Surgical complications and clinical outcomes after dose-escalated trimodality therapy for non-small cell lung cancer in the era of intensity-modulated radiotherapy

  • Author Footnotes
    1 Equally contributing first-authors.
    Kevin X. Liu
    Correspondence
    Corresponding authors at: Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Ave, Boston, MA 02215, United States (K.X. Liu). Department of Radiation Oncology, University of California, San Francisco, 1825 4th St, San Francisco, CA 94158, United States (L. Singer).
    Footnotes
    1 Equally contributing first-authors.
    Affiliations
    Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
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  • Author Footnotes
    1 Equally contributing first-authors.
    Kailan Sierra-Davidson
    Footnotes
    1 Equally contributing first-authors.
    Affiliations
    Department of Surgery, Massachusetts General Hospital, Boston, United States
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  • Kevin Tyan
    Affiliations
    Harvard Medical School, Boston, United States
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  • Lawrence T. Orlina
    Affiliations
    Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
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  • J. Paul Marcoux
    Affiliations
    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, United States
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  • Benjamin H. Kann
    Affiliations
    Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
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  • David E. Kozono
    Affiliations
    Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
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  • Raymond H. Mak
    Affiliations
    Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
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  • Abby White
    Affiliations
    Division of Thoracic Surgery, Brigham and Women’s Hospital, Boston, United States
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  • Lisa Singer
    Correspondence
    Corresponding authors at: Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Ave, Boston, MA 02215, United States (K.X. Liu). Department of Radiation Oncology, University of California, San Francisco, 1825 4th St, San Francisco, CA 94158, United States (L. Singer).
    Affiliations
    Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, United States

    Department of Radiation Oncology, University of California, San Francisco, United States
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  • Author Footnotes
    1 Equally contributing first-authors.
Published:October 22, 2021DOI:https://doi.org/10.1016/j.radonc.2021.10.012

      Highlights

      • Little is known about outcomes and toxicities after preplanned trimodality therapy with IMRT to higher doses.
      • Using IMRT, there was no difference in complications or overall survival for patients receiving <60 Gy and ≥60 Gy.
      • On univariate and multivariable analyses, increased length of hospital stay was significantly associated with worse overall survival.

      Abstract

      Background

      Trimodality therapy (TMT) with preoperative chemoradiation followed by surgical resection is used for locally-advanced non-small-cell lung cancer (LA-NSCLC). Traditionally, preoperative radiation doses ≤54 Gy are used due to concerns regarding excess morbidity, but little is known about outcomes and toxicities after TMT with intensity-modulated radiotherapy (IMRT) to higher doses.

      Methods

      A retrospective analysis of patients who received planned TMT with IMRT for LA-NSCLC at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2008 and 2017 was performed. Clinical and treatment characteristics, pathologic response, and surgical toxicity were assessed. Kaplan-Meier method and log-rank test was used for survival outcomes. Cox proportional-hazards regression was used for multivariable analysis.

      Results

      Forty-six patients received less than definitive doses of <60 Gy and 30 patients received definitive doses ≥60 Gy. Surgical outcomes, pathologic complete response, and postoperative toxicity did not differ significantly between the groups. With median follow-up of 3.6 years (range: 0.4–11.4), three-year locoregional recurrence-free survival (78.0% vs. 68.3%, p = 0.51) and overall survival (OS) (61.0% vs. 69.4%, p = 0.32) was not significantly different between patients receiving <60 Gy and ≥60 Gy, respectively. On multivariable analysis, older age, clinical stage, and length of hospital stay (LOS) >7 days were associated with OS.

      Conclusions

      With IMRT, there was no increased rate of surgical complications in patients receiving higher doses of radiation. Survival outcomes or LOS did not differ based on radiation dose, but increased LOS was associated with worse OS. Larger prospective studies are needed to further examine outcomes after IMRT in patients with LA-NSCLC receiving TMT.

