Small cell lung cancer

Section editor
	Travis Osterman, DO, MS Nashville, TN Twitter: TravisOsterman LinkedIn

50 regimens on this page 102 variants on this page

Guidelines

ASCO

• 2015: Rudin et al. Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians guideline PubMed

ESMO

• 2013: Früh et al. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed

NCCN

• NCCN Guidelines - Small Cell Lung Cancer

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. 2009	Phase III (C)	Carboplatin, Etoposide, Thalidomide, then RT	Seems not superior

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once on day 1, then 100 mg PO BID on days 2 & 3

21-day cycle for up to 6 cycles

Subsequent treatment

• Patients with complete or partial responses: Thoracic radiotherapy and prophylactic cranial irradiation, approximately 3 weeks after the last cycle, "according to local practice".

Variant #2, 1 day of oral etoposide per cycle

Study	Evidence	Comparator	Efficacy
Lee et al. 2009	Phase III (C)	Carboplatin, Etoposide, Thalidomide, then RT	Seems not superior

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once per day on days 1 & 2, then 100 mg PO BID on day 3

21-day cycle for up to 6 cycles

Subsequent treatment

• Patients with complete or partial responses: Thoracic radiotherapy and prophylactic cranial irradiation, approximately 3 weeks after the last cycle, "according to local practice".

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

CC/DE & RT

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

Regimen

Study	Evidence	Comparator	Efficacy
Arriagada et al. 1993	Phase III (E)	Lower-dose CC/DE	Seems to have superior OS

Here for historic reference.

Chemoradiotherapy

• Cyclophosphamide (Cytoxan)
• Cisplatin (Platinol)
• Doxorubicin (Adriamycin)
• Etoposide (Vepesid)
• External beam radiotherapy

References

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

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 given once per day x 5 fractions (total dose: 20 Gy) over 5 days between cycles 3 and 4.

Chemotherapy

• Cisplatin (Platinol) 25 mg/m² IV slow 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

Supportive medications

• Dexamethasone (Decadron) 10 mg IV once prior to chemotherapy
• Metoclopramide (Reglan) 10 mg IV or PO once prior to chemotherapy
• Prochlorperazine (Compazine) 10 mg PO/IM once 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

• Thoracic radiation

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)	Carboplatin, Etoposide, early HTRT	Might have superior ORR

Chemoradiotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 60 minutes 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 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

• Patients with CR: Prophylactic cranial irradiation

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.

Chemoradiotherapy

• 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
• 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

CEV & RT

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

Regimen

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

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

Chemoradiotherapy

• Cyclophosphamide (Cytoxan)
• Epirubicin (Ellence)
• Vincristine (Oncovin)
• Concurrent radiation therapy

Subsequent treatment

• Patients with CR: Prophylactic cranial irradiation

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, 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)	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, 1.50 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, 75/180/45, pre-planned dose reduction

Study	Evidence	Comparator	Efficacy	Toxicity
Bunn et al. 1995	Phase III (C)	Cisplatin, Etoposide, RT, GM-CSF	Seems not superior	Inferior hematologic toxicity

Note: toxicity was the primary endpoint in this study.

Chemoradiotherapy

• 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
• 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 #3, 70/300/52.5, early RT

Study	Evidence	Comparator	Efficacy	Toxicity
Sun et al. 2013	Phase III (C)	EP & late RT	Seems not superior	Seems to have higher rates of neutropenic fever

Chemoradiotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• 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 #4, 70/300/52.5, late RT

Study	Evidence	Comparator	Efficacy	Toxicity
Sun et al. 2013	Phase III (E)	EP & early RT	Seems not superior	Seems to have lower rates of neutropenic fever

Chemoradiotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• 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 #5, 75/300/45

Study	Evidence	Comparator	Efficacy
Faivre-Finn et al. 2017 (CONVERT)	Phase III (E)	Cisplatin, Etoposide, once per day RT	Seems not superior

Chemoradiotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• 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)	Cisplatin, Etoposide, once per day RT	Seems not superior

Chemoradiotherapy

• Cisplatin (Platinol) 25 mg/m² IV once per day on days 1 to 3
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• 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)	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

