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

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

Regimen, Fossella et al. 2003 (TAX 326)

Level of Evidence: Phase III

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

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

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

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.

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.

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

28-day cycles x 4 cycles

Regimen #2, Hotta et al. 2001

Level of Evidence: Phase II

21-day cycles x 4 cycles

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

Level of Evidence: Phase III

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.

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

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

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

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

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

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

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, ALK-positive

Ceritinib (Zykadia)

Regimen, Shaw et al. 2014

Phase I

Shaw et al. 2014 investigated dose levels of 50 to 750 mg daily; 750 mg is the FDA-approved dose.

given until progression of disease

References

  1. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. link to original article contains verified protocol PubMed

Crizotinib (Xalkori)

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

Level of Evidence: Phase III

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

Advanced or metastatic disease

Afatinib (Gliotrif)

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 (Gliotrif) 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 (Gliotrif) 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.

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

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

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, Sandler et al. 2006 (ECOG 4599), Ramalingam et al. 2008 (ECOG 4599), Socinski et al. 2012

Level of Evidence: Phase III

21-day cycles x 6 cycles; in Socinski et al. 2012: "could continue in the absence of progressive disease and unacceptable toxicity per the investigator's discretion"

Regimen #2, Schiller et al. 2002

Level of Evidence: Phase III

21-day cycles

Regimen #3, Lynch et al. 2012

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

21-day cycles x up to 6 cycles

Supportive medications:

  • Corticosteroids could be used as premedication for paclitaxel infusion.

Regimen #4, Quoix et al. 2011 (weekly paclitaxel, IFCT-0501)

Level of Evidence: Phase III

Study involved only patients 70 to 89 years old

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. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
  4. Subset analysis: 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 contains verified protocol PubMed
  5. 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
  6. 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
  7. 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
  8. 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

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 (PacCBev)

PacCBev: Paclitaxel, Carboplatin, Bevacizumab

Regimen #1, Johnson et al. 2004, Sandler et al. 2006 (ECOG 4599), Ramalingam et al. 2008 (ECOG 4599)

Level of Evidence: Phase III

Induction therapy

  • Carboplatin (Paraplatin) AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
  • Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
  • Bevacizumab (Avastin) 15 mg/kg IV on day 1, given third, starting 60 minutes after the completion of carboplatin
    • Infusion time for bevacizumab per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, bevacizumab was given over 30 to 60 minutes for cycles 2 and later

21-day cycles x up to 6 cycles, until progression of disease, or unacceptable toxicity; after 6 cycles, patients in Sandler et al. 2006 & Ramalingam et al. 2008 (ECOG 4599) who had stable disease or response continued to maintenance therapy

Maintenance therapy

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #3, Patel et al. 2013 (PointBreak)

Level of Evidence: Phase III

Induction therapy

Supportive medications:

  • Premedications per paclitaxel label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycles x 4 cycles; patients with complete response, partial response, and stable disease proceeded to maintenance therapy

Maintenance therapy

21-day cycles, given until progression of disease or unacceptable toxicity

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. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
  3. Subset analysis: 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 contains verified protocol PubMed
  4. Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, Ipilimumab

Regimen, Lynch et al. 2012 (phased ipilimumab)

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

Induction phase

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

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

Regimen #1, Grønberg et al. 2009

Level of Evidence: Phase III

21-day cycles

Supportive medications:

Regimen #2, Ardizzoni et al. 2012 (GOIRC 02-2006) & Zukin et al. 2013

Level of Evidence: Phase III

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

Supportive medications (Ardizzoni et al. 2012 contained more details):

  • 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
  3. Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized Phase III Trial of Single-Agent Pemetrexed Versus Carboplatin and Pemetrexed in Patients With Advanced Non-Small-Cell Lung Cancer and Eastern Cooperative Oncology Group Performance Status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. doi: 10.1200/JCO.2012.48.1911. Epub 2013 Jun 17. link to original article contains verified protocol PubMed

Carboplatin, Pemetrexed, Bevacizumab (PemCBev)

PemCBev: Pemetrexed, Carboplatin, Bevacizumab

Regimen, Patel et al. 2013 (PointBreak)

Level of Evidence: Phase III

Induction therapy

Supportive medications:

  • Premedications, folic acid, and vitamin supplementation per pemetrexed label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycles x 4 cycles; patients with complete response, partial response, and stable disease proceeded to maintenance therapy

Maintenance therapy

Supportive medications:

  • Premedications, folic acid, and vitamin supplementation per pemetrexed label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol PubMed

Cisplatin & Docetaxel

Regimen, Schiller et al. 2002

Level of Evidence: Phase III

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

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

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

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

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: Paz-Ares LG, 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. 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. J Clin Oncol. 2013 Aug 10;31(23):2895-902. doi: 10.1200/JCO.2012.47.1102. Epub 2013 Jul 8. link to original article contains verified protocol PubMed

Cisplatin, Pemetrexed, Bevacizumab

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

Induction phase

Level of Evidence: Non-randomized

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:

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.

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

Supportive medications:

References

  1. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. 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). J Clin Oncol. 2013 Jul 8. [Epub ahead of print] link to original article contains verified protocol PubMed

Docetaxel (Taxotere)

Example orders

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

Level of Evidence: Phase III

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

Supportive medications:

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

Level of Evidence: Phase III

28-day cycles

Supportive medications:

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

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

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

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

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

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

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

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

Level of Evidence: Phase III

21-day cycles; Ardizzoni et al. 2012 & Zukin et al. 2013 treated patients 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.

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: Paz-Ares LG, 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. 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. J Clin Oncol. 2013 Jul 8. [Epub ahead of print] link to original article contains verified protocol PubMed
  6. Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized Phase III Trial of Single-Agent Pemetrexed Versus Carboplatin and Pemetrexed in Patients With Advanced Non-Small-Cell Lung Cancer and Eastern Cooperative Oncology Group Performance Status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. doi: 10.1200/JCO.2012.48.1911. Epub 2013 Jun 17. link to original article contains verified protocol 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. 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: Paz-Ares LG, 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. 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. J Clin Oncol. 2013 Aug 10;31(23):2895-902. doi: 10.1200/JCO.2012.47.1102. Epub 2013 Jul 8. link to original article contains verified protocol PubMed

Vinorelbine (Navelbine)

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

Level of Evidence: Phase III

Study involved only patients 70 to 89 years old

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

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

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
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