Thymomas and Thymic Carcinomas

Thymomas and Thymic Carcinomas

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.

▶First-line Combination Chemotherapy Regimens for Thymoma1,a,b

REGIMEN

DOSING

Preferred Regimen

CAP (Cyclophosphamide / Doxorubicin / Cisplatin)2-5,c-e

Day 1: Cyclophosphamide 500mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Cisplatin 50mg/m2 IV over 1 hour.

Repeat cycle every 3 weeks for up to 8 cycles.

Other Recommended Regimens

ADOC (Doxorubicin / Cisplatin / Vincristine / Cyclophosphamide)2-4,6-9,c-e

Day 1: Doxorubicin 40mg/m2 IV push

Day 1: Cisplatin 50mg/m2 IV over 1 hour

Day 3: Vincristine 0.6mg/m2 (maximum 2mg) IV over 5-10 minutes

Day 4: Cyclophosphamide 700mg/m2 IV over 30 minutes.

Repeat cycle every 3 or 4 weeks for a maximum of 8 cycles.

CAP (Cyclophosphamide / Doxorubicin / Cisplatin) + Prednisone2-4,10,11,c-e

Day 1: Cyclophosphamide 500mg/m2 IV over 30 minutes

Days 1-3: Doxorubicin 20mg/m2 IV continuous infusion over 24 hours daily

Days 1-3: Cisplatin 30mg/m2 IV over 1 hour daily

Days 1-5: Prednisone 100mg orally once daily.

Repeat cycle every 3 or 4 weeks for a maximum of 8 cycles.

Carboplatin/Paclitaxel12-15,f
Premedication is required.

Day 1: Paclitaxel 200mg/m2 IV over 3 hours, followed by:

Day 1: Carboplatin AUC 6 IV over 30 minutes.

Repeat cycle every 3 weeks for up to 6 cycles.

Etoposide + Ifosfamide + Cisplatin4,16-18,c,g,h

Days 1-4: Etoposide 75mg/m2 IV over 1 hour daily

Days 1-4: Mesna 240mg/m2 IV over 15 minutes 3 times daily (one dose before Ifosfamide, then at 4 and 8 hours from the start of each Ifosfamide dose).

Days 1-4: Ifosfamide 1,200mg/m2 IV over 3 hours daily

Days 1-4: Cisplatin 20mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks for 4 cycles.

PE (Cisplatin / Etoposide)4,16,19,c

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

Days 1-3: Etoposide 120mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks for 8 cycles.

▶First-line Combination Chemotherapy Regimens for Thymic Carcinoma1,a,b

Preferred Regimen

Carboplatin + Paclitaxel12-15,f
Premedication is required.

Day 1: Paclitaxel 200mg/m2 IV over 3 hours, followed by:

Day 1: Carboplatin AUC 6 IV over 30 minutes.

Repeat cycle every 3 weeks for up to 6 cycles.

Other Recommended Regimens

ADOC (Doxorubicin / Cisplatin / Vincristine / Cyclophosphamide)2-4,6-9,c-e

Day 1: Doxorubicin 40mg/m2 IV push

Day 1: Cisplatin 50mg/m2 IV over 1 hour

Day 3: Vincristine 0.6mg/m2 (maximum 2mg) IV over 5-10 minutes

Day 4: Cyclophosphamide 700mg/m2 IV over 30 minutes.

Repeat cycle every 3 or 4 weeks for a maximum of 8 cycles.

CAP (Cyclophosphamide / Doxorubicin / Cisplatin)2-5,c-e

Day 1: Cisplatin 50mg/m2 IV over 1 hour

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Cyclophosphamide 500mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks for up to 8 cycles.

CAP (Cyclophosphamide / Doxorubicin / Cisplatin) + Prednisone2-4,10-11,c-e

Day 1: Cyclophosphamide 500mg/m2 IV over 30 minutes

Days 1-3: Doxorubicin 20mg/m2 IV continuous infusion over 24 hours daily

Days 1-3: Cisplatin 30mg/m2 IV over 1 hour daily

Days 1-5: Prednisone 100mg orally once daily.

Repeat cycle every 3 or 4 weeks for a maximum of 8 cycles.

Etoposide + Ifosfamide + Cisplatin4,16-18,c,g.h

Days 1-4: Etoposide 75mg/m2 IV over 1 hour daily

Days 1-4: Mesna 240mg/m2 IV over 15 minutes 3 times daily (one dose before Ifosfamide, then at 4 and 8 hours from the start of each Ifosfamide dose).

