Uterine Sarcoma Treatment Regimens

Uterine Sarcoma 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 only provided 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 National Comprehensive Cancer Network 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 NCCN 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 for Recurrent or Metastatic Disease11

REGIMEN

DOSING

Preferred Regimens

Docetaxel + Gemcitabine2,3
Premedication is required with Docetaxel.

Days 1,8: Gemcitabine 900mg/m2 IV at a rate of 10mg/m2/minute, followed by:

Day 8: Docetaxel 75-100mg/m2 IV over 1 hour.

Repeat cycle every 3 week.

OR

Days 1,8: Gemcitabine 675mg/m2 (if prior pelvic radiation) IV at a rate of 10mg/m2/minute, followed by:

Day 8: Docetaxel 75mg/m2 IV over 1 hour (if prior pelvic RT).

Repeat cycle every 3 weeks.

Doxorubicin6,7,c-e

Day 1: Doxorubicin 60-75mg/m2 IV push.

Repeat cycle every 3 weeks.

Other Recommended Regimens

Dacarbazine8-10,c

Days 1-5: Dacarbazine 250mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

OR

Days 1-5: Dacarbazine 187mg/m2 (if prior pelvic radiation) IV over 30 minutes.

Repeat cycle every 3 weeks.

OR

Day 1: Dacarbazine 1,000mg/m2 IV over 1 hour.

Repeat cycle every 3 weeks.

Doxorubicin/Dacarbazine7,8,11,12,c,d

Days 1-4: Doxorubicin 15mg/m2 IV continuous infusion over 24 hours daily

Days 1-4: Dacarbazine 187.5-250mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 3 weeks.

Doxorubicin/Ifosfamide7,13-15,c-e,g

Days 1-3: Doxorubicin 25mg/m2 IV push

Days 1-3: Ifosfamide 3,000mg/m2 IV continuous infusion over 24 hours daily

Days 1-3: Mesna 3,000mg/m2 IV continuous infusion over 24 hours concurrently with Ifosfamide (additional Mesna may be administered following the completion of Ifosfamide per institutional standard).

Repeat cycle every 3 weeks.

Epirubicin16,17,c,d

Day 1: Epirubicin 75mg/m2 IV push.

Repeat cycle every 3 weeks.

Eribulin (Category 2B)18-20,k

Days 1,8: Eribulin 1.4mg/m2 IV push.

Repeat cycle every 3 weeks.

Gemcitabine2,21,f

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

Repeat cycle every 4 weeks.

Gemcitabine/Dacarbazine2,8,22,j

Day 1: Gemcitabine 1,800mg/m2 IV at a rate of 10mg/m2/minute

Day 1: Dacarbazine 500mg/m2 IV over 1 hour.

Repeat cycle every 2 weeks.

Gemcitabine/Vinorelbine2,23,24,c

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

Days 1,8: Gemcitabine 800mg/m2 IV at a rate of 10mg/m2/minute.

Repeat cycle every 3 weeks.

Ifosfamide13,25,26,c,g

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

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

Repeat cycle every 3 weeks.

OR

Days 1-3: Ifosfamide 3,000mg/m2 IV continuous infusion over 24 hours daily

Days 1-3: Mesna 3,000mg/m2 IV continuous infusion over 24 hours concurrently with Ifosfamide (additional Mesna may be administered following the completion of Ifosfamide per institutional standard).

Repeat cycle every 3 weeks.

Liposomal Doxorubicin27-29,d,f,i

Day 1: Liposomal Doxorubicin 50mg/m2 IV.

Repeat cycle every 4 weeks.

Pazopanib30,31,h,k

Days 1-28: Pazopanib 800mg orally once daily

Repeat cycle every 4 weeks.

Temozolomide32-34.h,k

Days 1-5: Temozolomide 150-300mg/m2 orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-42: Temozolomide 75-100mg/m2 orally once daily.

Repeat cycle every 8 weeks.

Trabectedin35,36,k,l
Premedication is required with Trabectedin.

Day 1: Trabectedin 1.5mg/m2 IV continuous infusion over 24 hours.

Repeat cycle every 3 weeks.

