Small Cell Lung Cancer Treatment Regimens

Small Cell Lung Cancer Treatment Regimens

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶Systemic Therapy as Primary or Adjuvant Therapy1

REGIMEN

DOSING

Limited Stage, Primary or Adjuvant Therapy

Preferred Regimens

Cisplatin/Etoposide (Category 1 with RT)2-5,a

Day 1: Cisplatin 60mg/m2 IV over 60 minutes

Days 1–3: Etoposide 120mg/m2 IV over 60 minutes daily.

Repeat cycle every 3-4 weeks for 4 cycles.

OR

Day 1: Cisplatin 75mg/m2 IV over 2 hours

Days 1–3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3-4 weeks for 4 cycles.

Other Recommended Regimens

Carboplatin/Etoposide4-7,b

Day 1: Carboplatin AUC 5–6 IV over 30 minutes, followed by:

Days 1–3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3-4 weeks for 4 cycles.

Cisplatin/Etoposide (Category 1 with RT)2-5,a

Days 1-3: Cisplatin 25mg/m2 IV over 60 minutes daily

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3-4 weeks for 4 cycles.

Extensive Stage, Primary Therapy

Preferred Regimens

Atezolizumab + Carboplatin/Etoposide (Category 1 for every 3 week cycle)8-10,c

Day 1: Atezolizumab 1,200mg IV, followed by:

Day 1: Carboplatin AUC 5 IV over 30 minutes

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3 weeks for 4 cycles, followed by maintenance therapy with:

Day 1: Atezolizumab 840mg IV.

Repeat cycle every 2 weeks.

OR

Day 1: Atezolizumab 1,200mg IV, followed by:

Day 1: Carboplatin AUC 5 IV over 30 minutes

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3 weeks for 4 cycles, followed by maintenance therapy with:

Day 1: Atezolizumab 1,200mg IV.

Repeat cycle every 3 weeks.

OR

Day 1: Atezolizumab 1,200mg IV, followed by:

Day 1: Carboplatin AUC 5 IV over 30 minutes

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3 weeks for 4 cycles, followed by maintenance therapy with:

Day 1: Atezolizumab 1,680mg IV.

Repeat cycle every 4 weeks.

Durvalumab + Carboplatin/Etoposide (Category 1)11,12,c

Day 1: Durvalumab 1,500mg IV over 60 minutes, followed by:

Day 1: Carboplatin AUC 5-6 IV over 30 minutes

Days 1-3: Etoposide 80-100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3 weeks for 4 cycles, followed by maintenance therapy with:

Day 1: Durvalumab 1,500mg IV over 60 minutes.

Repeat cycle every 4 weeks.

Durvalumab + Cisplatin/Etoposide + (Category 1)11,12,a,c

Day 1: Durvalumab 1,500mg IV over 2 hours, followed by:

Day 1: Cisplatin 75-80mg/m2 IV over 2 hours

Days 1-3: Etoposide 80-100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3 weeks for 4 cycles, followed by maintenance therapy with:

Day 1: Durvalumab 1,500mg IV over 60 minutes.

Repeat cycle every 4 weeks.

Other Recommended Regimens

Carboplatin/Etoposide4-7

Day 1: Carboplatin AUC 5–6 IV over 30 minutes, followed by:

Days 1–3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3-4 weeks for 4–6 cycles.

Cisplatin/Etoposide4,6,13-15,a

Day 1: Cisplatin 75mg/m2 IV over 2 hours

Days 1–3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3-4 weeks for 4–6 cycles.

OR

Day 1: Cisplatin 80mg/m2 IV over 2 hours

Days 1–3: Etoposide 80mg/m2 IV over 60 minutes daily. Repeat cycle every 3-4 weeks for 4–6 cycles.

OR

Days 1–3: Cisplatin 25mg/m2 IV over 60 minutes

Days 1–3: Etoposide: 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 3-4 weeks for 4-6 cycles.

Useful in Certain Circumstances

Carboplatin + Irinotecan4,5,16

Day 1: Carboplatin AUC 5 IV over 30 minutes

Days 1,8,15: Irinotecan 50mg/m2 IV over 90 minutes.

Repeat cycle every 4 weeks for 4–6 cycles.

Cisplatin + Irinotecan4,5,17,18,a

Day 1: Cisplatin 60mg/m2 IV over 60 minutes

Days 1,8,15: Irinotecan 60mg/m2 IV over 90 minutes.

Repeat cycle every 4 weeks for 4-6 cycles.

OR

Days 1,8: Cisplatin 30mg/m2 IV over 60 minutes

Days 1,8: Irinotecan 65mg/m2 IV over 90 minutes.

Repeat cycle every 3 weeks for 4–6 cycles.

▶Subsequent Systemic Therapy (ECOG PS 0–2)1

Relapse ≤6 months or Primary Progressive Disease

Preferred Regimensh

Lurbinectedin19-21

Day 1: Lurbinectedin 3.2 mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks

Topotecan22-24

Days 1–5: Topotecan 1.5mg/m2 IV over 30 minutes daily.

