Non-small cell lung cancer

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Adjuvant therapy

Carboplatin & Paclitaxel

Regimen, Strauss, et al. 2008 (CALGB 9633)

Level of Evidence: Phase III

• Carboplatin (Paraplatin) AUC 6 IV over 45 to 60 minutes once on day 1
• Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1

21-day cycles x 4 cycles

References

1. Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains protocol PubMed

Cisplatin & Docetaxel

Example orders

• Example orders for adjuvant Cisplatin (Platinol) and Docetaxel (Taxotere) in non-small cell lung cancer

Regimen, Fossella, et al. 2003 (TAX 326)

Level of Evidence: Phase III

• Cisplatin (Platinol) 75 mg/m2 IV once on day 1
• Docetaxel (Taxotere) 75 mg/m2 IV once on day 1

21-day cycles x 4 cycles

References

1. Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. 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 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed

Cisplatin & Etoposide

Regimen, Arriagada, et al. 2004

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once on day 1
• Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3

28-day cycles x 4 cycles

References

1. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed

Cisplatin & Gemcitabine

Regimen, Scagliotti, et al. 2008

Level of Evidence: Phase III

• Cisplatin (Platinol) 75 mg/m2 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8

21-day cycles x 4 cycles

References

1. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol PubMed

Cisplatin & Pemetrexed

Regimen, Scagliotti, et al. 2008

Level of Evidence: Phase III

• Cisplatin (Platinol) 75 mg/m2 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m2 IV once on day 1

21-day cycles x 4 cycles

References

1. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol; note: reference was not for adjuvant therapy; patients in this study were stage IIIB or IV PubMed

Cisplatin & Vinblastine

Regimen, Arriagada, et al. 2004

Level of Evidence: Phase III

Note: Exact days for parts of the regimen were not specified by Arriagada, et al. 2004. This vinblastine schedule is extrapolated from regimen information in Table 1 in which vinblastine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.

• Cisplatin (Platinol) 80 mg/m2 IV once per day on days 1, 22, 43, 64
• Vinblastine (Velban) 4 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 43, 57

12-week course

References

1. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article contains verified protocol PubMed

Cisplatin & Vindesine

Regimen, Arriagada, et al. 2004

Level of Evidence: Phase III

Note: Exact days for parts of the regimen were not specified by Arriagada, et al. 2004. This vindesine schedule is extrapolated from regimen information in Table 1 in which vindesine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.

• Cisplatin (Platinol) 80 mg/m2 IV once per day on days 1, 22, 43, 64
• Vindesine (Eldisine) 3 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 43, 57

12-week course

References

1. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article contains verified protocol PubMed

Cisplatin & Vinorelbine

Regimen #1, Winton, et al. 2005 (JBR.10)

Level of Evidence: Phase III

• Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1, 8, 15, 22

28-day cycles x 4 cycles

Regimen #2, Hotta, et al. 2001

Level of Evidence: Phase II

• Cisplatin (Platinol) 75 to 80 mg/m2 IV once on day 1
• Vinorelbine (Navelbine) 25 to 30 mg/m2 IV once per day on days 1 & 8

21-day cycles x 4 cycles

Regimen #3, Arriagada, et al. 2004 & Douillard, et al. 2006 (ANITA)

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1, 8, 15, 22

28-day cycles x 4 cycles

References

1. Hotta K, Sekine I, Tamura T, Sawada M, Watanabe H, Kusaba H, Akiyama Y, Inoue A, Shimoyama T, Nokihara H, Ueda Y, Yamamoto N, Kunitoh H, Ohe Y, Kodama T, Saijo N. A phase I/II study of cisplatin and vinorelbine chemotherapy in patients with advanced non-small cell lung cancer. Jpn J Clin Oncol. 2001 Dec;31(12):596-600. link to original article contains protocol PubMed
2. Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. 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 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
3. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed content property of HemOnc.org
4. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article PubMed
5. Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. 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 Sep;7(9):719-27. link to original article PubMed

Placebo (Observation)

Regimen

Level of Evidence: Phase III

No treatment. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.