Subsequent treatment

• Patients with CR: Prophylactic cranial irradiation

Variant #8, 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

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

Subsequent treatment

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

Variant #9, 80/300/45, 4 cycles of chemo

Study	Evidence	Comparator	Efficacy
Takada et al. 2002 (JCOG 9104)	Phase III (E)	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

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

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. 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
6. 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
7. 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
8. 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

• Cisplatin, Etoposide, RT induction

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Irinotecan (Camptosar) 60 mg/m² IV once per day on days 1, 8, 15

Supportive medications

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

28-day cycle for 3 cycles

Subsequent treatment

• Patients with complete or good partial responses: Prophylactic cranial irradiation

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

Radiation therapy

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Regimen

Study	Evidence
Evans et al. 1985	Phase II

Preceding treatment

• EP x 6

Radiotherapy

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

• Evans et al. 1985: EP x 3
• Skarlos et al. 2001: EP & early HTRT versus EP & late HTRT

Radiotherapy

• Whole brain irradiation, 4 Gy fractions given once per day x 5 fractions (total dose: 20 Gy)

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

• EP & RT versus EP, then RT

Prophylactic whole-brain irradiation

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

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	Seems not superior

Preceding treatment

• Intergroup 0096: EP & once-daily RT versus EP & twice-daily RT
• WJTOG 9902: EP & RT, then IP x 3

Radiotherapy

• Whole brain irradiation, 2.5 Gy fractions x 10 fractions (total dose: 25 Gy)

Variant #4, 30 Gy

Study	Evidence
Sundstrøm et al. 2002	Non-randomized portion of RCT

Preceding treatment

• CEV & RT versus EP & RT

Radiotherapy

• Whole brain irradiation, 2 Gy fractions given once per day x 15 fractions (total dose: 30 Gy)

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

ACE

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

Regimen

Study	Evidence	Comparator	Efficacy
Klastersky et al. 1985	Phase II		ORR: 66%
Sculier et al. 1993	Phase III (C)	Multi-drug regimen	Seems not superior
Baka et al. 2008	Phase III (C)	EP	Seems not superior

Used as a comparator arm in older studies; here for reference purposes only. The non-randomized results of Klastersky et al. 1985 established this regimen as a standard control.

Chemotherapy

• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)
• Etoposide (Vepesid)

References

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

Belotecan & Cisplatin

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BP: Belotecan and Platinol (Cisplatin)

Regimen

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

• Belotecan (Camptobell) 0.5 mg/m² IV over 30 minutes once per day on days 1 to 4
• Cisplatin (Platinol) 60 mg/m² IV once on day 1

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

• Carboplatin (Paraplatin) AUC 4 (Chatelut formula) IV once on day 1
• Etoposide (Vepesid) 120 mg/m² PO once per day on days 1 to 5

21-day cycle for 4 cycles

Variant #2, AUC 5/240

Study	Evidence	Comparator	Efficacy
Okamoto et al. 2007 (JCOG 9702)	Phase III (E)	Split-dose PE	Seems not superior
Sekine et al. 2013	Phase III (C)	Amrubicin	Seems not superior

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Etoposide (Vepesid) 80 mg/m² IV once per day on days 1 to 3

Supportive medications

• JCOG 9702: G-CSF

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	Seems not superior
Jalal et al. 2017 (MATISSE)	Randomized Phase II (C)	PaCE	Might have superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

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

• CALGB 30504, SD or better: Observation versus sunitinib maintenance

Variant #4, AUC 5 or 6/360

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

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)	IP	Might have inferior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1
• Etoposide (Vepesid) 140 mg/m² IV over 90 minutes once per day on days 1 to 3

Supportive medications

• 5-HT3 antagonist IV before chemotherapy
• Loperamide (Imodium) 4 mg PO prn first episode of diarrhea, then loperamide 2 mg PO Q2H until diarrhea stops

21-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. 2009	Phase III (C)	Carboplatin, Etoposide, Thalidomide	Seems not superior
Seckl et al. 2017 (LUNGSTAR)	Phase III (C)	Carboplatin, Etoposide, Pravastatin	Seems not superior

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 (maximum dose of 1000 mg) 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
• Etoposide (Vepesid) 120 mg/m² IV once per day on days 1 & 2, then 100 mg PO BID 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. 2009	Phase III (C)	Carboplatin, Etoposide, Thalidomide	Seems not superior
Seckl et al. 2017 (LUNGSTAR)	Phase III (C)	Carboplatin, Etoposide, Pravastatin	Seems not superior

