Small cell lung cancer - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main SCLC page for current regimens.

32 regimens on this page
34 variants on this page


Limited stage, induction

CAV

CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Johnson et al. 1993 1982-1985 Phase 3 (C) CAV & RT Might have inferior OS24

Chemotherapy

21-day cycle for 6 cycles

References

  1. Johnson DH, Bass D, Einhorn LH, Crawford J, Perez CA, Bartolucci A, Omura GA, Greco FA; Southeastern Cancer Study Group. Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: a randomized trial of the Southeastern Cancer Study Group. J Clin Oncol. 1993 Jul;11(7):1223-9. link to original article contains dosing details in manuscript PubMed

CAV/PE

CAV/PE: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine alternating with Platinol (Cisplatin) & Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Feld et al. 1987 1981-1984 Randomized (E-switch-ic) CAV-PE Did not meet efficacy endpoints

Chemotherapy, CAV portion (cycles 1, 3, 5)

Chemotherapy, PE portion (cycles 2, 4, 6)

21-day cycle for 6 cycles

References

  1. Feld R, Evans WK, Coy P, Hodson I, MacDonald AS, Osoba D, Payne D, Shelley W, Pater JL. Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol. 1987 Sep;5(9):1401-9. link to original article contains dosing details in manuscript PubMed

MACC

MACC: Methotrexate, Adriamycin (Doxorubicin), Cyclophosphamide, CCNU (Lomustine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Maurer et al. 1985 (CALGB 7781) 1977-1981 Phase 3 (E-switch-ic) CCV/AV Did not meet endpoint of OS

Chemotherapy

References

  1. CALGB 7781: Maurer LH, Pajak T, Eaton W, Comis R, Chahinian P, Faulkner C, Silberfarb PM, Henderson E, Rege VB, Baldwin PE, Weiss R, Rafla S, Prager D, Carey R, Perry M, Choi NC. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III Cancer and Leukemia Group B Study. J Clin Oncol. 1985 Jul;3(7):969-76. link to original article PubMed

VMV-VAC

VMV-VAC: Vincristine, Methotrexate, VP-16 (Etoposide), VP-16 (Etoposide), Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study Evidence
Kies et al. 1987 Non-randomized part of RCT

Chemotherapy

References

  1. Kies MS, Mira JG, Crowley JJ, Chen TT, Pazdur R, Grozea PN, Rivkin SE, Coltman CA Jr, Ward JH, Livingston RB; SWOG. Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group study. J Clin Oncol. 1987 Apr;5(4):592-600. link to original article PubMed

Limited stage, definitive chemoradiotherapy

CC/DE & RT

CC/DE & RT: Cyclophosphamide & Cisplatin alternating with Doxorubicin & Etoposide, with Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Arriagada et al. 1993 1988-1991 Phase 3 (E-esc) CC/DE & RT; lower-dose Seems to have superior OS

Chemotherapy

Radiotherapy

References

  1. Arriagada R, Le Chevalier T, Pignon JP, Rivière A, Monnet I, Chomy P, Tuchais C, Tarayre M, Ruffié P. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med. 1993 Dec 16;329(25):1848-52. link to original article PubMed

CAV & RT

CAV & RT: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine, Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perez et al. 1984 1978-1982 Randomized (E-esc) CAV Might have superior DFS1
Jett et al. 1990 1979-1986 Randomized (C) CAVE & RT Did not meet endpoint of OS
Johnson et al. 1993 1982-1985 Phase 3 (E-esc) CAV Might have superior OS24
OS24: 33% vs 23.5%

1It is not clear from the manuscript what the primary endpont of the study was.

Chemotherapy

Radiotherapy

References

  1. Perez CA, Einhorn L, Oldham RK, Greco FA, Cohen HJ, Silberman H, Krauss S, Hornback N, Comas F, Omura G, Salter M, Keller JW, McLaren J, Kellermeyer R, Storaasli J, Birch R, Dandy M; Southeastern Cancer Study Group. Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: a preliminary report. J Clin Oncol. 1984 Nov;2(11):1200-8. link to original article PubMed
  2. Jett JR, Everson L, Therneau TM, Krook JE, Dalton RJ, Marschke RF Jr, Veeder MH, Brunk SF, Mailliard JA, Twito DI, Earle JD, Anderson RT; North Central Cancer Treatment Group. Treatment of limited-stage small-cell lung cancer with cyclophosphamide, doxorubicin, and vincristine with or without etoposide: a randomized trial of the North Central Cancer Treatment Group. J Clin Oncol. 1990 Jan;8(1):33-8. link to original article PubMed
  3. Johnson DH, Bass D, Einhorn LH, Crawford J, Perez CA, Bartolucci A, Omura GA, Greco FA; Southeastern Cancer Study Group. Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: a randomized trial of the Southeastern Cancer Study Group. J Clin Oncol. 1993 Jul;11(7):1223-9. link to original article contains dosing details in manuscript PubMed

CEV & RT

CEV & RT: Cyclophosphamide, Epirubicin, Vincristine, Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perry et al. 1987 (CALGB 8083) 1981-1984 Phase 3 (E-esc) 1. CEV Superior OS
2. CEV, then RT Not reported
Sundstrøm et al. 2002 1989-1994 Phase 3 (C) Cisplatin, Etoposide, RT Inferior OS

Chemotherapy

Radiotherapy

Subsequent treatment

References

  1. CALGB 8083: Perry MC, Eaton WL, Propert KJ, Ware JH, Zimmer B, Chahinian AP, Skarin A, Carey RW, Kreisman H, Faulkner C, Comis R, Green MR. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med. 1987 Apr 9;316(15):912-8. link to original article PubMed
  2. Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, Boye N, Wang M, Vigander T, Vilsvik J, Skovlund E, Hannisdal E, Aamdal S; Norwegian Lung Cancer Study Group. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol. 2002 Dec 15;20(24):4665-72. link to original article contains dosing details in manuscript PubMed

Methotrexate, RT, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence
Thatcher et al. 1982 1978-1981 Non-randomized part of RCT

Chemotherapy

Radiotherapy

11-week course

References

  1. Thatcher N, Barber PV, Hunter RD, Carroll KB, Jegarajah S, Wilkinson PM, Crowther D; Manchester Lung Tumour Group. 11-week course of sequential methotrexate, thoracic irradiation, and moderate-dose cyclophosphamide for "limited"-stage small-cell bronchogenic carcinoma: a study from the Manchester Lung Tumour Group. Lancet. 1982 May 8;1(8280):1040-3. link to original article PubMed

Extensive stage, induction

ACE

ACE: Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
AVE: Adriamycin (Doxorubicin), Vepesid (Etoposide), Endoxan (Cyclophosphamide)
CAE: Cyclophosphamide, Adriamycin (Doxorubicin), Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Klastersky et al. 1985 NR Phase 2 ORR: 66%
Sculier et al. 1993 1987-NR Phase 3 (C) Multi-drug regimen Did not meet primary endpoint of OS
Baka et al. 2008 1999-2005 Phase 3 (C) EP Did not meet primary endpoint of OS12

Note: Used as a comparator arm in older studies. The non-randomized results of Klastersky et al. 1985 established this regimen as a standard control.

Chemotherapy

References

  1. Klastersky J, Sculier JP, Dumont JP, Becquart D, Vandermoten G, Rocmans P, Michel J, Longeval E, Dalesio O. Combination chemotherapy with adriamycin, etoposide, and cyclophosphamide for small cell carcinoma of the lung: a study by the EORTC Lung Cancer Working Party (Belgium). Cancer. 1985 Jul 1;56(1):71-5. link to original article PubMed
  2. Sculier JP, Paesmans M, Bureau G, Dabouis G, Libert P, Vandermoten G, Van Cutsem O, Berchier MC, Ries F, Michel J, Sergysels R, Mommen P, Klastersky J. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol. 1993 Oct;11(10):1858-65. link to original article PubMed
  3. Baka S, Califano R, Ferraldeschi R, Aschroft L, Thatcher N, Taylor P, Faivre-Finn C, Blackhall F, Lorigan P. Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer. Br J Cancer. 2008 Aug 5;99(3):442-7. link to original article link to PMC article contains dosing details in abstract PubMed

BACO

BACO: Bleomycin, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine)

Regimen

Study Evidence
Einhorn et al. 1976 Non-randomized

Chemotherapy

References

  1. Einhorn LH, Fee WH, Farber MO, Livingston RB, Gottlieb JA. Improved chemotherapy for small-cell undifferentiated lung cancer. JAMA. 1976 Mar 22;235(12):1225-9. link to original article PubMed

Carboplatin & Etoposide (CE) & Pembrolizumab

CE & Pembrolizumab: Carboplatin, Etoposide, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rudin et al. 2020 (KEYNOTE-604) 2017-05-15 to 2018-07-30 Phase 3 (E-esc) 1a. CE
1b. EP 		Seems to have superior OS1 (co-primary endpoint)
OS24: 22.5% vs 11.2%
(HR 0.80, 95% CI 0.64-0.98)

1This result did not meet the pre-specified threshold for statistical significance, and was the basis for withdrawal of the FDA indication.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-604: Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csőszi T, Cheema PK, Rodriguez-Abreu D, Wollner M, Yang JC, Mazieres J, Orlandi FJ, Luft A, Gümüş M, Kato T, Kalemkerian GP, Luo Y, Ebiana V, Pietanza MC, Kim HR; KEYNOTE-604 Investigators. Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. 2020 Jul 20;38(21):2369-2379. Epub 2020 May 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03066778

CAV

CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine
CAO: Cyclophosphamide, Adriamycin (Doxorubicin), Oncovin (Vincristine)

Regimen variant #1, 1000/40/1, capped by BSA

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Bunn et al. 1986 NR in abstract Randomized (C) CDE Seems to have inferior OS
Johnson et al. 1987 1982-1984 Phase 3 (C) CAV; high-dose Did not meet endpoint of OS Less toxic

Note: the original manuscript with dosing for Bunn et al. 1986 is not available for review.

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #2, 1000/50/1.4, uncapped vincristine

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Ettinger et al. 1990 (ECOG E1582) 1982-1985 Phase 3 (C) CAV/HEM Inferior OS
Ettinger et al. 2002 (ECOG E1588) 1988-1990 Phase 3 (C) 1. Ifosfamide Did not meet primary endpoint of OS More toxic
2. Teniposide Did not meet primary endpoint of OS More toxic
Girling 1996 1992-1995 Phase 3 (C) Etoposide; oral Seems to have superior OS

Chemotherapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

  • ECOG E1588, CR: CAV x 2 (6 to 8 total), then PCI
  • ECOG E1588, PR: CAV until progression of disease, then salvage EP


Regimen variant #3, 1000/50/2, flat-dose vincristine

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Holoye et al. 1977 1973-1974 Non-randomized
Evans et al. 1987 1982-1985 Phase 3 (C) CAV/PE Seems to have inferior OS Similar toxicity
Maksymiuk et al. 1994 1987-1990 Non-randomized part of RCT

Chemotherapy

21-day cycle for 6 cycles

References

  1. Holoye PY, Samuels ML, Lanzotti VJ, Smith T, Barkley HT Jr. Combination chemotherapy and radiation therapy for small cell carcinoma. JAMA. 1977 Mar 21;237(12):1221-4. link to original article PubMed
  2. Bunn PA Jr, Greco FA, Einhorn L. Cyclophosphamide, doxorubicin, and etoposide as first-line therapy in the treatment of small-cell lung cancer. Semin Oncol. 1986 Sep;13(3 Suppl 3):45-53. PubMed
  3. Evans WK, Feld R, Murray N, Willan A, Coy P, Osoba D, Shepherd FA, Clark DA, Levitt M, MacDonald A, Wilson K, Shelley W, Pater J. Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: a multicenter, randomized clinical trial by the National Cancer Institute of Canada. Ann Intern Med. 1987 Oct;107(4):451-8. Erratum in: Ann Intern Med 1988 Mar;108(3):496. link to original article contains dosing details in abstract PubMed
  4. Johnson DH, Einhorn LH, Birch R, Vollmer R, Perez C, Krauss S, Omura G, Greco FA; Southeastern Cancer Study Group. A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol. 1987 Nov;5(11):1731-8. link to original article contains dosing details in manuscript PubMed
  5. ECOG E1582: Ettinger DS, Finkelstein DM, Abeloff MD, Ruckdeschel JC, Aisner SC, Eggleston JC; ECOG. A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group. J Clin Oncol. 1990 Feb;8(2):230-40. link to original article PubMed
  6. Maksymiuk AW, Jett JR, Earle JD, Su JQ, Diegert FA, Mailliard JA, Kardinal CG, Krook JE, Veeder MH, Wiesenfeld M, Tschetter LK, Levitt R; North Central Cancer Treatment Group. Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial. J Clin Oncol. 1994 Jan;12(1):70-6. link to original article PubMed
  7. Girling DJ; Medical Research Council Lung Cancer Working Party. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Lancet. 1996 Aug 31;348(9027):563-6. link to original article PubMed
  8. ECOG E1588: Ettinger DS, Finkelstein DM, Ritch PS, Lincoln ST, Blum RH; ECOG. Study of either ifosfamide or teniposide compared to a standard chemotherapy for extensive disease small cell lung cancer: an Eastern Cooperative Oncology Group randomized study (E1588). Lung Cancer. 2002 Sep;37(3):311-8. link to original article contains dosing details in manuscript PubMed

CAV/PE

CAV/PE: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine alternating with Platinol (Cisplatin) & Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goodman et al. 1990 (SWOG S8232) 1982-1984 Phase 3 (E-switch-ic) CAVE Did not meet primary endpoint of OS
Evans et al. 1987 1982-1985 Phase 3 (E-switch-ic) CAV Seems to have superior OS
Roth et al. 1992 1985-1989 Phase 3 (E-esc) 1. CAV
2. EP 		Did not meet primary endpoint of OS50%
Furuse et al. 1998 (JCOG9106) 1991-1995 Phase 3 (C) CODE Did not meet primary endpoint of OS50%
Murray et al. 1999 1992-1996 Phase 3 (C) CODE Did not meet primary endpoint of OS

Chemotherapy, CAV portion

Chemotherapy, PE portion

References

  1. Evans WK, Feld R, Murray N, Willan A, Coy P, Osoba D, Shepherd FA, Clark DA, Levitt M, MacDonald A, Wilson K, Shelley W, Pater J. Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: a multicenter, randomized clinical trial by the National Cancer Institute of Canada. Ann Intern Med. 1987 Oct;107(4):451-8. Erratum in: Ann Intern Med 1988 Mar;108(3):496. link to original article contains dosing details in abstract PubMed
  2. SWOG S8232: Goodman GE, Crowley JJ, Blasko JC, Livingston RB, Beck TM, Demattia MD, Bukowski RM. Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol. 1990 Jan;8(1):39-47. link to original article PubMed
  3. Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, Crawford J, Randolph JA, Goodlow JL, Broun GO, Omura GA, Greco FA; Southeastern Cancer Study Group. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol. 1992 Feb;10(2):282-91. link to original article PubMed
  4. JCOG9106: Furuse K, Fukuoka M, Nishiwaki Y, Kurita Y, Watanabe K, Noda K, Ariyoshi Y, Tamura T, Saijo N; JCOG. Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. J Clin Oncol. 1998 Jun;16(6):2126-32. link to original article PubMed
  5. Murray N, Livingston RB, Shepherd FA, James K, Zee B, Langleben A, Kraut M, Bearden J, Goodwin JW, Grafton C, Turrisi A, Walde D, Croft H, Osoba D, Ottaway J, Gandara D; National Cancer Institute of Canada Clinical Trials Group; SWOG. Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol. 1999 Aug;17(8):2300-8. link to original article PubMed

CAVE

CAVE: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine, Etoposide
CAV-E: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine, Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goodman et al. 1990 (SWOG S8232) 1982-1984 Phase 3 (C) CAV/PE Did not meet primary endpoint of OS
Tummarello et al. 1997 1990-1995 Phase 3 (C) CAV-T Did not meet primary endpoint of OS50%

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

References

  1. SWOG S8232: Goodman GE, Crowley JJ, Blasko JC, Livingston RB, Beck TM, Demattia MD, Bukowski RM. Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol. 1990 Jan;8(1):39-47. link to original article PubMed
  2. Tummarello D, Mari D, Graziano F, Isidori P, Cetto G, Pasini F, Santo A, Cellerino R. A randomized, controlled phase III study of cyclophosphamide, doxorubicin, and vincristine with etoposide (CAV-E) or teniposide (CAV-T), followed by recombinant interferon-alpha maintenance therapy or observation, in small cell lung carcinoma patients with complete responses. Cancer. 1997 Dec 15;80(12):2222-9. link to original article PubMed

CDE

CDE: Cyclophosphamide, Doxorubicin, Etoposide
CAE: Cyclophosphamide, Adriamycin (Doxorubicin), Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bunn et al. 1986 NR in abstract Randomized (E-switch-ic) CAV Seems to have superior OS
Postmus et al. 1996 1988-1992 Phase 3 (C) CDE/VIMP Did not meet primary endpoint of OS
Ardizzoni et al. 2002 (EORTC 08923) 1994-1999 Phase 3 (C) CDE; intensified Did not meet primary endpoint of OS
de Jong et al. 2007 (CKVO-9802) 1999-2005 Phase 3 (C) CP Did not meet primary endpoint of PFS

Chemotherapy

References

  1. Bunn PA Jr, Greco FA, Einhorn L. Cyclophosphamide, doxorubicin, and etoposide as first-line therapy in the treatment of small-cell lung cancer. Semin Oncol. 1986 Sep;13(3 Suppl 3):45-53. PubMed
  2. Postmus PE, Scagliotti G, Groen HJ, Gozzelino F, Burghouts JT, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G, Splinter TA. Standard versus alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: an EORTC phase III trial. Eur J Cancer. 1996 Aug;32A(9):1498-503. link to original article PubMed
  3. EORTC 08923: Ardizzoni A, Tjan-Heijnen VC, Postmus PE, Buchholz E, Biesma B, Karnicka-Mlodkowska H, Dziadziuszko R, Burghouts J, Van Meerbeeck JP, Gans S, Legrand C, Debruyne C, Giaccone G, Manegold C; EORTC-Lung Cancer Group. Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organisation for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol. 2002 Oct 1;20(19):3947-55. link to original article PubMed
  4. CKVO-9802: de Jong WK, Groen HJ, Koolen MG, Biesma B, Willems LN, Kwa HB, van Bochove A, van Tinteren H, Smit EF. Phase III study of cyclophosphamide, doxorubicin, and etoposide compared with carboplatin and paclitaxel in patients with extensive disease small-cell lung cancer. Eur J Cancer. 2007 Nov;43(16):2345-50. Epub 2007 Sep 10. link to original article PubMed NCT00003696

CEV (Cyclophosphamide/Epirubicin)

CEV: Cyclophosphamide, Epirubicin, Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sundstrøm et al. 2002 1989-1994 Phase 3 (C) Cisplatin & Etoposide Did not meet primary endpoint of OS

Chemotherapy

References

  1. Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, Boye N, Wang M, Vigander T, Vilsvik J, Skovlund E, Hannisdal E, Aamdal S; Norwegian Lung Cancer Study Group. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol. 2002 Dec 15;20(24):4665-72. link to original article contains dosing details in manuscript PubMed

CEV (Cyclophosphamide/Etoposide)

CEV: Cyclophosphamide, Etoposide, Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hong et al. 1989 NR Randomized (E-esc) 1. CAV
2. CV 		Superior OS

Chemotherapy

References

  1. Hong WK, Nicaise C, Lawson R, Maroun JA, Comis R, Speer J, Luedke D, Hurtubise M, Lanzotti V, Goodlow J, Rozencweig M; Bristol Lung Cancer Study Group. Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: a randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol. 1989 Apr;7(4):450-6. link to original article PubMed

CEV (Carboplatin/Etoposide)

CEV: Carboplatin, Etoposide, Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2003 1998-1999 Phase 3 (C) TEC Seems to have inferior OS

Chemotherapy

References

  1. Reck M, von Pawel J, Macha HN, Kaukel E, Deppermann KM, Bonnet R, Ulm K, Hessler S, Gatzemeier U. Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst. 2003 Aug 6;95(15):1118-27. link to original article PubMed

Cisplatin & Etoposide (EP) & Pembrolizumab

EP & Pembrolizumab: Etoposide, Platinol (Cisplatin), Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rudin et al. 2020 (KEYNOTE-604) 2017-05-15 to 2018-07-30 Phase 3 (E-esc) 1a. CE
1b. EP 		Seems to have superior OS1 (co-primary endpoint)
OS24: 22.5% vs 11.2%
(HR 0.80, 95% CI 0.64-0.98)

1This result did not meet the pre-specified threshold for statistical significance, and was the basis for withdrawal of the FDA indication.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-604: Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csőszi T, Cheema PK, Rodriguez-Abreu D, Wollner M, Yang JC, Mazieres J, Orlandi FJ, Luft A, Gümüş M, Kato T, Kalemkerian GP, Luo Y, Ebiana V, Pietanza MC, Kim HR; KEYNOTE-604 Investigators. Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. 2020 Jul 20;38(21):2369-2379. Epub 2020 May 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03066778

Cyclophosphamide & Lomustine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ettinger & Lagakos 1982 1973-1977 Phase 3 (C) Cyclophosphamide, Lomustine, Procarbazine Seems to have inferior ORR

Chemotherapy

References

  1. Ettinger DS, Lagakos S; ECOG. Phase III study of CCNU, cyclophosphamide, adriamycin, vincristine, and VP-16 in small-cell carcinoma of the lung. Cancer. 1982 Apr 15;49(8):1544-54. link to original article PubMed

Cyclophosphamide, Lomustine, Methotrexate

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cohen et al. 1979 1975-1977 Phase 3 (C) Chemotherapy & Thymosin fraction V Seems to have inferior OS

Chemotherapy

References

  1. Cohen MH, Chretien PB, Ihde DC, Fossieck BE Jr, Makuch R, Bunn PA Jr, Johnston AV, Shackney SE, Matthews MJ, Lipson SD, Kenady DE, Minna JD. Thymosin fraction V and intensive combination chemotherapy: prolonging the survival of patients with small-cell lung cancer. JAMA. 1979 Apr 27;241(17):1813-5. link to original article PubMed

Cyclophosphamide, Lomustine, Procarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ettinger & Lagakos 1982 1973-1977 Phase 3 (E-esc) Cyclophosphamide & Lomustine Seems to have superior ORR

Chemotherapy

References

  1. Ettinger DS, Lagakos S; ECOG. Phase III study of CCNU, cyclophosphamide, adriamycin, vincristine, and VP-16 in small-cell carcinoma of the lung. Cancer. 1982 Apr 15;49(8):1544-54. link to original article PubMed

EVI

EVI: Epirubicin, Vindesine, Ifosfamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sculier et al. 2001 1993-2000 Phase 3 (C) 1. EVI & GM-CSF; accelerated Did not meet primary endpoint of OS
2. Accelerated EVI & antibiotics Did not meet primary endpoint of OS

Note: Not commonly used but was a comparator arm for at least one RCT; here for reference purposes only.

Chemotherapy

References

  1. Sculier JP, Paesmans M, Lecomte J, Van Cutsem O, Lafitte JJ, Berghmans T, Koumakis G, Florin MC, Thiriaux J, Michel J, Giner V, Berchier MC, Mommen P, Ninane V, Klastersky J; European Lung Cancer Working Party. A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics. Br J Cancer. 2001 Nov 16;85(10):1444-51. link to original article link to PMC article PubMed

ICE

ICE: Ifosfamide, Carboplatin, Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lorigan et al. 2005 1994-2001 Phase 3 (C) Dose-dense ICE, then auto HSCT Did not meet primary endpoint of OS

Chemotherapy

References

  1. Lorigan P, Woll PJ, O'Brien ME, Ashcroft LF, Sampson MR, Thatcher N. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst. 2005 May 4;97(9):666-74. Erratum in: J Natl Cancer Inst. 2005 Jun 15;97(12):941. link to original article PubMed

ICE-V

ICE-V: Ifosfamide, Carboplatin, Etoposide, Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thatcher et al. 2005 (MRC LU21) 1996-03 to 2002-02 Phase 3 (E-esc) 1. CDE
2. EP 		Superior OS (primary endpoint)
Median OS: 15.6 vs 11.6 mo
(HR 0.74, 95% CI 0.60-0.91)

Chemotherapy

References

  1. MRC LU21: Thatcher N, Qian W, Clark PI, Hopwood P, Sambrook RJ, Owens R, Stephens RJ, Girling DJ. Ifosfamide, carboplatin, and etoposide with midcycle vincristine versus standard chemotherapy in patients with small-cell lung cancer and good performance status: clinical and quality-of-life results of the British Medical Research Council multicenter randomized LU21 trial. J Clin Oncol. 2005 Nov 20;23(33):8371-9. link to original article PubMed NCT00002822

PCDE

PCDE: Platinol (Cisplatin), Cyclophosphamide, EpiDoxorubicin (Epirubicin), Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pujol et al. 1997 1991-1994 Phase 3 (C) PCDE; high-dose Superior OS
Pujol et al. 2001 (FNCLCC 95012) 1996-1999 Phase 3 (E-esc) EP Superior OS
Pujol et al. 2007 (FNCLCC cleo04 IFCT 00-01) 2000-2004 Phase 3 (C) PCDE & Thalidomide Did not meet primary endpoint of OS

Chemotherapy

References

  1. Pujol JL, Douillard JY, Rivière A, Quoix E, Lagrange JL, Berthaud P, Bardonnet-Comte M, Polin V, Gautier V, Milleron B, Chomy F, Chomy P, Spaeth D, Le Chevalier T. Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol. 1997 May;15(5):2082-9. link to original article PubMed
  2. FNCLCC 95012: Pujol JL, Daurès JP, Rivière A, Quoix E, Westeel V, Quantin X, Breton JL, Lemarié E, Poudenx M, Milleron B, Moro D, Debieuvre D, Le Chevalier T. Etoposide plus cisplatin with or without the combination of 4'-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study. J Natl Cancer Inst. 2001 Feb 21;93(4):300-8. link to original article PubMed NCT00003606
  3. FNCLCC cleo04/IFCT 00-01: Pujol JL, Breton JL, Gervais R, Tanguy ML, Quoix E, David P, Janicot H, Westeel V, Gameroff S, Genève J, Maraninchi D. Phase III double-blind, placebo-controlled study of thalidomide in extensive-disease small-cell lung cancer after response to chemotherapy: an intergroup study FNCLCC cleo04 IFCT 00-01. J Clin Oncol. 2007 Sep 1;25(25):3945-51. link to original article PubMed

PCE

PCE: Paclitaxel, Carboplatin, Etoposide
TEC: Taxol (Paclitaxel) Etoposide), Carboplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2003 1998-1999 Phase 3 (E-switch-ic) CEV Seems to have superior OS

Chemotherapy

References

  1. Reck M, von Pawel J, Macha HN, Kaukel E, Deppermann KM, Bonnet R, Ulm K, Hessler S, Gatzemeier U. Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst. 2003 Aug 6;95(15):1118-27. link to original article PubMed

VIP

VIP: Vepesid (Etoposide), Ifosfamide, Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Loehrer et al. 1995 1989-1993 Phase 3 (E-esc) Cisplatin & Etoposide Seems to have superior OS

Chemotherapy

21-day cycle for 4 cycles

References

  1. Loehrer PJ Sr, Ansari R, Gonin R, Monaco F, Fisher W, Sandler A, Einhorn LH; Hoosier Oncology Group. Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study. J Clin Oncol. 1995 Oct;13(10):2594-9. link to original article contains dosing details in manuscript PubMed

VMV-VAC

VMV-VAC: Vincristine, Methotrexate, VP-16 (Etoposide), VP-16 (Etoposide), Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Livingston et al. 1984 (SWOG S7828) 1978-1980 Phase 3 (E-esc) 1. VAC
2. VMV 		Did not meet endpoint of OS

Chemotherapy

References

  1. SWOG S7828: Livingston RB, Mira JG, Chen TT, McGavran M, Costanzi JJ, Samson M. Combined modality treatment of extensive small cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1984 Jun;2(6):585-90. link to original article PubMed

Relapsed or refractory disease

CDE

CDE: Cyclophosphamide, Doxorubicin, Etoposide

Regimen

Study Dates of enrollment Evidence
Postmus et al. 1987 NR Phase 2

Chemotherapy

21-day cycle for 5 cycles

References

  1. Postmus PE, Berendsen HH, van Zandwijk N, Splinter TA, Burghouts JT, Bakker W. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol. 1987 Sep;23(9):1409-11. link to original article contains dosing details in manuscript PubMed

Ipilimumab & Nivolumab

Regimen variant #1

Study Dates of enrollment Evidence
Antonia et al. 2016 (CheckMate 032) 2013-2015 Phase 1/2 (RT)

Note: it is unclear which schedule of ipilimumab & nivolumab is preferred based on the abstract.

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles


Regimen variant #2

Study Dates of enrollment Evidence
Antonia et al. 2016 (CheckMate 032) 2013-2015 Phase 1/2 (RT)

Note: it is unclear which schedule of ipilimumab & nivolumab is preferred based on the abstract.

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles

References

  1. CheckMate 032: Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jäger D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin CS, Christensen O, Calvo E. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-95. Epub 2016 Jun 4. link to original article contains dosing details in abstract PubMed NCT01928394
    1. Update: Ready NE, Ott PA, Hellmann MD, Zugazagoitia J, Hann CL, de Braud F, Antonia SJ, Ascierto PA, Moreno V, Atmaca A, Salvagni S, Taylor M, Amin A, Camidge DR, Horn L, Calvo E, Li A, Lin WH, Callahan MK, Spigel DR. Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort. J Thorac Oncol. 2020 Mar;15(3):426-435. Epub 2019 Oct 17. link to original article PubMed

Nivolumab monotherapy

Regimen

Study Dates of enrollment Evidence
Antonia et al. 2016 (CheckMate 032) 2013-2015 Phase 1/2 (RT)

Immunotherapy

14-day cycles

References

  1. CheckMate 032: Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jäger D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin CS, Christensen O, Calvo E. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-95. Epub 2016 Jun 4. link to original article contains dosing details in abstract PubMed NCT01928394
    1. Update: Ready NE, Ott PA, Hellmann MD, Zugazagoitia J, Hann CL, de Braud F, Antonia SJ, Ascierto PA, Moreno V, Atmaca A, Salvagni S, Taylor M, Amin A, Camidge DR, Horn L, Calvo E, Li A, Lin WH, Callahan MK, Spigel DR. Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort. J Thorac Oncol. 2020 Mar;15(3):426-435. Epub 2019 Oct 17. link to original article PubMed

Pembrolizumab monotherapy

Regimen variant #1, 10 mg/kg q2wk

Study Dates of enrollment Evidence
Ott et al. 2017c (KEYNOTE-028) 2014-2015 Phase 1b (RT)

Immunotherapy

14-day cycle for up to 52 cycles (2 years)


Regimen variant #2, 200 mg q3wk

FDA-recommended dose
Study Evidence
Awaiting publication (KEYNOTE-158) Phase 2

Note: this arm of KEYNOTE-158 has not been published yet, to our knowledge.

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-028: Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, Piperdi B, Mehnert JM. Pembrolizumab in patients With extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017 Dec 1;35(34):3823-3829. Epub 2017 Aug 16. link to original article contains dosing details in abstract PubMed NCT02054806
  2. KEYNOTE-158: NCT02628067

Relapsed or refractory disease, second-line

Nivolumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Spigel et al. 2021 (CheckMate 331) 2015-2017 Phase 3 (E-switch-ooc) 1a. Amrubicin
1b. Topotecan 		Might have superior OS (primary endpoint)
Median OS: 7.5 vs 8.4 mo
(HR 0.86, 95% CI 0.72-1.04)

Immunotherapy

14-day cycles

References

  1. CheckMate 331: Spigel DR, Vicente D, Ciuleanu TE, Gettinger S, Peters S, Horn L, Audigier-Valette C, Pardo Aranda N, Juan-Vidal O, Cheng Y, Zhang H, Shi M, Luft A, Wolf J, Antonia S, Nakagawa K, Fairchild J, Baudelet C, Pandya D, Doshi P, Chang H, Reck M. Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331. Ann Oncol. 2021 May;32(5):631-641. Epub 2021 Feb 1. link to original article contains dosing details in manuscript PubMed NCT02481830
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