Difference between revisions of "Small cell lung cancer"

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Revision as of 18:14, 27 September 2013

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Limited stage

Carboplatin, Etoposide (EP), RT

EP: Etoposide, Paraplatin

Regimen #1, Skarlos, et al. 2001

Level of Evidence: Phase II

  • 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 daily 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 cycles x up to 6 cycles

Prophylactic cranial irradiation

Patients with complete responses to therapy received prophylactic cranial irradiation:

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

Regimen #2, Okamoto, et al. 1999

Level of Evidence: Randomized Phase II, >20 per arm

Patients in Okamoto, et al. 1999 were ≥70 years old.

  • 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 daily 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

28-day cycles x up to 4 cycles

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

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

CEV: Cisplatin, Epirubicin, Vincristine

Regimen

Level of Evidence: Phase III

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), RT

EP: Etoposide, Platinol

Regimen #1, Turrisi, et al. 1999

Level of Evidence: Phase III

  • Cisplatin (Platinol) 60 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 120 mg/m2 IV once daily 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 cycles x 4 cycles

Prophylactic cranial irradiation

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:

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

Regimen #2, Takada, et al. 2002 (JCOG 9104)

Level of Evidence: Phase III

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV once daily 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 cycles x 4 cycles

Prophylactic whole-brain irradiation

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:

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

Regimen #3, Sundstrøm, et al. 2002

Level of Evidence: Phase III

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

21-day cycles x up to 5 cycles

Supportive medications:

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

Prophylactic whole-brain irradiation

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

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

Regimen #4, Evans, et al. 1985

Level of Evidence: Phase II

  • Cisplatin (Platinol) 25 mg/m2 IV "slow IV push" once daily on days 1 to 3, given second, after etoposide
  • Etoposide (Vepesid) 100 mg/m2 IV over at least 30 minutes once daily 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 daily x 5 fractions (total dose: 20 Gy) over 5 days between cycles 3 and 4

21 to 28-day cycles x 6 cycles

Supportive medications:

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

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)

EP: Etoposide, Platinol
IP: Irinotecan, Platinol

Regimen

Level of Evidence: Phase II

Induction chemoradiotherapy

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV once daily 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 x 1 cycle, then proceed to consolidation chemotherapy

Consolidation chemotherapy

28-day cycles x 3 cycles

Supportive medications:

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

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)

EP: Etoposide, Paraplatin

Regimen #1, Schmittel, et al. 2006 & Schmittel, et al. 2011

Level of Evidence: Phase III

21-day cycles x up to 6 cycles

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

Regimen #2, Okamoto, et al. 1999

Level of Evidence: Phase II

Patients in Okamoto, et al. 1999 were ≥70 years old.

  • 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

28-day cycles x up to 4 cycles

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

Regimen #3, Quoix, et al. 2001

Level of Evidence: Phase II

Patients in Quoix, et al. 2001 were ≥70 years old.

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

Supportive medications:

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

Regimen #4, Socinski, et al. 2009

Level of Evidence: Phase III

21-day cycles x up to 6 cycles, progression of disease, or unacceptable toxicity

Supportive medications:

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

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. doi: 10.1200/JCO.2009.23.1548. 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)

IP: Irinotecan, Paraplatin

Regimen

Level of Evidence: Phase III

28-day cycles x up to 6 cycles

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

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 +/- EP, RT

CAV: Cyclophosphamide, Adriamycin, Vincristine
EP: Etoposide, Platinol

Regimen, Ettinger, et al. 2002 (ECOG E1588)

Level of Evidence: Phase III

Induction CAP therapy

21-day cycles x 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 induction chemotherapy.

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

Salvage EP therapy

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

CEV

CEV: Cisplatin, Epirubicin, Vincristine

Regimen

Level of Evidence: Phase III

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)

EP: Etoposide, Platinol

Regimen #1, Sundstrøm, et al. 2002

Level of Evidence: Phase III

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.

  • Cisplatin (Platinol) 75 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV once on day 1; then Etoposide (Vepesid) 200 mg/m2 PO once daily 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."

21-day cycles x up to 5 cycles

Supportive medications:

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

Regimen #2, Evans, et al. 1985

Level of Evidence: Phase II

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

21 to 28-day cycles x 6 cycles

Supportive medications:

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

Regimen #3, Hanna, et al. 2006

Level of Evidence: Phase III

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

Supportive medications:

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

Regimen #4, Noda, et al. 2002

Level of Evidence: Phase III

21-day cycles x 4 cycles

Supportive medications:

  • "Hydration and administration of antiemetic drugs."

