with higher

mediastinal clearance rates, although no significant correlation with improved survival has been

demonstrated.

LQE Strong 86%

2231


111

TABLE 3. Selected studies evaluating dose-escalation in the context of conventionally fractionated RT in patients with locally advanced NSCLC

Title, Author, Journal Eligibility Intervention Outcomes Conclusion

Impact of tumor control

on survival in carcinoma

of the lung treated with

irradiation.

Perez CA, et al. Int J

Radiat Oncol Biol Phys

1986 Apr;12(4): 539-47.

No age restriction, stage I -III

NSCLC, medically inoperable

or unresectable NSCLC

RTOG 73-01 Intervention:

1) 40 Gy split course

2) 40,50 or 60 Gy in 2 Gy#,

standardly fractioned

RTOG 73-01 Intervention:

30 Gy in 10 fractions over 2

weeks, 40 Gy in 4 weeks

continuous course, or 40 Gy in

a split course similar to the

one described above.

Response rate: A higher complete response

rate (24%) intrathoracic tumor

control (67%), and three year

survival (15%) was observed

with 60 Gy compared with the

lower doses. Patients treated

with 60 Gy had an overall

intrathoracic failure rate of

33% at 3 years, compared to

42% (50 Gy) and 44% (40 Gy

split course) and 52% (40 Gy

continuous) (p = 0.02).

Increased survival was noted

in patients with a complete

tumor response. Even in a

disease with a high

propensity for distant

metastasis, intrathoracic

tumor control can be directly

correlated with improved

survival.

Toxicity and outcome

results of RTOG 9311: a

phase I-II dose-escalation

study using three-

dimensional conformal

radiotherapy in patients

with inoperable non-

small-cell lung carcinoma.

Bradley J et al. Int J

Radiat Oncol Biol Phys.

2005 Feb 1;61(2):318-28.

Inclusion criteria:

histologically proven NSCLC,

gross tumor can be

encompassed by RT field, age

≥ 18 years, KPS ≥70%.

Chemotherapy allowed if

delivered within 4 months of

RT.

Exclusion criteria:

supraclavicular nodal

metastasis, concurrent

chemotherapy with RT, prior

RT or complete tumor

resection, recurrent disease, or

eligible for definitive surgery.

Intervention

179 Patients stratified by lung

V20 Gy. 25 patients received

neoadjuvant chemotherapy.

Group 1: V20 <25%: 70.9 Gy

/ 33#, 77.4 Gy / 36 #, 83.8 Gy

/ 39 #, and 90.3 Gy / 42 #.

Group 2: V20 of 25–36%:

70.9 Gy and 77.4 Gy.

Group 3: V20 >37%: Closed,

poor accrual due to perception

of increased risk for

pneumonitis.

Toxicity:

Acute: grade ≥3 in 7 pts in

group 1 and 2 in group 2.

Pneumonitis in 3 pts in group 1

and 2 in group 2. No grade 3

esophagitis.

Late: Grade ≥3 lung toxicity in

12 pts in group 1 and 7 in

group 2 (one death). Grade ≥3

esophageal toxicity in 5 pts in

group 1 and 1 in group 2 (one

death).

2-year survival:

Group 1: 46% (70.9 Gy), 50%

(77.4 Gy), 42% (83.8 Gy), 48%

(90.3 Gy)

Group 2: 20% (70.9 Gy), 42%

(77.4 Gy)

The radiation dose was safely

escalated using three-

dimensional conformal

techniques to 83.8 Gy for

patients with V20 values of

<25% (Group 1) and to 77.4

Gy for patients with V20

values between 25% and 36%

(Group 2), using fraction

sizes of 2.15 Gy. The 90.3-

Gy-dose level was too toxic,

resulting in dose-related

deaths in 2 patients. Elective

nodal failure occurred in

<10% of patients.


112

High-dose radiation

improved local tumor

control and overall

survival in patients with

inoperable/unresectable

non-small-cell lung

cancer: long-term results

of a radiation dose

escalation study.

Kong FM, et al. Int J

Radiat Oncol Biol Phys.

2005 Oct 1;63(2):324-33.

Inclusion criteria:

histologically confirmed stage

I-III NSCLC, no prior

thoracic radiation, PS 0–2,

prior malignancy. Patients

with locoregional recurrences

after surgery for stage I or II

eligible.

Exclusion criteria: biopsy-

proven supraclavicular

disease, malignant pleural

/pericardial effusion,

involvement of the parietal

pleura, small-cell histology.

Intervention:

106 patients with radiation

doses ranged from 63–103 Gy

based on Veff bins and the

timing of enrollment. 19% of

patients received neoadjuvant

chemo.

2- and 5-year overall

survival: 37% and 13%,

median 19 months. 85% of

deaths due to lung cancer, 9%

other diseases, 3% second

primary tumor, 3% massive

hemoptysis.

Recurrence: 89 patients, 21%

local only, 27% distant only,

46% both, 6% regional and

local-distant.

The 5-year control rate was

12%, 35%, and 49% for 63–69,

74–84, and 92–103 Gy,

respectively.

Conclusion: Higher dose

radiation is associated with

improved outcomes in

patients with NSCLC treated

in the

range of 63–103 Gy.

# = fractions; PS = performance status; RT = radiotherapy; NSCLC = non-small cell lung cancer; pts = patients; Gy = Gray; Veff = effective volume; V20 =

volume receiving 20 Gy or greater; RTOG = Radiation Therapy Oncology Group


113

# = fractions; RT = radiotherapy; NSCLC = non-small cell lung cancer; pts = patients; Gy = Gray; n = number

TABLE 4. Selected studies evaluating hypofractionated RT in patients with locally advanced NSCLC


Hypofractionated radiation

therapy in unresectable stage

III non-small cell lung cancer.

Slotman BJ, et al. Cancer.

1993 Sep 15;72(6):1885-93.

Inclusion criteria:

Stage III biopsy proven

NSCLC

Exclusion criteria:

n = 4 did not complete

treatment due to poor general

condition, n =1 excluded as

found to have synchronous

metastatic colon cancer.

Intervention:

Retrospective analysis of 3

groups:

A) 40-Gy split course

B) 30-32 Gy in 6 fractions

C) 24 Gy in 3 fractions

Stage IIIA - 40-Gy split

course had longer survival (P

< 0.005) and a lower local

relapse rate (p < 0.01), but a

higher distant failure rate (p <

0.01) than those receiving 24-

32 Gy.

1- and 5-year Survival:

Stage IIIA treated with 40 Gy

was 47% and 7%.

