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Year : 2008  |  Volume : 3  |  Issue : 6  |  Page : 97-99
Systemic therapy in non-small-cell lung cancer

1 King Abdulaziz Medical City for National Guard, Riyadh, Saudi Arabia
2 Riyadh Military Hospital, Riyadh, Saudi Arabia

Correspondence Address:
Abdul-Rahman Jazieh
Department of Oncology (Mail code 1777) P.O. Box 22490, Riyadh 11426
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

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The systemic treatment of lung cancer has evolved rapidly over the last two decades. Systemic therapy has become the standard of care for advanced lung cancer up to the third line.
The addition of antiangiogenesis agents to chemotherapy has proved to be beneficial in the first-line setting. Finally, systemic therapy has proven effective in the adjuvant setting in early-stage lung cancer.

Keywords: Lung cancer, systemic therapy, treatment

How to cite this article:
Jazieh AR, Saadeen A. Systemic therapy in non-small-cell lung cancer. Ann Thorac Med 2008;3, Suppl S2:97-9

How to cite this URL:
Jazieh AR, Saadeen A. Systemic therapy in non-small-cell lung cancer. Ann Thorac Med [serial online] 2008 [cited 2023 Mar 24];3, Suppl S2:97-9. Available from:

   Introduction Top

The systemic therapy of non-small-cell lung cancer (NSCLC) has evolved significantly over the last 15 years, with significant milestone events. The advancement in this area may have occurred in small increments, but at least it is in the right direction. In addition, a great deal of interest and enthusiasm has been infused into the study of a historically fatal disease which, as the number one cancer killer, has not received the attention it deserved.

While in the early 1990s, administering first line chemotherapy for NSCLC was controversial, the use of systemic therapy in the second and third line is a standard practice at present time.

Multiple studies were unable to show any benefit to the patient with the addition of biological agents to chemotherapy, but antiangiogenic agents broke the rule and showed survival benefits when given along with chemotherapy.

The benefit of systemic therapy was also demonstrated in the management of earlier stages of lung cancer as adjuvant treatment.

In this manuscript, the major evidences in the systemic therapy of NSCLC will be summarized.

   Adjuvant Treatment Top

Stage IA: No benefit to adjuvant chemotherapy was demonstrated in a convincing manner.

Stage IB: CALBG 9633 was positive for a survival advantage with carboplatin and paclitaxel at 3 years, but this turned out to be not significant after 4 years; this may have been due to the early closure of the study, the small sample size, and the use of carboplatin instead of cisplatin. [1] However, subgroup analysis showed some benefits to patients with lesions larger than 4 cm in diameter. Adjuvant uracil-tegafar (UFT) treatment showed a survival benefit in stage 1B in a randomized study of 979 patients conducted by the Japan Lung Cancer Research Group. Five-year survival was 85% vs. 74% in favor of UFT. [2]

Stage II/III: There are multiple phase III trials that have shown the benefits of chemotherapy to patients with resected stage II and stage III disease, using cisplatin combinations, especially cisplatin with venorelbine. [3],[4],[5] [Table 1]

   Combined Modality Treatment Top

For locally advanced lung cancer, including stage IIIA and stage IIIB (without pleural effusion), concurrent chemoradiotherapy is the standard of care approach, with surgical resection used in selected cases after the combined treatment. The preferred regimen is a cisplatin-based combination (with etoposide or vinblastin) although carboplatin / paclitaxel is also widely used. [6],[7],[8],[9],[10]

   First-line Therapy for Metastatic Disease Top

Various randomized clinical trials showed that combination chemotherapy with two agents is better than using a single agent; however, combination chemotherapy with three agents does not add any benefit over that provided by two agents. Therefore, chemotherapy doublet became the standard of care, with a platinum-based regimen being the preferred approach. Platinum combinations with docetaxel, gemcitabine, or paclitaxel, are equivalent. [11] In ECOG 1994, 1207 patients with NSCLC were randomized to receive a reference regimen of cisplatin and paclitaxel or one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel.

The response rate and overall survival did not differ significantly between the four arms. The new chemotherapy agents appear equivalent to each other, except for the venorelbine and cisplatin combination, which was shown to be inferior to docetaxel / platinum combinations in a phase III randomized clinical trial. [12]

Multiple randomized studies were conducted to evaluate the benefits of adding biologic agents to the chemotherapy doublets, including erlotinib, gefitinib, and many other agents. None of these studies revealed any additional benefit with these agents.

