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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. Is there a regimen missing from this list? See the main SCLC page for current regimens.
Last updated on 2024-09-06:33 regimens on this page
44 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 lower OS24
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 (maximum dose of 2000 mg) IV once on day 1
*Doxorubicin (Adriamycin) 40 mg/m2 (maximum dose of 100 mg) IV once on day 1
*Vincristine (Oncovin) 1 mg/m2 (maximum dose of 2 mg) IV once on day 1
21-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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)====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
====Chemotherapy, PE portion (cycles 2, 4, 6)====
*Cisplatin (Platinol) 25 mg/m2 IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV over 40 to 60 minutes once on day 1
21-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Methotrexate (MTX) 30 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 35 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
*Lomustine (CCNU) 30 mg/m2 PO once on day 1
21-day cycle for 2 cycles
====Subsequent treatment====
*RT consolidation
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==VMV/VAC==
VMV/VAC: Vincristine, Methotrexate, VP-16 (Etoposide) alternating with Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence
Kies et al. 1987	1979-1982 	Non-randomized part of RCT
====Chemotherapy, VMV portion (cycles 1 & 3)====
*Vincristine (Oncovin) as follows:
**Cycle 1: 2 mg IV once per day on days 1, 8, 15
*Methotrexate (MTX) 60 mg/m2 IV once on day 1
*Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5
====Chemotherapy, VAC portion (cycles 2 & 4)====
*Vincristine (Oncovin) as follows:
**Cycle 2: 2 mg IV once per day on days 1, 8, 15
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
21-day cycle for 4 cycles (VMV x 2; VAC x 2)
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
=Limited stage, definitive chemoradiotherapy=
==CCDE & RT==
CCDE/RT: Cyclophosphamide, Cisplatin, Doxorubicin, Etoposide, alternating with Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Arriagada et al. 1993	1988-1991 	Phase 3 (E-esc)	CCDE/RT; lower-dose	Seems to have longer OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycle 1: 300 mg/m2 IV once per day on days 2 to 5
**Cycles 2 to 6: 225 mg/m2 IV once per day on days 2 to 5
*Cisplatin (Platinol) as follows:
**Cycle 1: 100 mg/m2 IV once on day 2
**Cycles 2 to 6: 80 mg/m2 IV once on day 2
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 1 to 3
====Radiotherapy====
*External beam radiotherapy
6 cycles, alternating with radiation after the 2nd, 3rd, and 4th cycle
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 longer 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 higher OS24OS24: 33% vs 23.5%
1It is not clear from the manuscript what the primary endpont of the study was.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1 mg/m2 IV once on day 1
====Radiotherapy====
*Concurrent radiation therapy as follows:
**Cycle 1: 3000 cGy in 300 cGy fractions on days 1 to 5, 8 to 12
**Cycle 3: 1500 cGy in 300 cGy fractions on days 1 to 5
21-day cycle for 6 cycles
===References===
# 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 EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 	Longer OS
Perry et al. 1987 (CALGB 8083)	1981-1984 	Phase 3 (E-esc)	2. CEV, then RT	Not reported
Sundstrøm et al. 2002 	1989-1994 	Phase 3 (C) 	EP & RT 	Shorter OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 3, 5, 6: 1000 mg/m2 IV once on day 1
*Epirubicin (Ellence) as follows:
**Cycles 1 to 3, 5, 6: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 3, 5, 6: 2 mg IV once on day 1
====Radiotherapy====
*radiation therapy as follows:
**Cycle 4: 280 cGy once per day on days 1 to 5, 8 to 12, 15 to 19 (4200 cGy total)
21-day cycle for up to 6 cycles
====Subsequent treatment====
*CALGB 8083: Prophylactic cranial irradiation
*Sundstrøm et al. 2002, patients with CR: Prophylactic cranial irradiation
===References===
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cyclophosphamide, Methotrexate, RT==
===Regimen===
Study 	Dates of enrollment	Evidence
Thatcher et al. 1982	1978-1981 	Non-randomized part of RCT
====Chemotherapy====
*Methotrexate (MTX) 100 mg/m2 IV bolus once per day on days 1 & 15
*Cyclophosphamide (Cytoxan) 1500 mg/m2 IV bolus once on day 35, then 2500 mg/m2 IV bolus once on day 56, then 3500 mg/m2 IV bolus once on day 77
====Radiotherapy====
