Small cell lung cancer

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38 regimens on this page
61 variants on this page

Contents


Guidelines

ESMO

NCCN

Limited stage

Carboplatin, Etoposide (EP), RT

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

Regimen #1

Study Evidence Comparator Efficacy
Skarlos et al. 2001 Randomized Phase II Carboplatin, Etoposide, early HTRT Might have superior ORR

Chemoradiotherapy

  • Carboplatin (Paraplatin) AUC 6 IV over 1 hour once on day 1, given first, before etoposide
  • Etoposide (Vepesid) 100 mg/m2 IV over 2 hours once per day on days 1 to 3, given second, after carboplatin
  • Concurrent hyperfractionated throacic 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

Patients with complete responses to therapy received prophylactic cranial irradiation:

Prophylactic cranial irradiation

  • Radiation therapy, 4 Gy fractions given once per day x 5 fractions (total dose: 20 Gy) over 5 days

Regimen #2

Study Evidence
Okamoto et al. 1999 Phase II

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

Chemoradiotherapy

  • Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1, given first, before etoposide
  • Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes once per day on days 1 to 3, given second, after carboplatin
  • Thoracic radiation was given "after chemotherapy"--no details about dose or exact schedule given.
  • Palliative radiation therapy was allowed to control persistent pain from bony metastases

Supportive medications

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

Carboplatin, Etoposide (EP) -> RT

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

Regimen #1, 2 days of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009 Phase III Carboplatin, Etoposide, Thalidomide -> RT Seems not superior

Chemoradiotherapy

3-week cycle for up to 6 cycles

Patients with complete or partial responses to therapy received thoracic radiotherapy and prophylactic cranial irradiation, approximately 3 weeks after the last cycle, "according to local practice". Recommend doses:

Radiotherapy

  • Thoracic: 40 Gy in 15 fractions for a period of 3 weeks
  • Cranial: 25 Gy in 10 fractions for a period of 2 weeks

Regimen #2, 1 day of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009 Phase III Carboplatin, Etoposide, Thalidomide -> RT Seems not superior

Chemoradiotherapy

3-week cycle for up to 6 cycles

Patients with complete or partial responses to therapy received thoracic radiotherapy and prophylactic cranial irradiation, approximately 3 weeks after the last cycle, "according to local practice". Recommend doses:

Radiotherapy

  • Thoracic: 40 Gy in 15 fractions for a period of 3 weeks
  • Cranial: 25 Gy in 10 fractions for a period of 2 weeks

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

CEV & RT

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CEV: Cisplatin, Epirubicin, Vincristine
RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Sundstrøm et al. 2002 Phase III Cisplatin, Etoposide, RT Inferior OS

Inferior to EP & RT; placed here for reference reasons only.

References

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

Cisplatin, Etoposide (EP), RT

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EP: Etoposide, Platinol (Cisplatin)
RT: Radiation Therapy

Regimen #1

Study Evidence Comparator Efficacy
Turrisi et al. 1999 Phase III Cisplatin, Etoposide, once per day RT Seems to have superior OS

Chemoradiotherapy

  • Cisplatin (Platinol) 60 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 120 mg/m2 IV once per day on days 1 to 3
  • Concurrent radiation therapy, 1.5 Gy fractions given twice per day x 30 fractions (total dose: 45 Gy) over 3 weeks, given during cycle 1 of chemotherapy

21-day cycle for 4 cycles

After completing 4 cycles of chemotherapy, patients were restaged. Because of the high rate of brain metastases (50%), patients with complete responses to therapy were offered prophylactic cranial irradiation:

Prophylactic cranial irradiation

  • Radiation therapy, 2.5 Gy fractions given once per day x 10 fractions (total dose: 25 Gy) over 2 weeks

Regimen #2

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

Chemoradiotherapy

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
  • 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

Patients with complete or near-complete responses to therapy--"a scar-like shadow on chest films but no positive cytology and/or bronchoscopic biopsy"--received prophylactic whole-brain irradiation:

Prophylactic whole-brain irradiation

  • Radiation therapy, 1.5 Gy fractions given twice per day, 5 days per week, x 16 fractions (total dose: 24 Gy)

Regimen #3

Study Evidence Comparator Efficacy
Sundstrøm et al. 2002 Phase III CEV & RT Superior OS

Chemoradiotherapy

  • Cisplatin (Platinol) 75 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV once on day 1; then 200 mg/m2 PO once per day on days 2 to 4, taken on an empty stomach
  • Concurrent thoracic radiation therapy, 2.8 Gy fractions given 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

Patients who had a complete response to therapy received prophylactic whole-brain irradiation:

