Non-Small Cell Lung Cancer Treatment Protocols

Medscape Reference Reference News Reference Education MEDLINE Non-Small Cell Lung Cancer Treatment Protocols Author: Marvaretta M Stevenson, MD; Chief Editor: Jules E Harris, MD more... Updated: Oct 16, 2012 Treatment Recommendations, Early or Localized Disease Stage I or IIa disease Surgery is recommended for patients with stage I or II non-small cell lung cancer and may provide the best possibility for a cure Surgery (radiation if not a surgical candidate) with or without adjuvant chemotherapy based on risk factors for stages IB and II is generally appropriate Adjuvant chemotherapy after surgical resection provides an absolute increase in 5-y survival of approximately 5% [1] ; median 5-y overall survival rates range from 45-70% The benefit of adding adjuvant chemotherapy increases as disease stage increases; no benefit has been shown for adjuvant chemotherapy after surgery for stage I disease [1] Stereotactic body radiotherapy (SBRT) may be used in early stage NSCLC tumors that are smaller than 5 cm without lymph node involvement. This has become a viable and effective option among patients with early stage NSCLC who are not surgical candidates and among those with significant co-morbidities. Studies show high local control rates (approximately 90%) for these patients. However, the protocols for SBRT have varied among the published studies. Acceptable chemotherapy regimens for adjuvant chemotherapy for stage I or IIa (goal to complete 4 cycles) Cisplatin 50 mg/m 2 IV on days 1 and 8 plus vinorelbine 25 mg/m 2 IV on days 1, 8, 15, and 22 every 28d [1, 2, 3, 4, 5, 6] or Cisplatin 100 mg/m 2 IV on day 1 plus vinorelbine 30 mg/m 2 on days 1, 8, 15, and 22 every 28d [1, 2, 3, 4, 5, 6] or Cisplatin 75-80 mg/m 2 IV on day 1 plus vinorelbine 25-30 mg/m 2 IV on days 1 and 8 every 21d [1, 2, 3, 4, 5, 6] or Cisplatin 100 mg/m 2 IV on day 1 plus etoposide 100 mg/m 2 IV on days 1-3 every 28d [1, 2, 3] or Cisplatin 80 mg/m 2 IV on days 1, 22, 43, and 64 plus vinblastine 4 mg/m 2 IV on days 1, 8, 15, 22, and 29; then every 2wk after day 43 until completion of cisplatin every 21d [1, 2, 3] or Page 1 of 12

Cisplatin 75 mg/m 2 IV on day 1 plus gemcitabine 1250 mg/m 2 on days 1 and 8 every 21d [7] or Cisplatin 75 mg/m 2 IV on day 1 plus docetaxel 75 mg/m 2 IV on day 1 every 21d [8] or Cisplatin 75 mg/m 2 IV on day 1 plus pemetrexed 500 mg/m 2 IV on day 1 every 21d (for non-squamous histologies) [7] Patients with comorbidities or patients not able to tolerate cisplatin may alternatively use the following regimen Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m 2 IV on day 1 every 21d [9, 10] Chemoradiation Therapy, Locally Advanced Disease Stage IIIa or IIIb disease Treatment recommendations include the use of concurrent chemotherapy and radiation, or chemotherapy and radiation can be given sequentially if necessary Selected patients (predominantly stage IIIa) may be surgical candidates; these patients may receive chemotherapy alone or chemotherapy with radiation before surgical resection Stage IIIa and IIIb disease is typically treated with a combination of chemotherapy and radiation if the patient is not a surgical candidate It is preferred to give these therapies concurrently, but in patients with poor performance status, they may be given sequentially; the decision to treat the patient with concurrent chemoradiation rather than surgery, radiation, or chemotherapy individually should be made by a multidisciplinary tumor board (including a medical oncologist, radiation therapist, and thoracic surgeon) [7, 11, 12] Acceptable chemotherapy regimens used with concurrent chemotherapy/radiation therapy Cisplatin 50 mg/m 2 IV on days 1, 8, 29, and 36 plus etoposide (VP-16) 50 mg/m 2 IV on days 1-5 and days 29-33 [13, 14, 15, 16, 17] or Cisplatin 100 mg/m 2 IV on days 1 and 29 plus vinblastine 5 mg/m 2 /weekly IV for 5wk [7, 18] or Carboplatin AUC 2 IV weekly for 7wk plus paclitaxel 50 mg/m 2 IV weekly for 7wk; 3wk later, it can be followed by 2 cycles of consolidation chemotherapy with carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m 2 IV on day 1 every 21wk [19, 20] Acceptable chemotherapy regimens used with sequential chemotherapy/radiation therapy Cisplatin 100 mg/m 2 IV on days 1 and 29 plus vinblastine 5 mg/m 2 /weekly IV on days 1, 8, 15, 22, and 29, followed by radiation therapy beginning on day 50 [7, 18, 21, 22] or Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m 2 IV on day 1 every 21d for 2 cycles, followed by radiation therapy beginning on day 42 [7, 19, 20] First-Line Chemotherapy, Metastatic or Recurrent Disease Stage IV or recurrent disease Patients with metastatic disease (stage IV) or recurrent disease after primary therapy (such as surgery and/or radiation) should be considered for chemotherapy in order to improve quality of life, palliate symptoms, and improve overall survival [11, 7] Goal is to treat for 4-6 cycles unless otherwise outlined Drug regimens, including platinum-based doublets Cisplatin 75 mg/m 2 IV on day 1 plus paclitaxel 175 mg/m 2 IV on day 1 every 21d [23, 24] or Page 2 of 12