References

1. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article PubMed
2. Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. 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 Sep;7(9):719-27. link to original article PubMed
3. Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains protocol PubMed

Chemotherapy & radiation therapy

Carboplatin, Paclitaxel, concurrent RT

Regimen

Level of Evidence: Phase II

Note: This regimen is listed by the NCCN, Non-Small Cell Lung Cancer version 2.2012, but this differs from the Belani, et al. 2005 reference, in which additional consolidation chemotherapy is given after completion of concurrent chemotherapy & radiation therapy. That regimen is detailed here.

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
• Paclitaxel (Taxol) 45 mg/m2 IV over 1 hour once per day on days 1, 8, 15, given first

21-day cycles x 2 cycles, given with concurrent radiation therapy

Concurrent radiation therapy

• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given once per day 5 days per week, then 2 Gy fractions x 9 fractions (additional dose: 18 Gy), given once per day 5 days per week. Total dose: 63 Gy over a total 7 week course of treatment.

References

1. Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. 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 Sep 1;23(25):5883-91. link to original article contains protocol PubMed

Carboplatin, Paclitaxel, concurrent RT -> consolidation chemo

Regimen, Belani, et al. 2005

Level of Evidence: Phase II

Chemotherapy & radiation therapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
• Paclitaxel (Taxol) 45 mg/m2 IV over 1 hour once per day on days 1, 8, 15, given first

21-day cycles x 2 cycles, given with concurrent radiation therapy

Concurrent radiation therapy

• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given once per day 5 days per week, then 2 Gy fractions x 9 fractions (additional dose: 18 Gy), given once per day 5 days per week. Total dose: 63 Gy over a total 7 week course of treatment.

Consolidation chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first

21-day cycles x 2 cycles

References

1. Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. 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 Sep 1;23(25):5883-91. link to original article contains protocol PubMed

Carboplatin, Paclitaxel -> sequential RT

Regimen, Belani, et al. 2005

Level of Evidence: Phase II

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first

21-day cycles x 2 cycles, then proceed to radiation therapy

Radiation therapy

• Sequential radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given once per day 5 days per week, then 2 Gy fractions x 9 fractions (additional dose: 18 Gy), given once per day 5 days per week. Total dose: 63 Gy over a total 7 week course of treatment.

References

1. Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. 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 Sep 1;23(25):5883-91. link to original article contains protocol PubMed

Cisplatin, Etoposide, concurrent RT

Regimen, Albain, et al. 2002 (SWOG 9019)

Level of Evidence: Phase II

• Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1, 8, 29, 36
• Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5, 29 to 33
• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given 5 days per week, to start within 24 hours of chemotherapy

5-week initial course of chemotherapy & radiation; patients were reimaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 2 Gy per day x 8 fractions for a total of 61 Gy administered overall

References

1. Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. 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 Aug 15;20(16):3454-60. link to original article contains protocol PubMed

Cisplatin, Etoposide, concurrent RT -> consolidation chemo

Regimen, Albain, et al. 2002 (SWOG 9019)

Level of Evidence: Phase II

Note: The NCCN, Non-Small Cell Lung Cancer version 2.2012, describes "two extra cycles" of chemotherapy being given after completion of concurrent RT, but no primary reference can be found for this. It is unclear what the length of each cycle is supposed to be.

Chemotherapy & concurrent radiation therapy

• Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1, 8, 29, 36
• Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5, 29 to 33
• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given 5 days per week, to start within 24 hours of chemotherapy

5-week initial course of chemotherapy & radiation; patients were reimaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 2 Gy per day x 8 fractions for a total of 61 Gy administered overall

Consolidation chemotherapy

• Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
• Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5

28-day cycles x 2 cycles

References

1. Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. 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 Aug 15;20(16):3454-60. link to original article contains protocol--see note above PubMed

Cisplatin, Vinblastine, concurrent RT

Regimen, Curran, et al. 2011 (RTOG 9410)

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 29
• Vinblastine (Velban) 5 mg/m2 IV once per day on days 1, 8, 15, 22, 29
• Concurrent radiation therapy

5-week course of chemotherapy

References

1. Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. link to original article PubMed