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 (maximum dose of 1000 mg) 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
• Etoposide (Vepesid) 120 mg/m² IV once on day 1, then 100 mg PO BID 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

• 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 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. 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. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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

Carboplatin, Etoposide, Bevacizumab

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Regimen

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

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• 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

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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)	EC	Seems to have superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 4 (Chatelut formula) IV once on day 1
• Irinotecan (Camptosar) 175 mg/m² IV once on day 1

21-day cycle for 4 cycles

Variant #2, AUC 5/150

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

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1
• Irinotecan (Camptosar) 50 mg/m² IV over 30 minutes once per day on days 1, 8, 15

Supportive medications

• 5-HT3 antagonist IV before chemotherapy
• Loperamide (Imodium) 4 mg PO prn first episode of diarrhea, then 2 mg PO Q2H until diarrhea stops

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. 2011	Randomized Phase II (E)	1. Carboplatin & Paclitaxel	Seems to have superior irPFS
		2. Carboplatin, Paclitaxel, concurrent Ipilimumab	Not reported

Chemoimmunotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1
• 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

• Ipilimumab maintenance

Variant #2, concurrent ipilimumab

Study	Evidence	Comparator	Efficacy
Reck et al. 2011	Randomized Phase II (E)	1. Carboplatin & Paclitaxel	Seems not superior
		2. Carboplatin, Paclitaxel, phased Ipilimumab	Not reported

Chemoimmunotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1
• 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

• Ipilimumab maintenance

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

CAV

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CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Variant #1, 1000/40/1, capped by BSA

Study	Evidence	Comparator	Efficacy	Toxicity
Johnson et al. 1987	Phase III (C)	HDCAV	Seems not superior	Less toxic

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² (maximum dose of 2000 mg) IV once on day 1
• Doxorubicin (Adriamycin) 40 mg/m² (maximum dose of 80 mg) IV once on day 1
• Vincristine (Oncovin) 1 mg/m² (maximum dose of 2 mg) IV once on day 1

21-day cycle for 6 cycles

Variant #2, 1000/50/1.4, uncapped vincristine

Study	Evidence	Comparator	Efficacy	Toxicity
Girling 1996	Phase III (C)	Oral Etoposide	Seems to have superior OS
Ettinger et al. 2002 (ECOG E1588)	Phase III (C)	1. Ifosfamide	Seems not superior	More toxic
		2. Teniposide	Seems not superior	More toxic

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1

21-day cycle for 4 to 6 cycles

Subsequent treatment

• ECOG E1588, CR: 2 more cycles of CAV, then PCI
• ECOG E1588, PR: CAV until progression of disease, then salvage EP

Variant #3, 1000/50/2, flat-dose vincristine

Study	Evidence	Comparator	Efficacy	Toxicity
Evans et al. 1987	Phase III (C)	CAV/PE	Seems to have inferior OS	Similar toxicity

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1

21-day cycle 6 cycles

References

1. Evans WK, Feld R, Murray N, Willan A, Coy P, Osoba D, Shepherd FA, Clark DA, Levitt M, MacDonald A, Wilson K, Shelley W, Pater J. Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: a multicenter, randomized clinical trial by the National Cancer Institute of Canada. Ann Intern Med. 1987 Oct;107(4):451-8. Erratum in: Ann Intern Med 1988 Mar;108(3):496. link to original article contains protocol PubMed
2. Johnson DH, Einhorn LH, Birch R, Vollmer R, Perez C, Krauss S, Omura G, Greco FA. A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol. 1987 Nov;5(11):1731-8. link to original article contains verified protocol PubMed
3. Girling DJ; Medical Research Council Lung Cancer Working Party. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Lancet. 1996 Aug 31;348(9027):563-6. link to original article PubMed
4. 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

CDE

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CDE: Cyclophosphamide, Doxorubicin, Etoposide

Regimen

Study	Evidence	Comparator	Efficacy
Postmus et al. 1996	Phase III (C)	CDE/VIMP	Seems not superior

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

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)
• Etoposide (Vepesid)

References

1. Postmus PE, Scagliotti G, Groen HJ, Gozzelino F, Burghouts JT, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G, Splinter TA. Standard versus alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: an EORTC phase III trial. Eur J Cancer. 1996 Aug;32A(9):1498-503. link to original article PubMed

CEV

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CEV: Cyclophosphamide, Epirubicin, Vincristine

Regimen

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

Not commonly used; here for reference purposes only.

