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Non-Small Cell Lung Cancer Treatment (Professional) (cont.)

Recurrent NSCLC Treatment

Standard Treatment Options for Recurrent NSCLC

Standard treatment options for recurrent NSCLC include the following:

  1. Radiation therapy (for palliation).[1]
  2. Chemotherapy or kinase inhibitors alone, including the following for patients who have previously received platinum chemotherapy:
    • Docetaxel.[2,3]
    • Pemetrexed.[3]
    • Erlotinib after failure of both platinum-based and docetaxel chemotherapies.[4]
    • Gefitinib.[5]
    • Crizotinib for EML4-ALK translocations.[6,7]
  3. EGFR inhibitors in patients with or without EGFR mutations.
  4. EML4-ALK inhibitors in patients with EML-ALK translocations.
  5. Surgical resection of isolated cerebral metastasis (for highly selected patients).[8]
  6. Laser therapy or interstitial radiation therapy (for endobronchial lesions).[9]
  7. Stereotactic radiation surgery (for highly selected patients).[10,11]

Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[12][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[13,14] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

Evidence (chemotherapy and targeted therapy):

  1. Two prospective, randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[2,15] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[16]
  2. A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[17] In that analysis the following was shown:
    1. Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test).
    2. Significantly less-severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.
  3. A randomized, phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival (PFS), or overall survival (OS).[3][Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel and those with nonsquamous histologies appeared to benefit more from pemetrexed.[18]
  4. Two randomized, placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared to placebo [19,20] but does not improve survival compared to standard second-line chemotherapy with docetaxel or pemetrexed.[21]
    1. The trial of erlotinib versus best supportive care included 731 patients; 49% had received two prior chemotherapy regimens and 93% had received platinum-based chemotherapy.
      • OS was 6.7 months among those who had received two prior chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.[19][Level of evidence: 1iiA]
    2. In the trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy following progression on first-line platinum combination therapy, 424 patients were randomly assigned.
      • There was no difference in the primary endpoint of OS (median OS survival, 5.3 months vs. 5.5 months; HR, 0.96; 95% CI, 0.78–1.19).[21][Level of evidence: 1iiA]
  5. A randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed the following:
    • Gefitinib does not improve OS.
    • Median survival did not differ significantly between the groups in the overall population (5.6 mo for gefitinib and 5.1 mo for placebo; HR, 0.89; 95% CI, 0.77–1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 mo vs. 5.4 mo; HR, 0.84; CI, 0.68–1.03; P = .089).
    • Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49–0.92]; P = .012; median survival 8.9 mo vs. 6.1 mo) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48–0.91]; P = .01; median survival 9.5 mo vs. 5.5 mo).[22][Level of evidence: 1iiA]
  6. In a large, randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[5] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day orally; n = 733) or docetaxel (75 mg/m2 intravenously every 3 weeks; n = 733).
    • Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR, 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR, 1.09; 95% CI, 0.78–1.51; P = .62).
    • In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
    • This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.
  7. A study (NCT00585195) that screened 1,500 patients with NSCLC for ALK rearrangements identified 82 patients with advanced ALK-positive disease who were enrolled in a clinical trial that was an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib dual MET and ALK inhibitor of 250 mg twice daily in 28-day cycles.[6] Most of the patients had received previous treatment.
    • At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses, and 1 confirmed complete response); 27 patients (33%) had stable disease.[6][Level of evidence: 3iiiD]
    • The estimated probability of 6-month PFS was 72%.
    • 1-year OS was 74% (95% CI, 63–82), and 2-year OS was 54% (40–66).
    • Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls identified from a different cohort given any second-line therapy (median OS not reached [95% CI, 14 months–not reached] vs. 6 months [CI 4–17], 1-year OS, 70% [95% CI, 50–83] vs. 44% [23–64], and 2-year OS 55% [33–72] vs. 12% [2–30]; HR, 0.36; 95% CI, 0.17–0.75; P = .004).[7][Level of evidence: 3iiiD]
    • Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.
    • Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas.