Cisplatin, Vinblastine, sequential RT

Regimen, Curran, et al. 2011 (RTOG 9410)

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 29
• Vinblastine (Velban) 5 mg/m2 IV once per day on days 1, 8, 15, 22, 29

5-week total course of chemotherapy

• Radiation therapy given after chemotherapy is complete

References

1. Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. link to original article PubMed

Advanced or metastatic disease

Afatinib (BIBW 2992)

Regimen #1, Yang, et al. 2012 (LUX-Lung 2), Sequist, et al. 2013 (LUX-Lung 3), Yang, et al. 2013 (LUX-Lung 3)

Level of Evidence: Phase III

Patients in Yang, et al. 2012; Sequist, et al. 2013; and Yang, et al. 2013 were EGFR mutation positive.

• Afatinib (BIBW 2992) 40 mg PO once per day, given 1 hour before eating food (Yang, et al. 2012: "no food intake immediately before or after afatinib")
  • In Sequist, et al. 2013 (LUX-Lung 3) and Yang, et al. 2013 (LUX-Lung 3), patients could be increased to Afatinib (BIBW 2992) 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.

given until progressive disease, unacceptable toxicity, or withdrawal of consent

Regimen #2, Miller, et al. 2012 (LUX-Lung 1) and Katakami, et al. 2013 (LUX-Lung 4)

Level of Evidence: Phase III

In Katakami, et al. 2013 (LUX-Lung 4) 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants, who had progressed while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen.

• Afatinib (BIBW 2992) 50 mg PO once per day, given 1 hour before eating food

given until progressive disease, unacceptable toxicity, or withdrawal of consent

References

1. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. doi: 10.1016/S1470-2045(12)70087-6. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
2. Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012 May;13(5):539-48. doi: 10.1016/S1470-2045(12)70086-4. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
3. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1. [Epub ahead of print] link to original article contains verified protocol PubMed
4. Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1. [Epub ahead of print] link to original article contains verified protocol PubMed
5. Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both. J Clin Oncol. 2013 Jul 1. [Epub ahead of print] link to original article contains verified protocol PubMed

Carboplatin & Docetaxel

Regimen, Fossella, et al. 2003 (TAX 326)

Level of Evidence: Phase III

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Docetaxel (Taxotere) 75 mg/m2 IV once on day 1

21-day cycles

References

1. Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. 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 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed

Carboplatin & Gemcitabine

Regimen, Sederholm, et al. 2005 & Grønberg, et al. 2009

Level of Evidence: Phase III

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 to 1250 mg/m2 IV once per day on days 1 & 8

21-day cycles

References

1. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. link to original article contains verified protocol PubMed
2. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains protocol PubMed

Carboplatin & Paclitaxel

Regimen #1, Schiller, et al. 2002 & Socinski, et al. 2012

Level of Evidence: Phase III

• Carboplatin (Paraplatin) AUC 6 IV once on day 1, given second
• Paclitaxel (Taxol) 200 to 225 mg/m2 IV over 3 hours once on day 1, given first

21-day cycles

Regimen #2, Lynch, et al. 2012

Level of Evidence: Randomized Phase II, >20 per arm

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m2 IV once on day 1

21-day cycles x up to 6 cycles

Supportive medications:

• Corticosteroids could be used as premedication for paclitaxel infusion.

Regimen #3, Quoix, et al. 2011 (weekly paclitaxel, IFCT-0501)

Level of Evidence: Phase III

Study involved only patients 70 to 89 years old

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15

28-day cycles x up to 4 cycles

Supportive medications:

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3-4 neutropenia

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
2. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article PubMed
3. Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article PubMed
4. Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008 Feb 20;26(6):863-9. link to original article contains protocol PubMed
5. Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed
6. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
7. Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel, nanoparticle albumin-bound

Regimen, Socinski, et al. 2012

Level of Evidence: Phase III

• Carboplatin (Paraplatin) AUC 6 mg/mL/min (per Calvert formula) IV once on day 1, given second
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, given first

21-day cycles x 6 cycles; treatment could continue at physician's discretion if there was no progressive disease or unacceptable toxicity