Prophylactic whole-brain irradiation

  • Radiation therapy, 2 Gy fractions given once per day x 15 fractions (total dose: 30 Gy)

Regimen #4

Study Evidence
Evans et al. 1985 Phase II

Chemoradiotherapy

  • Cisplatin (Platinol) 25 mg/m2 IV "slow IV push" once per day on days 1 to 3, given second, after etoposide
  • Etoposide (Vepesid) 100 mg/m2 IV over at least 30 minutes once per day on days 1 to 3, given first, before cisplatin
  • "Patients who did not have evidence of tumor spread beyond the mediastinum and/or ipsilateral supraclavicular notes" received sequential radiation therapy, 250 rad (cGy) fractions x 10 fractions (total dose: 2500 rad (cGy)), given after cycle 6 of chemotherapy
  • Patients with limited stage disease responding to therapy received prophylactic cranial irradiation, 4 Gy fractions given once per day x 5 fractions (total dose: 20 Gy) over 5 days between cycles 3 and 4

Supportive medications

21 to 28-day cycle for 6 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. 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. 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

Cisplatin, Etoposide (EP), RT -> Cisplatin & Irinotecan (IP)

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EP: Etoposide, Platinol (Cisplatin)
RT: Radiation Therapy
IP: Irinotecan, Platinol (Cisplatin)

Regimen

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

Induction chemoradiotherapy

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
  • 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, then proceed to consolidation chemotherapy

Consolidation chemotherapy

Supportive medications

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

28-day cycle for 3 cycles, followed by:

Prophylactic cranial irradiation

Patients with complete or good partial responses to therapy received prophylactic cranial irradiation:

  • Radiation therapy, 2.5 Gy fractions x 10 fractions (total dose: 25 Gy)

References

  1. 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

Extensive stage

Carboplatin & Etoposide (EP)

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EP: Etoposide and Paraplatin (Carboplatin)
Ca/E: Carboplatin and Etoposide

Regimen #1

Study Evidence Comparator Efficacy
Seckl et al. 2017 (LUNGSTAR) Phase III Carboplatin, Etoposide, Pravastatin Seems not superior

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 or 6 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. Maximum dose = 1000 mg.
  • Etoposide (Vepesid) 120 mg/m2 IV once per day on days 1 to 3

21-day cycle for 6 cycles

Regimen #2, 2 days of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009 Phase III Carboplatin, Etoposide, Thalidomide Seems not superior
Seckl et al. 2017 (LUNGSTAR) Phase III Carboplatin, Etoposide, Pravastatin Seems not superior

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
    • Lee et al. 2009: 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. Maximum dose = 1000 mg.
  • Etoposide (Vepesid) 120 mg/m2 IV once on day 1, then 100 mg PO BID on days 2 & 3

3-week cycle for up to 6 cycles

Regimen #3, 1 day of oral etoposide per cycle

Study Evidence Comparator Efficacy
Lee et al. 2009 Phase III Carboplatin, Etoposide, Thalidomide Seems not superior
Seckl et al. 2017 (LUNGSTAR) Phase III Carboplatin, Etoposide, Pravastatin Seems not superior

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
    • Lee et al. 2009: 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. Maximum dose = 1000 mg.
  • Etoposide (Vepesid) 120 mg/m2 IV once per day on days 1 & 2, then 100 mg PO BID on day 3

3-week cycle for up to 6 cycles

Regimen #4

Study Evidence Comparator Efficacy
Socinski et al. 2009 Phase III Carboplatin & Pemetrexed Superior OS
Spigel et al. 2011 (SALUTE) Randomized Phase II Carboplatin, Etoposide, Bevacizumab Seems to have inferior PFS

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, progression of disease, or unacceptable toxicity

Regimen #5, higher-dose etoposide

Study Evidence Comparator Efficacy
Schmittel et al. 2006 Randomized Phase II IP Might have inferior OS

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Regimen #6, 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

  • Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1, given first
  • Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes once per day on days 1 to 3, given second
  • Palliative radiation therapy was allowed to control persistent pain from bony metastases

Supportive medications

  • Dexamethasone (Decadron) 8 mg IV once on days 1 to 3 prior to chemotherapy
  • Granisetron (Kytril) 40 mcg/kg IV once 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. 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
  5. 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
  6. 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
  7. 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

Carboplatin, Etoposide, Bevacizumab

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Regimen

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

Chemotherapy

21-day cycle for 4 cycles

Treatment followed by bevacizumab maintenance.

