Neoadjuvant Radiotherapy/Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer

Abstract

Locally advanced non-small cell lung cancer (NSCLC) consists of a heterogeneous group of patients, and the optimal treatment is still controversial. The current standard of care is concurrent chemoradiotherapy. The prognosis is still poor, with high rates of local and distant failure despite multimodality treatment. One of the efforts to improve outcomes in these patients is to use neoadjuvant treatment to improve resectability, and downstaging the nodal disease, which has a clear impact on prognosis. Radiotherapy as the sole neoadjuvant modality has been used historically without any survival benefit, but with increased toxicity. After the demonstrating a survival benefit by combining radiotherapy and chemotherapy, phase II studies were started to determine the neoadjuvant administration of these two modalities together. Although the results of these studies revealed a heterogeneous postinduction pathologic complete response, tumor and nodal downstaging can be achieved at the cost of a slightly higher morbidity and mortality. Subsequent phase III trials also failed to show a survival benefit to surgery, but indicated that there may be a subset of patients with locally advanced disease who can benefit from resection unless pneumonectomy is not provided. In order to increase the efficacy of radiotherapy, hyperfractionated-accelerated schedules have been used with promising complete pathologic response rates, which might improve prognosis. Recently, studies applying high radiotherapy doses in the neoadjuvant setting demonstrated the safety of resection after radiotherapy, with high nodal clearance rates and encouraging long-term survival results. In conclusion, neoadjuvant treatment of locally advanced NSCLC is one of the most challenging issues in the treatment of this disease, but it can be offered to appropriately selected patients, and should be done by a multidisciplinary team. Individual risk profiles, definite role of radiotherapy with optimal timing, and dose need to be clarified by carefully designed clinical trials.

Keywords

• Locally advanced non-small cell lung cancer, neoadjuvant chemoradiotherapy, neoadjuvant radiotherapy

References

1. 1. Ramnath N, Dilling TJ, Harris LJ, Kim AW, Michaud GC, Balekian AA, et al. Treatment of stage III non-small cell lung cancer. Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2013;143(Suppl):e314S-40.
2. 2. Bromley LL, Szur L. Combined radiotherapy and resection for carcinoma of the bronchus; experiences with 66 patients. Lancet 1955;269:937- 41. [CrossRef]
3. 3. Bloedorn FG, Cowley RA, Cuccia CA, Mercado R Jr, Wizenberg MJ, Linberg EJ. Preoperative irradiation in bronchogenic carcinoma. Am J Roentgenol Radium Ther Nucl Med 1964;92:77-87.
4. 4. Warram J. Preoperative irradiation of cancer of the lung: final report of a therapeutic trial. A collaborative study. Cancer 1975;36:914-25. [CrossRef]
5. 5. Wagner H Jr, Lad T, Piantadosi S, Ruckdeschel JC. Randomized phase 2 evaluation of preoperative radiation therapy and preoperative chemotherapy with mitomycin, vinblastine, and cisplatin in patients with technically unresectable stage IIIA and IIIB non-small cell cancer of the lung. LCSG 881. Chest 1994;106:S348-54. [CrossRef]
6. 6. Elias AD, Kumar P, Herndon J 3rd, Skarin AT, Sugarbaker DJ, Green MR. Radiotherapy versus chemotherapy plus radiotherapy in surgically treated IIIA N2 non-small cell lung cancer. Clin Lung Cancer 2002;4:95-103. [CrossRef]
7. 7. Eagan RT, Ruud C, Lee RE, Pairolero PC, Gail MH. Pilot study of induction therapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) and chest irradiation prior to thoracotomy in initially inoperable stage III M0 non-small cell lung cancer. Cancer Treat Rep 1987;71:895-900.
8. 8. Skarin A, Jochelson M, Sheldon T, Malcolm A, Oliynyk P, Overholt R, et al. Neoadjuvant chemotherapy in marginally resectable stage III M0 non-small cell lung cancer: long-term follow-up in 41 patients. J Surg Oncol 1989:40:266-74. [CrossRef]