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. 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
  3. 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
  4. 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 & Etoposide (EP) +/- CAV

EP: Etoposide, Platinol
CAV: Cyclophosphamide, Adriamycin, Vincristine

Regimen, Ihde, et al. 1994

Level of Evidence: Phase III

EP therapy

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 80 mg/m2 IV once daily 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"

21-day cycles x 4-8 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 CAV or "an individualized 3-drug in vitro-selected regimen (IVSR) during cycles 5 to 8 if drug-sensitivity testing data were available."

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.

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.

CAV

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.

21-day cycles x 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

Cisplatin & Irinotecan (IP)

IP: Irinotecan, Platinol

Regimen #1, Hanna, et al. 2006

Level of Evidence: Phase III

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

Supportive medications:

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

Regimen #2, Noda, et al. 2002

Level of Evidence: Phase III

28-day cycles x 4 cycles

Supportive medications:

  • "Hydration and administration of antiemetic drugs."

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)

Regimen

Level of Evidence: Phase II

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) +/- EP, RT

Regimen

Level of Evidence: Phase III

Induction therapy

  • Ifosfamide (Ifex) 1500 mg/m2 IV once daily on days 1 to 5
  • 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 cycles x 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 induction chemotherapy.

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

Salvage EP therapy

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

Teniposide (Vumon) +/- EP, RT

Regimen

Level of Evidence: Phase III

Induction therapy

21-day cycles x 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 induction chemotherapy.

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

Salvage EP therapy

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

Ipilimumab + Paclitaxel & Carboplatin

Regimen

Level of Evidence: Phase II

Induction therapy

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

CAV

CAV: Cyclophosphamide, Adriamycin, Vincristine

Regimen

Level of Evidence: Phase III

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.

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

Supportive medications:

  • G-CSF use per physician discretion

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

Docetaxel (Taxotere)

Regimen

Level of Evidence: Phase II

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)

Level of Evidence: Phase II

Regimen, Einhorn, et al. 1990 & Johnson, et al. 1990

  • Etoposide (Vepesid) 50 mg/m2 PO once daily on days 1-21, taken every morning on an empty stomach

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

Supportive medications:

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. 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)

Regimen, van der Lee, et al. 2001 & Masters, et al. 2003 (ECOG 1597)

Level of Evidence: Phase II

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

28-day cycles x 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)

Regimen

Level of Evidence: Phase II

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. contains protocol PubMed
  2. 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)

EI: Etoposide, Ifosfamide

Regimen

Level of Evidence: Phase II

28-day cycles x up to 6 cycles, until progression of disease, or unacceptable toxicity

Supportive medications:

  • G-CSF use per physician discretion

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. doi: 10.1016/j.lungcan.2011.07.012. Epub 2011 Aug 9. link to original article contains verified protocol PubMed

Irinotecan (Camptosar)

Regimen

Level of Evidence: Phase II, <20 patients reported

treatment given 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)

Regimen #1, Smit, et al. 1998 - every 3 weeks

Level of Evidence: Phase II

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

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

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

Regimen #2, Yamamoto, et al. 2006 - weekly paclitaxel

Level of Evidence: Phase II

8-week cycles

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 daily is given until WBC ≥10,000/uL, except on days that paclitaxel is given

References

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

PI: Paclitaxel, Ifosfamide

Regimen

Level of Evidence: Phase II

  • Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
  • Ifosfamide (Ifex) 2500 mg/m2 IV over 2 hours once daily on days 1 & 2
  • Mesna (Mesnex) 500 mg/m2 IV given three times per day (total dose: 1500 mg/m2/day) on days 1 & 2; 15 minutes before, 4 hours after, and 8 hours after ifosfamide

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)

Regimen

Level of Evidence: Phase II

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

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

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)

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. doi: 10.1158/1078-0432.CCR-11-2059. Epub 2012 Jan 6. link to original article contains verified protocol PubMed

Topotecan (Hycamtin)

Regimen #1, von Pawel, et al. 1999 & Eckardt, et al. 2007 - IV route

Level of Evidence: Phase III

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.

Supportive medications (varies depending on reference):

  • G-CSF use per physician discretion

Regimen #2, O'Brien, et al. 2006 & Eckardt, et al. 2007 - oral route

Level of Evidence: Phase III

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

Vinorelbine (Navelbine)

Regimen

Level of Evidence: Phase II

treatment given once per week

References

  1. Jassem J, Karnicka-Młodkowska 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. contains protocol PubMed
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