Days 1-4: Ifosfamide 1,200mg/m2 IV over 3 hours daily

Days 1-4: Cisplatin 20mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks for 4 cycles.

PE (Cisplatin / Etoposide)4,16,19,c

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

Days 1-3: Etoposide 120mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks for 8 cycles.

▶Second-Line Systemic Therapy for Thymoma1,b

Other Recommended Regimens

Etoposide16,19-22

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

Repeat cycle every 4 or 5 weeks.

OR

Days 1-3: Etoposide 120mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks.

Everolimus23,24,i

Days 1-28: Everolimus 10mg orally once daily.

Repeat cycle every 4 weeks.

Fluorouracil (continuous infusion) + Leucovorin25-29,j,k

Day 1: Leucovorin 400mg/m2 IV over 2 hours, followed by:

Day 1: Fluorouracil 400mg/m2 IV push, followed by:

Days 1-2: Fluorouracil 1,200mg/m2 IV continuous infusion daily (2,400mg/m2 IV over 46-48 hours).

Repeat cycle every 2 weeks.

Gemcitabine30-32

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

Repeat cycle every 3 weeks.

Gemcitabine + Capecitabine30-33

Days 1-14: Capecitabine 650mg/m2 orally twice daily

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

Repeat cycle every 3 weeks.

Ifosfamide17,34,g

Days 1-5: Ifosfamide 1,500mg/m2 IV over 3 hours daily

Days 1-5: Mesna 300mg/m2 IV over 15 minutes 3 times daily (one dose before Ifosfamide, then at 4 and 8 hours from the start of each Ifosfamide dose).

Repeat cycle every 3 weeks.

Octreotide and Octreotide LAR35-37,l,m

Days 1-28: Octreotide Acetate 500mcg subcutaneous three times daily

Once patient stabilized on subcutaenous Octreotide, may change to:

Day 1: Octreotide Acetate (LAR) 20-30mg IM.

Repeat cycle every 4 weeks.

Paclitaxel13,38,f
Premedication is required.

Days 1,8: Paclitaxel 80mg/m2 IV over 1 hour.

Repeat cycle every 3 weeks.

Pemetrexed39,40,n
Premedication is required.

Day 1: Pemetrexed 500mg/m2 IV over 10 minutes.

Repeat cycle every 3 weeks for 6 cycles.

▶Second-Line Systemic Therapy for Thymic Carcinoma1,b

Other Recommended Regimens

Everolimus23,24,i

Days 1-28: Everolimus 10mg orally once daily.

Repeat cycle every 4 weeks.

Fluorouracil (continuous infusion) + Leucovorin25-29,j,k

Day 1: Leucovorin 400mg/m2 IV over 2 hours, followed by:

Day 1: Fluorouracil 400mg/m2 IV push, followed by:

Days 1-2: Fluorouracil 1,200mg/m2 IV continuous infusion daily (2,400mg/m2 IV over 46-48 hours).

Repeat cycle every 2 weeks.

Gemcitabine30-32

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

Repeat cycle every 3 weeks.

Gemcitabine + Capecitabine30-33

Days 1-14: Capecitabine 650mg/m2 orally twice daily

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

Repeat cycle every 3 weeks.

Lenvatinib41,42,i

Days 1-28: Lenvatinib 24mg orally once daily.

Repeat cycle every 4 weeks.

Paclitaxel13,38,f
Premedication is required.

Days 1,8: Paclitaxel 80mg/m2 IV over 1 hour.

Repeat cycle every 3 weeks.

Pembrolizumab43-46,o

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.

Pemetrexed 39,40,n
Premedication is required.

Day 1: Pemetrexed 500mg/m2 IV over 10 minutes.

Repeat cycle every 3 weeks for 6 cycles.

Sunitinib47,48,i

Days 1-28: Sunitinib 50mg orally once daily.

Repeat cycle every 6 weeks (4 weeks on followed by 2 weeks off treatment).

Useful in Certain Circumstances

Etoposide16,19-22

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

Repeat cycle every 4 or 5 weeks until disease progression or unacceptable toxicity.

OR

Days 1-3: Etoposide 120mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks.

Ifosfamide17,34,g

Days 1-5: Ifosfamide 1,500mg/m2 IV over 3 hours daily

Days 1-5: Mesna 300mg/m2 IV over 15 minutes 3 times daily (one dose before Ifosfamide, then at 4 and 8 hours from the start of each Ifosfamide dose).