*Radiation therapy 375 cGy per fraction on days 16 to 19, 22 to 25
11-week course
===References===
# Maurer LH, Tulloh M, Weiss RB, Blom J, Leone L, Glidewell O, Pajak TF; CALGB. A randomized combined modality trial in small cell carcinoma of the lung: comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactiv whole brain irradiation. Cancer. 1980 Jan 1;45(1):30-9. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
=Extensive stage, induction=
==BACO==
BACO: Bleomycin, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine)
===Regimen===
Study 	Dates of enrollment	Evidence
Einhorn et al. 1976	1973-06 to 1974-07 	Non-randomized
====Chemotherapy====
*Bleomycin (Blenoxane) 15 units IV push, given second, 6 hours later
*Doxorubicin (Adriamycin) 50 mg/m2 IV push once on day 1, given with cyclophosphamide
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV push once on day 1, given with doxorubicin
*Vincristine (Oncovin) by the following age-based criteria:
**Younger than 50 years old: 1 mg IV push once on day 2, given first
**50 years old or older: 0.75 mg IV push once on day 2, given first
21-day cycle for up to 9 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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. CE1b. EP	Seems to have longer 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====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 5 IV once on day 1
*Etoposide (Vepesid) as follows:
**Cycles 1 to 4: 100 mg/m2 IV once per day on days 1 to 3
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03066778
##PRO analysis: Kim HR, 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, Santorelli ML, Pietanza MC, Rudin CM. Patient-Reported Health-Related Quality of Life in KEYNOTE-604: Pembrolizumab or Placebo Added to Etoposide and Platinum as First-Line Therapy for Extensive-Stage SCLC. JTO Clin Res Rep. 2023 Sep 9;4(11):100572. link to original article link to PMC article EuroPMC
==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 	Not reported in abstract	Randomized (C)	CDE 	Seems to have shorter 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====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 (maximum dose of 2000 mg) IV once on day 1
*Doxorubicin (Adriamycin) 40 mg/m2 (maximum dose of 80 mg) IV once on day 1
*Vincristine (Oncovin) 1 mg/m2 (maximum dose of 2 mg) IV once on day 1
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. 2002 (ECOG E1588)	1988-1990 	Phase 3 (C)	1. Ifosfamide 	Did not meet primary endpoint of OS	More toxic
Ettinger et al. 2002 (ECOG E1588)	1988-1990 	Phase 3 (C)	2. Teniposide 	Did not meet primary endpoint of OS	More toxic
Girling 1996 	1992-1995 	Phase 3 (C)	Etoposide; oral	Seems to have longer OS 	
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
21-day cycle for 4 to 6 cycles 
====Subsequent treatment====
*ECOG E1588, CR: CAV continuation x 2 (6 to 8 total), then prophylactic cranial irradiation
*ECOG E1588, PR: CAV continuation until progression of disease, then salvage EP
===Regimen variant #3, 1000/50/1.4, capped vincristine===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy	Comparative Toxicity
Ettinger et al. 1990 (ECOG E1582)	1982-1985 	Phase 3 (C)	CAV/HEM 	Shorter OS 	Less toxic
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
21-day cycle for 6 to 8 cycles 
===Regimen variant #4, 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 shorter OS	Similar toxicity
Maksymiuk et al. 1994	1987-1990 	Non-randomized part of RCT	 	 	
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
21-day cycle for 6 cycles 
===References===
# 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 EuroPMC
# 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. EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 longer OS
Roth et al. 1992 	1985-1989 	Phase 3 (E-esc) 	1. CAV2. 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 (Odd cycles)====
*Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
====Chemotherapy, PE portion (Even cycles)====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 (route not specified) once per day on days 1 to 3
21-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
==CAVE==
CAVE: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine, Etoposide
CAV-E: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine, Etoposide
EVAC: Etoposide, Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide
===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====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1 mg/m2 IV once per day on days 1 & 8
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 1 to 3
21-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
==CDE==
CDE: Cyclophosphamide, Doxorubicin, Etoposide
ACE: Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
AVE: Adriamycin (Doxorubicin), Vepesid (Etoposide), Endoxan (Cyclophosphamide)
CAE: Cyclophosphamide, Adriamycin (Doxorubicin), Etoposide
===Regimen variant #1, 1000/40/480===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Thatcher et al. 2005 (MRC LU21)	1996-03 to 2002-02 	Phase 3 (C)	ICE-V 	Shorter OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 2
*Etoposide (Vepesid) 120 mg/m2 IV once per day on days 2 & 3, then 240 mg/m2 PO once on day 3
21-day cycle for 6 cycles
===Regimen variant #2, 1000/45/240===
Study 	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Klastersky et al. 1985	Not reported 	Phase 2 	 	ORR: 66%
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====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 45 mg/m2 IV once on day 1
*Etoposide (Vepesid) 80 mg/m2 IV once per day on days 1 to 3
21-day cycle for up to 10 cycles
===Regimen variant #3, 1000/45/300===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bunn et al. 1986 	Not reported in abstract	Randomized (E-switch-ic)	CAV 	Seems to have longer 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
Note: The full manuscript for Bunn et al. 1986 was not available for review.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 45 mg/m2 IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
21-day cycle for 5 cycles
===Regimen variant #4, 1000/45/300, alternate etoposide schedule===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Postmus et al. 1996	1988-1992 	Phase 3 (C)	CDE/VIMP 	Did not meet primary endpoint of OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 45 mg/m2 IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1, 3, 5
21-day cycle for 5 cycles
===Regimen variant #5, 1000/50/240===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sculier et al. 1993	1987 to not reported	Phase 3 (C)	Multi-drug regimen	Did not meet primary endpoint of OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Etoposide (Vepesid) 80 mg/m2 IV once per day on days 1 to 3
21-day cycle for 6 cycles
===Regimen variant #6, 1000/50/600===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Baka et al. 2008	1999-2005 	Phase 3 (C)	EP 	Did not meet primary endpoint of OS12
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Etoposide (Vepesid) 120 mg/m2 IV once on day 1, then 240 mg/m2 PO once per day on days 2 & 3
21-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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. EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002822
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003696
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
21-day cycle for up to 5 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==CEV (Cyclophosphamide/Etoposide)==
CEV: Cyclophosphamide, Etoposide, Vincristine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hong et al. 1989	Not reported 	Randomized (E-esc)	1. CAV2. CV	Longer OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Etoposide (Vepesid) 50 mg/m2 IV once on day 1, then 100 mg/m2 PO once per day on days 2 to 5
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==CEV (Carboplatin/Etoposide)==
CEV: Carboplatin, Etoposide, Vincristine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Reck et al. 2003	1998-01 to 1999-12 	Phase 3 (C)	TEC 	Seems to have shorter OS
Note: cycle duration was not specified.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV over 30 to 60 minutes once on day 1
*Etoposide (Vepesid) by the following stage-specific criteria:
**Stage I-IIIB: 159 mg/m2 IV over 30 minutes once per day on days 1 to 3
**Stage IV: 125 mg/m2 IV over 30 minutes once per day on days 1 to 3
*Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
2 or more cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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. CE1b. EP	Seems to have longer 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====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1
*Etoposide (Vepesid) as follows:
**Cycles 1 to 4: 100 mg/m2 IV once per day on days 1 to 3
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03066778
##PRO analysis: Kim HR, 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, Santorelli ML, Pietanza MC, Rudin CM. Patient-Reported Health-Related Quality of Life in KEYNOTE-604: Pembrolizumab or Placebo Added to Etoposide and Platinum as First-Line Therapy for Extensive-Stage SCLC. JTO Clin Res Rep. 2023 Sep 9;4(11):100572. link to original article link to PMC article EuroPMC
==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 lower ORR
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 700 mg/m2 IV once per day on days 1 & 22
*Lomustine (CCNU) 70 mg/m2 PO once on day 1
42-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 shorter OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once on day 1, then 1000 mg/m2 IV once on day 22
*Lomustine (CCNU) 100 mg/m2 PO once on day 1
*Methotrexate (MTX) 15 mg/m2 (route not specified) on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32 (twice per week)
42-day course
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 higher ORR
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 700 mg/m2 IV once per day on days 1 & 22
*Lomustine (CCNU) 70 mg/m2 PO once on day 1
*Procarbazine (Matulane) 70 mg/m2 PO once per day on days 2 to 8, 22 to 28
42-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==EP-T==
EP-T: Etoposide and Platinol (Cisplatin) followed by Topotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Baka et al. 2010	2002-2006 	Phase 3 (C)	EP/T 	Did not meet primary endpoint of OS
====Chemotherapy, EP portion (cycles 1 to 4)====
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
====Chemotherapy, T portion (cycles 5 to 8)====
*Topotecan (Hycamtin) 1.5 mg/m2 IV once per day on days 1 to 5
21-day cycle for 8 cycles (EP x 4; T x 4)
===References===
# Baka S, Agelaki S, Kotsakis A, Veslemes M, Papakotoulas P, Agelidou M, Agelidou A, Tsaroucha E, Pavlakou G, Gerogianni A, Androulakis N, Vamvakas L, Kalbakis K, Mavroudis D, Georgoulias V. Phase III study comparing sequential versus alternate administration of cisplatin-etoposide and topotecan as first-line treatment in small cell lung cancer. Anticancer Res. 2010 Jul;30(7):3031-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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
Sculier et al. 2001	1993-2000 	Phase 3 (C)	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====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Vindesine (Eldisine) 3 mg/m2 IV once on day 1
*Ifosfamide (Ifex) 5000 mg/m2 IV once on day 1
====Supportive therapy====
*Mesna (Mesnex)
21-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Carboplatin (Paraplatin) 300 mg/m2 IV once on day 1
*Etoposide (Vepesid) 180 mg/m2 IV once per day on days 1 & 2
====Supportive therapy====
*Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 1
28-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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)	1a. CDE1b. EP	Longer OS (primary endpoint)Median OS: 15.6 vs 11.6 mo(HR 0.74, 95% CI 0.60-0.91)
====Chemotherapy====
*Ifosfamide (Ifex) 5000 mg/m2 IV once on day 1
*Carboplatin (Paraplatin) 300 mg/m2 IV once on day 1
*Etoposide (Vepesid) 120 mg/m2 IV once per day on days 1 & 2, then 240 mg/m2 PO once on day 3
*Vincristine (Oncovin) 1 mg/m2 IV once on day 14
====Supportive therapy====
*Mesna (Mesnex)
28-day cycle for 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002822
==PCDE==
PCDE: Platinol (Cisplatin), Cyclophosphamide, EpiDoxorubicin (Epirubicin), Etoposide
===Regimen variant #1, lower-dose etoposide===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pujol et al. 1997	1991-1994 	Phase 3 (C)	PCDE; high-dose	Longer OS
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once on day 2
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once per day on days 1 to 3
*Epirubicin (Ellence) 40 mg/m2 IV once on day 1
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 1 to 3
28-day cycle for 6 cycles
===Regimen variant #2, higher-dose etoposide===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pujol et al. 2001 (FNCLCC 95012) 	1996-1999 	Phase 3 (E-esc)	EP 	Longer 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====
*Cisplatin (Platinol) 100 mg/m2 IV once on day 2
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once per day on days 1 to 3
*Epirubicin (Ellence) 40 mg/m2 IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
28-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003606
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==PCE==
PCE: Paclitaxel, Carboplatin, Etoposide
TEC: Taxol (Paclitaxel) Etoposide), Carboplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Reck et al. 2003	1998-01 to 1999-12 	Phase 3 (E-switch-ic)	CEV 	Seems to have longer OS
Note: cycle duration was not specified.
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 4
*Carboplatin (Paraplatin) AUC 5 IV over 30 to 60 minutes once on day 4
*Etoposide (Vepesid) by the following stage-specific criteria:
**Stage I-IIIB: 125 mg/m2 IV over 30 minutes once per day on days 1 to 3
**Stage IV: 102.2 mg/m2 IV over 30 minutes once per day on days 1 to 3
2 or more cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 longer OS
====Chemotherapy====
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 1 to 4 
*Ifosfamide (Ifex) 1200 mg/m2 IV once per day on days 1 to 4
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4
21-day cycle for 4 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==VMV-VAC==
VMV-VAC: Vincristine, Methotrexate, VP-16 (Etoposide), followed by Vincristine, 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. VAC2. VMV	Did not meet endpoint of OS
====Chemotherapy, VMV portion (cycles 1 & 2)====
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
*Methotrexate (MTX) 50 mg/m2 IV once on day 1
*Etoposide (Vepesid) 60 mg/m2 IV once per day on days 1 to 5
====Chemotherapy, VAC portion (cycles 3 & 4)====
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
21-day cycle for 4 cycles (VMV x 2; VAC x 2)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
=Relapsed or refractory disease=
==CDE==
CDE: Cyclophosphamide, Doxorubicin, Etoposide
===Regimen===
Study 	Dates of enrollment	Evidence
Postmus et al. 1987	Not reported 	Phase 2
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 45 mg/m2 IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1, 3, 5
21-day cycle for 5 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Ipilimumab & Nivolumab==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Antonia et al. 2016 (CheckMate 032SCLC)	2013-2015 	Phase 1/2 (RT)
Note: it is unclear which schedule of ipilimumab & nivolumab is preferred based on the abstract.
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Cycles 1 to 4: 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles, then 14-day cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Antonia et al. 2016 (CheckMate 032SCLC)	2013-2015 	Phase 1/2 (RT)
Note: it is unclear which schedule of ipilimumab & nivolumab is preferred based on the abstract.
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Cycles 1 to 4: 3 mg/kg IV once on day 1
*Nivolumab (Opdivo) as follows:
**Cycles 1 to 4: 1 mg/kg IV once on day 1
**Cycle 5 onwards: 3 mg/kg IV once on day 1
21-day cycle for 4 cycles, then 14-day cycles
===References===
# CheckMate 032SCLC: 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT01928394
##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 EuroPMC
==Nivolumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Antonia et al. 2016 (CheckMate 032SCLC)	2013-2015 	Phase 1/2 (RT)
====Immunotherapy====
*Nivolumab (Opdivo) 3 mg/kg IV once on day 1
14-day cycles
===References===
# CheckMate 032SCLC: 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT01928394
##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 EuroPMC
==Pembrolizumab monotherapy==
===Regimen variant #1, 10 mg/kg q2wk===
Study 	Dates of enrollment	Evidence
Ott et al. 2017c (KEYNOTE-028SCLC)	2014-2015 	Phase 1b (RT)
====Immunotherapy====
*Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1
14-day cycle for up to 52 cycles (2 years)
===Regimen variant #2, 200 mg q3wk===
FDA-recommended dose
Study 	Evidence
Awaiting publication (KEYNOTE-158SCLC)	Phase 2
Note: this arm of KEYNOTE-158 has not been published yet, to our knowledge. KEYNOTE-158 was a basket study with multiple arms of different enrollment periods.
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
# KEYNOTE-028SCLC: 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT02054806
# KEYNOTE-158SCLC: 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. Amrubicin1b. Topotecan	Might have longer OS (primary endpoint)Median OS: 7.5 vs 8.4 mo(HR 0.86, 95% CI 0.72-1.04)
====Immunotherapy====
*Nivolumab (Opdivo) 240 mg IV over 30 minutes once on day 1
14-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02481830
Category:Small cell lung cancer regimens
Category:Historical regimens
Category:Disease-specific pages
Category:Lung cancers