      Abbreviations:

      3D-CRT (three-dimensional conformal radiation therapy), AJCC (American Joint Committee on Cancer), ARDS (acute respiratory distress syndrome), CI (confidence interval), CRT (chemoradiation), CT (computed tomography), DMFS (Distant metastasis-free survival), EBUS (endobronchial ultrasound), Gy (Gray), HR (hazard ratio), ICU (intensive care unit), IMRT (intensity-modulated radiotherapy), LA (locally advanced), LCCS (lung cancer-specific survival), LOS (length of hospital stay), LRRFS (Locoregional recurrence-free survival), MLD (mean lung dose), MNC (mediastinal nodal clearance), NSCLC (non-small cell lung cancer), OS (overall survival), pCR (pathologic complete response), PET/CT (positron emission tomography/computed tomography), PFS (progression-free survival), RTOG (Radiation Therapy Oncology Group), TMT (trimodality therapy), VATS (video-assisted thoracoscopic surgery)

      Keywords

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      References

        • Molina J.R.
        • Yang P.
        • Cassivi S.D.
        • Schild S.E.
        • Adjei A.A.
        Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship.
        Mayo Clin Proc. 2008; 83: 584-594
        • Albain K.S.
        • Rusch V.W.
        • Crowley J.J.
        • Rice T.W.
        • Turrisi 3rd, A.T.
        • Weick J.K.
        • et al.
        Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805.
        J Clin Oncol. 1995; 13: 1880-1892
        • Sugarbaker D.J.
        • Herndon J.
        • Kohman L.J.
        • Krasna M.J.
        • Green M.R.
        Results of cancer and leukemia group B protocol 8935. A multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer. Cancer and Leukemia Group B Thoracic Surgery Group.
        J Thorac Cardiovasc Surg. 1995; 109 (discussion 83–5): 473-483
        • Albain K.S.
        • Swann R.S.
        • Rusch V.W.
        • Turrisi 3rd, A.T.
        • Shepherd F.A.
        • Smith C.
        • et al.
        Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.
        Lancet. 2009; 374: 379-386
        • Eberhardt W.E.
        • Albain K.S.
        • Pass H.
        • Putnam J.B.
        • Gregor A.
        • Assamura H.
        • et al.
        Induction treatment before surgery for non-small cell lung cancer.
        Lung Cancer. 2003; 42: S9-S14
        • Fowler W.C.
        • Langer C.J.
        • Curran Jr., W.J.
        • Keller S.M.
        Postoperative complications after combined neoadjuvant treatment of lung cancer.
        Ann Thorac Surg. 1993; 55: 986-989
        • Allen A.M.
        • Shochat T.
        • Flex D.
        • Kramer M.R.
        • Zer A.
        • Peled N.
        • et al.
        High-dose radiotherapy as neoadjuvant treatment in non-small-cell lung cancer.
        Oncology. 2018; 95: 13-19
        • Cerfolio R.J.
        • Bryant A.S.
        • Spencer S.A.
        • Bartolucci A.A.
        Pulmonary resection after high-dose and low-dose chest irradiation.
        Ann Thorac Surg. 2005; 80 (discussion 30): 1224-1230
        • Donington J.S.
        • Paulus R.
        • Edelman M.J.
        • Krasna M.J.
        • Le Q.T.
        • Suntharalingam M.
        • et al.
        Resection following concurrent chemotherapy and high-dose radiation for stage IIIA non-small cell lung cancer.
        J Thorac Cardiovasc Surg. 2020; 160 (1331–45 e1)
        • Edelman M.J.
        • Suntharalingam M.
        • Burrows W.
        • Kwong K.F.
        • Mitra N.
        • Gamliel Z.
        • et al.