Stage IIIB - 30% and 2%.

Toxicity: No severe complications

Stage IIIA: survival in is

similar for 40 Gy split-course

and standardly fractionated

RT.

Stage IIIB: 24 Gy in 3

weekly fractions yields

comparable survival to higher

total doses given in more

fractions.

Accelerated hypofractionated

radiation therapy compared to

conventionally fractionated

radiation therapy for the

treatment of inoperable non-

small cell.

Amini A, et al. Radiat Oncol.

2012 Mar 15;7:33.

Inclusion criteria:

Stage III NSCLC between

1993 and 2009

Exclusion criteria:

Patients with small cell lung

cancer, thymic tumors and

carcinoid.

Intervention:

Group 1, Accelerated RT: 45

Gy in 15 # over 3 weeks

Group 2, Standard RT: 60-63

Gy, 1.8- 2 Gy #

Group 3, Standard RT2: >

63 Gy, 1.8-2 Gy #

Survival/recurrence: No local/distant control or

overall survival differences

between the RT groups.

Toxicity: Acute toxicity in Group 1 was

significantly less for Gr ≥ 2

dermatitis (p = 0.002), nausea

and vomiting (p =0.022), and

weight loss (p = 0.020).

Despite the limitations of a

retrospective analysis 45 Gy

in 15 fractions appears to be

an acceptable treatment

option for poor performance

status patients with stage III

inoperable tumors.


114

TABLE 5. Selected studies evaluating hyperfractionated +/- accelerated RT in patients with locally advanced NSCLC


A randomized phase I/II trial

of hyperfractionated radiation

therapy with total doses of

60.0 Gy to 79.2 Gy: possible

survival benefit with greater

than or equal to 69.6 Gy in

favorable patients with

RTOG stage III non-small-

cell lung carcinoma: report of

Radiation Therapy Oncology

Group 83-11.

Cox JD, et al. J Clin Oncol.

1990 Sep;8(9):1543-55.

Inclusion criteria:

No age restriction, stage II-IV

(without distant metastasis)

histologically or cytologically

proven, advanced,

unresectable NSCLC, KPS ≥

50

Exclusion criteria:

Prior RT, chemotherapy,

malignancy (other than skin),

cancer free for 5 years,

complete resection of the

tumor, or if they had

postoperative intrathoracic

recurrence.

Intervention:

Patients were randomized to

receive minimum total doses

of 60.0, 64.8, and 69.6 Gy.

After acceptable risks of

acute and late effects were

found, 74.4 Gy and 79.2 Gy

arms were added, and the

lowest total dose arms were

closed.

Toxicity:

No significant differences in

the risks of acute/ late normal

tissue effects; risks of severe

or life-threatening

pneumonitis were 2.6% for

60.0 to 64.8 Gy, 5.7% for

69.6 to 74.4 Gy, and 8.1% for

79.2 Gy.

Overall Survival

Survival with > 69.6 Gy

(median, 13.0 months) was

significantly (p = .02) better

than the lower doses.

Improvement in survival with

hyperfractionated RT at 69.6

Gy total dose without

increase in normal tissue

effects, justifies phase III

comparison with standard

fractionation alone and

combined with systemic

chemotherapy in this

common presentation of

NSCLC.

Final results of phase III trial

in regionally advanced

unresectable non-small cell

lung cancer.

Sause W, et al. Chest

2000;117:358-64.

Inclusion criteria:

Surgically inoperable stage

II-III NSCLC, KPS ≥ 70,

weight loss <5% 3 months

before the study, age > 18

years, no metastases.

Exclusion criteria:

Pleural effusions, prior

chemotherapy, RT, or

curative surgery.

Intervention: B) Sequential chemotherapy

+ RT, cisplatin + vinblastine

+ 60 Gy in 2 Gy #

C) Hyperfractionated RT,

69.6 Gy in 1.2 Gy #, BID

Comparator group: A) Standard RT 60 Gy in 2

Gy #

Median survival:

Group A - 11.4 months;

Group B - 12 months; and

Group C - 15.6 months. (p =

0.04)

Note: Squamous cell carcinoma in

Group B - 9% 5 year overall

survival vs. 2% in each of the

other arms.

Overall survival was

statistically superior for the

patients receiving

chemotherapy and RT vs. the

other two arms. The twice-

daily RT arm, although

better, was not statistically

superior in survival for those

patients receiving standard

radiation.

Continuous,

hyperfractionated, accelerated

radiotherapy (CHART)

versus conventional

radiotherapy in non-small cell

lung cancer: mature data from

Inclusion criteria:

No age restriction, stage I-III,

pathologically proven

NSCLC, WHO PS 0-1, WHO

performance status of 0 or 1,

inoperable NSCLC suitable

Intervention: CHART, which employs 36

fractions of 1.5 Gy 3 times

per day to give 54 Gy in 12

consecutive days.

Overall Survival:

2 year overall survival

improvement from 20 to 29%

(P =0.008)

Note:

CHART is superior to

conventional RT in achieving

local tumor control and

survival in locally advanced

NSCLC. Improved local

tumor control can reduce the


115

the randomised multicentre

trial. CHART Steering

committee.

Saunders M, et al. Radiother

Oncol. 1999 Aug; 52(2): 137-

48.

for RT Comparator group:

Conventional RT, 60 Gy in 2

GY #

Squamous cell patients had

an absolute improvement in 2

year survival of 13% from 20

to 33% (P =0.0007)

incidence of metastasis and

lead to an improvement in

long-term survival.

Experience with dose

escalation using

CHARTWEL (continuous

hyperfractionated accelerated

radiotherapy weekend less) in

non-small-cell lung cancer.

Saunders MI, et al. Br J

Cancer 1998;78:1323-8.

Inclusion criteria:

No age restriction, stage I-III

NSCLC from July 1990 to

September 1996. Thirty-five

patients. who were

considered unsuitable for the

randomized CHART trial,

were included betmeen July

1990 and April 1995. After

the conclusion of that trial, all

patients, except two, eligible

for radical radiotherapy

were treated with the 60 Gy

in 18 days CHARTWEL

protocol.

Intervention:

CHARTWEL schedule of 54

Gy in 16 days

Comparator group:

CHARTWEL schedule of 60

Gy in 18 days

Toxicity:

Acute dysphagia more severe

and lasted longer in patients

treated with CHARTWEL 60

Gy (P<= 0.02). After 6

months, there was a higher

incidence of mild pulmonary

toxicity compared with

CHARTWEL 54 Gy.