Repeat cycle every 3 weeks.

a  If patients cannot tolerate first-line combination regimens, consider second-line systemic therapy options.

b  Pembrolizumab is not recommended for patients with thymoma. In patients with thymic carcinoma, there is concern for a higher rate of immune-related adverse events than seen in most other malignancies treated with PD-1/PD-L1inhibitor therapy. For example, grade 3-4 myocarditis has been reported in 5%-9% of patients receiving pembrolizumab.

c  Hydration is required with supplemental electrolytes pre- and post-administration of cisplatin.

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 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.

g  Hydration is required pre- and post-administration of Ifosfamide.

h  Filgrastim (or clinically appropriate G-CSF agent) 5mcg/kg subcutaneously daily, recommended to start the day following or up to 3-4 days after completion of chemotherapy and to continue until post-nadir ANC recovery to normal or near-normal levels by laboratory standards. Same-day administration is not recommended. OR Pegfilgrastim (or clinically appropriate biosimilar) 6mg subcutaneously once, recommended to e given the day following or up to 3-4 days after completion of chemotherapy. There are insufficient data to support use of pegfilgrastim for cytotoxic chemotherapy regimens administered less frequently than every 2 weeks. Same-day administration is not recommended.

i  This agent has multiple potential drug-drug and drug-food interactions.

j  For Leucovorin: the dose listed above is based on racemic leucovorin product. Levoleucovorin is not interchangeable and the product doses are not equivalent.

k  For Fluorouracil: patients with dihydropyrimidine dehydrogenase (DPD) deficiency are unable to metabolize this agent normally and may have severe unexpected toxicity.

l  Dose and frequency of Octreotide Acetate may be further increased for symptom control as needed. Octreotide Acetate (LAR) would not be expected to be therapeutic for 10-14 days. Short-acting Octreotide can be added to Octreotide Acetate (LAR) for rapid relief of symptoms or breakthrough.

m  This regimen may also be administered with prednisone.

n  For Pemetrexed: Premedication and supplemental medications to reduce the incidence of severity of hematologic, gastrointestinal and cutaneous toxicities are required. The recommended dosing is: Vitamin B12 (cyanocobalamin) 1,000mcg IM during the week preceding the first cycle of Pemetrexed and every 3 cycles thereafter AND fofic acid 400-1,000mcg orally daily starting 7 days before the first cycle and continuing 21 days after the last dose of Pemetrexed AND dexamethasone 4mg orally twice daily for 3 days starting the day prior to Pemetrexed.

o  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.

References

 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thymomas and Thymic Carcinomas v.1.2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/thymic.pdf. Acccessed January 28, 2022.

 2. Cyclophosphamide (Cytoxan) [package insert]. Deerfield, IL: Baxter Healthcare Corporation; 2013.

 3. Doxorubicin (Adriamycin) [package insert]. New York, NY: Pfizer Labs; 2011.

 4. Cisplatin (Platinol) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2010.

 5. Loehrer PJ Sr, Kim K, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclo­phosphamide in metastatic or recurrent thymoma: Final results of an intergroup trial. The Easter Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 1994;12:1164-1168.

 6. Vincristine [package insert]. Lake Forest, IL: Hospira, Inc; 2021.

 7. Fornasiero A, Daniele O, Ghiotto C, et al. Chemotherapy for invasive thymoma. A 13-year experience. Cancer 1991;68:30-33.

 8. Koizumi T, Takabayashi Y, Yamagishi S, et al. Chemotherapy for advanced thymic carcinoma: clinical response to cisplatin, doxorubicin, vincristine, and cyclo­phosphamide (ADOC chemotherapy). Am J Clin Oncol. 2002;25(3):266-268.

 9. Agatsuma T, Koizumi T, Kanda S, et al. Combination chemotherapy with doxo­rubicin, vincristine, cyclophosphamide, and platinum compounds for advanced thymic carcinoma. J Thorac Oncol. 2011;6(12):2130-2134.

10. Prednisone [package insert]. Columbus, OH: Roxane Laboratories, Inc.; 2012.

11. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 2004;44:369-379.

12. Carboplatin (Paraplatin) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; 2010.

13. Paclitaxel (Taxol) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2011.

14. Lemma GL, Lee JW, Aisner SC, et al. Phase II study of carboplatin and paclitaxel in advanced thymoma and theymic carcinoma. J Clin Oncol 2011;29:2060-2065.