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

Carboplatin & Irinotecan (IP)

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IP: Irinotecan, Paraplatin (Carboplatin)

Regimen

Study Evidence Comparator Efficacy
Schmittel et al. 2006 Randomized Phase II 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

CAV

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CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Regimen

Study Evidence Comparator Efficacy Toxicity
Ettinger et al. 2002 (ECOG E1588) Phase III Ifosfamide Seems not superior More toxic
Teniposide Seems not superior More toxic

Chemotherapy

21-day cycle for 4 to 6 cycles

Patients with complete response received another 2 cycles of CAV. Patients with partial response received CAV until progression of disease, upon which they then received salvage EP therapy. Patients with complete response after 6 to 8 cycles of CAV received prophylactic whole-brain irradiation:

Prophylactic whole-brain irradiation

Radiation starts 1 week after completion of induction chemotherapy.

  • Radiation therapy, 2.5 Gy fractions x 10 fractions (total dose: 25 Gy)

References

  1. 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

CEV

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CEV: Cisplatin, Epirubicin, Vincristine

Regimen

Study Evidence Comparator Efficacy
Sundstrøm et al. 2002 Phase III Cisplatin & Etoposide Seems not superior

Not commonly used; here for reference purposes only.

References

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

Cisplatin & Etoposide (EP)

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

Regimen #1

Study Evidence Comparator Efficacy
Hanna et al. 2006 Phase III Cisplatin & Irinotecan Seems not superior
Seckl et al. 2017 (LUNGSTAR) Phase III Cisplatin, Etoposide, Pravastatin Seems not superior

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

Regimen #2, 2 days of oral etoposide per cycle

Study Evidence Comparator Efficacy
Seckl et al. 2017 (LUNGSTAR) Phase III Cisplatin, Etoposide, Pravastatin Seems not superior

Chemotherapy

3-week cycle for up to 6 cycles

Regimen #3, 1 day of oral etoposide per cycle

Study Evidence Comparator Efficacy
Seckl et al. 2017 (LUNGSTAR) Phase III Cisplatin, Etoposide, Pravastatin Seems not superior

Chemotherapy

3-week cycle for up to 6 cycles

Regimen #4

Study Evidence Comparator Efficacy
Spigel et al. 2011 (SALUTE) Randomized Phase II Cisplatin, Etoposide, Bevacizumab Seems to have inferior PFS

Chemotherapy

21-day cycle for 4 cycles

Regimen #5

Study Evidence Comparator Efficacy
Sundstrøm et al. 2002 Phase III CEV Seems not superior

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

Regimen #6

Study Evidence Comparator Efficacy
Noda et al. 2002 Phase III Cisplatin & Irinotecan Inferior OS

Chemotherapy

Supportive medications

  • "Hydration and administration of antiemetic drugs."

21-day cycle for 4 cycles

Regimen #7

Study Evidence Comparator Efficacy
Ihde et al. 1994 Phase III High-dose EP Seems not superior

Chemotherapy

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 80 mg/m2 IV once per day on days 1 to 3
  • Concurrent radiation therapy with the start of chemotherapy was given to patients with "brain metastases, epidural metastases, and impending pathologic bone fractures."
  • Patients with carcinomatous meningitis received Methotrexate (MTX) IT (dose/schedule not specified) and radiation to "functionally compromised areas of the CNS"

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

Patients with complete response after 4 cycles of therapy received an additional 4 cycles of EP therapy. Patients with partial response, no response, or progressive disease received either salvage CAV or "an individualized 3-drug in vitro-selected regimen (IVSR) during cycles 5 to 8 if drug-sensitivity testing data were available."

Prophylactic cranial irradiation

  • Some patients in Ihde et al. 1994 with complete responses to therapy were randomized to receive prophylactic cranial irradiation. Radiation could also be given at the patient's request. No details about dose/schedule given.

Regimen #8

Study Evidence
Evans et al. 1985 Phase II

Chemotherapy

  • Cisplatin (Platinol) 25 mg/m2 IV "slow IV push" once per day on days 1 to 3, given second
  • Etoposide (Vepesid) 100 mg/m2 IV over at least 30 minutes once per day on days 1 to 3, given first
  • 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

Supportive medications

21 to 28-day cycle for 6 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. Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, Edison M, Phelps RM, Lesar M, Phares JC et al. 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
  3. 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
  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. 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 PubMed
  6. 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
  7. 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
  8. 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 PubMed
  9. 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

Cisplatin, Etoposide, Bevacizumab

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Regimen

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

Chemotherapy

21-day cycle for 4 cycles

Treatment followed by bevacizumab maintenance.