CHARTWEL 60 Gy resulted

in an enhancement of

esophagitis and grade 1 lung

toxicity compared with

CHARTWEL 54 Gy.

Patients treated with

CHARTWEL 60 Gy

experience an increase both

in acute esophageal morbidity

and in grade 1 late lung

dysfunction compared with

patients treated with 54 Gy.

However, this enhancement

of normal tissue reactions

does not require a different or

more intensive type of

medical management, nor has

it affected the quality of life

of patients.

A randomised phase III study

of accelerated or standard

fraction radiotherapy with or

without concurrent

carboplatin in inoperable non-

small cell lung cancer: final

report of an Australian multi-

centre trial.

Ball D , et al. Radiother

Oncol. 1999 Aug;52(2):129-

36.

Inclusion criteria:

Histologically or

cytologically proven stage I-

III NSCLC confined to

primary site and regional

nodes, ECOG PS 0-1.

Exclusion criteria:

Involvement of cervical

lymph nodes or pleural

effusions, weight loss >10%,

or prior radiotherapy or

chemotherapy

Intervention:

1. Standard RT (60 Gy in 2

Gy # in 6 weeks)

2. Accelerated RT (60 Gy in

2 Gy # BID in 3 weeks)

3. Standard RT plus

carboplatin

4. Accelerated RT plus

carboplatin

Response: no significant

differences among arms.

2- and 5-year overall

survival: 31% and 10%,

median 15.7 months. No

significant differences.

Toxicity: Significantly more

thrombocytopenia,

neutropenia, and anemia, in

carboplatin arms. More

severe esophageal symptoms

in accelerated vs. standard RT

This study failed to show a

significant survival advantage

for any of the treatment arms

or factors. Halving overall

treatment time resulted in

significantly greater

esophageal toxicity with no

suggestion of a survival

advantage.


116

Final results of the

randomized phase III

CHARTWEL-trial (ARO 97-

1) comparing

hyperfractionated-accelerated

versus conventionally

fractionated radiotherapy

in non-small cell lung cancer

(NSCLC)

Baumann M, et al. Radiother

Oncol. 2011 Jul;100(1):76-85

Inclusion criteria:

Patients over 18 years of age

with histologically or

cytologically proven

inoperable stage I- III

NSCLC (or surgery refused),

and WHO PS 0-1. Tumor

volume and location must

allow for curative intent RT.

Exclusion criteria: distant

metastases, SCV lymph node

metastases, pleural effusion,

FEV1 < 1L, unintended

weight loss >15% within 6

months, prior RT, surgical

resection other than biopsy,

prior or concurrent cancer,

pacemaker within RT field

(unless ok by cardiology),

participation in other trial.

Intervention: 3D-planned

RT 60 Gy in 1.5 Gy # BID, in

2.5 weeks (CHARTWEL).

Comparator Group: 66 G in 2 Gy #, in 6.5 weeks

(conventional fractionation).

Overall survival At 2, 3 and 5 yr was not

significantly different after

CHARTWEL (31%, 22% and

11%) versus CF (32%, 18%

and 7%; p = 0.43). Local

control rates and distant

metastases did not

significantly differ. Acute

dysphagia and radiological

pneumonitis were more

pronounced after

CHARTWEL. Exploratory

analysis revealed a significant

trend for improved LC after

CHARTWEL versus CF with

increasing UICC, T or N

stage (p = 0.006–0.025) and

after neoadjuvant

chemotherapy (p = 0.019).

Conclusion:

Outcome after CHARTWEL

or conventional fractionation

was not different. The lower

total dose in the

CHARTWEL arm was

compensated by the shorter

overall treatment time,

confirming a time factor for

NSCLC. The higher efficacy

of CHARTWEL versus CF in

advanced stages and after

chemotherapy provides a

basis for further trials on

treatment intensification for

locally advanced NSCLC.

Hyperfractionated or

Accelerated Radiotherapy in

Lung Cancer: An Individual

Patient Data Meta-Analysis.

Mauguen A, et al. J Clin

Oncol. 2012 Aug

1;30(22):2788-97

Inclusion criteria:

Stage I-III non-metastatic

lung cancer, randomly

assigned to the modified RT

(accelerated +/-

hyperfractionated) or

conventional RT between

1970 -2005. Chemo (CT)

permitted if schedule and

dose the same in the two

arms.

Exclusion criteria: RCTs excluded due to

doublet, no randomization of

RT treatment, brain RT, no

Intervention: Authors performed an

individual patient data meta-

analysis in patients with

nonmetastatic lung cancer,

which included trials

comparing modified

fractionation radiotherapy

with conventional

radiotherapy.

Overall survival:

For NSCLC (10 trials, 2,000

patients), modified

fractionation improved

overall survival compared

with conventional RT ([HR]

=0.88, p = 0.009), and an

absolute benefit of 2.5%

(8.3% to 10.8%) at 5 years.

No evidence of heterogeneity

between trials was found.

Toxicity:

In both NSCLC and SCLC,

the use of modified RT

increased the risk of acute

Conclusion: Patients with nonmetastatic

NSCLC derived a significant

OS benefit from accelerated

or hyperfractionated

radiotherapy; a similar but

nonsignificant trend was

observed for SCLC.

Modified RT is associated

with increased acute

esophageal toxicity.


117

# = fractions; PS = performance status; RT = radiotherapy; NSCLC = non-small cell lung cancer; pts = patients; Gy = Gray; HR = hazard ratio; OR = odds ratio;

CF = conventional fractionation

arm with conventional RT,

same fractionation in the two

arms, confounded by

different CT in the two arms,

and phase I study

esophageal toxicity ([OR] =

2.44 in NSCLC and OR =

2.41 in SCLC; p = 0 .001)

with no impact on the risk of

other acute toxicities.


118

Table 6. Selected Phase III studies evaluating radiation schedules in the context of concurrent or sequential chemotherapy in LA NSCLC


Phase III study of the

Eastern Cooperative

Oncology Group (ECOG

2597): induction

chemotherapy followed by

either standard thoracic

radiotherapy or

hyperfractionated

accelerated radiotherapy

for patients with

unresectable stage IIIA

and B non-small-cell lung

cancer.