15. Hirai F, Yamanaka T, Taguchi K, et al. A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma. WJOG4207L. Ann Oncol 2015;26:363-368.

16. Etoposide (Etopophos) [package insert]. Deerfield, IL: Baxter Healthcare Corp.; 2010.

17. Ifosfamide (Ifex) [package insert]. Deerfield, IL: Baxter Healthcare Corp.; 2018.

18. Loehrer PJ Sr, Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer. 2001;91(11):2010-2015.

19. Giaccone G, Ardizzoni A, Kirkpatrick A, Clerico M, Sahmoud T, van Zandwijk N. Cisplatin and etoposide combination chemotherapy for locally advanced or meta­static thymoma. A phase II study of the European Organization for Research and Treat­ment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 1996;14(3):814-820.

20. Bluthgen MV, Boutros C, Fayard F, Remon J, Planchard D, Besse B. Activity and safety of oral etoposide in pretreated patients with metastatic or recurrent thymic epithelial tumors (TET): A single-institution experience. Lung Cancer. 2016;99:111-116.

21. 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;8(10):1613-1617.

22. Ottaviano M, Tortora M, Giuliano M, et al. Low-dose oral etoposide is an active option for patients with heavily pre-treated thymic epithelial tumors. J Clin Oncol. 2020 38:15_suppl, 9074-9074.

23. Everolimus (Afinitor) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021.

24. Zucali PA, De Pas T, Palmieri G, et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol. 2018;36(4):342-349.

25. Fluorouracil [package insert]. New York, NY: Pfizer Labs; 2016.

26. Leucovorin [package insert]. Bedford, OH: BenVenue Laboratories Inc,; 2011.

27. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol. 1999;17(7):2280-2289.

28. Stewart DJ, Dahrouge S, Soltys KM, Evans WK. A phase II study of 5-fluorouracil plus high-dose folinic acid in the treatment of recurrent small cell lung cancer. Am J Clin Oncol. 1995;18(2):130-132.

29. André T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999;35(9):1343-1347.

30. Gemcitabine (Gemzar) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.

31. Palmieri G, Merola G, Federico P, et al. Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs). Ann Oncol. 2010;21(6):1168-1172.

32. Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial. Future Oncol. 2014;10(14):2141-2147.

33. Capecitabine (Xeloda) [package insert]. South San Francisco, CA: Genentech USA, Inc; 2015.

34. Highley MS, Underhill CR, Parnis FX, et al. Treatment of invasive thymoma with single-agent ifosfamide. J Clin Oncol. 1999;17(9):2737-2744.

35. Octreotide acetate (Sandostatin) [package insert]. East Hanover, NJ: Novartis Pharmaceutical Corporation; March 2021.

36. Octreotide acetate (Sandostatin LAR DEPOT) [package insert]. Novartis Pharmaceutical Corporation; May 2021.

37. Loehrer Sr PJ, Wang W, Johnson DH, et al. Ocreotide acetate alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group phase II trial. J Clin Oncol. 2004;22(2):293-299.

38. Umemura S, Segawa Y, Fujiwara K, et al. A case of recurrent metastatic thymoma showing a marked response to paclitaxel monotherapy. Jpn J Clin Oncol. 2002; 32(7):262-265.

39. Pemetrexed (Alimta) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.

40. Gbolahan OB, Porter RF, Salter JT, et al. A phase II study of pemetrexed in patients with recurrent thymoma and thymic carcinoma. J Thorac Oncol. 2018;13(12):1940-1948.

41. Lenvatinib (Lenvima) [package insert]. Woodcliff Lake, NJ : Elsai, Inc; 2021.

42. Sato J, Satouchi M, Itoh S, et al. Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol. 2020; 21(6):843-850.

43. Pembolizumab (Keytruda) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2020.

44. Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol. 2018;19(3):347-355.

45. 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 J Cancer. 2020;131:68-75.

46. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for patients with Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol. 2019;37(24):2162-2170.

47. Sunitinib (Sutent) [package insert]. New York, NY: Pfizer Labs; 2020.

48. Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy- refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol. 2015;16(2):177-186.

(Revised 2/2022; NCCN Thymomas and Thymic Carcinomas Guidelines v1.2022) © 2022 by Haymarket Media, Inc.

Topics:

Endocrine Cancer Treatment Regimens