Small cell lung cancer

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Travis Osterman, DO, MS
Vanderbilt University
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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. If you still can't find it, please let us know so we can add it!.

46 regimens on this page
93 variants on this page

Contents


Guidelines

ASCO

ESMO

NCCN

Limited stage, induction

Carboplatin & Etoposide

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EP: Etoposide, Paraplatin (Carboplatin)

Variant #1, 2 days of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009a Phase III (C) Carboplatin, Etoposide, Thalidomide, then RT Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #2, 1 day of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009a Phase III (C) Carboplatin, Etoposide, Thalidomide, then RT Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. 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 verified protocol PubMed

Cisplatin & Etoposide

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EP: Etoposide, Platinol (Cisplatin)

Regimen

Study Evidence
Evans et al. 1985 Phase II

Patients with limited stage disease responding to therapy received prophylactic cranial irradiation, 4 Gy fractions once per day x 5 fractions (total dose: 20 Gy) over 5 days between cycles 3 and 4.

Chemotherapy

Supportive medications

  • 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 verified protocol PubMed

Limited stage, definitive chemoradiotherapy

Carboplatin, Etoposide, RT

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

Variant #1

Study Evidence Comparator Efficacy
Skarlos et al. 2001 Randomized Phase II (E-switch-ic) Carboplatin, Etoposide, early HTRT Might have superior ORR

Chemotherapy

Radiotherapy

  • Concurrent hyperfractionated thoracic radiation therapy (HTRT), 1.5 Gy fractions given twice per day (at least 4, but preferably 6 hours between fractions) x 30 fractions (total dose: 45 Gy) 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

Variant #2

Study Evidence
Okamoto et al. 1999 Phase II

Patients in Okamoto et al. 1999 were greater than or equal to 70 years old.

Chemotherapy

Radiotherapy

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

Supportive medications

  • 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 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 verified protocol 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. 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 verified protocol PubMed

Cisplatin, Etoposide, RT

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

Variant #1, 60/360/45

Study Evidence Comparator Efficacy
Turrisi et al. 1999 (Intergroup 0096) Phase III (E-esc) Cisplatin, Etoposide, once per day RT Seems to have superior OS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.50 Gy fractions given twice per day x 30 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 45 Gy)

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 Prophylactic cranial irradiation

Variant #2, 70/300/52.5, early RT

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Sun et al. 2013 Phase III (C) EP & late RT Non-inferior CR rate Seems to have higher rates of neutropenic fever

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 2.10 Gy fractions x 25 fractions over 5 weeks, given during cycle 1 of chemotherapy (total dose: 52.5 Gy)

21-day cycle for 4 cycles

Variant #3, 70/300/52.5, late RT

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Sun et al. 2013 Phase III (E-switch-ic) EP & early RT Non-inferior CR rate Seems to have lower rates of neutropenic fever

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 2.10 Gy fractions x 25 fractions over 5 weeks, given during cycle 3 of chemotherapy (total dose: 52.5 Gy)

21-day cycle for 4 cycles

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

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Bunn et al. 1995 Phase III (C) EP, RT, GM-CSF 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, 1.80 Gy fractions x 25 fractions (total dose: 45 Gy)

21-day cycle for 6 cycles

Variant #5, 75/300/45

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

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.50 Gy fractions given twice per day x 30 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 45 Gy)

21-day cycle for 4 or 6 cycles

Variant #6, 75/300/45, split doses of cisplatin

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

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.50 Gy fractions given twice per day x 30 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 45 Gy)

21-day cycle for 4 or 6 cycles

Variant #7, 75/700/42, partially oral etoposide

Study Evidence Comparator Efficacy
Sundstrøm et al. 2002 Phase III (E-switch-ic) CEV & RT Superior OS

Chemotherapy

Radiotherapy

  • Concurrent thoracic radiation therapy, 2.8 Gy fractions once per day x 15 fractions (total dose: 42 Gy) over 3 weeks, given "between the third and fourth chemotherapy courses"

Supportive medications

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

21-day cycle for up to 5 cycles

Subsequent treatment

Variant #8, 80/240/50

Study Evidence Comparator Efficacy
McClay et al. 2005 (CALGB 9235) Phase III (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: 50 Gy) over 5 weeks, started on cycle 4 day 1 of chemotherapy

21-day cycle for 5 cycles

Variant #9, 80/300/45, 1 cycle of chemo

Study Evidence
Saito et al. 2006 (WJTOG 9902) Phase II
Kubota et al. 2013 (JCOG0202) Non-randomized portion of RCT

