Adjuvant radiotherapy for resectable locally advanced non–small cell lung cancer: Benefit or harm?

Adjuvant radiotherapy for resectable locally advanced non–small cell lung cancer: Benefit or harm?

Accepted Manuscript Adjuvant Radiotherapy for Resectable Locally Advanced Non-Small Cell Lung Cancer: Benefit or Harm? Linda W. Martin, MD, MPH, FCCP,...

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Accepted Manuscript Adjuvant Radiotherapy for Resectable Locally Advanced Non-Small Cell Lung Cancer: Benefit or Harm? Linda W. Martin, MD, MPH, FCCP, FACS, Gail E. Darling, M.D., FRCSC FACS, Dennis A. Wigle, MD, PhD PII:

S0022-5223(15)01570-6

DOI:

10.1016/j.jtcvs.2015.09.003

Reference:

YMTC 9899

To appear in:

The Journal of Thoracic and Cardiovascular Surgery

Received Date: 31 August 2015 Accepted Date: 1 September 2015

Please cite this article as: Martin LW, Darling GE, Wigle DA, Adjuvant Radiotherapy for Resectable Locally Advanced Non-Small Cell Lung Cancer: Benefit or Harm?, The Journal of Thoracic and Cardiovascular Surgery (2015), doi: 10.1016/j.jtcvs.2015.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Invited Editorial:

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Adjuvant Radiotherapy for Resectable Locally Advanced Non-Small Cell Lung

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Cancer: Benefit or Harm?

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4 Linda W. Martin, MD, MPH, FCCP, FACS Vice- Chair, Thoracic Surgery Committee, Alliance for Clinical Trials Assistant Professor, Department of Surgery Division of Thoracic Surgery University of Maryland Medical School 29 S. Greene St., Suite 504 Baltimore, MD 21201 410-328-6366 410-328-0693 fax [email protected]

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None of the authors have any financial disclosures. No potential conflicts of interest exist.

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Gail E. Darling, M.D., FRCSC FACS Surgical Chair, NRG Lung Cancer Committee Kress Family Chair Esophageal Cancer University of Toronto Chair Royal College Thoracic Surgery Specialty Committee Director Clinical Research in Thoracic Surgery Toronto General Hospital, University Health Network 200 Elizabeth Street, 9N-955 Toronto, ON M5G 2C4 Canada 1 416 340-3121 1 416 340-3660 (fax) [email protected]

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Dennis A. Wigle, MD, PhD Chair, Thoracic Surgery Committee, Alliance for Clinical Trials Associate Professor and Chair, Division of Thoracic Surgery Department of Surgery, Mayo Clinic 200 First Street SW Rochester, MN 55905 1 507 284-8462 1 507 284-0058 (fax) [email protected]

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Central message

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Adjuvant radiation in NSCLC is controversial and never proven to improve survival.

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Technical improvements warrant re-evaluation.

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46 Perspective Statement

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The INT 0139 trial has increased the application of chest radiation in neoadjuvant

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protocols for surgically resectable locally advanced NSCLC, while PORT meta-analysis

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results dampened enthusiasm for its use in the adjuvant setting. Emerging modern data

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challenge this thinking. We discuss issues with old and new data, and review potential

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trials that could settle the question.

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The use of postoperative radiotherapy (PORT) for the patient with surgically resected,

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N2+ non-small cell lung cancer (NSCLC) continues to generate significant controversy.

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Advocates argue that if mediastinal radiation is beneficial in providing local control, then

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whether it is given pre- or post-operatively should not matter. Detractors counter with the

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results of the PORT meta-analysis,1 quoting not only lack of benefit, but outright harm for

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adjuvant radiation at least for stage I-II. Who is right and how did we get here?

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Approximately 30% of NSCLC cases are stage IIIA or IIIB, and most are inoperable

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either oncologically, technically, or medically, and are treated with concurrent

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chemoradiation to “definitive” doses of 60+Gy. At best, 30-40% of patients in the N2+,

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IIIA category may be operable.2,3 In North America, the standard of care treatment

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algorithms are the protocols used in the Intergroup 0139 trial.4 This study randomized

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patients with T1-3, N2+ NSCLC to either receive induction chemotherapy plus

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radiotherapy to 45 Gy, followed by surgery if no disease progression, or patients

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continued radiotherapy uninterrupted up to 61+ Gy. Approximately 200 patients were

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randomized to each arm. The study was widely interpreted as showing no benefit to

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trimodality therapy. Despite the overall conclusion, there were a number of key findings

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including: 1) Patients with N0 status at the time of thoracotomy following induction

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treatment have an improved overall 5-year survival than those who have residual

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mediastinal nodal disease; 2) Patients undergoing pneumonectomy following induction

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chemoradiation to 45 Gy had worse treatment-related and overall outcomes when

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compared with patients undergoing lobectomy; 3) Chemoradiation to 60+ Gy (without

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surgery) has a measureable cure rate; 4) Chemotherapy plus concurrent radiotherapy

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with and without resection are both acceptable treatment options for N2 NSCLC with

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measurable cure rates; 5) Patients with tumors that are resectable with lobectomy

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following chemoradiation (to 45 Gy) may have improved outcomes when compared with

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patients undergoing chemoradiation alone (to 60 Gy); 6) Disease Free Survival was

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higher in the trimodality arm; 7) Overall survival curves cross and then separate, with

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survival in the trimodality arm lower due to excess mortality in the intial postoperative

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deaths, mainly due to pneumonectomies, and then higher survival as patients were

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followed out to 5 years.