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Epirubicin (Ellence)
• Vincristine (Oncovin)

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

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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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

21-day cycle for 4 to 8 cycles

Variant #2, 60/360

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

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once per day on days 1 to 3

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)	Cisplatin, Etoposide, Pravastatin	Seems not superior

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once per day on days 1 & 2, then 100 mg PO BID on day 3

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)	Cisplatin, Etoposide, Pravastatin	Seems not superior

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once on day 1, then 100 mg PO BID on days 2 & 3

21-day cycle for up to 6 cycles

Variant #5, 75/240, split cisplatin

Study	Evidence	Comparator	Efficacy
Okamoto et al. 2007 (JCOG 9702)	Phase III (C)	CE	Seems not superior

Chemotherapy

• Cisplatin (Platinol) 25 mg/m² IV once per day on days 1 to 3
• Etoposide (Vepesid) 80 mg/m² IV once per day on days 1 to 3

21- to 28-day cycle for 4 cycles

Variant #6, 75/300

Study	Evidence	Comparator	Efficacy
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)	PE & Ipilimumab	Seems not superior

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

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

Variant #7, 75/300, split cisplatin

Study	Evidence	Comparator	Efficacy
Evans et al. 1985	Phase II
Tiseo et al. 2017 (GOIRC-AIFA FARM6PMFJM)	Phase III (C)	PE & Bevacizumab	Seems not superior

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

• Cisplatin (Platinol) 25 mg/m² IV slow 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

Supportive medications

• Dexamethasone (Decadron) 10 mg IV once prior to chemotherapy
• Metoclopramide (Reglan) 10 mg IV or PO once prior to chemotherapy
• Prochlorperazine (Compazine) 10 mg PO/IM once 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 #8, 75/700, 3 days of oral etoposide per cycle

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

• 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

Supportive medications

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

21-day cycle for up to 5 cycles

Variant #9, 80/240

Study	Evidence	Comparator	Efficacy
Ihde et al. 1994	Phase III (C)	High-dose EP	Seems not superior
Niell et al. 2005 (CALGB 9732)	Phase III (C)	PET	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

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 #10, 80/300

Study	Evidence	Comparator	Efficacy
Fukuoka et al. 1991	Phase III (C)	1. CAV	Not reported
		2. CAV/PE	Might have inferior OS
Miyamoto et al. 1992	Phase III (C)	PEI	Seems not superior
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	Seems not superior
Zatloukal et al. 2010	Phase III (C)	IP	Non-inferior OS
Ready et al. 2015 (CALGB 30504)	Non-randomized portion of RCT
Sun et al. 2016	Phase III (C)	Amrubicin & Cisplatin	Might have inferior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
  • Fukuoka et al. 1991 & Miyamoto et al. 1992 gave etoposide on days 1, 3, 5

Supportive medications

• "Hydration and administration of antiemetic drugs."

21-day cycle for 4 to 6 cycles

Subsequent treatment

• CALGB 30504, SD or better: Observation versus sunitinib maintenance

Variant #11, 80/400, split cisplatin

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

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 4

21-day cycle for 4 cycles

Variant #12, 80/600, 2 days of oral etoposide per cycle

Study	Evidence	Comparator	Efficacy
Baka et al. 2008	Phase III (E)	ACE	Seems not superior

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once on day 1, then 240 mg/m²/day PO on days 2 & 3

21-day cycle for 6 cycles

Variant #13, 100/300

Study	Evidence	Comparator	Efficacy
Pujol et al. 1991	Phase III (C)	PCDE	Inferior OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 2
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

21-day cycle for 6 cycles

Variant #14, 100/400, split cisplatin

Study	Evidence	Comparator	Efficacy
Roth et al. 1992	Phase III (C)	1. CAV 2. CAV/PE	Seems not superior

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 5
• Etoposide (Vepesid) 80 mg/m² IV once per day on days 1 to 5

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. 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. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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

Cisplatin, Etoposide, Bevacizumab

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Regimen

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Bevacizumab maintenance

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 & Irinotecan

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IP: Irinotecan, Platinol (Cisplatin)