Chemotherapy

Radiotherapy

  • Concurrent thoracic radiation therapy, 1.5 Gy fractions given twice per day (at least 4, but preferably 6 hours between fractions) x 30 fractions (total dose: 45 Gy) over 3 weeks, started on cycle 1 day 2 of chemotherapy

28-day cycle for 1 cycle

Subsequent treatment

Variant #10, 80/300/45, 4 cycles of chemo

Study Evidence Comparator Efficacy
Takada et al. 2002 (JCOG 9104) Phase III (E-switch-ic) Cisplatin, Etoposide, sequential RT Might have superior OS

Chemotherapy

Radiotherapy

  • Concurrent thoracic radiation therapy, 1.5 Gy fractions given twice per day (4 or more hours between fractions) x 30 fractions (total dose: 45 Gy) 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

Variant #11, 90/300/39.9

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

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 2.66 Gy fractions once per day x 15 fractions over 3 weeks, given during cycle 1 of chemotherapy (total dose: 39.9 Gy)

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. 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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol PubMed
  5. CALGB 9235: McClay EF, Bogart J, Herndon JE 2nd, Watson D, Evans L, Seagren SL, Green MR; Cancer and Leukemia Group B Study (9235). 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 protocol PubMed
  6. 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 9902. 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 verified protocol PubMed
  7. 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 (ELCWP). 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 verified protocol PubMed
  8. 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 verified protocol PubMed
  9. 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; Japan Clinical Oncology Group. 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 protocol PubMed
  10. 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 verified protocol PubMed

Limited state, consolidation after upfront therapy

Cisplatin & Irinotecan

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IP: Irinotecan, Platinol (Cisplatin)

Regimen

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

Preceding treatment

Chemotherapy

Supportive medications

  • 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 9902. 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 verified protocol PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Kelly et al. 1995 Phase III (C) IFN alfa-2a Did not meet primary endpoint of OS

No further treatment.

Preceding treatment

  • Chemoradiotherapy

References

  1. Kelly K, Crowley JJ, Bunn PA Jr, Hazuka MB, Beasley K, Upchurch C, Weiss GR, Hicks WJ, Gandara DR, Rivkin S, Livingston R. Role of recombinant interferon alfa-2a maintenance in patients with limited-stage small-cell lung cancer responding to concurrent chemoradiation: a Southwest Oncology Group study. J Clin Oncol. 1995 Dec;13(12):2924-30. link to original article PubMed

Radiation therapy

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Regimen

Study Evidence
Evans et al. 1985 Phase II

Preceding treatment

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: 25 Gy)

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 verified protocol PubMed
  2. 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 protocol PubMed

Whole brain irradiation

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PCI: Prophylactic Cranial Irradiation

Variant #1, 20 Gy

Study Evidence
Cox et al. 1981 Non-randomized
Evans et al. 1985 Phase II
Skarlos et al. 2001 Non-randomized portion of 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 x 3

Variant #2, 24 Gy

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

Preceding treatment

Radiotherapy

2-week course

Variant #3, 25 Gy

Study Evidence Comparator Efficacy
Turrisi et al. 1999 (Intergroup 0096) Non-randomized portion of RCT
Saito et al. 2006 (WJTOG 9902) Phase II
Le Péchoux et al. 2009 (PCI 99-01/EORTC 22003-08004/RTOG 0212/IFCT 99-01) Phase III (C) PCI x 36 Gy Did not meet primary endpoint of incidence of brain metastases at 2 years

Preceding treatment

Radiotherapy

2-week course

Variant #4, 30 Gy

Study Evidence
Sundstrøm et al. 2002 Non-randomized portion of 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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol 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 9902. 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 verified protocol 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

Extensive stage, induction

Belotecan & Cisplatin

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BP: Belotecan and Platinol (Cisplatin)

Regimen

Study Evidence Comparator Efficacy
Oh et al. 2016 (COMBAT) Phase III (E-switch-ic) EP 60/100 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

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 verified protocol PubMed

Carboplatin & Etoposide

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

Variant #1, AUC 4/600, PO etoposide

Study Evidence Comparator Efficacy
Hermes et al. 2008 Phase III (C) IC Seems to have inferior OS

Chemotherapy

21-day cycle for 4 cycles

Variant #2, AUC 5/240

Study Evidence Comparator Efficacy
Okamoto et al. 2007 (JCOG 9702) Phase III (E-switch-ic) EP; split-dose Did not meet primary endpoint of OS
Sekine et al. 2013 (D0702002) Phase III (C) Amrubicin Inconclusive whether non-inferior OS