Objective response rates to erlotinib and gefitinib are higher in patients who have never smoked, in females, in East Asians, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.[23,24,25,26,27,28,29] Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the EGFR [24,25,26,28,29] and with the absence of K-RAS mutations.[27,28,29][Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by fluorescence in situ hybridization studies,[28,29] although the clinical utility of EGFR testing by immunohistochemistry has been questioned.[30]

Treatment of second primary tumor

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.[31,32]

Treatment of brain metastases

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged DFS with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy (WBRT).[33,34] Unresectable brain metastases in this setting may be treated with radiation surgery.[10]

Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 1.8 Gy to 2.0 Gy. Because of the high risk of toxic effects observed with such treatments, higher daily doses over a shorter period of time (i.e., hypofractionated schemes) should be avoided.[35] Most patients who are not suitable for surgical resection should receive conventional WBRT.

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[8] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.[8,10] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[36][Level of evidence: 3iiiDiii]

Treatment Options Under Clinical Evaluation

  • Many patients with recurrent NSCLC are eligible for clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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  2. Shepherd FA, Dancey J, Ramlau R, et al.: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18 (10): 2095-103, 2000.
  3. Hanna N, Shepherd FA, Fossella FV, et al.: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22 (9): 1589-97, 2004.
  4. Shepherd FA, Pereira J, Ciuleanu TE, et al.: A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. [Abstract] J Clin Oncol 22 (Suppl 14): A-7022, 622s, 2004.
  5. Kim ES, Hirsh V, Mok T, et al.: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372 (9652): 1809-18, 2008.
  6. Kwak EL, Bang YJ, Camidge DR, et al.: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363 (18): 1693-703, 2010.
  7. Shaw AT, Yeap BY, Solomon BJ, et al.: Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12 (11): 1004-12, 2011.
  8. Arbit E, Wronski M, Burt M, et al.: The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer 76 (5): 765-73, 1995.
  9. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
  10. Loeffler JS, Kooy HM, Wen PY, et al.: The treatment of recurrent brain metastases with stereotactic radiosurgery. J Clin Oncol 8 (4): 576-82, 1990.
  11. Alexander E 3rd, Moriarty TM, Davis RB, et al.: Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 87 (1): 34-40, 1995.
  12. Souquet PJ, Chauvin F, Boissel JP, et al.: Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342 (8862): 19-21, 1993.
  13. Ellis PA, Smith IE, Hardy JR, et al.: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71 (2): 366-70, 1995.
  14. Girling DJ, et al.: Randomized trial of etoposide cyclophosphamide methotrexate and vincristine versus etoposide and vincristine in the palliative treatment of patients with small-cell lung cancer and poor prognosis. Br J Cancer 67 (Suppl 20): A-4;2, 14, 1993.
  15. Fossella FV, DeVore R, Kerr RN, et al.: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18 (12): 2354-62, 2000.
  16. Huisman C, Smit EF, Giaccone G, et al.: Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 18 (21): 3722-30, 2000.
  17. Di Maio M, Perrone F, Chiodini P, et al.: Individual patient data meta-analysis of docetaxel administered once every 3 weeks compared with once every week second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 25 (11): 1377-82, 2007.
  18. Scagliotti G, Hanna N, Fossella F, et al.: The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 14 (3): 253-63, 2009.
  19. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353 (2): 123-32, 2005.
  20. Bezjak A, Tu D, Seymour L, et al.: Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 24 (24): 3831-7, 2006.
  21. Ciuleanu T, Stelmakh L, Cicenas S, et al.: Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 13 (3): 300-8, 2012.
  22. Thatcher N, Chang A, Parikh P, et al.: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366 (9496): 1527-37, 2005 Oct 29-Nov 4.
  23. Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22 (6): 1103-9, 2004.
  24. Paez JG, Jänne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (5676): 1497-500, 2004.
  25. Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (21): 2129-39, 2004.
  26. Pao W, Miller V, Zakowski M, et al.: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (36): 13306-11, 2004.
  27. Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2 (1): e17, 2005.
  28. Tsao MS, Sakurada A, Cutz JC, et al.: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 353 (2): 133-44, 2005.
  29. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al.: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24 (31): 5034-42, 2006.
  30. Clark GM, Zborowski DM, Culbertson JL, et al.: Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1 (8): 837-46, 2006.
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  35. DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24 (6): 798-805, 1989.
  36. Hazuka MB, Kinzie JJ: Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys 15 (2): 433-7, 1988.
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