        Phase I/II trial of hyperfractionated radiation and chemotherapy followed by surgery in stage III lung cancer.
        Ann Thorac Surg. 2008; 86: 903-910
        • Sonett J.R.
        • Suntharalingam M.
        • Edelman M.J.
        • Patel A.B.
        • Gamliel Z.
        • Doyle A.
        • et al.
        Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer.
        Ann Thorac Surg. 2004; 78 (discussion 6): 1200-1205
        • Suntharalingam M.
        • Paulus R.
        • Edelman M.J.
        • Krasna M.
        • Burrows W.
        • Gore E.
        • et al.
        Radiation therapy oncology group protocol 02–29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung.
        Int J Radiat Oncol Biol Phys. 2012; 84: 456-463
        • Vyfhuis M.A.L.
        • Bhooshan N.
        • Burrows W.M.
        • Turner M.
        • Suntharalingam M.
        • Donahue J.
        • et al.
        Oncological outcomes from trimodality therapy receiving definitive doses of neoadjuvant chemoradiation (>/=60 Gy) and factors influencing consideration for surgery in stage III non-small cell lung cancer.
        Adv Radiat Oncol. 2017; 2: 259-269
        • Bueno R.
        • Richards W.G.
        • Swanson S.J.
        • Jaklitsch M.T.
        • Lukanich J.M.
        • Mentzer S.J.
        • et al.
        Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival.
        Ann Thorac Surg. 2000; 70: 1826-1831
        • Farray D.
        • Mirkovic N.
        • Albain K.S.
        Multimodality therapy for stage III non-small-cell lung cancer.
        J Clin Oncol. 2005; 23: 3257-3269
        • Lee H.
        • Ahn Y.C.
        • Pyo H.
        • Kim B.
        • Oh D.
        • Nam H.
        • et al.
        Pretreatment clinical mediastinal nodal bulk and extent do not influence survival in N2-positive stage IIIA non-small cell lung cancer patients treated with trimodality therapy.
        Ann Surg Oncol. 2014; 21: 2083-2090
        • Agrawal V.
        • Coroller T.P.
        • Hou Y.
        • Lee S.W.
        • Romano J.L.
        • Baldini E.H.
        • et al.
        Radiologic-pathologic correlation of response to chemoradiation in resectable locally advanced NSCLC.
        Lung Cancer. 2016; 102: 1-8
        • Sher D.J.
        • Fidler M.J.
        • Seder C.W.
        • Liptay M.J.
        • Koshy M.
        Relationship between radiation therapy dose and outcome in patients treated with neoadjuvant chemoradiation therapy and surgery for stage IIIA non-small cell lung cancer: A population-based, comparative effectiveness analysis.
        Int J Radiat Oncol Biol Phys. 2015; 92: 307-316
        • Bharadwaj S.C.
        • Vallieres E.
        • Wilshire C.L.
        • Blitz M.
        • Page B.
        • Aye R.W.
        • et al.
        Higher versus standard preoperative radiation in the trimodality treatment of stage IIIa lung cancer.
        Ann Thorac Surg. 2015; 100 (discussion 13–4): 207-213
        • Seder C.W.
        • Allen M.S.
        • Cassivi S.D.
        • Deschamps C.
        • Nichols F.C.
        • Olivier K.R.
        • et al.
        Stage IIIA non-small cell lung cancer: morbidity and mortality of three distinct multimodality regimens.
        Ann Thorac Surg. 2013; 95: 1708-1716
        • Chun S.G.
        • Hu C.
        • Choy H.
        • Komaki R.U.
        • Timmerman R.D.
        • Schild S.E.
        • et al.
        Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: A secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial.
        J Clin Oncol. 2017; 35: 56-62
      1. Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151:193-203.