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

Variant #3, AUC 5/300

Study Evidence Comparator Efficacy
Socinski et al. 2009 Phase III (C) Carboplatin & Pemetrexed Superior OS
Spigel et al. 2011 (SALUTE) Randomized Phase II (C) Carboplatin, Etoposide, Bevacizumab Seems to have inferior PFS
Ready et al. 2015 (CALGB 30504) Non-randomized portion of RCT
Reck et al. 2016 (CA184-156) Phase III (C) CE & Ipilimumab Did not meet primary endpoint of OS
Jalal et al. 2017 (MATISSE) Randomized Phase II (C) PaCE Might have superior OS
Horn et al. 2018 (IMpower133) Phase III (C) CE & Atezolizumab, then Atezolizumab maint. Inferior OS
Paz-Ares et al. 2019 (CASPIAN) Phase III (C) CE & Durvalumab, then Durvalumab maint. Inferior OS

Note: CASPIAN gave a range of dosing; see paper for details.

Chemotherapy

Supportive medications

  • 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

Variant #4, AUC 5 or 6/360

Study Evidence Comparator Efficacy
Seckl et al. 2017 (LUNGSTAR) Phase III (C) CE & Pravastatin Did not meet primary endpoint of OS

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 or 6 (maximum dose of 1000 mg) IV once on day 1
    • AUC 5 is used if eGFR calculated by EDTA; AUC 6 is used if eGFR calculated by Cockcroft Gault. If eGFR greater than 130 mL/min/1.73m2, dose calculation to be capped at GFR = 130 mL/min/1.73m2
  • Etoposide (Vepesid) 120 mg/m2 IV once per day on days 1 to 3

21-day cycle for 6 cycles

Variant #5, AUC 5/420

Study Evidence Comparator Efficacy
Schmittel et al. 2006 Randomized Phase II (E-switch-ic) IP Might have inferior OS
Heigener et al. 2009 Phase III (C) CE; dose-intense Did not meet primary endpoint of OS

Chemotherapy

Supportive medications

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

Variant #6, AUC 5 or 6/440, 1 day of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009a Phase III (C) CE & Thalidomide Did not meet primary endpoint of OS
Seckl et al. 2017 (LUNGSTAR) Phase III (C) CE & Pravastatin Did not meet primary endpoint of OS

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 or 6 (maximum dose of 1000 mg) IV once on day 1
    • Lee et al. 2009a: AUC 5 is used
    • LUNGSTAR: AUC 5 is used if eGFR calculated by EDTA; AUC 6 is used if eGFR calculated by Cockcroft Gault. If eGFR greater than 130 mL/min/1.73m2, dose calculation to be capped at GFR = mL/min/1.73m2
  • Etoposide (Vepesid) 120 mg/m2 IV once per day on days 1 & 2, then 100 mg PO twice per day on day 3

21-day cycle for up to 6 cycles

Variant #7, AUC 5 or 6/520, 2 days of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009a Phase III (C) CE & Thalidomide Did not meet primary endpoint of OS
Seckl et al. 2017 (LUNGSTAR) Phase III (C) CE & Pravastatin Did not meet primary endpoint of OS

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 or 6 (maximum dose of 1000 mg) IV once on day 1
    • Lee et al. 2009a: AUC 5 is used
    • LUNGSTAR: AUC 5 is used if eGFR calculated by EDTA; AUC 6 is used if eGFR calculated by Cockcroft Gault. If eGFR greater than 130 mL/min/1.73m2, dose calculation to be capped at GFR = mL/min/1.73m2
  • Etoposide (Vepesid) 120 mg/m2 IV once on day 1, then 100 mg PO twice per day on days 2 & 3

21-day cycle for up to 6 cycles

Variant #8, AUC 5/300, 28-day cycles

Study Evidence
Okamoto et al. 1999 Phase II
Quoix et al. 2001 Phase II

Patients in Okamoto et al. 1999 and Quoix et al. 2001 were greater than or equal to 70 years old.