Repeat cycle every 3 weeks.

OR

Days 1–5: Topotecan 2.3mg/m2 orally once daily.

Repeat cycle every 3 weeks.

Other Recommended Regimens

Bendamustine (Category 2B)25

Days 1,2: Bendamustine 120mg/m2 IV over 10–60 minutes (based on product selection) daily.

Repeat cycle every 3 weeks for 6 cycles.

Cyclophosphamide + Doxorubicin + Vincristine (CAV)23,d,e

Day 1: Cyclophosphamide 1,000mg/m2 IV over 60 minutes

Day 1: Doxorubicin 45mg/m2 IV push

Day 1: Vincristine 2mg IV over 5-10 minutes.

Repeat cycle every 3 weeks.

Docetaxel26,f
Premedication is required.

Day 1: Docetaxel 60-100 mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

Gemcitabine27,28

Days 1,8,15: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Irinotecan29

Days 1,8,15,22: Irinotecan 100mg/m2 IV over 90 minutes.

Repeat cycle every 4 weeks.

Nivolumab30-33,c

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Nivolumab 480mg IV over 30 minutes.

Repeat cycle every 4 weeks.

Oral Etoposide34,35

Days 1–21: Etoposide 50mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Paclitaxel36,37,g
Premedication is required.

Day 1: Paclitaxel 175mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks.

OR

Days 1,8,15,22,29,36: Paclitaxel 80mg/m2 IV over 60 minutes weekly.

Repeat cycle every 8 weeks (6 weeks on followed by 2 weeks off treatment).

Pembrolizumab38-42,c

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 3 weeks for up to 2 years.

OR

Day 1: Pembrolizumab 400mg IV over 30 minutes.

Repeat cycle every 6 weeks for up to 2 years.

Temozolomide43,44

Days 1–21: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-5: Temozolomide 200mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Vinorelbine45,46

Days 1,8,15: Vinorelbine 25–30mg/m2 IV over 5-10 minutes.

Repeat cycle every 3 weeks.

Relapse >6 months or Primary Progressive Disease

Preferred: Original Regimenh

Other Recommended Regimens

Bendamustine (Category 2B)25

Days 1,2: Bendamustine 120mg/m2 IV over 10–60 minutes (based on product selection) daily.

Repeat cycle every 3 weeks for 6 cycles.

Cyclophosphamide + Doxorubicin + Vincristine (CAV)23,d,e

Day 1: Cyclophosphamide 1,000mg/m2 IV over 60 minutes.

Day 1: Doxorubicin 45mg/m2 IV push.

Docetaxel26,f
Premedication is required.

Day 1: Docetaxel 60-100 mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

Gemcitabine27,28

Days 1,8,15: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Irinotecan29

Days 1,8,15,22: Irinotecan 100mg/m2 IV over 90 minutes.

Repeat cycle every 4 weeks.

Lurbinectedin19-21

Day 1: Lurbinectedin 3.2mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

Nivolumab30-33,c

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Nivolumab 480mg IV over 30 minutes.

Repeat cycle every 4 weeks.

Oral Etoposide34,35

Days 1–21: Etoposide 50mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Paclitaxel36,37,g
Premedication is required.

Day 1: Paclitaxel 175mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks.

OR

Days 1,8,15,22,29,36: Paclitaxel 80mg/m2 IV over 60 minutes weekly.

Repeat cycle every 8 weeks (6 weeks on followed by 2 weeks off treatment).

Pembrolizumab38-42,c

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 3 weeks for up to 2 years.

OR

Day 1: Pembrolizumab 400mg IV over 30 minutes.

Repeat cycle every 6 weeks for up to 2 years.

Temozolomide43,44

Days 1–21: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-5: Temozolomide 200mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Topotecan22-24

Days 1–5: Topotecan 1.5mg/m2 IV over 30 minutes daily.

Repeat cycle every 3 weeks.

OR

Days 1–5: Topotecan 2.3mg/m2 orally once daily.

Repeat cycle every 3 weeks.

Vinorelbine45,46

Days 1,8,15: Vinorelbine 25–30mg/m2 IV over 5-10 minutes.

Repeat cycle every 3 weeks.

a  Hydration is required with supplemental electrolytes pre- and post-administration of Cisplatin.

b  Cisplatin contraindicated or not tolerated.

c  Early and late-onset immune-related adverse events affecting multiple organ systems can occur in patients receiving immune checkpoint inhibitors. Patients with neurologic or life-threatening autoimmune disorders as well as those receiving high levels of immunosuppression for underlying disease should be approached with caution when considering immunotherapy. All patients will require extensive resources including ongoing intensive monitoring and supportive care.

d  Oral hydration is strongly encouraged with Cyclophosphamide: poorly hydrated patients may need supplemental IV hydration. Patients should attain combined oral and IV hydration of 2,000-3,000mL/day on day of chemotherapy

e  Doxorubicin is an anthracycline. Cumulative anthracycline dosage should be monitored.

f  For Docetaxel: Premedication with dexamethasone for fluid retention is required. One recommended dosing strategy is: Dexamethasone 8mg orally twice daily for three consecutive days starting day 1 prior to Docetaxel administration.