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

Cisplatin & Irinotecan (IP)

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IP: Irinotecan, Platinol (Cisplatin)

Regimen #1

Study Evidence Comparator Efficacy
Hanna et al. 2006 Phase III Cisplatin & Etoposide Seems not superior

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

Regimen #2

Study Evidence Comparator Efficacy
Noda et al. 2002 Phase III Cisplatin & Etoposide Superior OS

Chemotherapy

Supportive medications

  • "Hydration and administration of antiemetic drugs."

28-day cycle for 4 cycles

References

  1. 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

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 CAV Seems not superior Less toxic
Teniposide Seems not superior Not reported

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 300 mg/m2 (route not specified) given three times per day on days 1 to 5; 0, 4, and 8 hours after each dose of ifosfamide

21-day cycle for 4 to 6 cycles

Patients with complete response received another 2 cycles of ifosfamide. Patients with partial response received ifosfamide until progression of disease, upon which they then received salvage EP therapy. Patients with complete response after 6 to 8 cycles of ifosfamide received prophylactic whole-brain irradiation:

Prophylactic whole-brain irradiation

Radiation starts 1 week after completion of induction chemotherapy.

  • Radiation therapy, 2.5 Gy fractions x 10 fractions (total dose: 25 Gy)

References

  1. 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 CAV Seems not superior Less toxic
Ifosfamide Seems not superior Not reported

Chemotherapy

21-day cycle for 4 to 6 cycles

Patients with complete response received another 2 cycles of teniposide. Patients with partial response received teniposide until progression of disease, upon which they then received salvage EP therapy. Patients with complete response after 6 to 8 cycles of teniposide received prophylactic whole-brain irradiation:

Prophylactic whole-brain irradiation

Radiation starts 1 week after completion of induction chemotherapy.

  • Radiation therapy, 2.5 Gy fractions x 10 fractions (total dose: 25 Gy)

References

  1. 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

Ipilimumab, Paclitaxel, Carboplatin

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Regimen

Study Evidence Comparator Efficacy
Reck et al. 2011 Randomized Phase II Carboplatin & Paclitaxel Seems to have superior irPFS

Induction chemoimmunotherapy

21-day cycles for a maximum of 18 weeks during the induction phase

Patients without progression who continued to tolerate treatment received either ipilimumab (phased- and concurrent-ipilimumab arms) or placebo (control arm) once every 12 weeks as maintenance until progression, death or intolerance.

Concurrent Ipilimumab

Four doses of ipilimumab/paclitaxel/carboplatin followed by two doses of placebo/paclitaxel/carboplatin

Phased Ipilimumab

Two doses of placebo/paclitaxel/carboplatin followed by four doses of ipilimumab/paclitaxel/carboplatin

Control

Up to six doses of placebo/paclitaxel/carboplatin

References

  1. 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

Maintenance

Bevacizumab monotherapy

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Regimen

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

Treatment preceded by carboplatin, etoposide, bevacizumab induction x 4 or cisplatin, etoposide, bevacizumab induction x 4.

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

Relapsed or refractory disease

Amrubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
von Pawel et al. 2014 (ACT-1) Phase III 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 or until progression of disease

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

References

  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 ORR
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 PubMed

Best supportive care

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Regimen

Study Evidence Comparator Efficacy
O'Brien et al. 2006 Phase III 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

CAV

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CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Regimen #1

Study Evidence Comparator Efficacy
von Pawel et al. 1999 Phase III Topotecan Seems not superior

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

Chemotherapy

Supportive medications

  • G-CSF use per physician discretion

21-day cycles, 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.

Regimen #2

Study Evidence
Ihde et al. 1994 Non-randomized

Treatment given after progression on standard-dose EP versus high-dose EP. Ihde et al. 1994 did not specifically say that the three medications were all given on day 1, but this is assumed to be the case based on other CAV regimens.

Chemotherapy

21-day cycle for 4 cycles

References

  1. Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, Edison M, Phelps RM, Lesar M, Phares JC et al. 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
  2. von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-67. link to original article contains verified protocol PubMed

CDE

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CDE: Cyclophosphamide, Doxorubicin, Etoposide

Regimen

Study Evidence
Postmus et al. 1987 Phase II

Note: this regimen is here for historical purposes, only.

Chemotherapy

References

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

Cisplatin & Etoposide (EP)

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EP: Etoposide, Platinol (Cisplatin)

Regimen #1

Study Evidence
Ettinger et al. 2002 (ECOG E1588) Non-randomized portion of RCT

Treatment given after progression on CAV versus ifosfamide versus teniposide.