Chemotherapy

Radiotherapy

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

Supportive medications

  • 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 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

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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol 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 protocol 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 protocol 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 protocol PubMed
  7. 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 verified protocol PubMed
  8. 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 verified protocol PubMed
  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 verified protocol PubMed
  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 protocol PubMed
  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 verified protocol PubMed
  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 verified protocol PubMed
  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 verified protocol link to PMC article PubMed
  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 verified protocol PubMed
  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 verified protocol 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 Oct 4. [Epub ahead of print] link to original article PubMed

Carboplatin, Etoposide, Atezolizumab

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Regimen

Study Evidence Comparator Efficacy
Horn et al. 2018 (IMpower133) Phase III (E-RT-esc) See link See link

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

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 verified protocol PubMed

Carboplatin, Etoposide, Bevacizumab

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Regimen

Study Evidence Comparator Efficacy
Spigel et al. 2011 (SALUTE) Randomized Phase II (E-esc) Carboplatin & Etoposide Seems to have superior PFS

Chemotherapy

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 verified protocol PubMed

Carboplatin, Etoposide, Durvalumab

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Regimen

Study Evidence Comparator Efficacy
Paz-Ares et al. 2019 (CASPIAN) Phase III (E-esc) Carboplatin & Etoposide Superior OS

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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 Oct 4. [Epub ahead of print] link to original article contains verified protocol PubMed

Carboplatin & Irinotecan

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

Variant #1, AUC 4/175

Study Evidence Comparator Efficacy
Hermes et al. 2008 Phase III (E-switch-ic) EC Seems to have superior OS

Chemotherapy

21-day cycle for 4 cycles

Variant #2, AUC 5/150

Study Evidence Comparator Efficacy
Schmittel et al. 2006 Randomized Phase II (E-switch-ic) EP Might have superior OS

Chemotherapy

Supportive medications

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 verified protocol 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 verified protocol 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 protocol PubMed

Carboplatin, Paclitaxel, Ipilimumab

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Variant #1, phased ipilimumab

Study Evidence Comparator Efficacy
Reck et al. 2013 (CA184-041) Randomized Phase II (E-esc) 1. Carboplatin & Paclitaxel Seems to have superior irPFS
2. Carboplatin, Paclitaxel, concurrent Ipilimumab Not reported

Chemotherapy

Immunotherapy

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 & 2: no treatment
    • Cycles 3 to 6: 10 mg/kg IV once on day 1

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #2, concurrent ipilimumab

Study Evidence Comparator Efficacy
Reck et al. 2013 (CA184-041) Randomized Phase II (E-esc) 1. Carboplatin & Paclitaxel Did not meet secondary endpoints
2. Carboplatin, Paclitaxel, phased Ipilimumab Not reported

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

Chemotherapy

Immunotherapy

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 to 4: 10 mg/kg IV once on day 1
    • Cycles 5 & 6: no treatment

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. CA184-041: 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. link to original article contains verified protocol PubMed

Cisplatin & Etoposide

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

Variant #1, 60/300

Study Evidence Comparator Efficacy
Oh et al. 2016 (COMBAT) Phase III (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

Variant #2, 60/360

Study Evidence Comparator Efficacy
Hanna et al. 2006 Phase III (C) Cisplatin & Irinotecan Did not meet primary endpoint of OS
Seckl et al. 2017 (LUNGSTAR) Phase III (C) EP & Pravastatin Did not meet primary endpoint of OS

Chemotherapy

Supportive medications

  • 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

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

Study Evidence Comparator Efficacy
Seckl et al. 2017 (LUNGSTAR) Phase III (C) EP & Pravastatin Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

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

Study Evidence Comparator Efficacy
Seckl et al. 2017 (LUNGSTAR) Phase III (C) EP & Pravastatin Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #5, 70/300

Study Evidence Comparator Efficacy
Ruotsalainen et al. 1999 Phase III (C) EP & IFN-alpha Did not meet endpoint of OS50%
Kim et al. 2018 (CRCST-L-0001) Phase III (C) Cisplatin & Irinotecan Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #6, 75/240, split cisplatin

Study Evidence Comparator Efficacy
Okamoto et al. 2007 (JCOG 9702) Phase III (C) CE Did not meet primary endpoint of OS

Chemotherapy

21- to 28-day cycle for 4 cycles

Variant #7, 75/300

Study Evidence Comparator Efficacy
Ignatiadis et al. 2005 Phase III (C) EP/Topotecan Did not meet primary endpoint of OS
Spigel et al. 2011 (SALUTE) Randomized Phase II (C) Cisplatin, Etoposide, Bevacizumab Seems to have inferior PFS
Fink et al. 2012 Phase III (C) 1. Cisplatin & Topotecan Non-inferior OS
2. Etoposide & Topotecan Not reported
Reck et al. 2016 (CA184-156) Phase III (C) EP & Ipilimumab Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 4 (SALUTE) or 6 (Fink et al. 2012 & CA184-156) cycles

Variant #8, 75/300, split cisplatin

Study Evidence Comparator Efficacy
Evans et al. 1985 Phase II
Tiseo et al. 2017 (GOIRC-AIFA FARM6PMFJM) Phase III (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, 4 Gy fractions given daily x 5 fractions (total dose: 20 Gy) 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 medications

  • 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

Variant #9, 75/390, split cisplatin

Study Evidence Comparator Efficacy
Miller et al. 1995 Phase III (C) EP; oral etoposide Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 8 cycles

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

Study Evidence Comparator Efficacy
Sundstrøm et al. 2002 Phase III (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."