Belani CP, Wang W,

Johnson DH, Wagner H,

Schiller J, Veeder M,

Mehta M; Eastern

Cooperative Oncology

Group. J Clin Oncol. 2005

Jun 1;23(16):3760-7. Epub

2005 Apr 18.

Inclusion criteria: Stage III

NSCLC ;ECOG

performance status of 0 or

1; biopsy-proven

unresectable stage IIIA or

IIIB NSCLC;no pleural

effusion on chest x-ray;no

prior malignancies in the

preceding 5 years; no prior

radiation or chemotherapy

Exclusion criteria: tumor

location was such that

100% of the cardiac

volume would not receive

more than 45 Gy, or if

50% or more of the

cardiac volume would

receive no more than 50

Gy.

Induction chemotherapy

(2 cycles of paclitaxel and

carboplatin) followed by

randomization to RT. RT

consisted of arm 1

(qdRT), 64 Gy (2 Gy/d),

versus arm 2 (HART),

57.6 Gy (1.5 Gy tid for

2.5 weeks).

Of 141 patients enrolled,

83% were randomly

assigned after

chemotherapy to qdRT (n

=59)or HART (n =60).

Median survival: 20.3 and 14.9

months for HART and qdRT,

respectively (P =.28).

2- and 3-year survival: 44% and

34% for HART, and 24% and

14% for qdRT.

Toxicity: Grade 3 toxicities

included esophagitis in 14 v 9

patients, and pneumonitis in 0 v

6 patients for HART and qdRT,

respectively.

After two cycles of

induction

chemotherapy with

carboplatin-paclitaxel,

HART is feasible with

an acceptable toxicity

profile. Although

statistical significance

was not achieved and

the study closed early,

there was a positive

statistical trend

suggesting a survival

advantage with the

HART regimen

Final results of the

randomized phase III

CHARTWEL-trial (ARO

97-1) comparing

hyperfractionated-

accelerated versus

conventionally

fractionated radiotherapy

Inclusion criteria

Stage: I-III

NSCLC

WHO performance status

0 or 1, suitable for radical

radiotherapy

Exclusion criteria: distant

RT to 60 Gy (2.5 weeks)

[CHARTWEL]

Comparator group: 66 Gy

(6.5 weeks) [conventional

fractionation-CF]

Overall survival and local

control were not different with

CHARTWEL (p=0.43).

Significant trend for improved

LC after CHARTWEL vs. CF

with increasing UICC, T or N

stage and after neoadjuvant

chemotherapy.

Overall, outcome after

CHARTWEL or CF

was not different. The

higher efficacy of

CHARTWEL versus

CF in advanced stages

and after chemotherapy

provides a basis for


119

in non-small cell lung

cancer (NSCLC).

Baumann M, et al.

Radiother Oncol.

2011Jul;100(1):76-85.

metastases,

supraclavicular lymph

node metastases, pleural

effusion, FEV1 under

optimized treatment <1 l,

unintended weight loss

>15% within 6 months,

prior RT, resection other

than biopsy, prior or

concurrent malignant

disease

Toxicity: Early dysphagia due to

radiation esophagitis occurred

earlier and had higher

prevalence and grade after

CHARTWEL. No difference in

late dysphagia. Late radiation

pneumopathy grade ≥2 was

significantly more frequent after

CHARTWEL (HR = 1.4,

p=0.038).

further trials on

treatment

intensification for

locally advanced

NSCLC.

A randomized phase III

comparison of standard-

dose (60 Gy) versus high-

dose (74 Gy) conformal

chemoradiotherapy with

or without cetuximab for

stage III non-small cell

lung cancer: Results on

radiation dose in RTOG

0617.

Bradley, J., R. Paulus, et

al. (2013). Journal of

Clinical Oncology

31(supplement): abstract

7501.

Inclusion criteria

Newly diagnosed

unresectable stage III A or

B non-small cell lung

cancer, brod Performance

Status 0-1, V1 best value

≥ 1.2 liters/second or ≥

50% predicted

Exclusion criteria:

Spraclavicular or

contralateral hilar

Adenopathy, weight loss

greater than or equal to

10% in last 4 weeks,prior

systemic chemotherapy

and/or thoracic/neck

radiotherapy , malignancy

within the past 3 years

1. 60 Gy in 30 daily

fractions with weekly

paclitaxel/carboplatin

(PC)

2.74 Gy in 37 daily

fractions with weekly PC



plus cetuximab



plus cetuximab

Consolidation: 2 cycles

paclitaxel/carboplatin

(plus cetuximab in arms 3

and 4 )

Median survival: 28.7 months

(95% CI:22.0, NR) and 19.5

months (95% CI:22.0, NR) for

the 60 Gy and 74 Gy arms ,

respectively. PFS and Local

Relapse also inferior with 74

Gy.

Toxicity:Increased rate of severe

esophagitis associated with the

74 Gy arm (7% vs 21 %).

Grade 5 toxicity : 2 pts in 60 Gy

arm vs 10 pts in 74 Gy arm

74 Gy is not better and

likely leads to worse

overall survival

compared to 60 Gy.

Phase III trial comparing Inclusion criteria: Either standard q.d. RT No significant differences were This program of split-


120

chemotherapy plus once-

daily or twice-daily

radiotherapy in Stage

ACR Appropriateness

Criteria® 8 Nonsurgical

Treatment for NSCLC III

non-small-cell lung

cancer.

Schild SE, Stella PJ,

Geyer SM, et al. Int J

Radiat Oncol Biol Phys

2002; 54(2):370-378.

Unresectable Stage III

NSCLC that had not

spread beyond the site of

origin, ipsilateral hilum,

mediastinum, or ipsilateral

supraclavicular nodes,

forced expiratory volume

in 1 s >1 L or >40% of

the predicted value; and an

ECOG performance status

of 0 or 1.

Exclusion criteria: Patients

were excluded from the

study if they had a

myocardial infarction

within the past 3 months,

uncontrolled congestive

heartfailure, uncontrolled

arrhythmia, more than a

minimal pleural effusion,

prior chemotherapy or RT

for this malignancy,

weight loss >5% within

the past 3 months

(60 Gy in 30 daily

fractions) or split-course

b.i.d. RT (30 Gy in 20

fractions b.i.d.) followed

by a 2-week break and

then 30 Gy in 20 fractions

b.i.d. Both arms included

etoposide and cisplatin

(EP) during RT.

found between the q.d. and b.i.d.

RT arms in terms of time to

progression (p=0.9; median 9.4

and 9.6 months, respectively),

overall survival (p=0.4; median

14 and 15 months and 2-year

survival rate 37% and 40%,

respectively), and cumulative

incidence of local failure (p=0.6;

2-year rate 45% and 41%,

respectively).