Chemotherapy

21-day cycles

References

  1. 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 Topotecan Superior OS

Chemotherapy

Supportive medications

  • G-CSF SC once per day beginning on cycle 1 day 9, continued throughout except for days of chemotherapy

2-week cycle for 5 cycles

References

  1. 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. Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC. Eur J Cancer. 1994;30A(8):1058-60. 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

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

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

Gemcitabine monotherapy

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Regimen

Study Evidence
van der Lee et al. 2001 Phase II
Masters et al. 2003 (ECOG 1597) Phase II

Chemotherapy

  • Gemcitabine (Gemzar) 1000 mg/m2 in 250 mL normal saline IV over 30 minutes once per day on days 1, 8, 15
    • Patients in Masters et al. 2003 with less than grade 2 toxicity with cycle 1 received 1250 mg/m2 IV over 30 minutes once per day on days 1, 8, 15 of cycles 2 and on

28-day cycle for up to 5 cycles, given until progression of disease or unacceptable toxicity; varies depending on reference. Masters et al. 2003 did not specify a maximum number of 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. 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 & Etoposide (EI)

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EI: Etoposide, 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, until progression of disease, or unacceptable toxicity

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

Ipilimumab & Nivolumab

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Regimen #1

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

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

Immunotherapy

3-week cycle for four cycles

Treatment followed by nivolumab maintenance.

Regimen #2

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

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

Immunotherapy

3-week cycle for four cycles

Treatment followed by nivolumab maintenance.

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

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.

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

Immunotherapy

2-week cycles until progression or intolerance

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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Regimen #1, every 3 weeks

Study Evidence
Smit et al. 1998 Phase II

Chemotherapy

  • Paclitaxel (Taxol) 175 mg/m2 in 250 to 1000 mL of D5 or normal saline IV over 3 hours once on day 1

Supportive medications

21-day cycle for up to 5 cycles, progression of disease, or unacceptable toxicity

Regimen #2, weekly paclitaxel

Study Evidence
Yamamoto et al. 2006 Phase II

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 20 mg IV once 30 minutes prior to paclitaxel
  • Ranitidine (Zantac) 50 mg IV once 30 minutes prior to paclitaxel
  • Diphenhydramine (Benadryl) 50 mg IV once 30 minutes prior to paclitaxel
  • If ANC less than 1000/uL or WBC count less than 2 x 109/L, G-CSF 2 mcg/kg SC once per day is given until WBC count greater than or equal to 10 x 109/L, except on days that paclitaxel is given

8-week cycles

References

  1. Smit EF, Fokkema E, Biesma B, Groen HJ, Snoek W, Postmus PE. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer. 1998;77(2):347-51. 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

Paclitaxel & Ifosfamide (PI)

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PI: Paclitaxel, Ifosfamide

Regimen

Study Evidence
Park et al. 2007 Phase II

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 500 mg/m2 IV given three times per day on days 1 & 2: 15 minutes before, 4 hours after, and 8 hours after ifosfamide (total dose: 1500 mg/m2/day)

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

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

Temozolomide monotherapy

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Regimen #1

Study Evidence
Zauderer et al. 2014 Phase II

Chemotherapy

Supportive medications

28-day cycles

Regimen #2

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 prior to temozolomide prn nausea
  • Patients with at least grade 3 lymphopenia received prophylaxis for Pneumocystis carinii pneumonia (no specific medication/dose/schedule listed)

28-day cycles, given until progression of disease, unacceptable toxicity, or patient refusal

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. 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 PMC article PubMed

Topotecan monotherapy

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Regimen #1, 1.0 mg/m2

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

Chemotherapy

3-week cycle for 4 cycles

Regimen #2, 1.5 mg/m2

Study Evidence Comparator Efficacy
von Pawel et al. 1999 Phase III CAV Seems not superior
Eckardt et al. 2007 Phase III Oral topotecan Seems not superior
von Pawel et al. 2014 (ACT-1) Phase III 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.

Regimen #3, oral route

Study Evidence Comparator Efficacy
O'Brien et al. 2006 Phase III Best supportive care Seems to have superior OS
Eckardt et al. 2007 Phase III IV topotecan (1.5 mg/m2) Seems not superior

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. 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. 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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Regimen #1

Study Evidence
Furuse et al. 1996 Phase II

Chemotherapy

Regimen #2

Study Evidence
Jassem et al. 1993 Phase II

Chemotherapy

References

  1. Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, van Glabbeke M, Noseda MA, Ardizzoni A, Gozzelino F, Planting A, van Zandwijk N. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative Group. Eur J Cancer. 1993;29A(12):1720-2. link to SD 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. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group. Oncology. 1996 Mar-Apr;53(2):169-72. PubMed

Maintenance

Nivolumab monotherapy

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Regimen

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

Treatment preceded by ipilimumab & nivolumab salvage.

Immunotherapy

2-week cycles until progression or intolerance

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
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