Small cell lung cancer

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48 regimens on this page 100 variants on this page

Limited stage

Carboplatin, Etoposide (EP), RT

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

Regimen #1

Study	Evidence	Comparator
Skarlos et al. 2001	Randomized Phase II	Carboplatin, Etoposide, early HTRT

Chemoradiotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 1 hour once on day 1, given first, before etoposide
• Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 1 to 3, given second, after carboplatin
• Concurrent hyperfractionated throacic radiation therapy (HTRT), 1.5 Gy fractions given twice per day (at least 4, but preferably 6 hours between fractions) x 30 fractions (total dose: 45 Gy) over 3 weeks. Skarlos et al. 2001 examined two different timings for radiation therapy. There was no significant difference between early vs. late HTRT, though there was a trend toward higher response rate for late HTRT. Early HTRT is given during cycle 1 of chemotherapy; late HTRT is given during cycle 4 of chemotherapy.

21-day cycle for up to 6 cycles

Patients with complete responses to therapy received prophylactic cranial irradiation:

Prophylactic cranial irradiation

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

Regimen #2

Study	Evidence	Comparator
Okamoto et al. 1999	Randomized Phase II	Time-curve-based carboplatin & Etoposide

Patients in Okamoto et al. 1999 were >=70 years old.

Chemoradiotherapy

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

Supportive medications

• Dexamethasone (Decadron) 8 mg IV once per day on days 1 to 3 prior to chemotherapy
• Granisetron (Kytril) 40 ug/kg IV once per day on days 1 to 3 prior to chemotherapy
• G-CSF 2 ug/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: Cisplatin, Epirubicin, Vincristine
RT: Radiation Therapy

Regimen

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

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

References

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

Cisplatin, Etoposide (EP), RT

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

Regimen #1

Study	Evidence	Comparator
Turrisi et al. 1999	Phase III	Cisplatin, Etoposide, once per day RT

Chemoradiotherapy

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

21-day cycle for 4 cycles

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

Prophylactic cranial irradiation

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

Regimen #2

Study	Evidence	Comparator
Takada et al. 2002 (JCOG 9104)	Phase III	Cisplatin, Etoposide, sequential RT

Chemoradiotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• Concurrent thoracic radiation therapy, 1.5 Gy fractions given twice per day (4 or more hours between fractions) x 30 fractions (total dose: 45 Gy) over 3 weeks, started on cycle 1 day 2 of chemotherapy

28-day cycle for 4 cycles

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

Prophylactic whole-brain irradiation

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

Regimen #3

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

Chemoradiotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once on day 1; then 200 mg/m² PO once per day on days 2 to 4, taken on an empty stomach
• Concurrent thoracic radiation therapy, 2.8 Gy fractions given once per day x 15 fractions (total dose: 42 Gy) over 3 weeks, given "between the third and fourth chemotherapy courses"

Supportive medications

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

21-day cycle for up to 5 cycles

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

Prophylactic whole-brain irradiation

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

Regimen #4

Study	Evidence
Evans et al. 1985	Phase II

Chemoradiotherapy

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

Supportive medications

• Dexamethasone (Decadron) 10 mg IV once prior to chemotherapy
• Metoclopramide (Reglan) 10 mg IV/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

References

1. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471-7. link to original article contains verified protocol PubMed
2. Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28;340(4):265-71. link to original article contains verified protocol PubMed
3. Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, Nishiwaki Y, Watanabe K, Noda K, Tamura T, Fukuda H, Saijo N. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002 Jul 15;20(14):3054-60. link to original article contains verified protocol PubMed content property of HemOnc.org
4. Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, Boye N, Wang M, Vigander T, Vilsvik J, Skovlund E, Hannisdal E, Aamdal S; Norwegian Lung Cancer Study Group. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol. 2002 Dec 15;20(24):4665-72. link to original article contains verified protocol PubMed

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

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

Regimen

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

Induction chemoradiotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• Concurrent thoracic radiation therapy, 1.5 Gy fractions given twice per day (at least 4, but preferably 6 hours between fractions) x 30 fractions (total dose: 45 Gy) over 3 weeks, started on cycle 1 day 2 of chemotherapy

28-day cycle for 1 cycle, then proceed to consolidation chemotherapy

Consolidation chemotherapy

• 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, followed by:

Prophylactic cranial irradiation

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

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

References

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

Extensive stage

Carboplatin & Etoposide (EP)

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EP: Etoposide, Paraplatin (Carboplatin)

Regimen #1

Study	Evidence	Comparator
Schmittel et al. 2006	Randomized Phase II	IP
Schmittel et al. 2011	Phase III	IP

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 in 500 mL 5% glucose solution IV over 1 hour once on day 1
• Etoposide (Vepesid) 140 mg/m² in 1000 mL normal saline 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

Regimen #2

Study	Evidence
Okamoto et al. 1999	Phase II

Patients in Okamoto et al. 1999 were >=70 years old.