Cisplatin 100 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1, 8, and 15 every 28d [24] or Cisplatin 60 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1 and 8 every 21d [25, 26] or Cisplatin 75 mg/m 2 IV on day 1 plus docetaxel 75 mg/m 2 IV on day 1 every 21d [8, 24] or Carboplatin AUC 6 IV on day 1 plus paclitaxel 175-225 mg/m 2 IV on day 1 every 21d [24, 27] or Carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m 2 IV on days 1, 8, and 15 every 28d [28, 29, 30] or Paclitaxel protein bound 100 mg/m2 IV on days 1, 8, and 15 of every 21d plus carboplatin AUC 6 IV on day 1 [31] or Carboplatin AUC 6 IV on day 1 plus docetaxel 75 mg/m 2 IV on day 1 every 21d [17] or Carboplatin AUC 5 IV on day 1 plus gemcitabine 1250 mg/m 2 IV on days 1 and 8 every 21d [32, 33, 34] or Cisplatin 100 mg/m 2 IV on day 1 every 28d plus vinorelbine 25 mg/m 2 IV weekly [8] or Cisplatin 40 mg/m 2 IV on day 1 plus vinorelbine 25 mg/m 2 IV on days 1 and 8 every 21d [25] or Carboplatin AUC 5 IV on day 1 plus vinorelbine 30 mg/m 2 IV on days 1 and 8 every 21d [35] Bevacizumab-based chemotherapy for patients who meet eligibility requirements (non-squamous histology, treated brain metastases, no history of hemoptysis): Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m 2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21d (continue bevacizumab every 21d after 4-6 cycles are completed; continue until disease progression) [36] or Cisplatin 80 mg/m 2 IV on day 1 plus gemcitabine 1250 mg/m 2 IV on days 1 and 8 plus bevacizumab 7.5-15 mg/kg IV on day 1 every 21d (continue bevacizumab every 21d after 4-6 cycles are completed); continue until disease progression or Docetaxel 75 mg/m 2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21d until disease progression or 52wk of therapy [12] or Pemetrexed 500 mg/m 2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21d until disease progression or 52wk of therapy (remember folate and B12 supplements along with dexamethasone premeds for pemetrexed) [12] Pemetrexed-based chemotherapy for patients who meet eligibility requirements (non-squamous histology): Cisplatin 75 mg/m 2 IV on day 1 plus pemetrexed 500 mg/m 2 IV on day 1 every 21d (remember folate and B12 supplements along with dexamethasone premeds for pemetrexed) [37] or Carboplatin AUC 5 IV on day 1 plus pemetrexed 500 mg/m 2 IV on day 1 every 21d (remember folate and B12 supplements along with dexamethasone premeds for pemetrexed) [34, 38, 39] Treatment recommendations for tumors with epidermal growth factor receptor (EGFR) immunohistochemistry Cisplatin 80 mg/m 2 IV on day 1 plus vinorelbine 25 mg/m 2 IV on days 1 and 8 plus cetuximab 400 mg/m 2 IV loading dose, followed by 250 mg/m 2 IV weekly every 21d (continue cetuximab weekly after 4-6 cycles completed, until disease progression) [40, 41] Treatment recommendations for EGFR mutation or gene amplification: Erlotinib 150 mg PO daily until disease progression [7, 27, 42, 43, 44, 45, 46, 47, 48] Treatment recommendations for patients with contraindications to carboplatin or cisplatin: Gemcitabine 1100 mg/m 2 IV on days 1 and 8 plus docetaxel 100 mg/m 2 IV on day 8 every 21d [49, 50] or Gemcitabine 1000-1200 mg/m 2 IV on days 1 and 8 plus vinorelbine 25-30 mg/m 2 IV on days 1 and 8 every 21d [35, 51, 52, 53] Second-Line Chemotherapy, Metastatic or Recurrent Disease Page 3 of 12