Toxicity:

The incidence of severe (Grade

3 or greater) acute

nonhematologic toxicity (q.d.

RT, 53% vs. b.i.d. RT, 65%) and

severe (Grade 3 or greater)

hematologic

toxicities(thrombocytopenia,

41% q.d. RT vs. 39% b.i.d. RT;

neutropenia, 80% q.d. RT vs.

81% b.i.d. RT) was not

significantly different.

course b.i.d. RT plus

EP was not superior to

standard q.d. RT plus

EP. The toxicity, tumor

control, and survival

rates were similar with

either b.i.d. or q.d. RT.

A randomised phase III

study of accelerated or

standard fraction

radiotherapy with or

without concurrent

carboplatin in inoperable

non-small cell lung

cancer: final report of an

Australian multi-centre

Inclusion criteria:

Inclusion criteria: Stage: I-

III NSCLC confined to

primary site and regional

nodes and ECOG

performance status 0 or 1.

Exclusion criteria:

Involved pleural effusions,

1. Standard RT (60 Gy in

30 fractions in 6 weeks)

[R6]

2. Accelerated RT (60 Gy

in 30 fractions in 3 weeks)

[R3]

3. Standard RT plus

carboplatin [R6C]

4. Accelerated RT plus

2- and 5-year overall survival:

31% and 10%, median 15.7

months. No significant

differences.

2- and 5-year progression-free

survival: 20% and 7%, median

9.9 months. No significant

differences.

Halving overall

treatment time resulted

in significantly greater

esophageal toxicity

with no suggestion of a

survival advantage.


121

trial.

Ball D, Bishop J, Smith J,

et al. Radiother Oncol.

1999 Aug;52(2):129-36.

weight loss >10%, or prior

radiotherapy or

chemotherapy

carboplain [R3C] Toxicity: Significantly more

anemia, neutropenia, and

thrombocytopenia in carboplatin

arms. More severe oesophageal

symptoms in accelerated vs.

standard RT and (non-

significantly) in RT + chemo vs.

RT alone.

Sequential vs. concurrent

chemoradiation for stage

III non-small cell lung

cancer: randomized phase

III trial RTOG 9410.

Curran WJ Jr, Paulus R,

Langer CJ, et al. J Natl

Cancer Inst. 2011 Oct 5;

103(19): 1452-60.

Inclusion criteria:

medically or surgically

inoperable stage II, IIIA,

or IIIB newly diagnosed

histologically confirmed

NSCLC, Karnofsky

performance status ≥ 70, ≤

5% weight loss over 3

months before enrollment

Exclusion criteria:

pleural effusions with

malignant cytology or

visible on chest x-ray

1. sequential chemo

(cisplatin and vinblastine)

and thoracic RT

2. concurrent chemo

(cisplatin and vinblastine)

and thoracic RT

3. concurrent chemo

(cisplatin and etoposide)

5-year survival: Significantly

longer in arm 2, median 14.6,

17.0, and 15.6 months.

Response: 61% (30% complete)

in arm 1, 70% (42% complete)

in arm 2, 65% (33% complete)

in arm 3, (p<0.05 for arm 2 vs.

arm 1 but not vs. arm 3).

Recurrence: 39%, 30%, and

29% for local relapse. Infield

progression less in arm 3 than

arm 1 (P = .01).

Toxicity: grade ≥3 acute

esophagitis in 4%, 22%, and

45% in arms 1, 2, and 3

(p<0.001). No different in late

esophagitis.

Concurrent delivery of

cisplatin-based

chemotherapy with

TRT confers a long-

term survival benefit

compared with the

sequential delivery of

these therapies.

Hyperfractionated RT

resulted in increased

acute esophagitis and

did not improve

survival.


122

TABLE 7. Selected multicenter phase III randomized controlled trials comparing concurrent with sequential chemoradiotherapy

Study

Sequence

Pts

RT dose

(Gy)

CT

Locoregional

control Median

survival

(months)

Overall survival Acute

≥ grade 3

esophagitis

(%)

3-yr

(%)

5-yr

(%)

3-yr

(%)

5-yr

(%)

West Japan Lung

Cancer

Group

CT→qd RT 158 56 MVP n.r. n.r. 13.3 15 9 2

CT+ qd RT 156 56 (split

course) MVP n.r. n.r. 16.5 22 16 3

RTOG 9410

CT→qd RT 201 60 cddp/vinblastine n.r. n.r. 14.6 n.r. 10 4

CT+ qd RT 201 60 cddp/vinblastine n.r. n.r. 17 n.r. 16 23

CT+ bid RT 193 69.6 cddp/etoposide n.r. n.r. 15.1 n.r. 13 46

GLOT-GFPC NPC

95-01

CT→qd RT 101 66 cddp/vinorelbine 38 37 (4

yr) 14.5 19

14 (4

yr) 3

CT+ qd

RT→CT 100 66

cddp/etoposide →

cddp/vinorelbine 57

55 (4

yr) 16.3 25

21 (4

yr) 32

Czech Republic Study CT→qd RT 50 60 cddp/vinorelbine 40% n.r. 12.9 9.5 n.r. 4

CT+ qd RT 52 60 cddp/vinorelbine 58% n.r. 16.6 18.6 n.r. 18

Combined Seq CT→qd RT 510 56–66 14 3.2

Combined Con-qd CT+ qd RT 509 56–66 16.7 18.1

Combined Con-bid CT+ bid RT 193 69.6 15.1 46

The combined statistics are averages weighted by the number of patients in each group.

bid = twice daily; cddp = cisplatin; Con = concurrent; CT = chemotherapy; MVP = mitomycin, vindesine, and cisplatin; n.r. = not reported; Pts = number of

patients; qd = daily; RT = radiotherapy; Seq = sequential


123

TABLE 8. Selected Phase II trials comparing induction or consolidation chemotherapy with concurrent chemoradiotherapy

Study Sequence Pts RT dose

(Gy) CT

Locoregional

control Median

survival

(months)

Overall

survival Acute

≥ grade 3 esophagitis

(%) 3-yr (%) 5-yr (%) 3-yr

(%)

5-yr

(%)

SWOG S9019 CT+ qd

RT→CT 50 61 PE→PE n.r. n.r. 15 17 15 20

SWOG S9504 CT+ qd

RT→CT 83 61

PE

→docetaxel n.r. n.r. 26 40 29 n.r.