References

1. Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, Bevacizumab

Regimen, Johnson, et al. 2004 & Ramalingam, et al. 2008

Level of Evidence: Phase III

• Carboplatin (Paraplatin) AUC 6 IV once on day 1, given second
• Paclitaxel (Taxol) 200 to 225 mg/m2 IV over 3 hours once on day 1, given first
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article PubMed
2. Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article PubMed

Carboplatin, Paclitaxel, Ipilimumab

Regimen, Lynch, et al. 2012 (phased ipilimumab)

Level of Evidence: Randomized Phase II, >20 per arm

Induction phase

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1 of cycles 3 to 6

21-day cycles x up to 6 cycles; patients without progressive disease continued to receive maintenance therapy

Supportive medications:

• Corticosteroids could be used as premedication for paclitaxel infusion or for toxicity management.

Maintenance therapy

• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1

12-week cycles, given until progression of disease or unacceptable toxicity

References

1. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed

Carboplatin & Pemetrexed

Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen #1, Grønberg, et al. 2009

Level of Evidence: Phase III

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m2 IV once on day 1

21-day cycles

Supportive medications:

• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose prior to pemetrexed
• Folic acid 1 mg PO once per day

Regimen #2, Ardizzoni, et al. 2012 (GOIRC 02-2006)

Level of Evidence: Randomized Phase II, >20 per arm

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first

21-day cycles x up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal

Supportive medications:

• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO BID on the day before, the day of, and day after each dose of pemetrexed
• Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

References

1. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains protocol PubMed
2. Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. doi: 10.1200/JCO.2012.43.6758. Epub 2012 Oct 29. link to original article contains verified protocol PubMed

Cisplatin & Docetaxel

Regimen, Schiller, et al. 2002

Level of Evidence: Phase III

• Cisplatin (Platinol) 75 mg/m2 IV once on day 1
• Docetaxel (Taxotere) 75 mg/m2 IV once on day 1

21-day cycles

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

Regimen, Schiller, et al. 2002

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15

28-day cycles

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
2. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol PubMed

Cisplatin & Paclitaxel

Regimen, Schiller, et al. 2002

Level of Evidence: Phase III

• Paclitaxel (Taxol) 135 mg/m2 IV over 24 hours once on day 1
• Cisplatin (Platinol) 75 mg/m2 IV once on day 2

21-day cycles

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed

Cisplatin & Pemetrexed

Regimen #1, Scagliotti, et al. 2008, Sequist, et al. 2013 (LUX-Lung 3), Yang, et al. 2013 (LUX-Lung 3)

Level of Evidence: Phase III

• Cisplatin (Platinol) 75 mg/m2 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m2 IV once on day 1

21-day cycles; patients in Sequist, et al. 2013 and Yang, et al. 2013 were treated for up to 6 cycles

Supportive medications (as described in Scagliotti, et al. 2008):

• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to pemetrexed
• Folic acid 1 mg PO once per day
• In Sequist, et al. 2013: Patients "received folic acid, vitamin B12, and dexamethasone, as per package recommendations for pemetrexed."

Regimen #2, Paz-Ares, et al. 2012 & Paz-Ares, et al. 2013 (PARAMOUNT)

Level of Evidence: Non-randomized

• Cisplatin (Platinol) 75 mg/m2 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m2 IV once on day 1

21-day cycles x 4 cycles, subsequently patients were randomized to placebo or pemetrexed maintenance therapy

Supportive medications:

• Folic acid, Cyanocobalamin (Vitamin B12), prophylactic Dexamethasone (Decadron)
• "Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."