Variant #1, 30/65

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

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1 & 8
• Irinotecan (Camptosar) 65 mg/m² IV once per day on days 1 & 8

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)	EP	Superior OS
Lara et al. 2009 (SWOG S0124)	Phase III (E)	EP	Seems not superior
Satouchi et al. 2014 (JCOG 0509)	Phase III (C)	Amrubicin & Cisplatin	Superior OS

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Irinotecan (Camptosar) 60 mg/m² IV once per day on days 1, 8, 15

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)	EP	Non-inferior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Irinotecan (Camptosar) 65 mg/m² IV once per day on days 1 & 8

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

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

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

EVI

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EVI: Epirubicin, Vindesine, Ifosfamide

Regimen

Study	Evidence	Comparator	Efficacy
Sculier et al. 2001	Phase III (C)	1. Accelerated EVI & GM-CSF	Seems not superior
		2. Accelerated EVI & antibiotics	Seems not superior

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

Chemotherapy

• Epirubicin (Ellence)
• Vindesine (Eldisine)
• Ifosfamide (Ifex)

References

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

Ifosfamide monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Ettinger et al. 2002 (ECOG E1588)	Phase III (E)	1. CAV	Seems not superior	Less toxic
		2. Teniposide	Seems not superior	Not reported

Chemotherapy

• Ifosfamide (Ifex) 1500 mg/m² IV once per day on days 1 to 5

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

Subsequent treatment

• Patients with CR: another 2 cycles of ifosfamide, then prophylactic whole-brain irradiation if still in CR
• Patients with PR: ifosfamide until progression of disease, then salvage EP

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

Chemotherapy

• Teniposide (Vumon) 60 mg/m² IV once per day on days 1 to 5

21-day cycle for 4 to 6 cycles

Subsequent treatment

• Patients with CR received another 2 cycles of teniposide. Patients with PR 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.

• External beam radiotherapy, 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

VIP

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

Regimen

Study	Evidence	Comparator	Efficacy
Loehrer et al. 1995	Phase III (E)	Cisplatin & Etoposide	Seems to have superior OS

This is of historic interest; due to excess toxicity and the difficult administration schedule, it is not commonly used.

Chemotherapy

• Etoposide (Vepesid) 75 mg/m² IV once per day on days 1 to 4
• Ifosfamide (Ifex) 1200 mg/m² IV once per day on days 1 to 4
• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4

21-day cycle for 4 cycles

References

1. 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

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)	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

One 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

Bevacizumab monotherapy

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Regimen

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

Preceding treatment

• Carboplatin, Etoposide, Bevacizumab induction x 4 or Cisplatin, Etoposide, Bevacizumab induction x 4

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

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

Ipilimumab monotherapy

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Regimen

Study	Evidence
Reck et al. 2011	Non-randomized portion of RCT

Preceding treatment

• Carboplatin, Paclitaxel, Ipilimumab induction

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1

12-week cycles

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

Observation

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Regimen

Study	Evidence	Comparator	Efficacy
Schiller et al. 2001 (ECOG E7593)	Phase III (C)	Topotecan	Seems not superior
Ready et al. 2015 (CALGB 30504)	Randomized Phase II (C)	Sunitinib monotherapy	Seems to have inferior PFS

No further treatment.

Preceding treatment

• ECOG E7593: Cisplatin & Etoposide x 4
• CALGB 30504: Carboplatin & Etoposide or Cisplatin & Etoposide for 4 to 6 cycles

References

1. 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
2. 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

Sunitinib monotherapy

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Regimen

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

Preceding treatment

• Carboplatin & Etoposide or Cisplatin & Etoposide for 4 to 6 cycles

Chemotherapy

• Sunitinib (Sutent) 150 mg PO once on day 1, then 37.5 mg PO once per day

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)	Topotecan	Seems to have superior PFS

Chemotherapy

• Amrubicin (Calsed) 40 mg/m² IV over 5 minutes once per day on days 1 to 3

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. 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

• Bendamustine 120 mg/m² IV once per day on days 1 & 2

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

CAV

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CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Variant #1

Study	Evidence	Comparator	Efficacy
von Pawel et al. 1999	Phase III (C)	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

• Cyclophosphamide (Cytoxan) 1000 mg/m² (maximum dose of 2000 mg) (route not specified) once on day 1
• Doxorubicin (Adriamycin) 45 mg/m² (maximum dose of 100 mg) IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1

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.