g  For Paclitaxel: Premedication for hypersensitivity is required. H2 antagonist – famolidine 20mg IV or orally (or equivalent H2 blocker) 30-60 minutes pre-Paclitaxel AND H2 antagonist – diphenhydramine 12.5-50mg IV or orally 30-60 minutes pre-Paclitaxel AND dexamethasone (for 21-day regimen) – dexamethasone 20mg orally approximately 12 and 6 hours pre-Paclitaxel OR dexamethasone 20mg IV 30 minutes pre-Paclitaxel OR dexamethasone (for weekly regimen) – dexamethasone 10mg IV 30 minutes pre-Paclitaxel. In the absence of infusion reactions for Doses 1-3, may consider dexamethasone 4mg IV 30 minutes pre-Paclitaxel starting with Dose 4.

h  The use of immune checkpoint inhibitors is discouraged if there is a progression on maintenance atezolizumab or durvalumab at time of relapse.

References

 1.  Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™ Small Cell Lung Cancer. V2.2022. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/sclc.pdf. Accessed January 17, 2022.

 2.  Turrisi AT 3rd, Kim K, Blum R, et al. 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;340:265-271.

 3.   Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18:1116-1125.

 4.  Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol. 1987;23:1409-1411.

 5.  Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol. 1987;23:1697-1699.

 6.  Skarlos DV, Samantas E, Briassoulis E, et al. 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;12:1231-1238.

 7.  Okamoto H, Watanabe K, Nishiwaki Y, et al. 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;17:3540-3545.

 8.  Atezolizumab (Tecentriq). [package insert]. South San Francisco, CA: Genentech, Inc.; April 2021.

 9.  Horn L, Mansfield AS, Szcz sna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220-2229

10. Morrissey KM, Marchand M, Patel H, et al. Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting. Cancer Chemother Pharmacol. 2019;84:1257-1267.

11. Durvalumab (Imfinzi) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, LP: July 2021.

12. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive –stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394:1929-1939.

13. Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985;3:1471-1477.

14. Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011;29:2215-2222.

15. Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony- stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol. 2005;23:3752-3759.

16. Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. 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;17:663-667.

17. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346:85-91.

18. Hanna N, Bunn PA Jr, Langer C, et al. 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;24:2038-2043.

19. Lurbinectedin (Zepzelca) [package insert]. Palo Alto, CA: Jazz Phamaceuticals, Inc., June 2020.

20. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21:645-654.

21. Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer. 2020;150:90-96.

22. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol. 2007;25:2086-2092.

23. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small cell lung cancer. J Clin Oncol. 1999;17(2):658-667.

24. O’Brien ME, Ciuleanu TE, Tsekov H, et al. 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;24:5441-5447.

25. Lammers PE, Shyr Y, Li CI, et al. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol. 2014;9:559-562.

26. Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC. Eur J Cancer. 1994;30A:1058-1060.

27. van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol. 2001;12:557-561.

28. Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol. 2003;21:1550-1555.

29. Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol. 1992;10:1225-1229.

30. Nivolumab (Opdivo) [package insert]. [package insert]. Princeton, NJ: Bristol- Myers Squibb Co.; August, 2021.

31. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883-895.

32. Long GV, Tykodi SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018;29:2208-2213

33. Ready NE, Ott PA, Hellmann MD, et al. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort. J Thorac Oncol. 2020;15:426-435.

34. Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung cancer. Semin Oncol. 1990;17:32–35.

35. Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol. 1990; 8:1613–1617.

36. Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer. Anticancer Res. 2006;26:777-781.

37. Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer. 1998;77:347-351.

38. Pembrolizumab (Keytruda) [package insert] Whitehouse Station, NJ: Merck & Co., Inc.; August 2021.

39. Chung HC, Lopez-Martin JA, Kao SC-H, et al. Phase 2 study of pembrolizumab in advanced small cell lung cancer (SCLC): KEYNOTE-158. J Clin Oncol. 2018; 36(15-suppl):Abstract 8506.

40. Ott PA, Elez E, Hiret S, Kim DW, et al. Pembrolizumab in Patients With Extensive- Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol. 2017;35:3823-3829.

41. Chung HC, Piha-Paul SA, Lopez-Martin J, et al. Pembrolizumab after two or more lines of prior therapy in patients with advanced small-cell lung cancer (SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies [abstract]. AACR Annual Meeting 2019;13:abstr CT073

42. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur Cancer. 2020;131:68-75.

43. Pietanza MC, Kadota K, Huberman K, et al. 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;18:1138-1145.

44. Zauderer MG, Drilon A, Kadota K, et al. Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase. Lung Cancer. 2014;86:237-240.

45. Jassem J, Karnicka-Młodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative Group. Eur J Cancer. 1993;29A:1720-1722.

46. Furuse K, Kubota K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group. Oncology. 1996;53:169-172.

(Revised 1/2022; NCCN Small-Cell Lung Cancer Guidelines v1.2022) © 2022 by Haymarket Media, Inc.