CALGB 39801

CT→CT+ qd

RT 184 66 carbo/pac n.r. n.r. 14

54

(1 yr) n.r. 27% (neutropenia)

CT+ qd RT 182 66 carbo/pac n.r. n.r. 11.4 48

(1 yr) n.r. 15% (neutropenia)

LAMP

CT→ qd RT 91 63 carbo/pac n.r. n.r. 13.0 17 3

CT→CT+ qd

RT 74 63

carbo/pac → low

dose carbo/pac n.r. n.r. 12.7 15 n.r. 19

CT+ qd

RT→CT 92 63

low dose

carbo/pac→

carbo/pac

n.r. n.r. 16.3 17 n.r. 28

Combined Conc,

Cons

CT+ qd

RT→CT 225 61–63 19.6

Combined Conc CT+ qd RT 182 66 11.4

Combined Ind,

Conc

CT→CT+ qd

RT 258 63–66 13.6

The combined statistics are averages weighted by the number of patients in each group.

carbo/pac = carboplatin and paclitaxel; Conc = concurrent; Cons = consolidation; CT = chemotherapy; Ind = induction; n.r. = not reported; PE =

cisplatin/etoposide; Pts = number of patients; qd = daily; RT = radiotherapy


124

TABLE 9. Selected publications assessing post-operative radiotherapy after surgical resection in non-small cell lung cancer

Author

(reference)

Publication

Year

Treatment Stage Total pts in

study

Total

stage

III pts

in study

Number

of stage

III pts per

study arm

Total RT

dose in

Gy/ dose

per fx in

Gy

LRR

(%)

p DFS

(%)

p OS at

5 yrs

(%)

p Study

conclusions

Park (11) 2007 surgery +

PORT +/-

ADJ CHT

IIIA 111 111 56 50.4-

55.8/1.8-

2

41.1 0.1 37.5 0.22 NS impact

of ADJ on

DFS or OS

surgery +/-

ADJ CHT

55 28.9 29.8

Perry (23) 2007 surgery +

ADJ CHT

+ PORT

IIIA 37 37 19 50/25 42 33.7 m

(median

FFS)

NS 74 NS

surgery +

ADJ CHT

18 35 16.8 m

(median

FFS)

72

Walasek

(22)

2003 surgery +

PORT

III 138 96 49 50/25 8.7 16.3

for

stage

IIIA @

3 years

NS impact

of ADJ on

OS, S on

LRR

surgery 47 23.9 14.9

for

stage

IIIA @

3 years

Feng (12) 2000 surgery +

PORT

II-IIIB 365 (296

evaluable)

162 82 60/2 15.6 42.9 0.28 42.9 0.56 NS impact

on OS,

improves

LRR

surgery 80 37.5 38.2 40.5

Dautzenber

g (13)

1999 surgery +

PORT

I-IIIA 728 327 170 60/2-2.5 28 0.28 51 NS 25

(stage

III )

0.3 NS impact

on OS

surgery 157 34 46 30

(stage

III)

Mayer (14) 1997 surgery + I-III 155 58 30 56/2 for 3.3 <.05 45.5 @ NS NS impact


125

PORT N2 for

N2

5 years

for N2

on OS, S

improves

LRR

surgery 28 25

for

N2

40.6 @

5 years

for N2

Stephens

(15)

1996 surgery +

PORT

II-III 308 106 52 40/2.67 29 0.07 36 @ 3

years

NS trend to

survival

surgery 54 41 21 @ 3

yrs

Debevec

(16)

1996 surgery +

PORT

IIIA 74 74 35 30/3 NS 28 0.1 NS impact

on OS

surgery 39 23

LCSG (17) 1986 surgery +

PORT

II-III 210 148 76 50/1.8-2 6

cases

0.03 40 0.678 NS impact

on OS, S

improves

LRR

surgery 72 13

cases

40

van Houtte

(18)

1980 surgery +

PORT

no

stages

spec.

224 (175

evaluable)

Unk. 83 (all pts) 60/2 4

cases

24 NS NS impact

on OS,

improved

LRR

surgery 92 (all pts) 19

cases

43

PORT = postoperative radiotherapy; unk = unknown; NS = not significant; OS = overall survival; S = survival; LRR = local regional relapse; ADJ = adjuvant; FFS = failure free

survival


126

Table 10. Mediastinal pCR (N2 nodal clearance) rates by type of induction therapy

Study Patient

Number

Chemotherapy

Alone

Radiation Therapy and Concurrent

Chemotherapy

Pass 27 35%

O’Brien 52 17%

Van Zandwijk 47 53%

Betticher 90 32%

Thomas 154 29%

Albain (INT 0139) 161 38%

Albain (SWOG 8805) 75 56%

Choi N 42 24%

Eberhardt 52 79%

Thomas 142 46%

Suntharalingam (61.2 Gy) 57 63%


127

Appendix 1

Guideline Topic:

The Role of Radiotherapy in Locally Advanced Non-Small Cell Lung Cancer

Date Search Started: 03/11/13

Date Search Completed: 03/11/13

Key Question 1: What is the ideal external-beam dose-fractionation for the curative-intent treatment of locally-advanced non-small cell lung cancer with radiation therapy alone?

Population Intervention Comparison Outcomes

Curative-intent non-resectable Non-small cell Lung Cancer, Locally Advanced/ Stage III (IIIA or IIIB)

Biological Equivalent Dose Higher biological equivalent dose radical external-beam schedule(s)

Overall survival and local control. Regional and distant failure rates. Treatment toxicity (pneumonitis, esophagitis), compliance rates, hospitalization rates, Quality of life/HRQoL (general, pulmonary, and gastrointestinal).

Search Limits:

Age Range All Adult 19+

Language Only in English

Publication Date 1966 / 01/ 01 - 2013 / 12/ 31

Pub Med Search Strategy: Search Terms:


128

Non-small cell lung cancer

Non-resectable Unresectable Radiation Radiotherapy Unresected Inoperable External beam

Searches:

1. "Carcinoma, non-small-cell lung"[MeSH Terms] 2. "Unresectable" 3. "Non-resectable" 4. "Radiation" 5. "Radiotherapy" 6. Unresected 7. Inoperable 8. External Beam 9. “#1 AND #2 AND #4" 10. “#1 AND #2 AND #5" 11. “#1 AND #3 AND #4" 12. “#1 AND #3 AND #6" 13. “#1 AND #6 AND #4" 14. “#1 AND #6 AND #5" 15. “#1 AND #7 AND #4 AND #8" 16. “#1 AND #7 AND #5 AND #8"

TOTAL (all articles KQ 1) - 528 articles

Rationale for Abstract Exclusion:

1. Small Cell Lung Cancer 2. Metastatic disease 3. Non-curative intent 4. Pre-clinical data (non-human) 5. Pediatric patients 6. Carcinoid, Mesothelioma, or Thymic tumors


129

Key Question 2: What is the ideal external-beam dose-fractionation for the curative-intent treatment of locally-advanced non-small cell lung cancer with chemoradiotherapy?