References

1. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol PubMed
2. Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. doi: 10.1016/S1470-2045(12)70063-3. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
3. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1. [Epub ahead of print] link to original article contains verified protocol PubMed
4. Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1. [Epub ahead of print] link to original article contains verified protocol PubMed
5. Update: Luis G. Paz-Ares, Filippo de Marinis, Mircea Dediu, Michael Thomas, Jean-Louis Pujol, Paolo Bidoli, Olivier Molinier, Tarini Prasad Sahoo, Eckart Laack, Martin Reck, Jesús Corral, Symantha Melemed, William John, Nadia Chouaki, Annamaria H. Zimmermann, Carla Visseren-Grul, and Cesare Gridelli. PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer. JCO published online on July 8, 2013; DOI:10.1200/JCO.2012.47.1102. link to original article contains verified protocol

Cisplatin, Pemetrexed, Bevacizumab

Regimen, Barlesi, et al. 2013 (AVAPERL (MO22089))

Induction phase

Level of Evidence: Non-randomized

• Cisplatin (Platinol) 75 mg/m2 IV once over 2 hours on day 1
• Pemetrexed (Alimta) 500 mg/m2 IV once over 10 minutes on day 1
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1; Bevacizumab (Avastin) is administered over 90 minutes for the first dose, and if well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes

21-day cycles x 4 cycles; patients with complete response (CR), partial response (PR), or stable disease (SD) proceeded to the maintenance phase

Supportive medications:

• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 3 cycles (i.e. every 9 weeks), given throughout therapy
• Folic acid 350 to 1000 mcg PO once per day, given throughout therapy
• Dexamethasone (Decadron) 4 mg PO BID on days -1, 1, 2 of each cycle

Maintenance phase

Level of Evidence: Phase III

In Barlesi, et al. 2013, bevacizumab and pemetrexed had superior progression-free survival (PFS) compared to bevacizumab maintenance alone. The bevacizumab and pemetrexed arm is described here.

• Pemetrexed (Alimta) 500 mg/m2 IV once over 10 minutes on day 1
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles, given until progression, death, or withdrawal of consent

Supportive medications:

• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 3 cycles (i.e. every 9 weeks), given throughout therapy
• Folic acid 350 to 1000 mcg PO once per day, given throughout therapy
• Dexamethasone (Decadron) 4 mg PO BID on days -1, 1, 2 of each cycle

References

1. Fabrice Barlesi, Arnaud Scherpereel, Achim Rittmeyer, Antonio Pazzola, Neus Ferrer Tur, Joo-Hang Kim, Myung-Ju Ahn, Joachim G.J.V. Aerts, Vera Gorbunova, Anders Vikström, Elaine K. Wong, Pablo Perez-Moreno, Lada Mitchell, and Harry J.M. Groen. Randomized Phase III Trial of Maintenance Bevacizumab With or Without Pemetrexed After First-Line Induction With Bevacizumab, Cisplatin, and Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: AVAPERL (MO22089). JCO published online on July 8, 2013; DOI:10.1200/JCO.2012.42.3749. link to original article contains verified protocol

Crizotinib (Xalkori)

Regimen, Kwak, et al. 2010; Camidge, et al. 2012; Shaw, et al. 2013

Level of Evidence: Phase III

• Crizotinib (Xalkori) 250 mg PO BID on days 1 to 28

28-day cycles, given until progression of disease or unacceptable toxicity. Shaw, et al. 2013 used 21-day cycles, and crizotinib was similarly given 250 mg PO BID on all days.

References

1. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703. link to original article contains verified protocol PubMed
2. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate AJ, Camidge DR. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011 Oct;12(11):1004-12. doi: 10.1016/S1470-2045(11)70232-7. Epub 2011 Sep 18. link to original article PubMed
3. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Jänne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012 Oct;13(10):1011-9. doi: 10.1016/S1470-2045(12)70344-3. Epub 2012 Sep 4. link to original article contains verified protocol PubMed
4. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013 Jun 1. [Epub ahead of print] link to original article link to supplementary appendix contains verified protocol PubMed

Docetaxel (Taxotere)

Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen #1, Hanna, et al. 2004; Chen, et al. 2006; Shaw, et al. 2013

Level of Evidence: Phase III

• Docetaxel (Taxotere) 75 mg/m2 IV over 1 hour once on day 1

21-day cycles, given until progression of disease, unacceptable toxicity, or patient/physician choice

Supportive medications:

• Per Hanna, et al. 2004: Dexamethasone (Decadron) 8 mg PO BID the day before, the day of, and the day after docetaxel
• Per Chem, et al. 2006: Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, Dexamethasone (Decadron) 10 mg IV once 30 minutes before docetaxel, and Dexamethasone (Decadron) 8 mg PO 12 hours after docetaxel

Regimen #2, Chen, et al. 2006 (weekly docetaxel)

Level of Evidence: Phase III

• Docetaxel (Taxotere) 35 mg/m2 IV once per day on days 1, 8, 15

28-day cycles

Supportive medications:

• Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, Dexamethasone (Decadron) 10 mg IV once 30 minutes before docetaxel, and Dexamethasone (Decadron) 8 mg PO 12 hours after docetaxel

References

1. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains verified protocol PubMed
2. Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. link to original article contains verified protocol PubMed
3. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains protocol PubMed
4. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013 Jun 1. [Epub ahead of print] link to original article link to supplementary appendix contains verified protocol PubMed

Erlotinib (Tarceva)

Regimen, Shepherd, et al. 2005 & Lilenbaum, et al. 2008

Level of Evidence: Phase III

• Erlotinib (Tarceva) 150 mg PO once per day

References

1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. link to original article contains protocol PubMed
2. Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008 Feb 20;26(6):863-9. link to original article contains protocol PubMed

Gefitinib (Iressa)

Regimen, Kim, et al. 2008 (INTEREST)

Level of Evidence: Phase III

• Gefitinib (Iressa) 250 mg PO once per day

References

1. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains protocol PubMed

Gemcitabine (Gemzar)

Regimen #1, Quoix, et al. 2011 (IFCT-0501)

Level of Evidence: Phase III

Study involved only patients 70 to 89 years old

• Gemcitabine (Gemzar) 1150 mg/m2 IV once per day on days 1 & 8

21-day cycles x up to 5 cycles

Supportive medications:

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia

Regimen #2, Gridelli, et al. 2003 (MILES)

Level of Evidence: Phase III

Study involved only patients at least 70 years old

• Gemcitabine (Gemzar) 1200 mg/m2 IV once per day on days 1 & 8

21-day cycles x up to 6 cycles

Supportive medications:

• "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

Regimen #3, Sederholm, et al. 2005

Level of Evidence: Phase III

• Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8

21-day cycles

References

1. Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed
2. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. link to original article contains verified protocol PubMed
3. Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed

Gemcitabine (Gemzar) & Vinorelbine (Navelbine)

Regimen, Elderly Lung Cancer Vinorelbine Italian Study Group, 1999 & Gridelli, et al. 2003 (MILES)

Level of Evidence: Phase III

Study involved only patients at least 70 years old

• Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8

21-day cycles x up to 6 cycles

Supportive medications (varies depending on reference):

• Elderly Lung Cancer Vinorelbine Italian Study Group, 1999: Metoclopramide (Reglan) 20 mg IV bolus prior to vinorelbine
• Gridelli, et al. 2003: "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

References

1. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains verified protocol PubMed
2. Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed

Pemetrexed (Alimta)

Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen #1, Hanna, et al. 2004; Ardizzoni, et al. 2012 (GOIRC 02-2006); Shaw, et al. 2013

Level of Evidence: Phase III

• Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1

21-day cycles; Ardizzoni, et al. 2012 treated patient for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal

Supportive medications (per Ardizzoni, et al. 2012):

• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO BID on the day before, the day of, and day after each dose of pemetrexed
• Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
  • Hanna, et al. 2004 used folic acid 1 mg PO once per day
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

Regimen #2, Paz-Ares, et al. 2012 & Paz-Ares, et al. 2013 (maintenance therapy, PARAMOUNT)

Level of Evidence: Phase III

Patients in this study had received 4 cycles of induction therapy with Cisplatin (Platinol) & Pemetrexed (Alimta). Maintenance therapy started 21 to 42 days after cycle 4 day 1 of induction chemotherapy.

• Pemetrexed (Alimta) 500 mg/m2 IV once on day 1

21-day cycles, given until progression of disease, unacceptable toxicity, or physician/patient choice

Supportive medications:

• Folic acid, Cyanocobalamin (Vitamin B12), prophylactic Dexamethasone (Decadron)
• "Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."