Chemotherapy

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

Supportive medications

• Dexamethasone (Decadron) 8 mg IV once on days 1 to 3 prior to chemotherapy
• Granisetron (Kytril) 40 ug/kg IV once on days 1 to 3 prior to chemotherapy
• G-CSF 2 ug/kg SC given for grade 3 or greater leukopenia/neutropenia

28-day cycle for up to 4 cycles

Regimen #3

Study	Evidence
Quoix et al. 2001	Phase II

Patients in Quoix et al. 2001 were >=70 years old.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 in 250 mL D5W IV once on day 1
• Etoposide (Vepesid) 100 mg/m² in 100 mL D5W IV over 5 to 15 minutes once per day on days 1 to 3

Supportive medications

• "Haematopoietic growth factors were allowed as prophylactic or curative treatment only if grade 4 neutropenia > 7 days occurred"

28-day cycle for up to 6 cycles, progression of disease, or unacceptable toxicity

Regimen #4

Study	Evidence	Comparator
Socinski et al. 2009	Phase III	Carboplatin & Pemetrexed

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

• "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 up to 6 cycles, progression of disease, or unacceptable toxicity

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
4. 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
5. 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

Carboplatin & Irinotecan (IP)

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IP: Irinotecan, Paraplatin (Carboplatin)

Regimen

Study	Evidence	Comparator
Schmittel et al. 2006	Randomized Phase II	EP
Schmittel et al. 2011	Phase III	EP

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 in 500 mL 5% glucose solution IV over 1 hour once on day 1
• Irinotecan (Camptosar) 50 mg/m² in 250 mL normal saline 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
2. Schmittel A, Sebastian M, Fischer von Weikersthal L, Martus P, Gauler TC, Kaufmann C, Hortig P, Fischer JR, Link H, Binder D, Fischer B, Caca K, Eberhardt WE, Keilholz U; Arbeitsgemeinschaft Internistische Onkologie Thoracic Oncology Study Group. A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol. 2011 Aug;22(8):1798-804. Epub 2011 Jan 25. link to original article contains verified protocol PubMed

CAV

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CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Regimen

Study	Evidence	Comparator
Ettinger et al. 2002 (ECOG E1588)	Phase III	Ifosfamide Teniposide

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

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

Prophylactic whole-brain irradiation

Radiation starts 1 week after completion of induction chemotherapy.

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

References

1. Ettinger DS, Finkelstein DM, Ritch PS, Lincoln ST, Blum RH; Eastern Cooperative Oncology Group. Study of either ifosfamide or teniposide compared to a standard chemotherapy for extensive disease small cell lung cancer: an Eastern Cooperative Oncology Group randomized study (E1588). Lung Cancer. 2002 Sep;37(3):311-8. link to original article contains verified protocol PubMed

CEV

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CEV: Cisplatin, Epirubicin, Vincristine

Regimen

Study	Evidence	Comparator
Sundstrøm et al. 2002	Phase III	Cisplatin & Etoposide

Inferior to EP; placed here for reference reasons only.

References

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

Cisplatin & Etoposide (EP)

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EP: Etoposide, Platinol (Cisplatin)

Regimen #1

Study	Evidence	Comparator
Sundstrøm et al. 2002	Phase III	CEV

Note: The NCCN Guidelines, Small Cell Lung Cancer version 2.2013, lists etoposide as being 100 mg/m² on days 1 to 3, whereas its cited reference, Sundstrøm et al. 2002 used oral etoposide 200 mg on days 2 to 4.

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
• 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."

Supportive medications

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

21-day cycle for up to 5 cycles

Regimen #2

Study	Evidence	Comparator
Hanna et al. 2006	Phase III	Cisplatin & Irinotecan

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

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

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

Regimen #3

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

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

Supportive medications

• "Hydration and administration of antiemetic drugs."

21-day cycle for 4 cycles

Regimen #4

Study	Evidence	Comparator
Ihde et al. 1994	Phase III	High-dose EP

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, 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; see Ihde et al. 1994 for full details.