The only exception to this pattern was the ECOG 4599 by Sandler et al . In this phase III trial, 842 patients with nonsquamous cell lung cancer were randomized to receive carboplatin and paclitaxel or carboplatin, paclitaxel, and bevacizumab. The response rate, progression-free survival, and median survival was better with the addition of bevacizumab (medial survival was 12.5 vs. 10.2 months; P = 0.0075). Patients with nonsquamous cell cancer may benefit from the combination of bevacizumab, carboplatin, and paclitaxel according to this phase III randomized trial, which showed a 2-month survival advantage for the bevacizumab arm. [13]

   Second-line Therapy Top

Erlotinib, docetaxel, and pemetrexed are all FDA approved in the second-line setting. Docetaxel was the first agent to be approved in the second-line setting for patients who failed first-line therapy. [14],[15]

Pemetrexed was not inferior to docetaxel in a phase III trial. [16] In this study, 571 patients who failed first-line therapy were randomized to receive premetrexed (500 mg/m 2 every 3 weeks along with vitamin supplements) or docetaxel (75 mg/m 2 ). Both agents showed similar response rates, median survival rates, and 1-year survival. [16]

Erlotinib was also approved as second and third line treatment in NSCLC on the basis of a large randomized placebo-controlled double-blind trial of 731 patients. The response rate was 8.9% for erlotinib and overall survival was 6.7 months vs. 4.7 months for placebo (HR = 0.70; P <0.001). [17]

   Third-line Therapy and Beyond Top

Only erlotinib is proven to have benefits in the third line setting. [17] No other agent is approved by the regulatory agencies in the third line setting and no evidence of treatment benefit beyond third line of therapy.

In summary, advances have occurred over the last decade in the systemic therapy of NSCLC. The use of the customization and individualized therapy approaches will be the trend of the future.

   References Top

1.Strauss GM, Herndon JE 2nd, Maddaus MA; for the CALGB, Radiation Therapy Oncology Group. Adjuvant chemotherapy in stage IB non-small-cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CAL GB) protocol 9633. J Clin Oncol (Meeting Abstracts) 2006;24:7007.  Back to cited text no. 1    
2.Kato N, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, et al . A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713-21.  Back to cited text no. 2    
3.Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, et al . Cisplatin-based adjuvant chemotherapy in patients with completely resected non- small- cell lung cancer. N Engl J Med 2004;350:351-60.  Back to cited text no. 3    
4.Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al . Vinorelbine plus cisplatin vs. observation in resected non- small- cell lung cancer. N Engl J Med 2005;352:2589-97.  Back to cited text no. 4    
5.Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzαles-Larriba JL, et al . Adjuvant vinorelbine plus Cisplatin versus observation in Patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomized controlled trial. Lancet Oncol 2006;7:719-27.  Back to cited text no. 5    
6.Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, 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.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Socinski MA, Rosenman JG, Halle J, Schell MJ, Lin Y, Russo S, et al . Dose-escalating conformal thoracic radiation therapy with induction and concurrent carboplatin-paclitaxel in unresectable stage IIIA/B nonsmall cell lung carcinoma: A modified phase I/II trial. Cancer 2001;92:1213-23.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Albain KS, Swann RS, Rusch VW. Phase III study of concurrent chemotherapy and radiotherapy (CT-RT) vs CT-RT followed by surgical resection for stage IIIA (pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol (Meeting Abstracts) 2005;23:7014.  Back to cited text no. 8    
9.Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, et al . Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small cell lung cancer: A randomized phase II locally advanced multi-modality protocol. J Clin Oncol 2005;23:5883-91.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, et al . Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small cell lung cancer: A Southwest Oncology Group Phase II Study, SWOG 9019. J Clin Oncol 2002;20:3454-60.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al . Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, et al . Multinational, phase III Study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: The TAX 326 study group. J Clin Oncol 2003;21:3016-24.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al . Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Fosella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, 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 2000;18:2354-62.  Back to cited text no. 14    
15.Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, 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 2000;18:2095-103.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, 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 2004;22:1589-97.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al . Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]


  [Table 1]


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