Survival of Patients Treated with High-dose Radiotherapy and Concurrent Chemotherapy for Unresectable Non-small-cell Lung Cancer

US Oncological Review, 2010;6(1):32-5 DOI:


Radiotherapy (RT) has been used to treat cancers for 110 years. Today, megavoltage RT is delivered with very precise linear accelerators. Computed tomography and/or positron-emission tomography are used to define both tumor and normal tissue volumes. Powerful computers analyze these volumes in 3D space and design complex treatment plans. Over time, the ratio of dose administered to tumor compared with dose administered to the normal structures has increased, resulting in a better therapeutic index and improved survival. In the 1970s and 1980s, the five-year survival rate of unresectable non-small-cell lung carcinoma was 5% with standard RT alone. Adding chemotherapy before or after radiation improved the five-year survival to about 15%. More recently, concurrent chemotherapy and RT has achieved five-year survival rates of up to 29%. Pilot trials employing chemotherapy and higher-dose RT have resulted in still better local control and survival. A phase III trial of chemotherapy plus either standard-dose RT (60Gy/30) or high-dose RT (74Gy/37) is ongoing. New technology is providing ways to improve the therapeutic ratio and administer greater RT doses more safely.
Keywords: Lung cancer, radiation therapy, radiotherapy (RT), chemotherapy, high-dose radiotherapy, 3D treatment planning
Disclosure: Steven E Schild and Helen J Ross are members of the North Central Cancer Treatment Group (NCCTG) Lung Cancer Committee. NCCTG provides support for their lung cancer research.
Received: January 28, 2010 Accepted October 06, 2010
Correspondence: Steven E Schild, MD, Professor and Chairman, Department of Radiation Oncology, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259. E:

Lung cancer is the leading cause of cancer deaths, having caused an estimated 1.18 million deaths worldwide in 2002.1 In the US alone, lung cancer resulted in an estimated 159,300 deaths in 2009.2 Most deaths are from non-small-cell lung cancer (NSCLC), which accounts for more than 80% of lung cancers diagnosed in the US. Sadly, most patients present with advanced, inoperable disease. While stage IV patients remain incurable, there is now potentially curative therapy that can be offered to most patients with stage III NSCLC.3
Radiotherapy Becomes Standard Treatment for Unresectable Non-small-cell Lung Cancer
Over 40 years ago, Wolf et al. established the role of RT in the treatment of lung cancer. Their randomized phase III trial compared radiotherapy (RT) versus placebo for clinically inoperable lung cancer (including both small-cell and NSCLC). RT was delivered with 200–250kV X-rays and included the delivery of 40–50Gy in 1.5–2.0Gy daily fractions. The median survival of patients given RT was 142 days compared with 112 days for those who received the placebo (p=0.05).4 A phase III Radiation Therapy Oncology Group (RTOG) trial evaluated the effect of dose on outcome by randomly assigning patients to receive 40Gy in 20 daily fractions, 50Gy in 25 daily fractions, or 60Gy in 30 daily fractions. The local failure rates determined with serial chest X-rays were 48% with 40Gy, 38% with 50Gy, and 27% with 60Gy. Although the differences in survival were not significant, this study defined the standard RT dose as 60Gy in 30 daily fractions.5 This dose fractionation pattern remained the standard of care for decades. Conventional RT alone resulted in a median survival of 10 months and a five-year survival of 5%. Until the 1990s, the standard treatment for locally advanced inoperable lung cancer was RT alone.5
Combined Radiotherapy (RT) plus Chemotherapy Supplants RT Alone as Standard Therapy
In order to improve the outcome of treatment, chemotherapy was added to RT. Phase III trials demonstrated a survival advantage following the addition of chemotherapy to RT for NSCLC.6,7 The Cancer and Leukemia Group B reported that induction chemotherapy (cisplatin plus vinblastine) followed by conventional RT (60Gy/30 fractions) resulted in significantly better survival than conventional RT alone.6 The median and five-year survivals were 13.7 months and 17% for the combined therapy versus 9.6 months and 6% for RT alone (p=0.012).6
  1. Parkin DM, Bray F, Ferlay J, et al., Global cancer statistics, 2002, CA Cancer J Clin, 2005;55:74–108.
  2. Jemal, A, Siegel, R, Ward, et al., Cancer statistics, 2009, CA Cancer J Clin, 2009;59:225–49.
  3. Videtic G, Vokes E, Turrisi A, et al., The survival of patients treated for stage III non-small cell lung cancer in North America has increased during the past 25 years, Proc Am Soc Clin Oncol, 2003;22: abstract 2557. Available at: (accessed 9 June 2010).
  4. Wolf J, Patno ME, Roswit B, et al., Controlled study of survival of patients with clinically inoperable lung cancer treated with radiation therapy, Am J Med, 1966;40:360–7.
  5. Perez C, Non-small cell carcinoma of the lung. Dose-time parameters, Cancer Treat Symp, 1985;2:131–42.
  6. Dillman RO, Herndon J, Seagren SL, et al., Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial, J Natl Cancer Inst, 1996;88:1210–5.
  7. Sause WT, Scott C, Taylor S, et al., Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer, J Natl Cancer Inst, 1995;87:198–205.
  8. Schaake-Koning C, van den Bogaert W, Dalesio O, et al., Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer, N Engl J Med, 1992;326:524–30.
  9. Le Chevalier T, Arriagada R, Tarayre M, et al., Significant effect of adjuvant chemotherapy on survival in locally advanced non-small-cell lung carcinoma, J Natl Cancer Inst, 1992;84:58.
  10. Chemotherapy in non-small cell lung cancer: a metaanalysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group, BMJ, 1995;311:899–909.
  11. Furuse K, Fukuoka M, Kawahara M, et al., Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer, J Clin Oncol, 1999;17:2692–9.
  12. Komaki R, Seiferheld W, Curran W, et al., Sequential vs. concurrent chemotherapy and radiation therapy for inoperable non-small cell lung cancer (NSCLC): Analysis of failures in a phase III study (RTOG 9410) (abstract 5), Proceedings of the 42nd Annual ASTRO Meeting, 2000;113.
  13. Gandara DR, Chansky K, Albain KS, et al., Long-term survival with concurrent chemoradiation therapy followed by consolidation docetaxel in stage IIIB non-small-cell lung cancer: a phase II Southwest Oncology Group Study (S9504), Clin Lung Cancer, 2006;8:116–21.
  14. Fletcher GH, Shukovsky LJ, The interplay of radiocurability and tolerance in the irradiation of human cancers, J Radiol Electrol Med Nucl, 1975;56:383–400.
  15. Mehta M, Scrimger R, Mackie R, et al., A new approach to dose escalation in non-small-cell lung cancer, Int J Radiat Oncol Biol Phys, 2001;49:23–33.
  16. Bradley J, Graham MV, Winter K, et al. 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, Int J Radiat Oncol Biol Phys, 2005;61:318–28.
  17. Bradley JD, Graham M, Suzanne S, et al., Phase I Results of RTOG L-0117; a Phase I/II Dose Intensification Study Using 3DCRT and Concurrent Chemotherapy for Patients with Inoperable NSCLC, J Clin Oncol, 2005 ASCO Annual Meeting Proceedings, 23(16S):7063.
  18. Sim S, Rosenzweig KE, Schindelheim R, et al., Induction chemotherapy plus three-dimensional conformal radiation therapy in the definitive treatment of locally advanced non-small-cell lung cancer, Int J Radiat Oncol Biol Phys, 2001;51:660–5.
  19. Rosenzweig KE, Sim SE, Mychalczak B, et al., Elective nodal irradiation in the treatment of non-small-cell lung cancer with three-dimensional conformal radiation therapy, Int J Radiat Oncol Biol Phys, 2001;50:681–5.
  20. Belderbos, JS, De Jaeger, K, Heemsbergen, WD, et al. First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy, Radiother Oncol, 2003;66:119–26.
  21. Senan S, Burgers S, Samson MJ, et al., Can elective nodal irradiation be omitted in stage III non-small-cell lung cancer? Analysis of recurrences in a phase II study of induction chemotherapy and involved-field radiotherapy, Int J Radiat Oncol Biol Phys, 2002;54:999–1006.
  22. Hayman JA, Martel MK, Ten Haken RK, et al., Dose escalation in non-small-cell lung cancer using threedimensional conformal radiation therapy: update of a phase I trial, J Clin Oncol, 2001;19:127–36.
  23. Schild SE, Korte SM, Wong WW, et al., Treatment planning for dose escalation in non-small cell lung cancer (NSCLC), Med Dosim, 2004;29:196–203.
  24. Rosenzweig KE, Amols H, Ling CC, New radiotherapy technologies, Semin Surg Oncol, 2003;21:190–5.
  25. Rosenzweig KE, Sura S, Jackson A, et al., Involved-field radiation therapy for inoperable non small-cell lung cancer, J Clin Oncol, 2007;25:5557–61.
  26. Sura, S, Yorke, E, Jackson, A, Rosenzweig, KE. High-dose radiotherapy for the treatment of inoperable non-small cell lung cancer, Cancer J, 2007;13(4):238–42.
  27. Wang, L, Correa, CR, Zhao, L, et al. The effect of radiation dose and chemotherapy on overall survival in 237 patients with Stage III non-small-cell lung cancer, Int J Radiat Oncol Biol Phys, 2009;73:1383–90.
  28. Rades D, Setter C, Schild SE, Dunst J, Effect of smoking during radiotherapy, respiratory insufficiency, and hemoglobin levels on outcome in patients irradiated for non-small-cell lung cancer, Int J Radiat Oncol Biol Phys, 2008;71:1134–42.
  29. Socinski MA, Morris DE, Halle JS, et al., Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial, J Clin Oncol, 2004;22:4341–50.
  30. Stinchcombe TE, Lee CB, Moore DT, et al., Long-term follow-up of a phase I/II trial of dose escalating threedimensional conformal thoracic radiation therapy with induction and concurrent carboplatin and paclitaxel in unresectable stage IIIA/B non-small cell lung cancer, J Thorac Oncol, 2008;3:1279–85.
  31. Schild SE, McGinnis WL, Graham D, et al., Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer, Int J Radiat Oncol Biol Phys, 2006;65:1106–11.
  32. Bradley D, Bae, K, Graham, MV, et al., Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117, J Clin Oncol, 2010;28:2475–80.
  33. Schild SE, Graham DL, Hillman SL, et al., Survival of patients treated with high-dose radiotherapy and concurrent chemotherapy for unresectable non-small cell lung cancer, J Thoracic Oncol, 2009;4:S336.
  34. Yuan S, Sun X, Li M, et al., A randomized study of involvedfield irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer, Am J Clin Oncol, 2007;30:239–44.
Keywords: Lung cancer, radiation therapy, radiotherapy (RT), chemotherapy, high-dose radiotherapy, 3D treatment planning