9. 9. Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi AT 3rd, Weick JK, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stagesIIIA (N2) and IIIB non-small cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880-92.
10. 10. Faber LP, Kittle CF, Warren WH, Bonomi PD, Taylor SG 4th, Reddy S, et al. Preoperative chemotherapy and irradiationfor stage III non-small cell lung cancer. Ann Thorac Surg 1989;47:669-75. [CrossRef]
11. 11. Law A, Karp DD, Dipetrillo T, Daly BT. Emergence of increased cerebral metastasis after high-dose preoperative radiotherapy with chemotherapy in patients with locally advanced nonsmall cell lung carcinoma. Cancer 2001;92:160-4. [CrossRef]
12. 12. Strauss GM, Herndon JF, Sherman DD, Mathisen DJ, Carey RW, Choi NC, et al. Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study. J Clin Oncol 1992;10:1237- 44.
13. 13. Weiden PL, Piantodosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small cell lung cancer: A phase 2 study of the LCSG. Chest 1994;106(6Suppl):S344-7. [CrossRef]
14. 14. Albain KS, Swann S, Rusch VW, Turrisi AT 3rd, Shepherd FA, 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;374:379-86. [CrossRef]
15. 15. Koshy M, Fedewa SA, Malik R, Ferguson MK, Vigneswaran WT, Feldman L, et al. Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer. J Thorac Oncol 2013;8:915-22. [CrossRef]
16. 16. Choi N, Carey R, Daly W, Mathisen D, Wain J, Wright C, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small cell lung cancer. J Clin Oncol 1997;15:712-22.
17. 17. Eberhardt W, Wilke H, Stamatis G, Stuschke M, Harstrick A, Menker H, et al. Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small cell lung cancer: mature results of a phase II trial. J Clin Oncol 1998;16:622-34.
18. 18. Thomas M, Rübe C, Semik M, Macha HN, Freitag L, Linder A, et al. Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer. J Clin Oncol 1999;17:1185-93.
19. 19. DeCamp MM, Rice TW, Adelstein DJ, Chidel MA, Rybicki LA, Murthy SC, et al. Value of accelerated multimodality therapy in stage IIIA and IIIB non-small cell lung cancer. J Thora Cardiovasc Surg 2003;126:17- 27. [CrossRef]
20. 20. Thomas M, Rübe C, Hoffknecht P, Macha HN, Freitag L, Linder A, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small cell lung cancer. Lancet Oncol 2008;9:636-48. [CrossRef]
21. 21. Eberhardt WE, Gauler TC, Le Pechoux C, Stamatis G, Bildat S, Krbek T, et al. 10-year long-term survival (LTS) of induction chemotherapy with three cycles cisplatin/paclitaxel followed by concurrent chemoradiation cisplatin/etoposide/45 Gy (1.5 Gy bid) plus surgery in locally advanced non-small cell lung cancer (NSCLC)-A multicenter phase-II trial (CISTAXOL). Lung Cancer 2013;82:83-9. [CrossRef]
22. 22. Eberhardt WEE, Gauler TC, Pöttgen C, Friedel G, Veit S, Heinrich V, et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with operable stage IIIA(N2)/selected IIIB non-small cell lung cancer following induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol 2014;32(15 Suppl):5s.
23. 23. Pöttgen C, Eberhardt W, Graupner B, Theegarten D, Gauler T, Freitag L, et al. Accelerated hyperfractionated radiotherapy within trimodality therapy concepts for stage IIIA/B non-small cell lung cancer: markedly higher rate of pathologic complete remissions than with conventional fractionation. Eur J Cancer 2013;49:2107-15. [CrossRef]
24. 24. Mauguen A, Le Péchoux C, Saunders MI, Schild SE, Turrisi AT, Baumann M, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788-97. [CrossRef]
25. 25. Fowler WC, Langer CJ, Curran WG, Keller SM. Postoperative complications after combined neoadjuvant treatment of lung cancer. Ann Thorac Surg 1993;55:986-9. [CrossRef]
26. 26. Sonett JR, Suntharalingam M, Edelman MJ, Patel AB, 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;78:1200-5. [CrossRef]
27. 27. Cerfolio RJ, Bryant AS, Spencer SA, Bartolucci AA. Pulmonary resection after high-dose and low-dose chest irradiation. Ann Thorac Surg 2005;80:1224-30. [CrossRef]
28. 28. Daly BD, Fernando HC, Ketchedjian A, Dipetrillo TA, Kachnic LA, Morelli DM, et al. Pneumonectomy after high-dose radiation and concurrent chemotherapy for nonsmall cell lung cancer. Ann Thorac Surg 2006;82:227-31. [CrossRef]
29. 29. Suntharalingam M, Paulus R, Edelman MJ, 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 fulldose 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;84:456-63. [CrossRef]
30. 30. Grunenwald DH, AndréF, Le Péchoux C, Girard P, Lamer C, Laplanche A, et al. Benefit of surgery after chemoradiotherapy in stage IIIB (T4 and/or N3) non-small cell lung cancer. J Thorac Cardiovasc Surg 2001;122:796-802. [CrossRef]
31. 31. Stupp R, Mayer M, Kann R, Weder W, Zouhair A, Betticher DC, et al. Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: A multicentre phase II trial. Lancet Oncol 2009;10:785-93. [CrossRef]