Chemotherapy

Supportive medications

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

21-day cycle for up to 5 cycles

Variant #11, 80/240

Study Evidence Comparator Efficacy
Ihde et al. 1994 Phase III (C) EP; high-dose Did not meet primary endpoint of CR rate
Niell et al. 2005 (CALGB 9732) Phase III (C) PET (Etoposide) 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 medications

  • "Half-normal saline was infused for 2 to 6 hours with Cisplatin (Platinol), 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: an additional 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."

Variant #12, 80/300

Study Evidence Comparator Efficacy
Fukuoka et al. 1991 (JCOG8502) Phase III (C) 1. CAV Not reported
2. CAV/PE Might have inferior OS
Miyamoto et al. 1992 Phase III (C) PEI Did not meet primary endpoint of OS
Noda et al. 2002 (JCOG 9511) Phase III (C) IP Inferior OS
Eckardt et al. 2006 Phase III (C) Cisplatin & Topotecan Non-inferior OS
Lara et al. 2009 (SWOG S0124) Phase III (C) IP Did not meet primary endpoint of OS
Zatloukal et al. 2010 Phase III (C) IP Non-inferior OS
Baka et al. 2010 Phase III (C) EP/T Did not meet primary endpoint of OS
Ready et al. 2015 (CALGB 30504) Non-randomized portion of RCT
Sun et al. 2016 (D0750018) Phase III (C) Amrubicin & Cisplatin Might have inferior OS

Chemotherapy

Supportive medications

  • "Hydration and administration of antiemetic drugs."

21-day cycle for 4 to 6 cycles

Subsequent treatment

Variant #13, 80/400, split cisplatin

Study Evidence Comparator Efficacy
Loehrer et al. 1995 Phase III (C) VIP Seems to have inferior OS

Chemotherapy

21-day cycle for 4 cycles

Variant #14, 80/600, 2 days of oral etoposide per cycle

Study Evidence Comparator Efficacy
Baka et al. 2008 Phase III (E-switch-ic) ACE Did not meet primary endpoint of OS12

Chemotherapy

21-day cycle for 6 cycles

Variant #15, 100/300

Study Evidence Comparator Efficacy
Pujol et al. 2001 Phase III (C) PCDE Inferior OS
Artal-Cortés et al. 2004 Phase III (C) Cisplatin & Epirubicin Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 6 cycles

Variant #16, 100/400, split cisplatin

Study Evidence Comparator Efficacy
Roth et al. 1992 Phase III (C) 1. CAV
2. CAV/PE
Did not meet primary endpoint of OS50%
Hainsworth et al. 1995 Randomized Phase II (E-RT-switch-ic) Cisplatin & Etoposide Did not meet efficacy endpoints

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 verified protocol 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 protocol 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 protocol 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. 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 verified protocol 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 verified protocol 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. 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 protocol PubMed
  8. Loehrer PJ Sr, Ansari R, Gonin R, Monaco F, Fisher W, Sandler A, Einhorn LH. 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 verified protocol 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 protocol PubMed
  10. 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 protocol PubMed
  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; Japan Clinical Oncology Group. 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 verified protocol 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 verified protocol 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 protocol 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; Cancer and Leukemia Group. 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 verified protocol PubMed
  15. Ignatiadis M, Mavroudis D, Veslemes M, Boukovinas J, Syrigos K, Agelidou M, Agelidou A, Gerogianni A, Pavlakou G, Tselepatiotis E, Nikolakopoulos J, Georgoulias V. 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 protocol PubMed
  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 verified protocol PubMed
  17. 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 protocol PubMed
  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 protocol 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 protocol 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 protocol PubMed
  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 protocol PubMed
  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 protocol 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 verified protocol PubMed
  24. 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 protocol PubMed
  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 verified protocol PubMed
  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 verified protocol PubMed
  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 verified protocol PubMed
  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 verified protocol PubMed
  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 verified protocol PubMed
  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 verified protocol link to PMC article PubMed
  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 protocol PubMed