Variant #2

Study	Evidence
Ihde et al. 1994	Non-randomized portion of RCT

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

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 45 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

21-day cycle for 4 cycles

References

1. Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, Edison M, Phelps RM, Lesar M, Phares JC, Grayson J, Minna JD, Johnson BE. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol. 1994 Oct;12(10):2022-34. link to original article contains 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

• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)
• Etoposide (Vepesid)

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

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EP: Etoposide, Platinol (Cisplatin)

Variant #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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once per day on days 1 to 3

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 (E)	Topotecan	Superior OS

Chemotherapy

• Cisplatin (Platinol) 25 mg/m² IV once per day on days 1 & 8
• Etoposide (Vepesid) 60 mg/m² IV once per day on days 1 to 3
• Irinotecan (Camptosar) 90 mg/m² IV once on day 8

Supportive medications

• G-CSF SC once per day beginning on cycle 1 day 9, 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

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

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

• Etoposide (Vepesid) 50 mg/m² PO once per day, taken every morning on an empty stomach

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

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Ifosfamide (Ifex) 3000 mg/m² IV once per day on days 1 & 2

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

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 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 cycle 2 onwards

28-day cycle for up to 5 cycles (Lee et al. 2001) or indefinitely (ECOG 1597)

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

• Ifosfamide (Ifex) 5000 mg/m² IV once on day 1

Supportive medications

• Mesna (Mesnex) 5000 mg/m² IV once on day 1

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. 2007	Phase II

Chemotherapy

• Ifosfamide (Ifex) 2500 mg/m² IV over 2 hours once per day on days 1 & 2
• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

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

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

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

Immunotherapy

• Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Nivolumab maintenance

Variant #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

• Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
• Nivolumab (Opdivo) 1 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Nivolumab maintenance

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

• Irinotecan (Camptosar) 100 mg/m² IV over 90 minutes once per week

Supportive medications

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

Continued indefinitely

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

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day 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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Variant #1, every 3 weeks

Study	Evidence
Smit et al. 1998	Phase II

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

Supportive medications

• Dexamethasone (Decadron) 8 mg PO given twice, 12 and 6 hours prior to paclitaxel
• Clemastine (Tavist) 2 mg IV push once 30 minutes prior to paclitaxel
• One of the following H2 blockers:
  • Cimetidine (Tagamet) 300 mg IV push once 30 minutes prior to paclitaxel
  • Ranitidine (Zantac) 50 mg IV push once 30 minutes prior to paclitaxel

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

Variant #2, weekly paclitaxel

Study	Evidence
Yamamoto et al. 2006	Phase II

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36

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

Temozolomide monotherapy

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Variant #1

Study	Evidence
Zauderer et al. 2014	Phase II

Chemotherapy

• Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5

Supportive medications

• Ondansetron (Zofran) 8 mg PO once 30 minutes prior to each dose

28-day cycles

Variant #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

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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Variant #1, 1.0 mg/m²

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

Chemotherapy

• Topotecan (Hycamtin) 1.0 mg/m² IV over 30 minutes once per day on days 1 to 5

21-day cycle for 4 cycles

Variant #2, 1.5 mg/m²

Study	Evidence	Comparator	Efficacy
von Pawel et al. 1999	Phase III (E)	CAV	Seems not superior
Eckardt et al. 2007	Phase III (C)	Oral topotecan	Seems not superior
von Pawel et al. 2014 (ACT-1)	Phase III (C)	Amrubicin	Seems to have inferior PFS

Chemotherapy

• Topotecan (Hycamtin) 1.5 mg/m² IV over 30 minutes once per day on days 1 to 5

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)	Best supportive care	Seems to have superior OS
Eckardt et al. 2007	Phase III (E)	IV topotecan (1.5 mg/m2)	Seems not superior

Chemotherapy

• Topotecan (Hycamtin) 2.3 mg/m² PO once per day on days 1 to 5

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. 1996	Phase II

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per week

Continued indefinitely

Variant #2, 30 mg/m²

Study	Evidence
Jassem et al. 1993	Phase II

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per week

Continued indefinitely

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

Preceding treatment

• Ipilimumab & Nivolumab

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles until progression or intolerance

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