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

Prophylactic cranial irradiation

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

Regimen #5

Study	Evidence
Evans et al. 1985	Phase II

Chemotherapy

• Cisplatin (Platinol) 25 mg/m² IV "slow IV push" once per day on days 1 to 3, given second, after etoposide
• Etoposide (Vepesid) 100 mg/m² IV over at least 30 minutes once per day on days 1 to 3, given first, before cisplatin
• Patients with disease responding to therapy received prophylactic cranial irradiation, 4 Gy fractions given daily x 5 fractions (total dose: 20 Gy) over 5 days between cycles 3 and 4
• Locoregional radiation therapy was only used if symptoms persisted after 6 cycles of treatment: Radiation therapy, 250 cGy/rad fractions x 10 fractions (total dose: 2500 cGy/rad), given after cycle 6 of chemotherapy

Supportive medications

• Dexamethasone (Decadron) 10 mg IV once prior to chemotherapy
• Metoclopramide (Reglan) 10 mg IV/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

References

1. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471-7. link to original article contains verified protocol PubMed
2. Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, Edison M, Phelps RM, Lesar M, Phares JC et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol. 1994 Oct;12(10):2022-34. link to original article contains verified protocol PubMed
3. Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N; Japan Clinical Oncology Group. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):85-91. link to original article contains verified protocol PubMed
4. Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, Boye N, Wang M, Vigander T, Vilsvik J, Skovlund E, Hannisdal E, Aamdal S; Norwegian Lung Cancer Study Group. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol. 2002 Dec 15;20(24):4665-72. link to original article contains verified protocol PubMed
5. 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

Cisplatin & Irinotecan (IP)

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IP: Irinotecan, Platinol (Cisplatin)

Regimen #1

Study	Evidence	Comparator
Hanna et al. 2006	Phase III	Cisplatin & Etoposide

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

Regimen #2

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

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

References

1. Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N; Japan Clinical Oncology Group. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):85-91. link to original article contains verified protocol PubMed
2. Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, Ansari R, Ellis P, Byrne M, Morrison M, Hariharan S, Wang B, Sandler A. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006 May 1;24(13):2038-43. link to original article contains verified protocol PubMed

Docetaxel (Taxotere)

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Regimen

Study	Evidence
Hesketh et al. 1999	Phase II

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 1 hour 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

Ifosfamide (Ifex)

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Regimen

Study	Evidence	Comparator
Ettinger et al. 2002 (ECOG E1588)	Phase III	CAV Teniposide

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

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

Prophylactic whole-brain irradiation

Radiation starts 1 week after completion of induction chemotherapy.

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

References

1. Ettinger DS, Finkelstein DM, Ritch PS, Lincoln ST, Blum RH; Eastern Cooperative Oncology Group. Study of either ifosfamide or teniposide compared to a standard chemotherapy for extensive disease small cell lung cancer: an Eastern Cooperative Oncology Group randomized study (E1588). Lung Cancer. 2002 Sep;37(3):311-8. link to original article contains verified protocol PubMed

Teniposide (Vumon)

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Regimen

Study	Evidence	Comparator
Ettinger et al. 2002 (ECOG E1588)	Phase III	CAV Ifosfamide

Chemotherapy

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

21-day cycle for 4 to 6 cycles

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

Prophylactic whole-brain irradiation

Radiation starts 1 week after completion of induction chemotherapy.

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

References

1. Ettinger DS, Finkelstein DM, Ritch PS, Lincoln ST, Blum RH; Eastern Cooperative Oncology Group. Study of either ifosfamide or teniposide compared to a standard chemotherapy for extensive disease small cell lung cancer: an Eastern Cooperative Oncology Group randomized study (E1588). Lung Cancer. 2002 Sep;37(3):311-8. link to original article contains verified protocol PubMed

Ipilimumab, Paclitaxel, Carboplatin

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Regimen

Study	Evidence	Comparator
Reck et al. 2011	Randomized Phase II	Carboplatin & Paclitaxel

Induction chemoimmunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV once per day on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once per day on day 1
• Carboplatin (Paraplatin) AUC 6 IV once per day on day 1

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

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

Concurrent Ipilimumab

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

Phased Ipilimumab

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

Control

Up to six doses of placebo/paclitaxel/carboplatin

References

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

Relapsed or refractory disease

Amrubicin (Calsed)

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Regimen

Study	Evidence	Comparator
von Pawel et al. 2014 (ACT-1)	Phase III	Topotecan

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. 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

Best supportive care

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Regimen

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

No active antineoplastic treatment.

References

1. O'Brien ME, Ciuleanu TE, Tsekov H, Shparyk Y, Cuceviá B, Juhasz G, Thatcher N, Ross GA, Dane GC, Crofts T. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006 Dec 1;24(34):5441-7. link to original article contains verified protocol PubMed

CAV

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CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine

Regimen #1

Study	Evidence	Comparator
von Pawel et al. 1999	Phase III	Topotecan

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 per cycle: 2000 mg) (route not specified) once on day 1
• Doxorubicin (Adriamycin) 45 mg/m² (maximum dose per cycle: 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.