Cisplatin, Etoposide, Bevacizumab

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Regimen

Study Evidence Comparator Efficacy
Spigel et al. 2011 (SALUTE) Randomized Phase II (E-esc) Cisplatin & Etoposide Seems to have superior PFS

Chemotherapy

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 verified protocol PubMed

Cisplatin, Etoposide, Durvalumab

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Regimen

Study Evidence Comparator Efficacy
Paz-Ares et al. 2019 (CASPIAN) Phase III (E-esc) Cisplatin & Etoposide Superior OS

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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 Oct 4. [Epub ahead of print] link to original article contains verified protocol PubMed

Cisplatin & Irinotecan

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IP: Irinotecan, Platinol (Cisplatin)

Variant #1, 30/65

Study Evidence Comparator Efficacy
Hanna et al. 2006 Phase III (E-switch-ic) Cisplatin & Etoposide Did not meet primary endpoint of OS

Chemotherapy

Supportive medications

  • 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

Variant #2, 60/60

Study Evidence Comparator Efficacy
Noda et al. 2002 (JCOG 9511) Phase III (E-switch-ic) EP Superior OS
Lara et al. 2009 (SWOG S0124) Phase III (E-switch-ic) EP Did not meet primary endpoint of OS
Satouchi et al. 2014 (JCOG 0509) Phase III (C) Amrubicin & Cisplatin Superior OS

Chemotherapy

Supportive medications

  • "Hydration and administration of antiemetic drugs."

28-day cycle for 4 cycles

Variant #3, 80/65

Study Evidence Comparator Efficacy
Zatloukal et al. 2010 Phase III (E-switch-ic) EP Non-inferior OS

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; Japan Clinical Oncology Group. 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 verified protocol 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 verified protocol 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 protocol PubMed
  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 protocol PubMed
  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 verified protocol PubMed

Docetaxel monotherapy

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Regimen

Study Evidence
Hesketh et al. 1999 Phase II

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. 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 protocol PubMed

Ifosfamide monotherapy

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Regimen

Study Evidence Comparator Efficacy Toxicity
Ettinger et al. 2002 (ECOG E1588) Phase III (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 medications

  • 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 (Ifex) (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; Eastern Cooperative Oncology Group. 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 verified protocol PubMed

Teniposide monotherapy

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Regimen

Study Evidence Comparator Efficacy Toxicity
Ettinger et al. 2002 (ECOG E1588) Phase III (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; Eastern Cooperative Oncology Group. 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 verified protocol PubMed

Extensive stage, consolidation after first-line therapy

Whole brain irradiation

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PCI: Prophylactic Cranial Irradiation

Regimen

Study Evidence Comparator Efficacy
Ettinger et al. 2002 (ECOG E1588) Non-randomized portion of RCT
Slotman et al. 2007 (EORTC 22993) Phase III (E-esc) Observation Superior OS

Preceding treatment

  • ECOG E1588: CAV versus Ifosfamide versus Teniposide
  • EORTC 22993: Chemotherapy x 4 to 6 cycles (regimen not specified)

Radiotherapy

  • Whole brain irradiation by one of the following: 20 Gy in 5 or 8 fractions, 24 Gy in 12 fractions, 25 Gy in 10 fractions, or 30 Gy 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; Eastern Cooperative Oncology Group. 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 verified protocol 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 and 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 protocol PubMed

Extensive stage, maintenance after first-line therapy

Atezolizumab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Horn et al. 2018 (IMpower133) Phase III (E-RT-esc) See link See link

Preceding treatment

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 verified protocol PubMed

Bevacizumab monotherapy

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Regimen

Study Evidence
Spigel et al. 2011 (SALUTE) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

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 verified protocol PubMed

Durvalumab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Paz-Ares et al. 2019 (CASPIAN) Phase III (E-esc) Cisplatin & Etoposide Superior OS

Preceding treatment

Chemotherapy

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 Oct 4. [Epub ahead of print] link to original article contains verified protocol PubMed

Ipilimumab monotherapy

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Regimen

Study Evidence
Reck et al. 2013 (CA184-041) Non-randomized portion of RCT

Preceding treatment

Immunotherapy

12-week cycles

References

  1. CA184-041: 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. link to original article contains verified protocol PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Jett et al. 1994 Phase III (C) IFN gamma Did not meet primary endpoint of OS
van Zandwijk et al. 1997 Phase III (C) IFN gamma Did not meet primary endpoint of OS
Schiller et al. 2001 (ECOG E7593) Phase III (C) Topotecan Did not meet primary endpoint of OS50%
Hanna et al. 2002 Phase III (C) Etoposide Might have inferior OS
Ready et al. 2015 (CALGB 30504) Randomized Phase II (C) Sunitinib monotherapy Seems to have inferior PFS

No further treatment.