Biological Equivalent Dose Higher biological equivalent dose radical external-beam schedule(s)

Overall survival and local control. Regional and distant failure rates. Treatment toxicity (pneumonitis, esophagitis), compliance rates, hospitalization rates, Quality of life/HRQoL (general, pulmonary, and gastrointestinal).

Search Limits:




Pub Med Search Strategy:

Search Terms:

Non-small cell lung cancer

Non resectable Unresectable Chemo Radiation Radiotherapy Unresected Inoperable


130

Searches:

1. "Carcinoma, non-small-cell lung"[MeSH Terms] 2. "Unresectable" 3. "Non-resectable" 4. Chemo 5. "Radiation" 6. "Radiotherapy" 7. "Unresected" 8. "Inoperable" 9. “#1 AND #2 AND #4 AND #5" 10. “#1 AND #2 AND #4 AND #6” 11. “#1 AND #3 AND #4 AND #5" 12. “#1 AND #3 AND #4 AND #6” 13. “#1 AND #7 AND #4 AND #5" 14. “#1 AND #7 AND #4 AND #6” 15. “#1 AND #8 AND #4 AND #5" 16. “#1 AND #8 AND #4 AND #6”

TOTAL (all articles KQ 2) - 42 articles

Rationale for Abstract Exclusion: 1. Small Cell Lung Cancer 2. Metastatic disease 3. Non-curative intent 4. Pre-clinical data (non-human) 5. Pediatric patients 6. Carcinoid, Mesothelioma, or Thymic tumors

Key Question 3: What is the ideal timing of external-beam radiation therapy in relation to systemic chemotherapy for the curative-intent treatment of locally-advanced non-small cell lung cancer?


Curative-intent non-resectable Non-small cell

Immediate concurrent chemoradiotherapy

Sequential chemotherapy followed by radiation

Overall survival and local control.


131

Lung Cancer, Locally Advanced/ Stage III (IIIA or IIIB)

therapy (or chemoradiotherapy)

Search Limits:




Pub Med Search Strategy: NOTE: Same as KQ 2 Rationale for Abstract Exclusion:


Key Question 4: What are the indications for adjuvant post-operative radiotherapy for the curative-intent treatment of locally-advanced non-small cell lung cancer?



Adjuvant radiotherapy

No Adjuvant radiotherapy

Overall survival and surgical resectability

Search Limits:



132



Pub Med Search Strategy: NOTE: Same as KQ 1 Rationale for Abstract Exclusion:


Key Question 5: When is neoadjuvant radiotherapy prior to surgery indicated for the curative-intent treatment of locally-advanced non-small cell lung cancer?



Neo-adjuvant radiotherapy (with or without chemotherapy)

No radiotherapy

Overall survival and surgical resectability

Search Limits:




Pub Med Search Strategy: NOTE: Same as KQ 1

Rationale for Abstract Exclusion:

1. Small Cell Lung Cancer


133

2. Metastatic disease 3. Non-curative intent 4. Pre-clinical data (non-human) 5. Pediatric patients 6. Carcinoid, Mesothelioma, or Thymic tumors

Conference Proceedings

Number of Articles for KQ1

Number of Articles for

KQ2

Number of Articles for

KQ3

Number of Articles for KQ4

Number

of Articles for KQ5

Total Number

of Articles

ASTRO None None None None None None

ESTRO None None None None None None

ASCO None None None None None None

AAPM None None None None None None

ACR None None None None None None

Additional Resources Searched (X) Number of Articles Identified

Website/ Reference

Citation Tracking/ Hand searching

Author Communication 20 Guidelines identified by Dr. Rodrigues


134


135

APPENDIX 2

American College of Physicians (ACP) Process for Assigning Strength of Recommendation and Grading of

Quality of Evidence

Strong Recommendation

Evidence suggests that the benefit of the intervention outweighs the risk, or vice versa, and the panel has reached

uniform consensus.

Weak Recommendation

Evidence suggests that the benefit of the intervention equals the risk, or vice versa, and the panel has reached uniform or

non-uniform consensus.

High Quality Evidence


136

Evidence is considered high quality when it is obtained from 1 or more well-designed and well-executed randomized,

controlled trials (RCTs) that yield consistent and directly applicable results. This also means that further research is very

unlikely to change our confidence in the estimate of effect.

Moderate-Quality Evidence

Evidence is considered moderate quality when it is obtained from RCTs with important limitations—for example, biased

assessment of the treatment effect, large loss to follow-up, lack of blinding, unexplained heterogeneity (even if it is

generated from rigorous RCTs), indirect evidence originating from similar (but not identical) populations of interest, and

RCTs with a very small number of participants or observed events. In addition, evidence from well-designed controlled

trials without randomization, well-designed cohort or case– control analytic studies, and multiple time series with or

without intervention are in this category. Moderate-quality evidence also means that further research will probably have an

important effect on our confidence in the estimate of effect and may change the estimate.

Low Quality Evidence

Evidence obtained from observational studies would typically be rated as low quality because of the risk for bias. Low-

quality evidence means that further research is very likely to have an important effect on our confidence in the estimate of


137

effect and will probably change the estimate. However, the quality of evidence may be rated as moderate or even high,

depending on circumstances under which evidence is obtained from observational studies. Factors that may contribute to

upgrading the quality of evidence include a large magnitude of the observed effect, a dose–response association, or the

presence of an observed effect when all plausible confounders would decrease the observed effect.


138

Appendix 3. Clinical Practice Guideline Statements

KQ1: What is the ideal external-beam dose-fractionation for the curative-intent treatment of locally advanced non-small cell lung cancer with radiation therapy alone?

A. Radiotherapy alone has been shown to be superior to observation strategies or chemotherapy alone for LA NSCLC in terms of overall survival but at the cost of treatment-related side effects such as esophagitis and pneumonitis (MQE).

B. Radiotherapy alone may be used as definitive radical treatment for patients with LA NSCLC who are ineligible for combined modality therapy (i.e. due to poor performance status, medical comorbidity, extensive weight loss, and/or patient preferences) but with a tradeoff of survival for improved treatment tolerability (HQE).

C. In the context of conventionally fractionated (1.80-2.15 Gy) radiotherapy, a minimum dose of 60 Gy is recommended to optimize important clinical outcomes such as local control (HQE).

D. Altered fractionation schedules that have been explored in the medical literature include hyperfractionation (lower dose per fraction over the standard treatment duration), accelerated fractionation (conventional fraction size and same total dose, given in a shorter period of time), accelerated hyperfractionation (combination of these two), and hypofractionation (higher dose per fraction and fewer fractions).

E. Specific altered fractionation schemes that have been investigated in various comparative effectiveness research investigations (including randomized controlled trials) include 45 Gy/15 fractions (hypofractionation), 69.6 Gy/58 fractions BID (hyperfractionation), 54 Gy/36 fractions TID over 12 consecutive days (CHART, accelerated hyperfractionation), and 60 Gy/25 fractions BID (CHARTWEL, accelerated hyperfractionation).

KQ2: What is the ideal external-beam dose fractionation for the curative-intent treatment of locally advanced non-small cell lung cancer with chemoradiotherapy?

A. The standard thoracic radiotherapy dose-fractionation for patients treated with concurrent chemotherapy, recently validated in a phase III RTOG trial (RTOG 0617), is 60 Gy given in 2 Gy once daily fractions over 6 weeks (HQE).

B. Dose escalation beyond 60 Gy with conventional fractionation has not been proven to be associated with any clinical benefits including overall survival (HQE).


139

C. Hyperfractionated radiotherapy regimens that do not result in acceleration of the treatment course, even though the total nominal radiotherapy dose may be modestly increased, do not appear to improve outcomes compared with conventionally fractionated therapy (MQE).

D. The optimal thoracic radiotherapy regimen for patients receiving sequential chemotherapy and radiotherapy is not known; however results from the CHARTWEL and HART phase III studies suggest, but do not prove, that increasing the biologic equivalent dose by using accelerated hyperfractionated radiotherapy may be of benefit following induction chemotherapy in locally advanced non-small cell lung cancer (MQE).

E. Although the impact of increasing the predicted biologic equivalent dose via accelerated radiotherapy regimens is not clear, further study of accelerated hypofractionated regimens is of interest to optimize the therapeutic ratio of treatment, particularly in the context of advanced imaging, radiotherapy planning, and treatment delivery.

KQ3: What is the ideal timing of external-beam radiation therapy in relation to systemic chemotherapy for the curative-intent treatment of locally advanced non-small cell lung cancer?

A. There is phase III evidence demonstrating improved overall survival, local control, and response rate associated with concurrent chemoradiation when compared against sequential chemotherapy followed by radiation (HQE).

B. There is no proven role for the routine use of induction chemotherapy prior to chemoradiotherapy; although, this treatment paradigm can be considered for the management of bulky tumors to allow for radical planning after chemotherapy response (MQE).

C. There are no phase III data specifically supporting the role for consolidation chemotherapy after chemoradiotherapy for the improvement of overall survival; however, this treatment is still routinely given to manage potential micrometastatic disease particularly if full systemic chemotherapy doses were not delivered during radiotherapy (MQE).

D. For patients that cannot tolerate concurrent chemoradiotherapy, sequential chemotherapy followed by radical radiation has been shown to be associated with an overall survival benefit when compared to radiotherapy alone (HQE).

E. The ideal concurrent chemotherapy regimen has not been determined; however, the two most common regimens (cisplatin/etoposide and carboplatin/paclitaxel) are the subject of a completed phase III clinical trial (NCT01494558).

KQ4: What are the indications for adjuvant post-operative radiotherapy for the curative-intent treatment of locally advanced non-small cell lung cancer?


140

A. Phase III studies and meta-analyses of postoperative radiotherapy (PORT) in completed resected (R0) LA NSCLC with N2 disease suggest that its addition to surgery does not improve overall survival but may improve local control when compared to observation strategies (MQE).

B. Phase III studies and meta-analyses of PORT in completely resected (R0) LA NSCLC withN0-1 disease demonstrate inferior survival when compared to observation strategies (MQE).

C. Since level 1 evidence supports the administration of adjuvant chemotherapy for completely resected (R0) LA NSCLC based on improvements in overall survival compared to patients on observation, any PORT therapy should be delivered sequentially after chemotherapy in order not to interfere with standard of care chemotherapy (LQE).

D. For patients receiving adjuvant PORT for R0 disease, conventionally fractionated doses in the range of 50 Gy to 54 Gy (in 1.8-2.0 Gy/day) should be utilized (LQE)

E. Patients with microscopic residual (R1) primary disease (i.e., positive margin) and/or microscopic (i.e., extra-capsular extension) nodal disease may be appropriate candidates for PORT (ideally given concurrently with chemotherapy) with conventionally fractionated doses in the range of 54 Gy to 60 Gy (in 1.8-2.0 Gy/day fraction size) in order to improve local control (LQE).

F. Patients with high-risk features after resection (gross residual primary and/or macroscopic (R2) nodal disease) of LA NSCLC may be

appropriate candidates for PORT (ideally given concurrently with chemotherapy) with conventionally fractionated doses of at least 60 Gy (in 1.8-2.0 Gy/day fraction size) in order to improve local control (LQE).

KQ5: When is neoadjuvant radiotherapy prior to surgery indicated for the curative-intent treatment of locally advanced non-small cell lung cancer?

A. There is no level I evidence recommending the use of induction radiotherapy (or chemoradiotherapy) followed by surgery for patients with resectable stage III NSCLC (HQE).

B. In those patients who are selected for trimodality approach, preoperatively planned lobectomy (as opposed to pneumonectomy), based on best surgical judgment, is preferable, since it was associated with survival benefit in the exploratory post-hoc INT 0139 analysis (MQE).

C. No definitive statement can be made about best patient selection criteria for the trimodality therapy, although no weight loss, female gender, and one (vs. more) involved nodal stations were associated with improved outcome in INT 0139 (MQE).


141

D. The ideal preoperative radiotherapy dose is currently not known; however, a minimum of 45 Gy should be delivered consistent with the INT 0139 trial (LQE).

E. Preoperative conventionally fractionated doses up to 60 Gy are reported to be associated with higher mediastinal clearance rates, although no significant correlation with improved survival has been demonstrated. (LQE).

Documents

NOT TO BE COPIED, DISSEMINATED OR REFERENCED...118 approved using an a-priori defined consensus-building methodology supported 119 by ASTRO approved tools for the grading of evidence