Regimen #2

Study	Evidence
Ihde et al. 1994	Non-randomized

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

Chemotherapy

• 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 per cycle: 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 et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol. 1994 Oct;12(10):2022-34. link to original article contains verified protocol PubMed
2. von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-67. link to original article contains verified protocol PubMed

Cisplatin & Etoposide (EP)

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EP: Etoposide, Platinol (Cisplatin)

Regimen #1

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

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

Docetaxel (Taxotere)

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Regimen

Study	Evidence
Smyth et al. 1994	Phase II

Chemotherapy

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

21-day cycles

References

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

Etoposide (Vepesid)

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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, given until progression of disease or unacceptable toxicity

References

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

Gemcitabine (Gemzar)

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Regimen

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

Chemotherapy

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

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

References

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

Ifosfamide (Ifex)

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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 & Etoposide (EI)

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EI: Etoposide, Ifosfamide

Regimen

Study	Evidence
Jacot et al. 2012	Phase II

Chemotherapy

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

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

Irinotecan (Camptosar)

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Regimen

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

Chemotherapy

• Irinotecan (Camptosar) 100 mg/m² in 500 mL normal saline IV over 90 minutes once per week

Supportive medications

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

References

1. Masuda N, Fukuoka M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Negoro S, Nishioka M, Nakagawa K, Takada M. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol. 1992 Aug;10(8):1225-9. link to original article contains verified protocol PubMed

Paclitaxel (Taxol)

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Regimen #1, every 3 weeks

Study	Evidence
Smit et al. 1998	Phase II

Chemotherapy

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

Supportive medications

• Dexamethasone (Decadron) 8 mg PO given twice, 12 and 6 hours prior to paclitaxel
• Clemastine (Tagevil) 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

Regimen #2, weekly paclitaxel

Study	Evidence
Yamamoto et al. 2006	Phase II

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 1 hour 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 <1000/uL or WBC <2000/uL, G-CSF 2 ug/kg SC once per day is given until WBC >=10,000/uL, except on days that paclitaxel is given

8-week cycles

References

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

Paclitaxel & Ifosfamide (PI)

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PI: Paclitaxel, Ifosfamide

Regimen

Study	Evidence
Park et al. 2007	Phase II

Chemotherapy

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

Supportive medications

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

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

References

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

Temozolomide (Temodar)

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Regimen

Study	Evidence
Pietanza et al. 2012	Phase II

Chemotherapy

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

Supportive medications

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

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

References

1. Pietanza MC, Kadota K, Huberman K, Sima CS, Fiore JJ, Sumner DK, Travis WD, Heguy A, Ginsberg MS, Holodny AI, Chan TA, Rizvi NA, Azzoli CG, Riely GJ, Kris MG, Krug LM. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res. 2012 Feb 15;18(4):1138-45. Epub 2012 Jan 6. link to original article contains verified protocol PubMed

Topotecan (Hycamtin)

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Regimen #1, intravenous route

Study	Evidence	Comparator
von Pawel et al. 1999	Phase III	CAV
Eckardt et al. 2007	Phase III	Oral topotecan
von Pawel et al. 2014 (ACT-1)	Phase III	Amrubicin

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; details vary depending on reference:

• In von Pawel et al. 1999 treatment is given until progression of disease, unacceptable toxicity, or 6 cycles beyond maximal response. Patients with stable disease after 4 cycles could have treatment discontinued at physician discretion.
• In Eckardt et al. 2007, patients with complete or partial response continued treatment progression of disease or 2 cycles beyond best response. Patients with stable disease received at least 4 cycles therapy.
• In von Pawel et al. 2014 (ACT-1), treatment was given for 6 cycles or until progression of disease. Patients who had at least stable disease by cycle 6 could receive another 6 cycles of treatment.

Regimen #2, oral route

Study	Evidence	Comparator
O'Brien et al. 2006	Phase III	Best supportive care
Eckardt et al. 2007	Phase III	Intravenous topotecan

Chemotherapy

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

21-day cycles; 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 therapy.

References

1. von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-67. link to original article contains verified protocol PubMed
2. O'Brien ME, Ciuleanu TE, Tsekov H, Shparyk Y, Cuceviá B, Juhasz G, Thatcher N, Ross GA, Dane GC, Crofts T. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006 Dec 1;24(34):5441-7. link to original article contains verified protocol PubMed
3. Eckardt JR, von Pawel J, Pujol JL, Papai Z, Quoix E, Ardizzoni A, Poulin R, Preston AJ, Dane G, Ross G. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol. 2007 May 20;25(15):2086-92. link to original article contains verified protocol PubMed
4. von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, Steins M, Bosquée L, Bubis J, Nackaerts K, Trigo JM, Clingan P, Schütte W, Lorigan P, Reck M, Domine M, Shepherd FA, Li S, Renschler MF. Randomized Phase III Trial of Amrubicin Versus Topotecan As Second-Line Treatment for Patients With Small-Cell Lung Cancer. J Clin Oncol. 2014 Dec 10;32(35):4012-9. Epub 2014 Nov 10. link to original article contains verified protocol PubMed

Vinorelbine (Navelbine)

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Regimen

Study	Evidence
Jassem et al. 1993	Phase II

Chemotherapy

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

References

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