Preceding treatment

References

  1. Jett JR, Maksymiuk AW, Su JQ, Mailliard JA, Krook JE, Tschetter LK, Kardinal CG, Twito DI, Levitt R, Gerstner JB. Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer. J Clin Oncol. 1994 Nov;12(11):2321-6. link to original article PubMed
  2. van Zandwijk N, Groen HJ, Postmus PE, Burghouts JT, ten Velde GP, Ardizzoni A, Smith IE, Baas P, Sahmoud T, Kirkpatrick A, Dalesio O, Giaccone G. Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer: a randomised phase III study of the EORTC Lung Cancer Cooperative Group. Eur J Cancer. 1997 Oct;33(11):1759-66. link to original article PubMed
  3. ECOG E7593: Schiller JH, Adak S, Cella D, DeVore RF 3rd, Johnson DH. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2001 Apr 15;19(8):2114-22. link to original article PubMed
  4. Hanna NH, Sandier AB, Loehrer PJ Sr, Ansari R, Jung SH, Lane K, Einhorn LH. Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study. Ann Oncol. 2002 Jan;13(1):95-102. link to original article PubMed
  5. 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 verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Shepherd et al. 2002 Phase III (C) Marimastat Did not meet primary endpoint of OS

No further antineoplastic treatment.

References

  1. Shepherd FA, Giaccone G, Seymour L, Debruyne C, Bezjak A, Hirsh V, Smylie M, Rubin S, Martins H, Lamont A, Krzakowski M, Sadura A, Zee B. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol. 2002 Nov 15;20(22):4434-9. link to original article PubMed

Sunitinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Ready et al. 2015 (CALGB 30504) Randomized Phase II (E-esc) Observation Seems to have superior PFS

Preceding treatment

Chemotherapy

Continued indefinitely

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 verified protocol PubMed

Relapsed or refractory disease

Amrubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
von Pawel et al. 2014 (ACT-1) Phase III (E-switch-ic) Topotecan Seems to have superior PFS

Chemotherapy

Supportive medications

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

21-day cycle for 6 cycles

Subsequent treatment

  • Patients who had at least stable disease by cycle 6 could receive another 6 cycles of treatment

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 verified protocol PubMed

Bendamustine monotherapy

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Regimen

Study Evidence Efficacy
Lammers et al. 2014 Phase II 33% (95% CI, 14-52%)

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. 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 PMC article contains verified protocol PubMed

Best supportive care

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Regimen

Study Evidence Comparator Efficacy
O'Brien et al. 2006 Phase III (C) Oral topotecan Seems to have inferior OS

No active antineoplastic treatment.

References

  1. 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 verified protocol PubMed

Cisplatin & Etoposide

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EP: Etoposide, Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
O'Bryan et al. 1990 (SWOG S8215) Phase III (E-switch-ic) BTOC Did not meet efficacy endpoints
Ettinger et al. 2002 (ECOG E1588) Non-randomized portion of 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; Eastern Cooperative Oncology Group. 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 verified protocol PubMed

Cisplatin, Etoposide, Irinotecan

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Regimen

Study Evidence Comparator Efficacy
Goto et al. 2016 (JCOG0605) Phase III (E-esc) Topotecan Superior OS

Chemotherapy

Supportive medications

  • 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; JCOG0605 investigators. 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 protocol PubMed

Docetaxel monotherapy

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Regimen

Study Evidence
Smyth et al. 1994 Phase II

Chemotherapy

21-day cycles

References

  1. Smyth JF, Smith IE, Sessa C, Schoffski P, Wanders J, Franklin H, Kaye SB; The 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 SD article contains protocol PubMed

Etoposide monotherapy

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Regimen

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

Chemotherapy

Supportive medications

  • No routine antiemetics used.

21-day cycles

References

  1. Einhorn LH, Pennington K, McClean J. 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 verified protocol PubMed

Epirubicin & Ifosfamide

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EI: Epirubicin, Ifosfamide

Regimen

Study Evidence
Jacot et al. 2012 Phase II

Chemotherapy

Supportive medications

  • 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 verified protocol PubMed

Gemcitabine monotherapy

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Variant #1, 5 cycles

Study Evidence
van der Lee et al. 2001 Phase II

Chemotherapy

28-day cycle for up to 5 cycles

Variant #2, indefinite

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

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 verified protocol PubMed
  2. ECOG E1597: Masters GA, Declerck L, Blanke C, Sandler A, DeVore R, Miller K, Johnson D; Eastern Cooperative Oncology Group. 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 verified protocol PubMed