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The results of this trial remain very controversial, with differing interpretations both from

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medical and radiation oncologists and from surgeons with regard to the respective value

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of their treatments within a multimodality regimen. However, all agree that surgery alone

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is clearly not an acceptable treatment strategy, with inferior outcomes compared to

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combination with either adjuvant or neoadjuvant therapy. Many surgeons, ourselves

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included, have contested the perceived morbidity of operating after irradiation with either

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45 or 60 Gy, and a number of small trials and retrospective studies have suggested that

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this could be done safely with far better outcomes than those achieved within the INT

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0139 study.5

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Despite these data, an important question persists: is radiation a critical part of neoadjuvant regimens for surgically resectable N2+ disease? Many groups have

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contested this assumption, with a number of leading cancer centers advocating

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neoadjuvant chemotherapy only and reserving adjuvant radiation for persistent N2

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disease at the time of surgery, or skipping it entirely for surgically resected disease.

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Furthermore, what about the surprise N2+ disease situation, which occurs 5-10% of the

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time even in the era of modern imaging and invasive mediastinal staging?6 If radiation

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adds value in the neoadjuvant setting, why wouldn’t it in the adjuvant setting?

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107 A key study in the field is the PORT meta-analysis.1 This includes results of 11 trials,

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involving 2343 patients in randomized studies. Overall, the results revealed 5%

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decreased survival at 2 years with PORT for stages I-III (from 58% to 53%). This

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represents an 18% increased relative risk of death for all groups who received PORT.

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However, subset analysis indicated that pN0-N1 patients experienced an inferior

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outcome with adjuvant radiation whereas N2 patients did not experience increased risk

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of death and notably had improved local control. Lally et al.7 showed that patients in the

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SEER database who were pN0 or pN1 had worse outcomes with PORT, similar to the

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findings in the ANITA trial post-hoc analysis.8 These modern, confirmatory findings lead

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to the conclusion that PORT should not be recommended for completely resected stage

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1 and 2 NSCLC.

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There are important limitations of the PORT meta-analysis. Patient accrual to the trials

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was from 1965-1995; there was no CT planning; no CT-PETs; 7 of the 11 trials used

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Cobalt radiation; there were many more squamous than adenocarcinoma patients (in

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some studies this was the exclusive histology which is not reflective of current

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epidemiology); follow up was only 4.4 years on average; the interval between surgery

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and radiation was beyond standard of care in many cases; and information and quality

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control of the extent of surgical lymph node sampling or resection was not available.

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Despite these problems, there still was a substantial reduction in local recurrence. The

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lack of survival benefit is likely due to death from excessive early and late toxicity.

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With modern techniques both toxicity and effectiveness are improved. CT and PET/CT

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simulation, 3 dimensional planning, and respiratory gating yield better target coverage

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and lower normal tissue irradiation. Several studies using more modern techniques7,9,10

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noted insignificant increases in deaths from intercurrent disease rather than death due to

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lung cancer. Specifically, the incidence of cardiac deaths over different time periods

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decreased as radiation techniques became modernized. These improvements decrease

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the risk of treatment related death compared to the historical studies evaluated in the

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PORT meta-analysis.

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Should adjuvant radiation for locally advanced, N2+ disease be considered? From the

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PORT meta-analysis, in pN2 patients, local control is 25-35% better with PORT. Local

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recurrence after treatment of clinical N2 disease with induction chemotherapy alone

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followed by surgery is 20 to 40% at 5 years.11,12 Such patients may benefit from PORT if

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only from the perspective of local control.

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More recent, albeit retrospective data, suggests PORT enhances survival as well as

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local control in pN2+ cases. In the SEER study, N2 patients achieved 5 year survival of

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27% with PORT, 20% without.7 In the ANITA unplanned analysis, pN2 patients who got

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radiation in addition to chemo had the best outcome: 47% 5 year survival compared to

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34% with adjuvant chemotherapy alone.8 A recent analysis13 of the National Cancer

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Database of 4483 patients who had surgery with at least lobectomy, followed by

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sequential adjuvant chemotherapy and radiation indicates that PORT was associated

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with enhanced overall survival on multivariable analysis: 5 year survival increased from

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34.8% to 39.3%, median survival 40.7 months to 45.2 months, p = 0.014.

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There is currently no actively accruing, cooperative group trial in North America for

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resectable stage IIIA disease. In Europe, Lung Adjuvant Radiation Trial (Lung ART) is

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randomizing pN2 patients to adjuvant radiation, 54 Gy, after chemotherapy and

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complete resection.14 It has been relatively slow to accrue (300 patients in 8 years,

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target of 700) but is picking up some momentum as it opens across more European

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sites. Results from well-designed, prospective clinical trials are needed in this era of

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better surgery, better postoperative care, rigorously defined and documented nodal

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dissection, better staging, and modern radiotherapy that is less toxic, well executed and

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targeted. We expect a positive impact of PORT on outcomes for surgically resected pN2

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patients, but await confirmatory trial data to change practice for this difficult and

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controversial disease stage.

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