Stage IV or recurrent disease Second-line chemotherapy is given for advanced or recurrent disease after disease progression following first-line therapy Docetaxel 75 mg/m 2 IV on day 1 every 21d (goal 4-6 cycles) [54, 55, 56, 57, 58] or Pemetrexed 500 mg/m 2 IV on day 1 (non-squamous histology) every 21d (goal 4-6 cycles; remember folate and B12 supplements along with dexamethasone premeds for pemetrexed) [58] or Erlotinib 150 mg PO daily for patients with EGFR mutation or gene amplification; given until disease progression [7, 27, 42, 43, 44, 45, 46, 47, 48] International Review Board (IRB)-approved clinical trial: For adenocarcinoma, consider testing for EML4- ALK fusion gene to determine if patient is a candidate for an ALK inhibitor available through clinical trials A study by Herbst et al confirms that bevacizumab and erlotinib should not be used together for refractory or recurrent NSCLC at this time. Erlotinib alone in second-line and third-line settings remains the standard of care. [59] Third-Line Chemotherapy, Metastatic or Recurrent Disease Stage IV or recurrent disease Third-line chemotherapy is given for advanced or recurrent disease after disease progression following firstline and second-line therapy Erlotinib 150 mg PO daily [7, 27, 42, 43, 44, 45, 46, 47, 48] for patients with EGFR mutation or gene amplification; give until disease progression IRB-approved clinical trial: For adenocarcinoma, consider testing for EML4-ALK fusion gene to determine if patient is a candidate for an ALK inhibitor available through clinical trials Single-Agent Therapy, Metastatic or Recurrent Disease Stage IV or recurrent disease Single-agent therapy is a reasonable first-line option in patients with good performance status (ECOG score! 2) disease or in the elderly; goal is to complete 4-6 cycles Paclitaxel 200 mg/m 2 IV every 21d [60, 61] or Docetaxel 35 mg/m 2 IV weekly for 3wk every 4wk [50, 54, 57, 62] or Docetaxel 75 mg/m 2 IV every 21d [54, 55, 56, 57] or Gemcitabine 1000 mg/m 2 IV on days 1, 8, and 15 every 4wk [63, 64] or Gemcitabine 1250 mg/m 2 IV on days 1 and 8 every 21d [32, 51] or Vinorelbine 25 mg/m 2 IV weekly [65, 66] or Vinorelbine 30 mg/m 2 IV on days 1 and 8 every 21d [51, 67, 68] or Pemetrexed 500 mg/m 2 IV every 21d [58] (non-squamous histology) Systemic chemotherapy is not indicated for patients with poor performance status (ECOG 3-4), except for erlotinib in patients who are EGFR-mutation positive [7] Maintenance Chemotherapy, Metastatic or Recurrent Disease Stage IV disease Maintenance chemotherapy may be considered for patients with advanced (stage IV) disease who have a disease response or stable disease after completing first-line chemotherapy Switching maintenance chemotherapy involves giving chemotherapy that is different from the agents used as first-line therapy; this chemotherapy is given after completing first-line chemotherapy until disease progression or unacceptable toxicities, and it is associated with improvements in progression-free survival for all 3 agents listed below and improvements in overall survival for pemetrexed and erlotinib Page 4 of 12