Ifosfamide monotherapy

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Regimen

Study Evidence
Cantwell et al. 1988 Phase II

Chemotherapy

Supportive medications

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 SD article contains protocol 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

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PI: Paclitaxel, Ifosfamide

Regimen

Study Evidence
Park et al. 2007a Phase II

Chemotherapy

Supportive medications

  • 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 verified protocol PubMed

Ipilimumab & Nivolumab

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Variant #1

Study Evidence
Antonia et al. 2016 (CheckMate 032) Phase I/II (RT)

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

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #2

Study Evidence
Antonia et al. 2016 (CheckMate 032) Phase I/II (RT)

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

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. CheckMate 032: Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jäger D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin CS, Christensen O, Calvo E. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-95. Epub 2016 Jun 4. link to original article contains protocol PubMed

Irinotecan monotherapy

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Regimen

Study Evidence
Masuda et al. 1992 Phase II, <20 pts

Chemotherapy

Supportive medications

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

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 verified protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence
Antonia et al. 2016 (CheckMate 032) Phase I/II (RT)

Immunotherapy

14-day cycles

References

  1. Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jäger D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin CS, Christensen O, Calvo E. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-95. Epub 2016 Jun 4. link to original article contains protocol PubMed

Paclitaxel monotherapy

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Variant #1, every 3 weeks

Study Evidence
Smit et al. 1998 Phase II

Chemotherapy

Supportive medications

21-day cycle for up to 5 cycles

Variant #2, weekly paclitaxel

Study Evidence
Yamamoto et al. 2006 Phase II

Chemotherapy

Supportive medications

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. contains verified protocol 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 verified protocol PubMed

Pembrolizumab monotherapy

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Variant #1, 10 mg/kg q2wk

Study Evidence
Ott et al. 2017 (KEYNOTE-028) Phase 1b (RT)

Immunotherapy

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

Variant #2, 200 mg q3wk

FDA-recommended dose
Study Evidence
KEYNOTE-158 Phase II

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

Immunotherapy

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

References

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

Temozolomide monotherapy

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

Study Evidence
Pietanza et al. 2012 Phase II

Chemotherapy

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

Supportive medications

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

28-day cycles

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

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

Chemotherapy

Supportive medications

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 verified protocol 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. contains verified protocol link to original article link to PMC article PubMed

Topotecan monotherapy

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Variant #1, 1 mg/m2

Study Evidence Comparator Efficacy
Goto et al. 2016 (JCOG0605) Phase III (C) Cisplatin, Etoposide, Irinotecan Inferior OS

Chemotherapy

21-day cycle for 4 cycles

Variant #2, 1.5 mg/m2

Study Evidence Comparator Efficacy
von Pawel et al. 1999 Phase III (E-RT-de-esc) CAV Did not meet primary endpoints of ORR/DOR
Eckardt et al. 2007 Phase III (C) Topotecan; oral Did not meet primary endpoint of ORR
von Pawel et al. 2014 (ACT-1) Phase III (C) Amrubicin Seems to have inferior PFS

Chemotherapy

Supportive medications

  • (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 von Pawel et al. 2014 (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.

Variant #3, oral route

Study Evidence Comparator Efficacy
O'Brien et al. 2006 Phase III (E-esc) Best supportive care Seems to have superior OS
Eckardt et al. 2007 Phase III (E-switch-ic) Topotecan; IV (1.5 mg/m2) Did not meet primary endpoint of ORR

Chemotherapy

21-day cycles

Duration of treatment details vary depending on reference. In O'Brien et al. 2006, 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.

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 verified protocol PubMed
  2. 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 verified protocol PubMed
  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 verified protocol 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 verified protocol PubMed
  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; JCOG0605 investigators. 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 protocol PubMed

Vinorelbine monotherapy

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Variant #1, 25 mg/m2

Study Evidence
Furuse et al. 1996a Phase II

Chemotherapy

21-day cycles

Variant #2, 30 mg/m2

Study Evidence
Jassem et al. 1993 Phase II

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 protocol 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 protocol PubMed

Maintenance after salvage therapy

Nivolumab monotherapy

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Regimen

Study Evidence
Antonia et al. 2016 (CheckMate 032) Phase I/II (RT)

Preceding treatment

Immunotherapy

14-day cycles

References

  1. CheckMate 032: Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jäger D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin CS, Christensen O, Calvo E. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-95. Epub 2016 Jun 4. link to original article contains protocol PubMed