References

1. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains protocol PubMed
2. Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. doi: 10.1016/S1470-2045(12)70063-3. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
3. Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. doi: 10.1200/JCO.2012.43.6758. Epub 2012 Oct 29. link to original article contains verified protocol PubMed
4. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013 Jun 1. [Epub ahead of print] link to original article link to supplementary appendix contains verified protocol PubMed
5. Update: Luis G. Paz-Ares, Filippo de Marinis, Mircea Dediu, Michael Thomas, Jean-Louis Pujol, Paolo Bidoli, Olivier Molinier, Tarini Prasad Sahoo, Eckart Laack, Martin Reck, Jesús Corral, Symantha Melemed, William John, Nadia Chouaki, Annamaria H. Zimmermann, Carla Visseren-Grul, and Cesare Gridelli. PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer. JCO published online on July 8, 2013; DOI:10.1200/JCO.2012.47.1102. link to original article contains verified protocol

Placebo (Observation)

Regimen

Level of Evidence: Phase III

No treatment. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.

References

1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. link to original article contains protocol PubMed
2. Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. doi: 10.1016/S1470-2045(12)70063-3. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
3. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. doi: 10.1016/S1470-2045(12)70087-6. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
4. Update: Luis G. Paz-Ares, Filippo de Marinis, Mircea Dediu, Michael Thomas, Jean-Louis Pujol, Paolo Bidoli, Olivier Molinier, Tarini Prasad Sahoo, Eckart Laack, Martin Reck, Jesús Corral, Symantha Melemed, William John, Nadia Chouaki, Annamaria H. Zimmermann, Carla Visseren-Grul, and Cesare Gridelli. PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer. JCO published online on July 8, 2013; DOI:10.1200/JCO.2012.47.1102. link to original article contains verified protocol

Vinorelbine (Navelbine)

Regimen #1, Quoix, et al. 2011 (IFCT-0501)

Level of Evidence: Phase III

Study involved only patients 70 to 89 years old

• Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8

21-day cycles x up to 5 cycles

Supportive medications:

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia

Regimen #2, Elderly Lung Cancer Vinorelbine Italian Study Group, 1999 & Gridelli, et al. 2003 (MILES)

Level of Evidence: Phase III

Study involved only patients at least 70 years old

• Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8

21-day cycles x up to 6 cycles

Supportive medications (varies depending on reference):

• Elderly Lung Cancer Vinorelbine Italian Study Group, 1999: Metoclopramide (Reglan) 20 mg IV bolus prior to vinorelbine
• Gridelli, et al. 2003: "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

Regimen #3, Jassem, et al. 2001

Level of Evidence: Randomized Phase II, >20 per arm

• Vinorelbine (Navelbine) 30 mg/m2 IV over 5 to 10 minutes once per week

treatment given once per week

Supportive medications:

• Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive G-CSF (dose/schedule/duration not specified)
• Metoclopramide (Reglan) (dose/schedule/route not specified) used first for nausea
• Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as ondansetron (Zofran) or granisetron (Kytril) (dose/schedule/route not specified) prn nausea

Regimen #4, Jassem, et al. 2001 (oral route)

Level of Evidence: Randomized Phase II, >20 per arm

• Vinorelbine (Navelbine) 60 mg/m2 PO once per week, increased to 80 mg/m2 PO once per week with 4th dose, if no severe neutropenia

treatment given once per week

Supportive medications:

• Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive G-CSF (dose/schedule/duration not specified)
• Metoclopramide (Reglan) (dose/schedule/route not specified) used first for nausea
• Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as ondansetron (Zofran) or granisetron (Kytril) (dose/schedule/route not specified) prn nausea

References

1. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains verified protocol PubMed
2. Jassem J, Ramlau R, Karnicka-Młodkowska H, Krawczyk K, Krzakowski M, Zatloukal P, Lemarié E, Hartmann W, Novakova L, O'Brien M, Depierr A. A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients. Ann Oncol. 2001 Oct;12(10):1375-81. link to original article contains verified protocol PubMed
3. Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed
4. Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed