Small cell lung cancer

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 Amit Kulkarni, MBBS
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.

47 regimens on this page
99 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

ASCO-Ontario Health

ESMO

NCCN

SITC

Limited stage, induction

Carboplatin & Etoposide (CE)

EP: Etoposide, Paraplatin (Carboplatin)

Regimen variant #1, 2 days of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2009 (LLCG-STUDY-12) 2003-2006 Phase 3 (C) CE & Thalidomide, then RT Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment


Regimen variant #2, 1 day of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2009 (LLCG-STUDY-12) 2003-2006 Phase 3 (C) CE & Thalidomide, then RT Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. LLCG-STUDY-12: Lee SM, Woll PJ, Rudd R, Ferry D, O'Brien M, Middleton G, Spiro S, James L, Ali K, Jitlal M, Hackshaw A. Anti-angiogenic therapy using thalidomide combined with chemotherapy in small cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst. 2009 Aug 5;101(15):1049-57. Epub 2009 Jul 16. link to original article contains dosing details in manuscript PubMed NCT00061919

Cisplatin & Etoposide (EP)

EP: Etoposide, Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence
Evans et al. 1985 1981-1984 Phase 2

Note: Patients with limited stage disease responding to therapy received prophylactic cranial irradiation, 400 cGy fractions once per day x 5 fractions (total dose: 2000 cGy) over 5 days between cycles 3 and 4.

Chemotherapy

Supportive therapy

  • Dexamethasone (Decadron) 10 mg IV once per day on days 1 to 3, prior to chemotherapy
  • Metoclopramide (Reglan) 10 mg IV or PO once per day on days 1 to 3, prior to chemotherapy
  • Prochlorperazine (Compazine) 10 mg IM or PO once per day on days 1 to 3, prior to chemotherapy
  • "No special efforts were made to hydrate the patients," though PO fluid intake was encouraged, and 500 mL normal saline was given with etoposide infusion.

21- to 28-day cycle for 6 cycles

Subsequent treatment

References

  1. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471-7. link to original article contains dosing details in manuscript PubMed

Limited stage, definitive chemoradiotherapy

Carboplatin, Etoposide, RT

EP & RT: Etoposide, Paraplatin (Carboplatin), Radiation Therapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Skarlos et al. 2001 1993-1999 Randomized Phase 2 (E-switch-ic) Carboplatin, Etoposide, RT; early HTRT Might have superior ORR (primary endpoint)

Chemotherapy

Radiotherapy

  • Concurrent hyperfractionated thoracic radiation therapy (HTRT), 150 cGy fractions given twice per day (at least 4, but preferably 6 hours between fractions) x 30 fractions (total dose: 4500 cGy) over 3 weeks. Skarlos et al. 2001 examined two different timings for radiation therapy. There was no significant difference between early vs. late HTRT, though there was a trend toward higher response rate for late HTRT. Early HTRT is given during cycle 1 of chemotherapy; late HTRT is given during cycle 4 of chemotherapy.

21-day cycle for up to 6 cycles

Subsequent treatment


Regimen variant #2

Study Evidence
Okamoto et al. 1999 Phase 2

Eligibility criteria

  • At least 70 years old

Chemotherapy

Radiotherapy

  • Thoracic radiation, given third
  • Palliative radiation therapy was allowed to control persistent pain from bony metastases

Supportive therapy

  • Dexamethasone (Decadron) 8 mg IV once per day on days 1 to 3, prior to chemotherapy
  • Granisetron 40 mcg/kg IV once per day on days 1 to 3, prior to chemotherapy
  • G-CSF (type not specified) 2 mcg/kg SC given for grade 3 or greater leukopenia/neutropenia

28-day cycle for up to 4 cycles

References

  1. Okamoto H, Watanabe K, Nishiwaki Y, Mori K, Kurita Y, Hayashi I, Masutani M, Nakata K, Tsuchiya S, Isobe H, Saijo N. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol. 1999 Nov;17(11):3540-5. link to original article contains dosing details in manuscript PubMed
  2. Skarlos DV, Samantas E, Briassoulis E, Panoussaki E, Pavlidis N, Kalofonos HP, Kardamakis D, Tsiakopoulos E, Kosmidis P, Tsavdaridis D, Tzitzikas J, Tsekeris P, Kouvatseas G, Zamboglou N, Fountzilas G; Hellenic Cooperative Oncology Group. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2001 Sep;12(9):1231-8. link to original article contains dosing details in manuscript PubMed

Cisplatin, Etoposide, RT

EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy
PE + RT: Platinol (Cisplatin), Etoposide, Radiation Therapy

Regimen variant #1, 60/360/45

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Turrisi et al. 1999 (Intergroup 0096) 1989-1992 Phase 3 (E-esc) EP & RT; once per day RT Seems to have superior OS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 150 cGy fractions given twice per day x 30 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 4500 cGy)

21-day cycle for 4 cycles

Subsequent treatment

  • After completing 4 cycles of chemotherapy, patients were restaged. Because of the high rate of brain metastases (50%), patients with CR were offered prophylactice cranial irradiation


Regimen variant #2, 70/300/52.5, early RT

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Sun et al. 2013 (SMC 2003-02-016) 2003-2010 Phase 3 (C) EP & RT; late RT Non-inferior CR rate Seems to have higher rates of neutropenic fever

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 210 cGy fractions x 25 fractions over 5 weeks, given during cycle 1 of chemotherapy (total dose: 5250 cGy)

21-day cycle for 4 cycles


Regimen variant #3, 70/300/52.5, late RT

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Sun et al. 2013 (SMC 2003-02-016) 2003-2010 Phase 3 (E-switch-ic) EP & RT; early RT Non-inferior CR rate (primary endpoint) Seems to have lower rates of neutropenic fever

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 210 cGy fractions x 25 fractions over 5 weeks, given during cycle 3 of chemotherapy (total dose: 5250 cGy)

21-day cycle for 4 cycles


Regimen variant #4, 75/180/45, pre-planned dose reduction

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Bunn et al. 1995 1989-1991 Phase 3 (C) EP & RT; with GM-CSF support Did not meet secondary endpoints Less toxic

Note: toxicity was the primary endpoint in this study.

Chemotherapy

  • Cisplatin (Platinol) as follows:
    • Cycles 1 to 3: 25 mg/m2 IV once per day on days 1 to 3
    • Cycles 4 to 6: 40 mg/m2 IV once on day 1
  • Etoposide (Vepesid) as follows:
    • Cycles 1 to 3: 60 mg/m2 IV once per day on days 1 to 3
    • Cycles 4 to 6: 50 mg/m2 IV once per day on days 1 to 3

Radiotherapy

  • Concurrent radiation therapy during cycles 1 & 2, 180 cGy fractions x 25 fractions (total dose: 4500 cGy)

21-day cycle for 6 cycles


Regimen variant #5, 75/300/45

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faivre-Finn et al. 2017 (CONVERT) 2008-2013 Phase 3 (E-esc) EP & RT; once per day RT Did not meet primary endpoint of OS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 150 cGy fractions given twice per day x 30 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 4500 cGy)

21-day cycle for 4 or 6 cycles


Regimen variant #6, 75/300/45, split doses of cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faivre-Finn et al. 2017 (CONVERT) 2008-2013 Phase 3 (E-esc) EP & RT; once per day RT Did not meet primary endpoint of OS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 150 cGy fractions given twice per day x 30 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 4500 cGy)

21-day cycle for 4 or 6 cycles


Regimen variant #7, 75/700/42, partially oral etoposide

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sundstrøm et al. 2002 1989-1994 Phase 3 (E-switch-ic) CEV & RT Superior OS

Note: Oral etoposide to be taken on an empty stomach.

Chemotherapy

Radiotherapy

  • Concurrent thoracic radiation therapy, 280 cGy fractions once per day x 15 fractions (total dose: 4200 cGy) over 3 weeks, given "between the third and fourth chemotherapy courses"

Supportive therapy

  • "Standard prehydration and posthydration procedures were followed in conjunction with cisplatin administration."

21-day cycle for up to 5 cycles

Subsequent treatment


Regimen variant #8, 80/240/50

Study Dates of enrollment Evidence Comparator Comparative Efficacy
McClay et al. 2005 (CALGB 9235) 1993-1999 Phase 3 (E-de-esc) EP, Tamoxifen, RT Did not meet primary endpoint of OS

Chemotherapy

Radiotherapy

  • Concurrent thoracic radiation therapy, 200 cGy fractions once per day x 25 fractions (total dose: 5000 cGy) over 5 weeks, started on cycle 4 day 1 of chemotherapy

21-day cycle for 5 cycles


Regimen variant #9, 80/300/45, 1 cycle of chemo

Study Dates of enrollment Evidence
Saito et al. 2006 (WJTOG 9902) 2000-2002 Phase 2
Kubota et al. 2013 (JCOG0202) 2002-2006 Non-randomized part of phase 3 RCT

Chemotherapy

Radiotherapy

  • Concurrent thoracic radiation therapy, 150 cGy fractions given twice per day (at least 4, but preferably 6 hours between fractions) x 30 fractions (total dose: 4500 cGy) over 3 weeks, started on cycle 1 day 2 of chemotherapy

28-day course

Subsequent treatment

  • WJTOG 9902: IP consolidation
  • JCOG0202: EP x 3 versus IP consolidation


Regimen variant #10, 80/300/45, 4 cycles of chemo

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Takada et al. 2002 (JCOG 9104) 1991-1995 Phase 3 (E-switch-ic) EP, then RT Might have superior OS

Chemotherapy

Radiotherapy

  • Concurrent thoracic radiation therapy, 150 cGy fractions given twice per day (4 or more hours between fractions) x 30 fractions (total dose: 4500 cGy) over 3 weeks, started on cycle 1 day 2 of chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

  • JCOG 9104, patients with CR or near-CR ("a scar-like shadow on chest films but no positive cytology and/or bronchoscopic biopsy"): Prophylactic cranial irradiation


Regimen variant #11, 90/300/39.9

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sculier et al. 2008 1993-2006 Phase 3 (E-switch-ic) EP & RT; daily cisplatin Did not meet primary endpoint of OS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 266 cGy fractions once per day x 15 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 3990 cGy)

21-day cycle for up to 6 cycles

References

  1. Bunn PA Jr, Crowley J, Kelly K, Hazuka MB, Beasley K, Upchurch C, Livingston R; SWOG. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol. 1995 Jul;13(7):1632-41. Erratum in: J Clin Oncol 1995 Nov;13(11):2860. link to original article contains dosing details in manuscript PubMed
  2. Intergroup 0096: Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28;340(4):265-71. link to original article contains dosing details in manuscript PubMed
  3. JCOG 9104: Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, Nishiwaki Y, Watanabe K, Noda K, Tamura T, Fukuda H, Saijo N. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002 Jul 15;20(14):3054-60. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  4. 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
  5. Schild SE, Bonner JA, Shanahan TG, Brooks BJ, Marks RS, Geyer SM, Hillman SL, Farr GH Jr, Tazelaar HD, Krook JE, Geoffroy FJ, Salim M, Arusell RM, Mailliard JA, Schaefer PL, Jett JR. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):943-51. link to original article PubMed
  6. CALGB 9235: McClay EF, Bogart J, Herndon JE 2nd, Watson D, Evans L, Seagren SL, Green MR; CALGB. A phase III trial evaluating the combination of cisplatin, etoposide, and radiation therapy with or without tamoxifen in patients with limited-stage small cell lung cancer: Cancer and Leukemia Group B Study (9235). Am J Clin Oncol. 2005 Feb;28(1):81-90. link to original article contains dosing details in abstract PubMed
  7. WJTOG 9902: Saito H, Takada Y, Ichinose Y, Eguchi K, Kudoh S, Matsui K, Nakagawa K, Takada M, Negoro S, Tamura K, Ando M, Tada T, Fukuoka M; West Japan Thoracic Oncology Group. Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J Clin Oncol. 2006 Nov 20;24(33):5247-52. link to original article contains dosing details in manuscript PubMed
  8. Sculier JP, Lafitte JJ, Efremidis A, Florin MC, Lecomte J, Berchier MC, Richez M, Berghmans T, Scherpereel A, Meert AP, Koumakis G, Leclercq N, Paesmans M, Van Houtte P; European Lung Cancer Working Party. A phase III randomised study of concomitant induction radiochemotherapy testing two modalities of radiosensitisation by cisplatin (standard versus daily) for limited small-cell lung cancer. Ann Oncol. 2008 Oct;19(10):1691-7. Epub 2008 May 25. link to original article contains dosing details in manuscript PubMed
  9. SMC 2003-02-016: Sun JM, Ahn YC, Choi EK, Ahn MJ, Ahn JS, Lee SH, Lee DH, Pyo H, Song SY, Jung SH, Jo JS, Jo J, Sohn HJ, Suh C, Lee JS, Kim SW, Park K. Phase III trial of concurrent thoracic radiotherapy with either first- or third-cycle chemotherapy for limited-disease small-cell lung cancer. Ann Oncol. 2013 Aug;24(8):2088-92. Epub 2013 Apr 16. Erratum in: Ann Oncol. 2014 Aug;25(8):1672. link to original article contains dosing details in manuscript PubMed NCT01125995
  10. JCOG0202: Kubota K, Hida T, Ishikura S, Mizusawa J, Nishio M, Kawahara M, Yokoyama A, Imamura F, Takeda K, Negoro S, Harada M, Okamoto H, Yamamoto N, Shinkai T, Sakai H, Matsui K, Nakagawa K, Shibata T, Saijo N, Tamura T; JCOG. Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study. Lancet Oncol. 2014 Jan;15(1):106-13. Epub 2013 Dec 3. link to original article contains dosing details in abstract PubMed NCT00144989
  11. CONVERT: Faivre-Finn C, Snee M, Ashcroft L, Appel W, Barlesi F, Bhatnagar A, Bezjak A, Cardenal F, Fournel P, Harden S, Le Pechoux C, McMenemin R, Mohammed N, O'Brien M, Pantarotto J, Surmont V, Van Meerbeeck JP, Woll PJ, Lorigan P, Blackhall F; CONVERT Study Team. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017 Aug;18(8):1116-1125. Epub 2017 Jun 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00433563
  12. CALGB 30610: NCT00632853

Limited stage, adjuvant therapy

Cisplatin & Etoposide (EP)

EP: Etoposide & Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kenmotsu et al. 2020 (JCOG1205/1206) 2013-2018 Phase 3 (C) Cisplatin & Irinotecan Did not meet primary endpoint of RFS

Preceding treatment

Chemotherapy

21-day cycle for up to 4 cycles

References

  1. JCOG1205/1206: Kenmotsu H, Niho S, Tsuboi M, Wakabayashi M, Ishii G, Nakagawa K, Daga H, Tanaka H, Saito H, Aokage K, Takahashi T, Menju T, Kasai T, Yoshino I, Minato K, Okada M, Eba J, Asamura H, Ohe Y, Watanabe SI. Randomized Phase III Study of Irinotecan Plus Cisplatin Versus Etoposide Plus Cisplatin for Completely Resected High-Grade Neuroendocrine Carcinoma of the Lung: JCOG1205/1206. J Clin Oncol. 2020 Dec 20;38(36):4292-4301. Epub 2020 Nov 2. link to original article contains dosing details in manuscript PubMed UMIN000010298

Limited stage, consolidation after upfront therapy

Cisplatin & Irinotecan (IC)

IP: Irinotecan, Platinol (Cisplatin)

Regimen

Study Evidence
Saito et al. 2006 (WJTOG 9902) Phase 2

Preceding treatment

Chemotherapy

Supportive therapy

  • G-CSF (no additional details given) starting after day 4

28-day cycle for 3 cycles

Subsequent treatment

References

  1. WJTOG 9902: Saito H, Takada Y, Ichinose Y, Eguchi K, Kudoh S, Matsui K, Nakagawa K, Takada M, Negoro S, Tamura K, Ando M, Tada T, Fukuoka M; West Japan Thoracic Oncology Group. Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J Clin Oncol. 2006 Nov 20;24(33):5247-52. link to original article contains dosing details in manuscript PubMed

Radiation therapy

Regimen

Study Dates of enrollment Evidence
Evans et al. 1985 1981-1984 Phase 2

Preceding treatment

  • Induction EP x 6

Radiotherapy

  • "Patients who did not have evidence of tumor spread beyond the mediastinum and/or ipsilateral supraclavicular notes" received thoracic radiation in 250 cGy fractions x 10 fractions (total dose: 2500 cGy)

References

  1. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471-7. link to original article contains dosing details in manuscript PubMed
  2. LLCG-STUDY-12: Lee SM, Woll PJ, Rudd R, Ferry D, O'Brien M, Middleton G, Spiro S, James L, Ali K, Jitlal M, Hackshaw A. Anti-angiogenic therapy using thalidomide combined with chemotherapy in small cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst. 2009 Aug 5;101(15):1049-57. Epub 2009 Jul 16. link to original article does not contain dosing details PubMed NCT00061919

Whole brain irradiation

PCI: Prophylactic Cranial Irradiation

Regimen variant #1, 2000 cGy

Study Dates of enrollment Evidence
Cox et al. 1981 1975-1978 Non-randomized
Evans et al. 1985 1981-1984 Phase 2
Skarlos et al. 2001 1993-1999 Non-randomized part of phase 2 RCT

Note: in Evans et al. 1985, the WB-XRT is given in-between cycles 3 & 4.

Preceding treatment

Radiotherapy

1-week course

Subsequent treatment

  • Evans et al. 1985: EP consolidation x 3


Regimen variant #2, 2400 cGy

Study Evidence
Takada et al. 2002 (JCOG 9104) Non-randomized part of phase 3 RCT

Preceding treatment

  • Definitive EP & RT versus EP induction followed by definitive RT

Radiotherapy

2-week course


Regimen variant #3, 2500 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Turrisi et al. 1999 (Intergroup 0096) 1989-1992 Non-randomized part of phase 3 RCT
Le Péchoux et al. 2009 (PCI 99-01/EORTC 22003-08004/RTOG 0212/IFCT 99-01) 1999-2005 Phase 3 (C) PCI x 36 Gy Did not meet primary endpoint of incidence of brain metastases at 2 years
Saito et al. 2006 (WJTOG 9902) 2000-2002 Phase 2

Preceding treatment

Radiotherapy

2-week course


Regimen variant #4, 3000 cGy

Study Evidence
Sundstrøm et al. 2002 Non-randomized part of phase 3 RCT

Preceding treatment

Radiotherapy

3-week course

References

  1. Cox JD, Stanley K, Petrovich Z, Paig C, Yesner R. Cranial irradiation in cancer of the lung of all cell types. JAMA. 1981 Feb 6;245(5):469-72. link to original article PubMed
  2. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471-7. link to original article contains dosing details in manuscript PubMed
  3. Intergroup 0096: Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28;340(4):265-71. link to original article contains dosing details in manuscript PubMed
  4. Meta-analysis: Aupérin A, Arriagada R, Pignon JP, Le Péchoux C, Gregor A, Stephens RJ, Kristjansen PE, Johnson BE, Ueoka H, Wagner H, Aisner J; Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 1999 Aug 12;341(7):476-84. link to original article PubMed
  5. JCOG 9104: Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, Nishiwaki Y, Watanabe K, Noda K, Tamura T, Fukuda H, Saijo N. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002 Jul 15;20(14):3054-60. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  6. 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
  7. WJTOG 9902: Saito H, Takada Y, Ichinose Y, Eguchi K, Kudoh S, Matsui K, Nakagawa K, Takada M, Negoro S, Tamura K, Ando M, Tada T, Fukuoka M; West Japan Thoracic Oncology Group. Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J Clin Oncol. 2006 Nov 20;24(33):5247-52. link to original article contains dosing details in manuscript PubMed
  8. PCI 99-01/EORTC 22003-08004/RTOG 0212/IFCT 99-01: Le Péchoux C, Dunant A, Senan S, Wolfson A, Quoix E, Faivre-Finn C, Ciuleanu T, Arriagada R, Jones R, Wanders R, Lerouge D, Laplanche A; Prophylactic Cranial Irradiation (PCI) Collaborative Group. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009 May;10(5):467-74. Epub 2009 Apr 20. link to original article PubMed NCT00005062

Extensive stage, induction

Belotecan & Cisplatin

BP: Belotecan and Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oh et al. 2016 (COMBAT) 2009-2013 Phase 3 (E-switch-ic) EP; 60/100 Non-inferior RR (primary endpoint)

Note: the total number of planned cycles is not described in the manuscript; total duration information here was provided by the authors.

Chemotherapy

21-day cycle for 4 to 8 cycles

References

  1. COMBAT: Oh IJ, Kim KS, Park CK, Kim YC, Lee KH, Jeong JH, Kim SY, Lee JE, Shin KC, Jang TW, Lee HK, Lee KY, Lee SY. Belotecan/cisplatin versus etoposide/cisplatin in previously untreated patients with extensive-stage small cell lung carcinoma: a multi-center randomized phase III trial. BMC Cancer. 2016 Aug 26;16:690. link to original article link to original article contains dosing details in manuscript PubMed NCT00826644

Carboplatin & Etoposide (CE)

CE: Carboplatin & Etoposide
EP: Etoposide & Paraplatin (Carboplatin)
EC: Etoposide & Carboplatin
Ca/E: Carboplatin & Etoposide

Regimen variant #1, AUC 4/600, PO etoposide

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hermes et al. 2008 2001-2005 Phase 3 (C) Carboplatin & Irinotecan Inferior OS

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, AUC 5/240

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Okamoto et al. 2007 (JCOG 9702) 1998-2004 Phase 3 (E-switch-ic) EP; split-dose Did not meet primary endpoint of OS
Sekine et al. 2013 (D0702002) 2006-07-04 to 2007-09-05 Phase 3 (C) Amrubicin Inconclusive whether non-inferior OS

Chemotherapy

Supportive therapy

21-day cycle for 4 to 6 cycles


Regimen variant #3, AUC 5/300, 21-day cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Socinski et al. 2009 (JMHO) 2006-08 to 2007-12 Phase 3 (C) Carboplatin & Pemetrexed Superior OS
Spigel et al. 2011 (SALUTE) 2007-2008 Randomized Phase 2 (C) 1a. CE & Bevacizumab
1b. EP & Bevacizumab 		Seems to have inferior PFS
Ready et al. 2015 (CALGB 30504) 2007-2011 Non-randomized part of phase 2 RCT
Reck et al. 2016 (CA184-156) 2012-2014 Phase 3 (C) 1a. CE & Ipilimumab
1b. EP & Ipilimumab 		Did not meet primary endpoint of OS
Jalal et al. 2017 (MATISSE) 2012-2013 Randomized Phase 2 (C) PaCE Might have superior OS
Horn et al. 2018 (IMpower133) 2016-06-06 to 2017-05-31 Phase 3 (C) CE & Atezolizumab Seems to have inferior OS1
Paz-Ares et al. 2019 (CASPIAN) 2017-03-27 to 2018-05-29 Phase 3 (C) 1a. CE & Durvalumab
1b. EP & Durvalumab 		Inferior OS
Rudin et al. 2020 (KEYNOTE-604) 2017-05-15 to 2018-07-30 Phase 3 (C) 1a. CE & Pembrolizumab
1b. EP & Pembrolizumab 		Seems to have inferior OS
Wang et al. 2022 (CAPSTONE-1) 2018-2020 Phase 3 (C) CE & Adebrelimab Inferior OS

1Reported efficacy for IMpower133 is based on the 2020 update.
Note: CASPIAN gave a range of dosing; see paper for details.

Chemotherapy

Supportive therapy

  • Socinksi et al. 2009: "supportive therapies, such as erythropoietic agents or granulocyte colony-stimulating factors, were administered according to the American Society of Clinical Oncology guidelines"

21-day cycle for 4 to 6 cycles

Subsequent treatment


Regimen variant #4, AUC 5/300, 28-day cycles

Study Dates of enrollment Evidence
Okamoto et al. 1999 1995-1996 Phase 2
Quoix et al. 2001 1997-1999 Phase 2

Eligibility criteria

  • At least 70 years old

Chemotherapy

Supportive therapy

  • Dexamethasone (Decadron) 8 mg IV once per day on days 1 to 3, prior to chemotherapy
  • Granisetron 40 mcg/kg IV once per day on days 1 to 3, prior to chemotherapy
  • Okamoto et al. 1999: G-CSF (type not specified) 2 mcg/kg SC given for grade 3 or greater leukopenia/neutropenia
  • Quiox et al. 2001: "Haematopoietic growth factors were allowed as prophylactic or curative treatment only if grade 4 neutropenia greater than 7 days occurred"

28-day cycle for 4 to 6 cycles

Subsequent treatment

  • Palliative radiation therapy was allowed to control persistent pain from bony metastases


Regimen variant #5, AUC 5/360

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #6, AUC 5/420

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heigener et al. 2009 2000-2003 Phase 3 (C) CE; dose-intense Did not meet primary endpoint of OS
Schmittel et al. 2006 2002-2008 Randomized Phase 2 (E-switch-ic) IP Might have inferior OS (secondary endpoint)

Chemotherapy

Supportive therapy

21- to 28-day cycle for up to 6 cycles


Regimen variant #7, AUC 5/440, 1 day of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2009 (LLCG-STUDY-12) 2003-2006 Phase 3 (C) CE & Thalidomide Did not meet primary endpoint of OS
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #8, AUC 5/520, 2 days of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2009 (LLCG-STUDY-12) 2003-2006 Phase 3 (C) CE & Thalidomide Did not meet primary endpoint of OS
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #9, AUC 6/360

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #10, AUC 6/440, 1 day of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #11, AUC 6/520, 2 days of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. Okamoto H, Watanabe K, Nishiwaki Y, Mori K, Kurita Y, Hayashi I, Masutani M, Nakata K, Tsuchiya S, Isobe H, Saijo N. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol. 1999 Nov;17(11):3540-5. link to original article contains dosing details in manuscript PubMed
  2. Quoix E, Breton JL, Daniel C, Jacoulet P, Debieuvre D, Paillot N, Kessler R, Moreau L, Coëtmeur D, Lemarié E, Milleron B. Etoposide phosphate with carboplatin in the treatment of elderly patients with small-cell lung cancer: a phase II study. Ann Oncol. 2001 Jul;12(7):957-62. link to original article contains dosing details in manuscript PubMed
  3. Schmittel A, Fischer von Weikersthal L, Sebastian M, Martus P, Schulze K, Hortig P, Reeb M, Thiel E, Keilholz U. A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol. 2006 Apr;17(4):663-7. Epub 2006 Jan 19. link to original article contains dosing details in manuscript PubMed
    1. Update: Schmittel A, Sebastian M, Fischer von Weikersthal L, Martus P, Gauler TC, Kaufmann C, Hortig P, Fischer JR, Link H, Binder D, Fischer B, Caca K, Eberhardt WE, Keilholz U; Arbeitsgemeinschaft Internistische Onkologie Thoracic Oncology Study Group. A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol. 2011 Aug;22(8):1798-804. Epub 2011 Jan 25. link to original article contains dosing details in manuscript PubMed
  4. JCOG 9702: Okamoto H, Watanabe K, Kunikane H, Yokoyama A, Kudoh S, Asakawa T, Shibata T, Kunitoh H, Tamura T, Saijo N. Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer. 2007 Jul 16;97(2):162-9. Epub 2007 Jun 19. link to original article link to PMC article contains dosing details in abstract PubMed
  5. Hermes A, Bergman B, Bremnes R, Ek L, Fluge S, Sederholm C, Sundstrøm S, Thaning L, Vilsvik J, Aasebø U, Sörenson S. Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive small-cell lung cancer: a randomized phase III trial. J Clin Oncol. 2008 Sep 10;26(26):4261-7. link to original article contains dosing details in abstract PubMed
  6. Heigener DF, Manegold C, Jäger E, Saal JG, Zuna I, Gatzemeier U. Multicenter randomized open-label phase III study comparing efficacy, safety, and tolerability of conventional carboplatin plus etoposide versus dose-intensified carboplatin plus etoposide plus lenograstim in small-cell lung cancer in "extensive disease" stage. Am J Clin Oncol. 2009 Feb;32(1):61-4. link to original article contains dosing details in abstract PubMed
  7. LLCG-STUDY-12: Lee SM, Woll PJ, Rudd R, Ferry D, O'Brien M, Middleton G, Spiro S, James L, Ali K, Jitlal M, Hackshaw A. Anti-angiogenic therapy using thalidomide combined with chemotherapy in small cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst. 2009 Aug 5;101(15):1049-57. Epub 2009 Jul 16. link to original article contains dosing details in manuscript PubMed NCT00061919
  8. JMHO: Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, Blakely J, Serwatowski P, Karaseva NA, Ciuleanu T, Jassem J, Dediu M, Hong S, Visseren-Grul C, Hanauske AR, Obasaju CK, Guba SC, Thatcher N. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol. 2009 Oct 1;27(28):4787-92. Epub 2009 Aug 31. link to original article contains dosing details in manuscript PubMed NCT00363415
  9. SALUTE: Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, Huang JE, Karlin DA, Faoro L, Scappaticci FA, Socinski MA. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011 Jun 1;29(16):2215-22. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed NCT00403403
  10. D0702002: Sekine I, Okamoto H, Horai T, Nakagawa K, Ohmatsu H, Yokoyama A, Katakami N, Shibuya M, Saijo N, Fukuoka M. A randomized phase III study of single-agent amrubicin vs carboplatin/etoposide in elderly patients with extensive-disease small-cell lung cancer. Clin Lung Cancer. 2014 Mar;15(2):96-102. Epub 2013 Nov 14. link to original article contains dosing details in abstract PubMed NCT00286169
  11. CALGB 30504: Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, Baggstrom M, Masters GA, Graziano SL, Crawford J, Bogart J, Vokes EE. Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small-cell lung cancer: A randomized, double-blind, placebo-controlled phase II study-CALGB 30504 (Alliance). J Clin Oncol. 2015 May 20;33(15):1660-5. Epub 2015 Mar 2. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00453154
  12. CA184-156: Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, Pietanza MC, Wu YL, Zielinski C, Thomas M, Felip E, Gold K, Horn L, Aerts J, Nakagawa K, Lorigan P, Pieters A, Kong Sanchez T, Fairchild J, Spigel D. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. 2016 Nov 1;34(31):3740-3748. link to original article contains dosing details in manuscript PubMed NCT01450761
  13. LUNGSTAR: Seckl MJ, Ottensmeier CH, Cullen M, Schmid P, Ngai Y, Muthukumar D, Thompson J, Harden S, Middleton G, Fife KM, Crosse B, Taylor P, Nash S, Hackshaw A. Multicenter, phase III, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in small-cell lung cancer (LUNGSTAR). J Clin Oncol. 2017 May 10;35(14):1506-1514. Epub 2017 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00433498
  14. MATISSE: Jalal SI, Lavin P, Lo G, Lebel F, Einhorn L. Carboplatin and etoposide with or without palifosfamide in untreated extensive-stage small-cell lung cancer: A multicenter, adaptive, randomized phase III study (MATISSE). J Clin Oncol. 2017 Aug 10;35(23):2619-2623. Epub 2017 Jun 12. link to original article contains dosing details in manuscript PubMed NCT01555710
  15. IMpower133: Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018 Dec 6;379(23):2220-2229. Epub 2018 Sep 25. link to original article contains dosing details in manuscript PubMed NCT02763579
    1. PRO analysis: Mansfield AS, Każarnowicz A, Karaseva N, Sánchez A, De Boer R, Andric Z, Reck M, Atagi S, Lee JS, Garassino M, Liu SV, Horn L, Wen X, Quach C, Yu W, Kabbinavar F, Lam S, Morris S, Califano R. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol. 2020 Feb;31(2):310-317. Epub 2019 Dec 9. link to original article PubMed
    2. Update: Liu SV, Reck M, Mansfield AS, Mok T, Scherpereel A, Reinmuth N, Garassino MC, De Castro Carpeno J, Califano R, Nishio M, Orlandi F, Alatorre-Alexander J, Leal T, Cheng Y, Lee JS, Lam S, McCleland M, Deng Y, Phan S, Horn L. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021 Feb 20;39(6):619-630. Epub 2021 Jan 13. link to original article link to PMC article PubMed
  16. CASPIAN: Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Kazarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Shire N, Jiang H, Goldman JW; CASPIAN investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1929-1939. Epub 2019 Oct 4. link to original article PubMed NCT03043872
    1. PRO analysis: Goldman JW, Garassino MC, Chen Y, Özgüroğlu M, Dvorkin M, Trukhin D, Statsenko G, Hotta K, Ji JH, Hochmair MJ, Voitko O, Havel L, Poltoratskiy A, Losonczy G, Reinmuth N, Patel N, Laud PJ, Shire N, Jiang H, Paz-Ares L. Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. Lung Cancer. 2020 Nov;149:46-52. Epub 2020 Sep 10. link to original article PubMed
    2. Update: Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Każarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Thiyagarajah P, Jiang H, Paz-Ares L; CASPIAN investigators. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):51-65. Epub 2020 Dec 4. link to original article PubMed
  17. 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
  18. CAPSTONE-1: Wang J, Zhou C, Yao W, Wang Q, Min X, Chen G, Xu X, Li X, Xu F, Fang Y, Yang R, Yu G, Gong Y, Zhao J, Fan Y, Liu Q, Cao L, Yao Y, Liu Y, Li X, Wu J, He Z, Lu K, Jiang L, Hu C, Zhao W, Zhang B, Shi W, Zhang X, Cheng Y; CAPSTONE-1 Study Group. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Jun;23(6):739-747. Epub 2022 May 13. link to original article contains dosing details in abstract PubMed NCT03711305

Carboplatin & Etoposide (CE) & Atezolizumab

CE & Atezolizumab: Carboplatin, Etoposide, Atezolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Horn et al. 2018 (IMpower133) 2016-06-06 to 2017-05-31 Phase 3 (E-RT-esc) CE Seems to have superior OS1 (co-primary endpoint)
Median OS: 12.3 vs 10.3 mo
(HR 0.76, 95% CI 0.60-0.95)
Rudin et al. 2023 (SKYSCRAPER-02) 2020-02 to 2021-03 Phase 3 (C) CE, Atezolizumab, Tiragolumab Did not meet co-primary endpoints of PFS/OS

1Reported efficacy for IMpower133 is based on the 2020 update.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. IMpower133: Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018 Dec 6;379(23):2220-2229. Epub 2018 Sep 25. link to original article contains dosing details in manuscript PubMed NCT02763579
    1. PRO analysis: Mansfield AS, Każarnowicz A, Karaseva N, Sánchez A, De Boer R, Andric Z, Reck M, Atagi S, Lee JS, Garassino M, Liu SV, Horn L, Wen X, Quach C, Yu W, Kabbinavar F, Lam S, Morris S, Califano R. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol. 2020 Feb;31(2):310-317. Epub 2019 Dec 9. link to original article PubMed
    2. Update: Liu SV, Reck M, Mansfield AS, Mok T, Scherpereel A, Reinmuth N, Garassino MC, De Castro Carpeno J, Califano R, Nishio M, Orlandi F, Alatorre-Alexander J, Leal T, Cheng Y, Lee JS, Lam S, McCleland M, Deng Y, Phan S, Horn L. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021 Feb 20;39(6):619-630. Epub 2021 Jan 13. link to original article link to PMC article PubMed
  2. SKYSCRAPER-02: Rudin CM, Liu SV, Soo RA, Lu S, Hong MH, Lee JS, Bryl M, Dumoulin DW, Rittmeyer A, Chiu CH, Ozyilkan O, Johnson M, Navarro A, Novello S, Ozawa Y, Tam SH, Patil NS, Wen X, Huang M, Hoang T, Meng R, Reck M. SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2024 Jan 20;42(3):324-335. Epub 2023 Nov 17. link to original article contains dosing details in manuscript PubMed NCT04256421
  3. IMforte: NCT05091567

Carboplatin & Etoposide (CE) & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Spigel et al. 2011 (SALUTE) 2007-2008 Randomized Phase 2 (E-esc) 1a. CE
1b. EP 		Seems to have superior PFS (primary endpoint)
Median PFS: 5.5 vs 4.4 mo
(HR 0.53, 95% CI 0.32-0.86)

Chemotherapy

Targeted therapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. SALUTE: Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, Huang JE, Karlin DA, Faoro L, Scappaticci FA, Socinski MA. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011 Jun 1;29(16):2215-22. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed NCT00403403

Carboplatin & Etoposide (CE) & Durvalumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2019 (CASPIAN) 2017-03-27 to 2018-05-29 Phase 3 (E-RT-esc) 1a. CE
1b. EP 		Superior OS1 (primary endpoint)
Median OS: 12.9 vs 10.5 mo
(HR 0.75, 95% CI 0.62-0.91)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Immunotherapy

  • Durvalumab (Imfinzi) as follows:
    • Cycles 1 to 4: 1500 mg IV once on day 1
    • Cycle 5 onwards: 1500 mg IV once on day 1

21-day cycle for 4 cycles, then 28-day cycles

References

  1. CASPIAN: Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Kazarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Shire N, Jiang H, Goldman JW; CASPIAN investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1929-1939. Epub 2019 Oct 4. link to original article contains dosing details in abstract PubMed NCT03043872
    1. PRO analysis: Goldman JW, Garassino MC, Chen Y, Özgüroğlu M, Dvorkin M, Trukhin D, Statsenko G, Hotta K, Ji JH, Hochmair MJ, Voitko O, Havel L, Poltoratskiy A, Losonczy G, Reinmuth N, Patel N, Laud PJ, Shire N, Jiang H, Paz-Ares L. Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. Lung Cancer. 2020 Nov;149:46-52. Epub 2020 Sep 10. link to original article PubMed
    2. Update: Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Każarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Thiyagarajah P, Jiang H, Paz-Ares L; CASPIAN investigators. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):51-65. Epub 2020 Dec 4. link to original article PubMed

Carboplatin & Etoposide (CE) & Serplulimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cheng et al. 2022 (ASTRUM-005) 2019-09-12 to 2021-04-27 Phase 3 (E-RT-esc) CE Superior OS (primary endpoint)
Median OS: 15.4 vs 10.9 mo
(HR 0.63, 95% CI 0.49-0.82)

Note: the original capped dose of carboplatin was 800 mg; this was modified in a protocol amendment.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. ASTRUM-005: Cheng Y, Han L, Wu L, Chen J, Sun H, Wen G, Ji Y, Dvorkin M, Shi J, Pan Z, Shi J, Wang X, Bai Y, Melkadze T, Pan Y, Min X, Viguro M, Li X, Zhao Y, Yang J, Makharadze T, Arkania E, Kang W, Wang Q, Zhu J; ASTRUM-005 Study Group. Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial. JAMA. 2022 Sep 27;328(12):1223-1232. link to original article contains dosing details in manuscript link to PMC article PubMed NCT04063163

Carboplatin & Irinotecan

IC: Irinotecan & Carboplatin
IP: Irinotecan & Paraplatin (Carboplatin)

Regimen variant #1, AUC 4/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hermes et al. 2008 2001-2005 Phase 3 (E-switch-ic) CE Superior OS (primary endpoint)
Median OS: 8.5 vs 7.1 mo
(HR 0.71, 95% CI 0.53-0.94)

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, AUC 5/150

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schmittel et al. 2006 2002-2008 Randomized Phase 2 (E-switch-ic) CE Might have superior OS (secondary endpoint)

Chemotherapy

Supportive therapy

28-day cycle for up to 6 cycles

References

  1. Schmittel A, Fischer von Weikersthal L, Sebastian M, Martus P, Schulze K, Hortig P, Reeb M, Thiel E, Keilholz U. A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol. 2006 Apr;17(4):663-7. Epub 2006 Jan 19. link to original article contains dosing details in manuscript PubMed
    1. Update: Schmittel A, Sebastian M, Fischer von Weikersthal L, Martus P, Gauler TC, Kaufmann C, Hortig P, Fischer JR, Link H, Binder D, Fischer B, Caca K, Eberhardt WE, Keilholz U; Arbeitsgemeinschaft Internistische Onkologie Thoracic Oncology Study Group. A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol. 2011 Aug;22(8):1798-804. Epub 2011 Jan 25. link to original article contains dosing details in manuscript PubMed
  2. Hermes A, Bergman B, Bremnes R, Ek L, Fluge S, Sederholm C, Sundstrøm S, Thaning L, Vilsvik J, Aasebø U, Sörenson S. Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive small-cell lung cancer: a randomized phase III trial. J Clin Oncol. 2008 Sep 10;26(26):4261-7. link to original article contains dosing details in abstract PubMed

Carboplatin & Paclitaxel (CP) & Ipilimumab

Regimen variant #1, phased ipilimumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2012 (CA184-041SCLC) 2008-2009 Randomized Phase 2 (E-esc) 1. CP Seems to have superior irPFS (primary endpoint)
2. CP & Ipilimumab; concurrent Ipilimumab Not reported

Chemotherapy

Immunotherapy

21-day cycle for up to 6 cycles

Subsequent treatment


Regimen variant #2, concurrent ipilimumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2012 (CA184-041SCLC) 2008-2009 Randomized Phase 2 (E-esc) 1. CP Did not meet secondary endpoints
2. CP & Ipilimumab; phased Ipilimumab Not reported

Note: all efficacy endpoints in the ED-SCLC cohort were secondary.

Chemotherapy

Immunotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. CA184-041SCLC: Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Lu H, Cuillerot JM, Lynch TJ. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. Epub 2012 Aug 2. link to original article contains dosing details in manuscript PubMed NCT00527735

Cisplatin & Etoposide (EP)

EP: Etoposide and Platinol (Cisplatin)
PE: Platinol (Cisplatin) and Etoposide

Regimen variant #1, 60/300

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oh et al. 2016 (COMBAT) 2009-2013 Phase 3 (C) BP Non-inferior RR

Note: the total number of planned cycles is not described in the manuscript; total duration information here was provided by the authors.

Chemotherapy

21-day cycle for 4 to 8 cycles


Regimen variant #2, 60/360

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hanna et al. 2006 2000-2003 Phase 3 (C) Cisplatin & Irinotecan Did not meet primary endpoint of OS
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

Supportive therapy

  • Per Hanna et al. 2006:
    • G-CSF used according to 1999 American Society of Clinical Oncology guidelines
    • "Erythropoietin was allowed at the discretion of the treating physician."

21-day cycle for 4 to 6 cycles


Regimen variant #3, 60/440, 1 day of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #4, 60/520, 2 days of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seckl et al. 2017 (LUNGSTAR) 2007-2012 Phase 3 (C) 1a. CE & Pravastatin
1b. EP & Pravastatin 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #5, 70/300

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ruotsalainen et al. 1999 NR in abstract Phase 3 (C) EP & IFN-alpha Did not meet endpoint of OS50%
Kim et al. 2018 (CRCST-L-0001) 2006-2011 Phase 3 (C) Cisplatin & Irinotecan Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #6, 75/240, split cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Okamoto et al. 2007 (JCOG 9702) 1998-2004 Phase 3 (C) CE Did not meet primary endpoint of OS

Chemotherapy

21- to 28-day cycle for 4 cycles


Regimen variant #7, 75/300

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fink et al. 2012 (GSK 104864-A/479) 2002-2006 Phase 3 (C) 1. Cisplatin & Topotecan Non-inferior OS
2. Etoposide & Topotecan Not reported
Spigel et al. 2011 (SALUTE) 2007-2008 Randomized Phase 2 (C) 1a. CE & Bevacizumab
1b. EP & Bevacizumab 		Seems to have inferior PFS
Reck et al. 2016 (CA184-156) 2012-2014 Phase 3 (C) 1a. CE & Ipilimumab
1b. EP & Ipilimumab 		Did not meet primary endpoint of OS
Rudin et al. 2020 (KEYNOTE-604) 2017-05-15 to 2018-07-30 Phase 3 (C) 1a. CE & Pembrolizumab
1b. EP & Pembrolizumab 		Seems to have inferior OS

Chemotherapy

21-day cycle for 4 (SALUTE & KEYNOTE-604) or 6 (GSK 104864-A/479 & CA184-156) cycles


Regimen variant #8, 75/300, split cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Evans et al. 1985 1981-1984 Phase 2
Tiseo et al. 2017 (GOIRC-AIFA FARM6PMFJM) 2009-2015 Phase 3 (C) EP & Bevacizumab Did not meet primary endpoint of OS

Note: in Evans et al. 1985, patients with disease responding to therapy received prophylactic cranial irradiation, 400 cGy fractions given daily x 5 fractions (total dose: 2000 cGy) over 5 days between cycles 3 and 4; Locoregional radiation therapy was only used if symptoms persisted after 6 cycles of treatment: Radiation therapy, 250 cGy/rad fractions x 10 fractions (total dose: 2500 cGy/rad), given after cycle 6 of chemotherapy.

Chemotherapy

Supportive therapy

  • Dexamethasone (Decadron) 10 mg IV once per day on days 1 to 3, prior to chemotherapy
  • Metoclopramide (Reglan) 10 mg IV or PO once per day on days 1 to 3, prior to chemotherapy
  • Prochlorperazine (Compazine) 10 mg IM or PO once per day on days 1 to 3, prior to chemotherapy
  • "No special efforts were made to hydrate the patients," though PO fluid intake was encouraged, and 500 mL normal saline was given with etoposide infusion.

21- to 28-day cycle for up to 6 cycles


Regimen variant #9, 75/390, split cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miller et al. 1995 1990-1993 Phase 3 (C) EP; oral etoposide Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #10, 75/700, 3 days of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sundstrøm et al. 2002 1989-1994 Phase 3 (E-switch-ic) CEV Did not meet primary endpoint of OS

Note: Patients in Sundstrøm et al. 2002 with extensive stage disease did not routinely receive radiation therapy. "However, chest or cranial irradiation was optional if severe symptoms could not be palliated by chemotherapy." Oral etoposide to be taken on an empty stomach.

Chemotherapy

Supportive therapy

  • "Standard prehydration and posthydration procedures were followed in conjunction with cisplatin administration."

21-day cycle for up to 5 cycles


Regimen variant #11, 80/240

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ihde et al. 1994 1983-1991 Phase 3 (C) EP; high-dose Did not meet primary endpoint of CR rate
Niell et al. 2005 (CALGB 9732) 1998-2001 Phase 3 (C) PET Did not meet endpoints of FFS50%/OS50%

Note: Concurrent radiation therapy with the start of chemotherapy was given to patients with brain metastases, epidural metastases, and impending pathologic bone fractures.

Chemotherapy

Supportive therapy

  • "Half-normal saline was infused for 2 to 6 hours with cisplatin, usually in conjunction with a diuretic."
  • Corticosteroids were usually given for patients receiving radiation therapy for brain and epidural metastases.

21-day cycle for 4 to 8 cycles

CNS therapy

  • Patients with carcinomatous meningitis received Methotrexate (MTX) IT (dose/schedule not specified) and radiation to functionally compromised areas of the CNS

Subsequent treatment

  • Ihde et al. 1994, CR after 4 cycles: EP continuation x 4 cycles. Some patients were randomized to receive prophylactic cranial irradiation. Radiation could also be given at the patient's request. No details about dose/schedule given.
  • Ihde et al. 1994, PR, no response, or progressive disease: Salvage CAV or "an individualized 3-drug in vitro-selected regimen (IVSR) during cycles 5 to 8 if drug-sensitivity testing data were available."


Regimen variant #12, 80/300

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fukuoka et al. 1991 (JCOG8502) 1985-1988 Phase 3 (C) 1. CAV Not reported
2. CAV/PE Might have inferior OS
Miyamoto et al. 1992 NR in abstract Phase 3 (C) PEI Did not meet primary endpoint of OS
Noda et al. 2002 (JCOG 9511) 1995-1998 Phase 3 (C) IP Inferior OS
Eckardt et al. 2006 (GSK 104864-A/389) 2001-2003 Phase 3 (C) Cisplatin & Topotecan Non-inferior OS
Lara et al. 2009 (SWOG S0124) 2002-2007 Phase 3 (C) IP Did not meet primary endpoint of OS
Baka et al. 2010 2002-2006 Phase 3 (C) EP/T Did not meet primary endpoint of OS
Zatloukal et al. 2010 2003-2007 Phase 3 (C) IP Non-inferior OS
Ready et al. 2015 (CALGB 30504) 2007-2011 Non-randomized part of phase 2 RCT
Sun et al. 2016 (D0750018) 2008-2010 Phase 3 (C) Amrubicin & Cisplatin Might have inferior OS

Chemotherapy

Supportive therapy

  • "Hydration and administration of antiemetic drugs."

21-day cycle for 4 to 6 cycles

Subsequent treatment


Regimen variant #13, 80/360

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thatcher et al. 2005 (MRC LU21) 1996-03 to 2002-02 Phase 3 (C) ICE-V Inferior OS

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #14, 80/400, split cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Loehrer et al. 1995 1989-1993 Phase 3 (C) VIP Seems to have inferior OS

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #15, 80/600, 2 days of oral etoposide per cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Baka et al. 2008 1999-2005 Phase 3 (E-switch-ic) ACE Did not meet primary endpoint of OS12

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #16, 100/300

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Artal-Cortés et al. 2004 1994-1998 Phase 3 (C) Cisplatin & Epirubicin Did not meet primary endpoint of OS
Pujol et al. 2001 (FNCLCC 95012) 1996-1999 Phase 3 (C) PCDE Inferior OS

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #17, 100/400, split cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Roth et al. 1992 1985-1989 Phase 3 (C) 1. CAV
2. CAV/PE 		Did not meet primary endpoint of OS50%
Hainsworth et al. 1995 1992-1993 Randomized Phase 2 (E-RT-switch-ic) Cisplatin & Etoposide phosphate Not compared

Chemotherapy

21-day cycle for 4 cycles

References

  1. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471-7. link to original article contains dosing details in manuscript PubMed
  2. JCOG8502: Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, Shimoyama M, Suemasu K. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst. 1991 Jun 19;83(12):855-61. link to original article contains dosing details in abstract PubMed
  3. Miyamoto H, Nakabayashi T, Isobe H, Akita H, Kawakami Y, Arimoto T, Asakawa M, Suzuki A, Fujikane T, Shimizu T, Sakai E. A phase III comparison of etoposide/cisplatin with or without added ifosfamide in small-cell lung cancer. Oncology. 1992;49(6):431-5. link to original article contains dosing details in abstract PubMed
  4. 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 contains dosing details in manuscript PubMed
  5. Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, Edison M, Phelps RM, Lesar M, Phares JC, Grayson J, Minna JD, Johnson BE. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol. 1994 Oct;12(10):2022-34. link to original article contains dosing details in manuscript PubMed
  6. Hainsworth JD, Levitan N, Wampler GL, Belani CP, Seyedsadr MS, Randolph J, Schacter LP, Greco FA. Phase II randomized study of cisplatin plus etoposide phosphate or etoposide in the treatment of small-cell lung cancer. J Clin Oncol. 1995 Jun;13(6):1436-42. link to original article PubMed
  7. Miller AA, Herndon JE 2nd, Hollis DR, Ellerton J, Langleben A, Richards F 2nd, Green MR; CALGB. Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: a randomized phase III study of the Cancer and Leukemia Group B. J Clin Oncol. 1995 Aug;13(8):1871-9. link to original article contains dosing details in abstract PubMed
  8. 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
  9. Ruotsalainen TM, Halme M, Tamminen K, Szopinski J, Niiranen A, Pyrhönen S, Riska H, Maasilta P, Jekunen A, Mäntylä M, Kajanti M, Joensuu H, Sarna S, Cantell K, Mattson K. Concomitant chemotherapy and IFN-alpha for small cell lung cancer: a randomized multicenter phase III study. J Interferon Cytokine Res. 1999 Mar;19(3):253-9. link to original article contains dosing details in abstract PubMed
  10. 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 contains dosing details in abstract PubMed NCT00003606
  11. JCOG 9511: Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N; JCOG. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):85-91. link to original article contains dosing details in manuscript PubMed
  12. 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
  13. Artal-Cortés A, Gomez-Codina J, Gonzalez-Larriba JL, Barneto I, Carrato A, Isla D, Camps C, Garcia-Giron C, Font A, Meana A, Lomas M, Vadell C, Arrivi A, Alonso C, Maestu I, Campbell J, Rosell R. Prospective randomized phase III trial of etoposide/cisplatin versus high-dose epirubicin/cisplatin in small-cell lung cancer. Clin Lung Cancer. 2004 Nov;6(3):175-83. link to original article contains dosing details in abstract PubMed
  14. CALGB 9732: Niell HB, Herndon JE 2nd, Miller AA, Watson DM, Sandler AB, Kelly K, Marks RS, Perry MC, Ansari RH, Otterson G, Ellerton J, Vokes EE, Green MR; CALGB. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol. 2005 Jun 1;23(16):3752-9. link to original article contains dosing details in manuscript PubMed NCT00003299
  15. 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 contains dosing details in manuscript PubMed NCT00002822
  16. Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, Ansari R, Ellis P, Byrne M, Morrison M, Hariharan S, Wang B, Sandler A. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006 May 1;24(13):2038-43. link to original article contains dosing details in manuscript PubMed
  17. GSK 104864-A/389: Eckardt JR, von Pawel J, Papai Z, Tomova A, Tzekova V, Crofts TE, Brannon S, Wissel P, Ross G. Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol. 2006 May 1;24(13):2044-51. link to original article contains dosing details in abstract PubMed NCT00043927
  18. JCOG 9702: Okamoto H, Watanabe K, Kunikane H, Yokoyama A, Kudoh S, Asakawa T, Shibata T, Kunitoh H, Tamura T, Saijo N. Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer. 2007 Jul 16;97(2):162-9. Epub 2007 Jun 19. link to original article link to PMC article contains dosing details in abstract PubMed
  19. 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
  20. SWOG S0124: Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, Jett J, Langer CJ, Kuebler JP, Dakhil SR, Chansky K, Gandara DR. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009 May 20;27(15):2530-5. Epub 2009 Apr 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00045162
  21. Zatloukal P, Cardenal F, Szczesna A, Gorbunova V, Moiseyenko V, Zhang X, Cisar L, Soria JC, Domine M, Thomas M. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol. 2010 Sep;21(9):1810-6. Epub 2010 Mar 15. link to original article contains dosing details in manuscript PubMed NCT00143455
  22. 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 contains dosing details in abstract PubMed
  23. SALUTE: Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, Huang JE, Karlin DA, Faoro L, Scappaticci FA, Socinski MA. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011 Jun 1;29(16):2215-22. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed NCT00403403
  24. GSK 104864-A/479: Fink TH, Huber RM, Heigener DF, Eschbach C, Waller C, Steinhauer EU, Virchow JC, Eberhardt F, Schweisfurth H, Schroeder M, Ittel T, Hummler S, Banik N, Bogenrieder T, Acker T, Wolf M; “Aktion Bronchialkarzinom” (ABC Study Group). Topotecan/cisplatin compared with cisplatin/etoposide as first-line treatment for patients with extensive disease small-cell lung cancer: final results of a randomized phase III trial. J Thorac Oncol. 2012 Sep;7(9):1432-9. link to original article contains dosing details in abstract PubMed NCT00320359
  25. CALGB 30504: Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, Baggstrom M, Masters GA, Graziano SL, Crawford J, Bogart J, Vokes EE. Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small-cell lung cancer: A randomized, double-blind, placebo-controlled phase II study-CALGB 30504 (Alliance). J Clin Oncol. 2015 May 20;33(15):1660-5. Epub 2015 Mar 2. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00453154
  26. D0750018: Sun Y, Cheng Y, Hao X, Wang J, Hu C, Han B, Liu X, Zhang L, Wan H, Xia Z, Liu Y, Li W, Hou M, Zhang H, Xiu Q, Zhu Y, Feng J, Qin S, Luo X. Randomized phase III trial of amrubicin/cisplatin versus etoposide/cisplatin as first-line treatment for extensive small-cell lung cancer. BMC Cancer. 2016 Apr 9;16:265. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00660504
  27. COMBAT: Oh IJ, Kim KS, Park CK, Kim YC, Lee KH, Jeong JH, Kim SY, Lee JE, Shin KC, Jang TW, Lee HK, Lee KY, Lee SY. Belotecan/cisplatin versus etoposide/cisplatin in previously untreated patients with extensive-stage small cell lung carcinoma: a multi-center randomized phase III trial. BMC Cancer. 2016 Aug 26;16:690. link to original article link to original article contains dosing details in manuscript PubMed NCT00826644
  28. CA184-156: Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, Pietanza MC, Wu YL, Zielinski C, Thomas M, Felip E, Gold K, Horn L, Aerts J, Nakagawa K, Lorigan P, Pieters A, Kong Sanchez T, Fairchild J, Spigel D. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. 2016 Nov 1;34(31):3740-3748. link to original article contains dosing details in manuscript PubMed NCT01450761
  29. GOIRC-AIFA FARM6PMFJM: Tiseo M, Boni L, Ambrosio F, Camerini A, Baldini E, Cinieri S, Brighenti M, Zanelli F, Defraia E, Chiari R, Dazzi C, Tibaldi C, Turolla GM, D'Alessandro V, Zilembo N, Trolese AR, Grossi F, Riccardi F, Ardizzoni A. Italian, multicenter, phase III, randomized study of cisplatin plus etoposide with or without bevacizumab as first-line treatment in extensive-disease small-cell lung cancer: the GOIRC-AIFA FARM6PMFJM trial. J Clin Oncol. 2017 Apr 20;35(12):1281-1287. Epub 2017 Jan 30. link to original article contains dosing details in manuscript PubMed EudraCT 2007-007949-13
  30. LUNGSTAR: Seckl MJ, Ottensmeier CH, Cullen M, Schmid P, Ngai Y, Muthukumar D, Thompson J, Harden S, Middleton G, Fife KM, Crosse B, Taylor P, Nash S, Hackshaw A. Multicenter, phase III, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in small-cell lung cancer (LUNGSTAR). J Clin Oncol. 2017 May 10;35(14):1506-1514. Epub 2017 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00433498
  31. CRCST-L-0001: Kim DW, Kim HG, Kim JH, Park K, Kim HK, Jang JS, Kim BS, Kang JH, Lee KH, Kim SW, Ryoo HM, Kim JS, Lee KH, Kwon JH, Choi JH, Shin SW, Hahn S, Heo DS. Randomized phase III trial of irinotecan plus cisplatin versus etoposide plus cisplatin in chemotherapy-naïve Korean patients with extensive-disease small cell lung cancer. Cancer Res Treat. 2019 Jan;51(1):119-127. Epub 2018 Mar 12. link to original article link to PMC article contains dosing details in abstract PubMed NCT00349492
  32. 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

Cisplatin & Etoposide (EP) & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Spigel et al. 2011 (SALUTE) 2007-2008 Randomized Phase 2 (E-esc) 1a. CE
1b. EP 		Seems to have superior PFS (primary endpoint)
Median PFS: 5.5 vs 4.4 mo
(HR 0.53, 95% CI 0.32-0.86)

Chemotherapy

Targeted therapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. SALUTE: Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, Huang JE, Karlin DA, Faoro L, Scappaticci FA, Socinski MA. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011 Jun 1;29(16):2215-22. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed NCT00403403

Cisplatin & Etoposide (EP) & Durvalumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2019 (CASPIAN) 2017-03-27 to 2018-05-29 Phase 3 (E-RT-esc) 1a. CE
1b. EP 		Superior OS1 (primary endpoint)
Median OS: 12.9 vs 10.5 mo
(HR 0.75, 95% CI 0.62-0.91)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Immunotherapy

  • Durvalumab (Imfinzi) as follows:
    • Cycles 1 to 4: 1500 mg IV once on day 1
    • Cycle 5 onwards: 1500 mg IV once on day 1

21-day cycle for 4 cycles, then 28-day cycles

References

  1. CASPIAN: Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Kazarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Shire N, Jiang H, Goldman JW; CASPIAN investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1929-1939. Epub 2019 Oct 4. link to original article contains dosing details in manuscript PubMed NCT03043872
    1. PRO analysis: Goldman JW, Garassino MC, Chen Y, Özgüroğlu M, Dvorkin M, Trukhin D, Statsenko G, Hotta K, Ji JH, Hochmair MJ, Voitko O, Havel L, Poltoratskiy A, Losonczy G, Reinmuth N, Patel N, Laud PJ, Shire N, Jiang H, Paz-Ares L. Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. Lung Cancer. 2020 Nov;149:46-52. Epub 2020 Sep 10. link to original article PubMed
    2. Update: Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Każarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Thiyagarajah P, Jiang H, Paz-Ares L; CASPIAN investigators. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):51-65. Epub 2020 Dec 4. link to original article PubMed

Cisplatin & Irinotecan (IC)

IP: Irinotecan, Platinol (Cisplatin)

Regimen variant #1, 30/65

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hanna et al. 2006 2000-2003 Phase 3 (E-switch-ic) Cisplatin & Etoposide Did not meet primary endpoint of OS

Chemotherapy

Supportive therapy

  • G-CSF used according to 1999 American Society of Clinical Oncology guidelines
  • "Erythropoietin was allowed at the discretion of the treating physician."

21-day cycle for 4 cycles; additional cycles could be given at physician discretion


Regimen variant #2, 60/60

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Noda et al. 2002 (JCOG 9511) 1995-1998 Phase 3 (E-switch-ic) EP Superior OS (primary endpoint)
Median OS: 12.8 vs 9.4 mo
(HR 0.60, 95% CI 0.43-0.83)
Lara et al. 2009 (SWOG S0124) 2002-2007 Phase 3 (E-switch-ic) EP Did not meet primary endpoint of OS
Satouchi et al. 2014 (JCOG 0509) 2007-2010 Phase 3 (C) Amrubicin & Cisplatin Superior OS

Chemotherapy

Supportive therapy

  • "Hydration and administration of antiemetic drugs."

28-day cycle for 4 cycles


Regimen variant #3, 80/65

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zatloukal et al. 2010 2003-2007 Phase 3 (E-switch-ic) EP Non-inferior OS (primary endpoint)
Median OS: 10.2 vs 9.7 mo
(HR 0.81, 95% CI 0.65-1.01)

Note: this dosing was the result of a mid-protocol amendment.

Chemotherapy

21-day cycle for 6 cycles

References

  1. JCOG 9511: Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N; JCOG. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):85-91. link to original article contains dosing details in manuscript PubMed
  2. Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, Ansari R, Ellis P, Byrne M, Morrison M, Hariharan S, Wang B, Sandler A. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006 May 1;24(13):2038-43. link to original article contains dosing details in manuscript PubMed
  3. SWOG S0124: Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, Jett J, Langer CJ, Kuebler JP, Dakhil SR, Chansky K, Gandara DR. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009 May 20;27(15):2530-5. Epub 2009 Apr 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00045162
  4. Zatloukal P, Cardenal F, Szczesna A, Gorbunova V, Moiseyenko V, Zhang X, Cisar L, Soria JC, Domine M, Thomas M. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol. 2010 Sep;21(9):1810-6. Epub 2010 Mar 15. link to original article contains dosing details in manuscript PubMed NCT00143455
  5. JCOG 0509: Satouchi M, Kotani Y, Shibata T, Ando M, Nakagawa K, Yamamoto N, Ichinose Y, Ohe Y, Nishio M, Hida T, Takeda K, Kimura T, Minato K, Yokoyama A, Atagi S, Fukuda H, Tamura T, Saijo N. Phase III study comparing amrubicin plus cisplatin with irinotecan plus cisplatin in the treatment of extensive-disease small-cell lung cancer: JCOG 0509. J Clin Oncol. 2014 Apr 20;32(12):1262-8. Epub 2014 Mar 17. link to original article contains dosing details in manuscript PubMed UMIN000000720

Docetaxel monotherapy

Regimen

Study Evidence
Hesketh et al. 1999 Phase 2

Chemotherapy

21-day cycles

References

  1. Hesketh PJ, Crowley JJ, Burris HA 3rd, Williamson SK, Balcerzak SP, Peereboom D, Goodwin JW, Gross HM, Moore DF Jr, Livingston RB, Gandara DR; SWOG. Evaluation of docetaxel in previously untreated extensive-stage small cell lung cancer: a Southwest Oncology Group phase II trial. Cancer J Sci Am. 1999 Jul-Aug;5(4):237-41. contains dosing details in abstract PubMed

EP-Topotecan

EP-Topotecan: Etoposide and Platinol (Cisplatin), followed by Topotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ignatiadis et al. 2005 2000-2003 Phase 3 (C) EP/Topotecan Did not meet primary endpoint of OS

Chemotherapy, EP portion (cycles 1 to 4)

Chemotherapy, Topotecan portion (cycles 5 to 8)

21-day cycle for 8 cycles

References

  1. Ignatiadis M, Mavroudis D, Veslemes M, Boukovinas J, Syrigos K, Agelidou M, Agelidou A, Gerogianni A, Pavlakou G, Tselepatiotis E, Nikolakopoulos J, Georgoulias V; Hellenic Oncology Research Group. Sequential versus alternating administration of cisplatin/etoposide and topotecan as first-line treatment in extensive-stage small-cell lung cancer: preliminary results of a Phase III Trial of the Hellenic Oncology Research Group. Clin Lung Cancer. 2005 Nov;7(3):183-9. link to original article contains dosing details in abstract PubMed

Ifosfamide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Ettinger et al. 2002 (ECOG E1588) 1988-1990 Phase 3 (E-switch-ic) 1. CAV Did not meet primary endpoint of OS Less toxic
2. Teniposide Did not meet primary endpoint of OS Not reported

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 300 mg/m2 IV three times per day on days 1 to 5, given 0, 4, and 8 hours after each dose of ifosfamide (total dose per cycle: 4500 mg/m2)

21-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. 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

IVE

IVE: Ifosfamide, VP-16 (Etoposide), Epirubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Berghmans et al. 2017 (ELCWP 01994) 2000-2013 Phase 3 (C) EP Did not meet primary endpoint of OS

Note: This combination is based on a commonly used backbone in Europe. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 300 mg/m2 IV once on day 1, given just before ifosfamide, then 300 mg/m2 IV once every 4 hours for 72 hours (total dose per cycle: 5700 mg/m2)

21-day cycles

References

  1. ELCWP 01994: Berghmans T, Scherpereel A, Meert AP, Giner V, Lecomte J, Lafitte JJ, Leclercq N, Paesmans M, Sculier JP; European Lung Cancer Working Party (ELCWP). A Phase III Randomized Study Comparing a Chemotherapy with Cisplatin and Etoposide to a Etoposide Regimen without Cisplatin for Patients with Extensive Small-Cell Lung Cancer. Front Oncol. 2017 Sep 19;7:217. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00658580

Teniposide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Ettinger et al. 2002 (ECOG E1588) 1988-1990 Phase 3 (E-switch-ic) 1. CAV Did not meet primary endpoint of OS Less toxic
2. Ifosfamide Did not meet primary endpoint of OS Not reported

Chemotherapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. 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

Extensive stage, consolidation after first-line therapy

Whole brain irradiation

PCI: Prophylactic Cranial Irradiation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ettinger et al. 2002 (ECOG E1588) 1988-1990 Non-randomized part of phase 3 RCT
Slotman et al. 2007 (EORTC 22993) 2001-2006 Phase 3 (E-esc) Observation Superior OS (secondary endpoint)
Median OS: 6.7 vs 5.4 mo
(HR 0.68, 95% CI 0.52-0.88)

Preceding treatment

Radiotherapy

  • Whole brain irradiation by one of the following: 2000 cGy in 5 or 8 fractions, 2400 cGy in 12 fractions, 2500 cGy in 10 fractions, or 3000 cGy in 10 or 12 fractions

1- to 3-week course

References

  1. Meta-analysis: Aupérin A, Arriagada R, Pignon JP, Le Péchoux C, Gregor A, Stephens RJ, Kristjansen PE, Johnson BE, Ueoka H, Wagner H, Aisner J; Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 1999 Aug 12;341(7):476-84. link to original article PubMed
  2. 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
  3. EORTC 22993: Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, Postmus P, Collette L, Musat E, Senan S; EORTC Radiation Oncology Group; EORTC Lung Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72. link to original article contains dosing details in abstract PubMed NCT00016211

Extensive stage, maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

Study Evidence
Spigel et al. 2011 (SALUTE) Non-randomized part of phase 2 RCT

Preceding treatment

Targeted therapy

21-day cycles

References

  1. Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, Huang JE, Karlin DA, Faoro L, Scappaticci FA, Socinski MA. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011 Jun 1;29(16):2215-22. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed NCT00403403

Ipilimumab monotherapy

Regimen

Study Dates of enrollment Evidence
Reck et al. 2012 (CA184-041SCLC) 2008-2009 Non-randomized part of phase 2 RCT

Preceding treatment

Immunotherapy

12-week cycles

References

  1. CA184-041SCLC: Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Lu H, Cuillerot JM, Lynch TJ. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. Epub 2012 Aug 2. link to original article contains dosing details in manuscript PubMed NCT00527735

Sunitinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ready et al. 2015 (CALGB 30504) 2007-2011 Randomized Phase 2 (E-esc) Observation Seems to have superior PFS (primary endpoint)
Median PFS: 3.7 vs 2.1 mo
(HR 0.62, 95% CI 0.38-0.98)

Preceding treatment

Targeted therapy

  • Sunitinib (Sutent) as follows:
    • Cycle 1: 150 mg PO once on day 1, then 37.5 mg PO once per day on days 2 to 28
    • Cycle 2 onwards: 37.5 mg PO once per day on days 1 to 28

28-day cycles

References

  1. CALGB 30504: Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, Baggstrom M, Masters GA, Graziano SL, Crawford J, Bogart J, Vokes EE. Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small-cell lung cancer: A randomized, double-blind, placebo-controlled phase II study-CALGB 30504 (Alliance). J Clin Oncol. 2015 May 20;33(15):1660-5. Epub 2015 Mar 2. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00453154

Relapsed or refractory disease, second-line

Amrubicin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Pawel et al. 2014 (ACT-1) 2007-2010 Phase 3 (E-switch-ic) Topotecan Did not meet primary endpoint of OS
Median OS: 7.5 vs 7.8 mo
(HR 0.88, 95% CI 0.73-1.06)
Spigel et al. 2021 (CheckMate 331) 2015-2017 Phase 3 (C) Nivolumab Might have inferior OS

Chemotherapy

Supportive therapy

  • "Prophylactic antibiotics were recommended for patients at high risk of infectious complications."

21-day cycle for at least 6 cycles

References

  1. ACT-1: von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, Steins M, Bosquée L, Bubis J, Nackaerts K, Trigo JM, Clingan P, Schütte W, Lorigan P, Reck M, Domine M, Shepherd FA, Li S, Renschler MF. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014 Dec 10;32(35):4012-9. Epub 2014 Nov 10. link to original article contains dosing details in manuscript PubMed NCT00547651
  2. 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

Carboplatin & Etoposide (CE)

EC: Etoposide & Carboplatin
EP: Etoposide & Paraplatin (Carboplatin)
CE: Carboplatin & Etoposide
Ca/E: Carboplatin & Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Baize et al. 2020 (GFPC 01-2013) 2013-2018 Phase 3 (E-switch-ic) Topotecan Superior PFS (primary endpoint)
Median PFS: 4.7 vs 2.7 mo
(HR 0.57, 90% CI 0.41-0.73)

Chemotherapy

21-day cycle for 6 cycles

References

  1. GFPC 01-2013: Baize N, Monnet I, Greillier L, Geier M, Lena H, Janicot H, Vergnenegre A, Crequit J, Lamy R, Auliac JB, Letreut J, Le Caer H, Gervais R, Dansin E, Madroszyk A, Renault PA, Le Garff G, Falchero L, Berard H, Schott R, Saulnier P, Chouaid C; Groupe Français de Pneumo-Cancérologie. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1224-1233. link to original article contains dosing details in abstract PubMed NCT02738346

Cisplatin, Etoposide, Irinotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goto et al. 2016 (JCOG0605) 2007-2012 Phase 3 (E-esc) Topotecan Superior OS (primary endpoint)
Median OS: 18.2 vs 12.5 mo
(HR 0.67, 90% CI 0.51-0.88)

Chemotherapy

Supportive therapy

  • G-CSF, started on cycle 1 day 9: (dose not specified) SC once per day, continued throughout except for days of chemotherapy

14-day cycle for 5 cycles

References

  1. JCOG0605: Goto K, Ohe Y, Shibata T, Seto T, Takahashi T, Nakagawa K, Tanaka H, Takeda K, Nishio M, Mori K, Satouchi M, Hida T, Yoshimura N, Kozuki T, Imamura F, Kiura K, Okamoto H, Sawa T, Tamura T; JCOG. Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1147-57. Epub 2016 Jun 14. link to original article contains dosing details in abstract PubMed UMIN000000828

Lurbinectedin monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Trigo et al. 2020 (PM1183-B-005-14) 2015-2019 Phase 2 (RT) ORR: 35.2% (95% CI, 26.2-45.2%)

Chemotherapy

Supportive therapy

  • "All patients received antiemetic prophylaxis."

21-day cycles

References

  1. PM1183-B-005-14: Trigo J, Subbiah V, Besse B, Moreno V, López R, Sala MA, Peters S, Ponce S, Fernández C, Alfaro V, Gómez J, Kahatt C, Zeaiter A, Zaman K, Boni V, Arrondeau J, Martínez M, Delord JP, Awada A, Kristeleit R, Olmedo ME, Wannesson L, Valdivia J, Rubio MJ, Anton A, Sarantopoulos J, Chawla SP, Mosquera-Martinez J, D'Arcangelo M, Santoro A, Villalobos VM, Sands J, Paz-Ares L. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020 May;21(5):645-654. link to original article contains dosing details in manuscript Epub 2020 Mar 27. PubMed NCT02454972

Relapsed or refractory disease, subsequent lines

This section includes studies that do not specify an exact line or have yet to be categorized.

Bendamustine monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Lammers et al. 2014 (VICC THO 0920) 2009-2012 Phase 2 ORR: 33% (95% CI, 14-52%)

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. VICC THO 0920: Lammers PE, Shyr Y, Li CI, Hutchison AS, Sandler A, Carbone DP, Johnson DH, Keedy VL, Horn L. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol. 2014 Apr;9(4):559-62. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00984542

CAV

CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Regimen variant #1, no capping

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aix et al. 2022 (ATLANTIS) 2016-2018 Phase 3 (C) Doxorubicin & Lurbinectedin Did not meet primary endpoint of OS

Chemotherapy

21-day cycles


Regimen variant #2, capped

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Pawel et al. 1999 NR Phase 3 (C) Topotecan Did not meet co-primary endpoints of ORR/DOR

Note: von Pawel et al. 1999 does not clearly state the duration of each cycle, but 21 days is used in other CAV regimens, and there was no information in the paper that contradicted this.

Chemotherapy

Supportive therapy

  • G-CSF use per physician discretion

21-day cycle for up to 6 cycles beyond maximal response Patients with stable disease after 4 cycles could have treatment discontinued at physician discretion.


Regimen variant #3

Study Dates of enrollment Evidence
Ihde et al. 1994 1983-1991 Non-randomized part of phase 3 RCT

Note: Ihde et al. 1994 did not specifically say that the three medications were all given on day 1, but this is assumed to be the case based on other CAV regimens.

Preceding treatment

  • EP; standard-dose versus EP; high-dose, with progression

Chemotherapy

21-day cycle for 4 cycles

References

  1. Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, Edison M, Phelps RM, Lesar M, Phares JC, Grayson J, Minna JD, Johnson BE. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol. 1994 Oct;12(10):2022-34. link to original article contains dosing details in manuscript PubMed
  2. von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-67. link to original article contains dosing details in manuscript PubMed
  3. ATLANTIS: Aix SP, Ciuleanu TE, Navarro A, Cousin S, Bonanno L, Smit EF, Chiappori A, Olmedo ME, Horvath I, Grohé C, Farago AF, López-Vilariño JA, Cullell-Young M, Nieto A, Vasco N, Gómez J, Kahatt C, Zeaiter A, Carcereny E, Roubec J, Syrigos K, Lo G, Barneto I, Pope A, Sánchez A, Kattan J, Zarogoulidis K, Waller CF, Bischoff H, Juan-Vidal O, Reinmuth N, Dómine M, Paz-Ares L. Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial. Lancet Respir Med. 2023 Jan;11(1):74-86. Epub 2022 Oct 14. link to original article contains dosing details in abstract PubMed NCT02566993

Cisplatin & Etoposide (EP)

EP: Etoposide, Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
O'Bryan et al. 1990 (SWOG S8215) NR Phase 3 (E-switch-ic) BTOC Did not meet efficacy endpoints
Ettinger et al. 2002 (ECOG E1588) 1988-1990 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

21-day cycles

References

  1. SWOG S8215: O'Bryan RM, Crowley JJ, Kim PN, Epstein RB, Neilan B, Coltman CA Jr, Stuckey WJ, Pazdur R. Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell lung cancer: a Southwest Oncology Group Study. Cancer. 1990 Feb 15;65(4):856-60. link to original article PubMed
  2. 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

Docetaxel monotherapy

Regimen

Study Evidence
Smyth et al. 1994 Phase 2

Chemotherapy

21-day cycles

References

  1. Smyth JF, Smith IE, Sessa C, Schoffski P, Wanders J, Franklin H, Kaye SB; Early Clinical Trials Group of the EORTC. Activity of docetaxel (Taxotere) in small cell lung cancer. Eur J Cancer. 1994;30A(8):1058-60. link to original article contains dosing details in abstract PubMed

Epirubicin & Ifosfamide

EI: Epirubicin, Ifosfamide

Regimen

Study Dates of enrollment Evidence
Jacot et al. 2012 1992-2010 Phase 2

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) (dose/route/schedule not specified) on days 1 & 2
  • G-CSF use per physician discretion

28-day cycle for up to 6 cycles

References

  1. Jacot W, Pujol JL, Chakra M, Molinier O, Bozonnat MC, Gervais R, Quantin X. Epirubicin and ifosfamide in relapsed or refractory small cell lung cancer patients. Lung Cancer. 2012 Feb;75(2):213-6. Epub 2011 Aug 9. link to original article contains dosing details in manuscript PubMed

Etoposide monotherapy

Regimen

Study Evidence
Einhorn et al. 1990 Phase 2
Johnson et al. 1990 Phase 2

Chemotherapy

21-day cycles

References

  1. Einhorn LH, Pennington K, McClean J; Hoosier Oncology Group. Phase II trial of daily oral VP-16 in refractory small cell lung cancer: a Hoosier Oncology Group study. Semin Oncol. 1990 Feb;17(1 Suppl 2):32-5. Not available online; abstract contains protocol PubMed
  2. Johnson DH, Greco FA, Strupp J, Hande KR, Hainsworth JD. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol. 1990 Oct;8(10):1613-7. link to original article contains dosing details in manuscript PubMed

Gemcitabine monotherapy

Regimen variant #1, 5 cycles

Study Evidence
van der Lee et al. 2001 Phase 2

Chemotherapy

28-day cycle for up to 5 cycles


Regimen variant #2, indefinite

Study Evidence
Masters et al. 2003 (ECOG E1597) Phase 2

Note: dose escalation was carried out if patients had less than grade 2 toxicity with cycle 1.

Chemotherapy

  • Gemcitabine (Gemzar) as follows:
    • Cycle 1: 1000 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
    • Cycle 2 onwards: 1250 mg/m2 IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

References

  1. van der Lee I, Smit EF, van Putten JW, Groen HJ, Schlösser NJ, Postmus PE, Schramel FM. Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol. 2001 Apr;12(4):557-61. link to original article contains dosing details in manuscript PubMed
  2. ECOG E1597: Masters GA, Declerck L, Blanke C, Sandler A, DeVore R, Miller K, Johnson D; ECOG. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol. 2003 Apr 15;21(8):1550-5. link to original article contains dosing details in manuscript PubMed

Ifosfamide monotherapy

Regimen

Study Evidence
Cantwell et al. 1988 Phase 2

Chemotherapy

Supportive therapy

21-day cycles

References

  1. Cantwell BM, Bozzino JM, Corris P, Harris AL. The multidrug resistant phenotype in clinical practice; evaluation of cross resistance to ifosfamide and mesna after VP16-213, doxorubicin and vincristine (VPAV) for small cell lung cancer. Eur J Cancer Clin Oncol. 1988 Feb;24(2):123-9. link to original article contains dosing details in abstract PubMed
  2. Review: Marangolo M, Giovanis P. Ifosfamide in small cell lung cancer. Oncology. 2003;65 Suppl 2:46-9. Review. link to original article PubMed

Ifosfamide & Paclitaxel

PI: Paclitaxel, Ifosfamide

Regimen

Study Evidence
Park et al. 2007a Phase 2

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 500 mg/m2 IV three times per day on days 1 & 2, given 15 minutes before, 4 hours after, and 8 hours after ifosfamide (total dose per cycle: 3000 mg/m2)

21-day cycles

References

  1. Park S, Ahn MJ, Ahn JS, Lee J, Hong YS, Park BB, Lee SC, Hwang IG, Park JO, Lim H, Kang WK, Park K. Combination chemotherapy with paclitaxel and ifosfamide as the third-line regimen in patients with heavily pretreated small cell lung cancer. Lung Cancer. 2007 Oct;58(1):116-22. Epub 2007 Jul 12. link to original article contains dosing details in manuscript PubMed

Irinotecan monotherapy

Regimen variant #1, weekly

Study Evidence
Masuda et al. 1992 Phase 2, fewer than 20 pts

Chemotherapy

Supportive therapy

  • No routine prophylaxis against diarrhea, nausea, or vomiting used.

21-day cycles


Regimen variant #2, q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Edelman et al. 2022 (DISTINCT) 2017-NR Phase 3 (C) 1. Irinotecan & Dinutuximab Did not meet primary endpoint of OS
2. Topotecan Not reported

Chemotherapy

21-day cycles

References

  1. Masuda N, Fukuoka M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Negoro S, Nishioka M, Nakagawa K, Takada M. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol. 1992 Aug;10(8):1225-9. link to original article contains dosing details in manuscript PubMed
  2. DISTINCT: Edelman MJ, Dvorkin M, Laktionov K, Navarro A, Juan-Vidal O, Kozlov V, Golden G, Jordan O, Deng CQ, Bentsion D, Chouaid C, Dechev H, Dowlati A, Fernández Núñez N, Ivashchuk O, Kiladze I, Kortua T, Leighl N, Luft A, Makharadze T, Min Y, Quantin X; DISTINCT study investigators. Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer. Lung Cancer. 2022 Apr;166:135-142. Epub 2022 Mar 4. link to original article contains dosing details in abstract PubMed NCT03098030

Paclitaxel monotherapy

Regimen variant #1, every 3 weeks

Study Evidence
Smit et al. 1998 Phase 2

Chemotherapy

Supportive therapy

21-day cycle for up to 5 cycles


Regimen variant #2, weekly paclitaxel

Study Evidence
Yamamoto et al. 2006 Phase 2

Chemotherapy

Supportive therapy

  • Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, 22, 29, 36; 30 minutes prior to paclitaxel
  • Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22, 29, 36; 30 minutes prior to paclitaxel
  • Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22, 29, 36; 30 minutes prior to paclitaxel
  • If ANC less than 1000/μL or WBC count less than 2 x 109/L, G-CSF (type not specified) 2 mcg/kg SC once per day is given until WBC count more than or equal to 10 x 109/L, except on days that paclitaxel is given

8-week cycles

References

  1. Smit EF, Fokkema E, Biesma B, Groen HJ, Snoek W, Postmus PE. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer. 1998;77(2):347-51. link to original article contains dosing details in manuscript link to PMC article PubMed
  2. Yamamoto N, Tsurutani J, Yoshimura N, Asai G, Moriyama A, Nakagawa K, Kudoh S, Takada M, Minato Y, Fukuoka M. Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer. Anticancer Res. 2006 Jan-Feb;26(1B):777-81. link to original article contains dosing details in manuscript PubMed

Temozolomide monotherapy

Regimen variant #1, 75 mg/m2/d, 21 out of 28 days

Study Dates of enrollment Evidence
Pietanza et al. 2012 2008-2010 Phase 2

Chemotherapy

  • Temozolomide (Temodar) 75 mg/m2 PO once per day on days 1 to 21 (no food within 2 hours before or 1 hour after temozolomide)

Supportive therapy

  • Ondansetron (Zofran) 8 mg PO once per day on days 1 to 21, taken prior to temozolomide prn nausea
  • Patients with at least grade 3 lymphopenia received prophylaxis for Pneumocystis carinii pneumonia (no specific medication/dose/schedule listed)

28-day cycles


Regimen variant #2, 200 mg/m2/d, 5 out of 28 days

Study Evidence
Zauderer et al. 2014 (MSKCC 08-065) Phase 2

Chemotherapy

Supportive therapy

28-day cycles

References

  1. Pietanza MC, Kadota K, Huberman K, Sima CS, Fiore JJ, Sumner DK, Travis WD, Heguy A, Ginsberg MS, Holodny AI, Chan TA, Rizvi NA, Azzoli CG, Riely GJ, Kris MG, Krug LM. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res. 2012 Feb 15;18(4):1138-45. Epub 2012 Jan 6. link to original article contains dosing details in manuscript PubMed
  2. MSKCC 08-065: Zauderer MG, Drilon A, Kadota K, Huberman K, Sima CS, Bergagnini I, Sumner DK, Travis WD, Heguy A, Ginsberg MS, Holodny AI, Riely GJ, Kris MG, Krug LM, Pietanza MC. Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase. Lung Cancer. 2014 Nov;86(2):237-40. Epub 2014 Aug 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00740636

Topotecan monotherapy

Regimen variant #1, 1 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goto et al. 2016 (JCOG0605) 2007-2012 Phase 3 (C) Cisplatin, Etoposide, Irinotecan Inferior OS

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, 1.5 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Pawel et al. 1999 NR Phase 3 (E-RT-de-esc) CAV Did not meet co-primary endpoints of ORR/DOR
Eckardt et al. 2007 1999-2001 Phase 3 (C) Topotecan; oral Did not meet primary endpoint of ORR
von Pawel et al. 2014 (ACT-1) 2007-2010 Phase 3 (C) Amrubicin Did not meet primary endpoint of OS
Spigel et al. 2021 (CheckMate 331) 2015-2017 Phase 3 (C) Nivolumab Might have inferior OS
Aix et al. 2022 (ATLANTIS) 2016-2018 Phase 3 (C) Doxorubicin & Lurbinectedin Did not meet primary endpoint of OS
Blackhall et al. 2021 (TAHOE) 2017-04-11 to 2018-12-07 Phase 3 (C) Rovalpituzumab tesirine Superior OS
Edelman et al. 2022 (DISTINCT) 2017-NR Phase 3 (C) 1. Irinotecan & Dinutuximab Did not meet primary endpoint of OS
2. Irinotecan Not reported

Chemotherapy

Supportive therapy

  • (varies depending on reference):
  • G-CSF use per physician discretion
  • In von Pawel et al. 2014 (ACT-1), "Prophylactic antibiotics were recommended for patients at high risk of infectious complications."

21-day cycles Duration varies depending on reference:

  • In von Pawel et al. 1999 treatment is given until progression of disease, unacceptable toxicity, or 6 cycles beyond maximal response. Patients with stable disease after 4 cycles could have treatment discontinued at physician discretion.
  • In Eckardt et al. 2007, patients with complete or partial response continued treatment progression of disease or 2 cycles beyond best response. Patients with stable disease received at least 4 cycles therapy.
  • In ACT-1, treatment was given for 6 cycles or until progression of disease. Patients who had at least stable disease by cycle 6 could receive another 6 cycles of treatment.


Regimen variant #3, oral route

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eckardt et al. 2007 1999-2001 Phase 3 (E-switch-ic) Topotecan; IV (1.5 mg/m2) Did not meet primary endpoint of ORR
O'Brien et al. 2006 (GSK 104864/478) 2000-2004 Phase 3 (E-esc) Best supportive care Seems to have superior OS (primary endpoint)
Baize et al. 2020 (GFPC 01-2013) 2013-2018 Phase 3 (C) Carboplatin & Etoposide Inferior PFS
Spigel et al. 2021 (CheckMate 331) 2015-2017 Phase 3 (C) Nivolumab Might have inferior OS

Note: Duration of treatment details vary depending on reference. In GSK 104864/478, treatment is given for at least 4 cycles, though this depended on tolerability and response. In Eckardt et al. 2007, patients with complete or partial response continued treatment progression of disease or 2 cycles beyond best response. Patients with stable disease received at least 4 cycles of therapy. Patients enrolled in GFPC 01-2013 received 6 cycles.

Chemotherapy

21-day cycle for 4 or more cycles (see note)

References

  1. von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-67. link to original article contains dosing details in manuscript PubMed
  2. GSK 104864/478: O'Brien ME, Ciuleanu TE, Tsekov H, Shparyk Y, Cuceviá B, Juhasz G, Thatcher N, Ross GA, Dane GC, Crofts T. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006 Dec 1;24(34):5441-7. link to original article contains dosing details in manuscript PubMed NCT00276276
  3. Eckardt JR, von Pawel J, Pujol JL, Papai Z, Quoix E, Ardizzoni A, Poulin R, Preston AJ, Dane G, Ross G. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol. 2007 May 20;25(15):2086-92. link to original article contains dosing details in manuscript PubMed
  4. ACT-1: von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, Steins M, Bosquée L, Bubis J, Nackaerts K, Trigo JM, Clingan P, Schütte W, Lorigan P, Reck M, Domine M, Shepherd FA, Li S, Renschler MF. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014 Dec 10;32(35):4012-9. Epub 2014 Nov 10. link to original article contains dosing details in manuscript PubMed NCT00547651
  5. JCOG0605: Goto K, Ohe Y, Shibata T, Seto T, Takahashi T, Nakagawa K, Tanaka H, Takeda K, Nishio M, Mori K, Satouchi M, Hida T, Yoshimura N, Kozuki T, Imamura F, Kiura K, Okamoto H, Sawa T, Tamura T; JCOG. Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1147-57. Epub 2016 Jun 14. link to original article contains dosing details in abstract PubMed UMIN000000828
  6. GFPC 01-2013: Baize N, Monnet I, Greillier L, Geier M, Lena H, Janicot H, Vergnenegre A, Crequit J, Lamy R, Auliac JB, Letreut J, Le Caer H, Gervais R, Dansin E, Madroszyk A, Renault PA, Le Garff G, Falchero L, Berard H, Schott R, Saulnier P, Chouaid C; Groupe Français de Pneumo-Cancérologie. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1224-1233. link to original article contains dosing details in abstract PubMed NCT02738346
  7. 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
  8. TAHOE: Blackhall F, Jao K, Greillier L, Cho BC, Penkov K, Reguart N, Majem M, Nackaerts K, Syrigos K, Hansen K, Schuette W, Cetnar J, Cappuzzo F, Okamoto I, Erman M, Langer SW, Kato T, Groen H, Sun Z, Luo Y, Tanwani P, Caffrey L, Komarnitsky P, Reinmuth N. Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study. J Thorac Oncol. 2021 Sep;16(9):1547-1558. Epub 2021 Feb 16. link to original article contains dosing details in abstract PubMed NCT03061812
  9. DISTINCT: Edelman MJ, Dvorkin M, Laktionov K, Navarro A, Juan-Vidal O, Kozlov V, Golden G, Jordan O, Deng CQ, Bentsion D, Chouaid C, Dechev H, Dowlati A, Fernández Núñez N, Ivashchuk O, Kiladze I, Kortua T, Leighl N, Luft A, Makharadze T, Min Y, Quantin X; DISTINCT study investigators. Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer. Lung Cancer. 2022 Apr;166:135-142. Epub 2022 Mar 4. link to original article contains dosing details in abstract PubMed NCT03098030
  10. ATLANTIS: Aix SP, Ciuleanu TE, Navarro A, Cousin S, Bonanno L, Smit EF, Chiappori A, Olmedo ME, Horvath I, Grohé C, Farago AF, López-Vilariño JA, Cullell-Young M, Nieto A, Vasco N, Gómez J, Kahatt C, Zeaiter A, Carcereny E, Roubec J, Syrigos K, Lo G, Barneto I, Pope A, Sánchez A, Kattan J, Zarogoulidis K, Waller CF, Bischoff H, Juan-Vidal O, Reinmuth N, Dómine M, Paz-Ares L. Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial. Lancet Respir Med. 2023 Jan;11(1):74-86. Epub 2022 Oct 14. link to original article contains dosing details in abstract PubMed NCT02566993

Vinorelbine monotherapy

Regimen variant #1, 25 mg/m2

Study Evidence
Furuse et al. 1996a Phase 2

Chemotherapy

21-day cycles


Regimen variant #2, 30 mg/m2

Study Dates of enrollment Evidence
Jassem et al. 1993 NR in abstract Phase 2

Chemotherapy

21-day cycles

References

  1. Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, van Glabbeke M, Noseda MA, Ardizzoni A, Gozzelino F, Planting A, van Zandwijk N; EORTC Lung Cancer Cooperative Group. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. Eur J Cancer. 1993;29A(12):1720-2. link to original article contains dosing details in abstract PubMed
  2. Furuse K, Kubota K, Kawahara M, Takada M, Kimura I, Fujii M, Ohta M, Hasegawa K, Yoshida K, Nakajima S, Ogura T, Niitani H; Japan Lung Cancer Vinorelbine Study Group. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Oncology. 1996 Mar-Apr;53(2):169-72. link to original article contains dosing details in abstract PubMed
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