        • Hermanek P.
        • Wittekind C.
        The pathologist and the residual tumor (R) classification.
        Pathol Res Pract. 1994; 190: 115-123
        • Boyle J.
        • Ackerson B.
        • Gu L.
        • Kelsey C.R.
        Dosimetric advantages of intensity modulated radiation therapy in locally advanced lung cancer.
        Adv Radiat Oncol. 2017; 2: 6-11
        • Yegya-Raman N.
        • Zou W.
        • Nie K.
        • Malhotra J.
        • Jabbour S.K.
        Advanced radiation techniques for locally advanced non-small cell lung cancer: intensity-modulated radiation therapy and proton therapy.
        J Thorac Dis. 2018; 10: S2474-S2491
        • Jiang Z.Q.
        • Yang K.
        • Komaki R.
        • Wei X.
        • Tucker S.L.
        • Zhuang Y.
        • et al.
        Long-term clinical outcome of intensity-modulated radiotherapy for inoperable non-small cell lung cancer: the MD Anderson experience.
        Int J Radiat Oncol Biol Phys. 2012; 83: 332-339
        • Liao Z.X.
        • Komaki R.R.
        • Thames Jr., H.D.
        • Liu H.H.
        • Tucker S.L.
        • Mohan R.
        • et al.
        Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy.
        Int J Radiat Oncol Biol Phys. 2010; 76: 775-781
        • Wang J.
        • Zhou Z.
        • Liang J.
        • Feng Q.
        • Xiao Z.
        • Hui Z.
        • et al.
        Intensity-modulated radiation therapy may improve local-regional tumor control for locally advanced non-small cell lung cancer compared with three-dimensional conformal radiation therapy.
        Oncologist. 2016; 21: 1530-1537
        • Yom S.S.
        • Liao Z.
        • Liu H.H.
        • Tucker S.L.
        • Hu C.S.
        • Wei X.
        • et al.
        Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy.
        Int J Radiat Oncol Biol Phys. 2007; 68: 94-102
        • Faivre-Finn C.
        • Vicente D.
        • Kurata T.
        • Planchard D.
        • Paz-Ares L.
        • Vansteenkiste J.F.
        • et al.
        Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial.
        J Thorac Oncol. 2021; 16: 860-867
        • Liang J.
        • Bi N.
        • Wu S.
        • Chen M.
        • Lv C.
        • Zhao L.
        • et al.
        Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial.
        Ann Oncol. 2017; 28: 777-783
        • Senan S.
        • Brade A.
        • Wang L.H.
        • Vansteenkiste J.
        • Dakhil S.
        • Biesma B.
        • et al.
        PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer.
        J Clin Oncol. 2016; 34: 953-962
        • Dasenbrock H.H.
        • Liu K.X.
        • Devine C.A.
        • Chavakula V.
        • Smith T.R.
        • Gormley W.B.
        • et al.
        Length of hospital stay after craniotomy for tumor: a National Surgical Quality Improvement Program analysis.
        Neurosurg Focus. 2015; 39: E12
        • Rajaram R.
        • Mohanty S.
        • Bentrem D.J.
        • Pavey E.S.
        • Odell D.D.
        • Bharat A.
        • et al.
        Nationwide assessment of robotic lobectomy for non-small cell lung cancer.
        Ann Thorac Surg. 2017; 103: 1092-1100
        • Wright C.D.
        • Gaissert H.A.
        • Grab J.D.
        • O'Brien S.M.
        • Peterson E.D.
        • Allen M.S.
        Predictors of prolonged length of stay after lobectomy for lung cancer: a Society of Thoracic Surgeons General Thoracic Surgery Database risk-adjustment model.
        Ann Thorac Surg. 2008; 85 (discussion 65): 1857-1865
        • Ma L.
        • Li J.
        • Shao L.
        • Lin D.
        • Xiang J.
        Prolonged postoperative length of stay is associated with poor overall survival after an esophagectomy for esophageal cancer.
        J Thorac Dis. 2015; 7: 2018-2023
        • Gao S.J.
        • Corso C.D.
        • Wang E.H.
        • Blasberg J.D.
        • Detterbeck F.C.
        • Boffa D.J.
        • et al.
        Timing of surgery after neoadjuvant chemoradiation in locally advanced non-small cell lung cancer.
        J Thorac Oncol. 2017; 12: 314-322
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • Vicente D.
        • Murakami S.
        • Hui R.
        • et al.
        Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
        N Engl J Med. 2018; 379: 2342-2350
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • Vicente D.
        • Murakami S.
        • Hui R.
        • et al.
        Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
        N Engl J Med. 2017; 377: 1919-1929
        • White A.A.
        • Lee D.N.
        • Mazzola E.
        • Kucukak S.
        • Polhemus E.
        • Jaklitsch M.T.
        • et al.
        Adjuvant therapy following induction therapy and surgery improves survival in N2-positive non-small cell lung cancer.
        J Surg Oncol. 2021; 123: 579-586