Small cell lung cancer

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Limited stage

Carboplatin, Etoposide (EP), RT

EP: Etoposide, Paraplatin

Regimen #1, Skarlos, et al. 2001

• 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

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

Cisplatin, Etoposide (EP), RT

EP: Etoposide, Platinol

Regimen #1, Turrisi, et al. 1999

• 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

• 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

• 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

• 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 cGy/rad fractions x 10 fractions (total dose: 2500 cGy/rad), 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

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

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

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

• 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 daily on days 1 to 3

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

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
• 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. 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
3. 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

• 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 daily on days 1, 8, 15

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

Cisplatin & Etoposide (EP)

EP: Etoposide, Platinol

Regimen #1, Sundstrøm, et al. 2002

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

• 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

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

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

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

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

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.

• 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 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

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

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

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

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