Docetaxel 75 mg/m 2 IV every 21d [69] or Pemetrexed 500 mg/m 2 IV every 21d [70] (non-squamous histology) or Erlotinib 150 mg PO daily (1h before or 2h after meals) [71] Continuation maintenance therapy involves giving chemotherapy that was part of the firstline therapy after completing 4-6 cycles of first-line therapy This chemotherapy is given until disease progression or unacceptable toxicities The regimens below have been associated with improvements in progression-free survival and overall survival Cisplatin 80 mg/m 2 IV on day 1 plus vinorelbine 25 mg/m 2 IV on days 1 and 8 plus cetuximab 400 mg/m2 IV loading dose, followed by 250 mg/m2 IV weekly every 21d; continue cetuximab weekly after 4-6 cycles completed, until disease progression [40, 41] (for tumors with EGFR-positive immunohistochemistry) Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21d; continue bevacizumab every 21d after 4-6 cycles completed, until disease progression for patients who meet eligibility requirements (non-squamous histology, treated brain metastases, no history of hemoptysis) [36] Special Considerations Patients with the following special situations being considered for curative surgical resection should undergo invasive mediastinal staging and extrathoracic imaging (head CT/MRI with either whole body PET or abdominal CT + bone scan; involvement of mediastinal nodes and/or metastatic disease represents a contraindication to resection [11, 7] : Pancoast tumor (superior sulcus tumor) Clinical T4N0/1M0 tumors Two synchronous primary NSCLCs A metachronous NSCLC Stage I or II primary lung cancer with an isolated brain metastasis Isolated adrenal metastasis NSCLC tumor invading the chest wall Histology must be designated by pathologic review for NSCLC Pemetrexed is only indicated for non-squamous tumors [11, 7] Bevacizumab is contraindicated for squamous tumors due to the risk of pulmonary hemorrhage Erlotinib has higher response rates for adenocarcinomas with EGFR mutations Erlotinib should be considered for patients with EGFR mutations (activating mutations in exons 19 or 21) or gene amplification; patients with the highest response rates typically are Asian, are female, have never smoked or are light smokers, and have adenocarcinomas; response rates in unselected populations can be 10-20% or lower but increase to up to 90% in selected populations [7, 27, 42, 43, 44, 45, 46, 47, 48] Treatment recommendations for anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic tumors Crizotinib 250 mg PO BID until disease progression; dosing interruption and/or dose reduction to 200 mg PO BID may be required based on safety and tolerability; decrease to 250 mg PO daily if further reduction is needed [72] Contributor Information and Disclosures Author Marvaretta M Stevenson, MD Medical Instructor, Thoracic Oncology Program, Duke University Medical Center Page 5 of 12

Disclosure: Nothing to disclose. Specialty Editor Board Jasmeet Anand, PharmD, RPh Adjunct Instructor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Nothing to disclose. Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital Disclosure: Nothing to disclose. Chief Editor Jules E Harris, MD Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research Disclosure: Nothing to disclose. References 1. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-9. 2. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351-60. 3. Arriagada R, Dunant A, Pignon JP, et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010;28:35-42. 4. Douillard JY, Rosell R, De Lena M, 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 randomised controlled trial. Lancet Oncol. 2006;7:719-27. 5. Pepe C, Hasan B, Winton TL, et al. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol. 2007;25:1553-61. 6. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-smallcell lung cancer. N Engl J Med. 2005;352:2589-97. 7. National Comprehensive Cancer Network. Available at http://www.nccn.org. 8. Fossella F, Pereira JR, von Pawel J, et al. Randomized, 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. 9. Strauss GM, Herndon J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection of stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633. 2004 ASCO annual meeting, Abstract 7019. 10. Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. 2006 ASCO annual meeting, Abstract 7007. Page 6 of 12

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