▶Biomarker-Directed Systemic Therapy for Second-Line Treatment1

Useful in Certain Circumstances (No Preferred or Other Recommended Regimens)

Entrectinib (for NTRK gene fusion-positive tumors) (Category 2B)37,h

See NCCN Uterine Neoplasms Guidelines1

Larotrectinib (for NTRK gene fusion-positive tumors) (Category 2B)38,h

See NCCN Uterine Neoplasms Guidelines1

Niraparib (for BRCA2-altered uLMS)39,a

See NCCN Uterine Neoplasms Guidelines1

Olaparib (for BRCA2-altered uLMS)40,41

See NCCN Uterine Neoplasms Guidelines1

Pembrolizumab (for TMB-H tumors)42,a,m,n

See NCCN Uterine Neoplasms Guidelines1

Rucaparib (for BRCA2-altered uLMS)43

See NCCN Uterine Neoplasms Guidelines1

▶Anti-Estrogen Therapy for Low-Grade Endometrial Stromal Sarcoma or Adenosarcoma without SO or Hormone Receptor-Positive (ER and/PR) Uterine Sarcomas1,o

Preferred Regimens

Aromatase inhibitors for low-grade ESS or adenosarcoma without SOa

See NCCN Uterine Neoplasms Guidelines1

Other Recommended Regimens

Aromatase inhibitors (for ER/PR-positive uterine sarcomas)a

See NCCN Uterine Neoplasms Guidelines1

Fulvestrant44

See NCCN Uterine Neoplasms Guidelines1

GnRH Analogs (Category 2B for low-grade ESS, adenocarcinoma without SO, and ER/PR-positive uterine sarcomas)a

See NCCN Uterine Neoplasms Guidelines1

Megestrol Acetate (Category 2B for ER/PR-positive uterine sarcomas)

See NCCN Uterine Neoplasms Guidelines1

Medroxyprogesterone Acetate (Category 2B for ER/PR-positive uterine sarcomas)

See NCCN Uterine Neoplasms Guidelines1

  a ER, estrogen receptor; ESS, endometrial stromal sarcoma; GnRH, gonadotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; PR, progesterone receptor; RT, radiation therapy; SO, sarcomatous overgrowth; TMB-H, tumor mutational burden-high; uLMS, uterine leiomyosarcomas.

  b 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 1 day prior to Docetaxel administration.

  c When administered in primary or adjuvant settings: repeat cycle every 3 weeks for 4-6 cycles.

  d Doxorubicin and Epirubicin are anthracyclines. Cumulative anthracycline dosage should be monitored.

  e Administration of myeloid growth factor therapy is recommended with this regimen.

  f When administered in primary or adjuvant settings: repeat cycle every 4 weeks for 4-6 cycles.

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

  h Pazopanib, Temozolomide, Eribulin, and Larotrectinib or Entrectinib may be considered for use in patients with recurrent or metastatic disease that has progressed on prior cytotoxic chemotherapy.

  i Liposomal Doxorubicin may have altered functional properties relative to standard Doxorubicin. Do not substitute on a mg per mg basis with standard Doxorubicin. Product doses are not equivalent.

  j When administered in the adjuvant or primary settings: repeat cycle every 2 weeks for 4-6 cycles.

  k Not recommended in primary or adjuvant settings.

  l For Trabectedin: Premedication for hypersensitivity is required. The recommended dosing is: Dexamethasone 20mg IV 30 minutes pre-Trabectedin. Trabectedin is for patients with uLMS that has been treated with a prior anthracycline-containing regimen.

  m For the treatment of patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] tumors, as determined by a validated and/or FDA-approved test, that have progressed following prior treatment and have no satisfactory alternative treatment options.

  n 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 their underlying disease should be approached with caution when considering immunotherapy. All patients will require extensive resources including ongoing intensive monitoring and supportive care.

  o These hormaonal therapies may be considered for patients with uterine sarcomas that are ER/PR-positive, preferably with small tumor volume or an indolent growth pace.

References

1. Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™, Uterine Neoplasms. V1.2022. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf; Accessed September 1, 2022.

2.Gemcitabine [package insert]. Schamburg, IL: Sagent Pharmaceuticals. May 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=44bcc16c-341d-49e8-a1c6-95d084667aca&type=display. Accessed September 1, 2022.

3.Docetaxel [package insert]. Lake Forest, IL: Hospira Inc., December 2021; https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=00c61d11-d6b7-4618-b6f6-2592dbcc8af7&type=display. Accessed September 1, 2022.

4.Hensley ML, Miller A, O’Malley DM, et al. Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol. 2015; 33:1180-1185.

5.Pautier P, Floquet A, Penel N, et al. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: A Federation Nationale Des Centres De Lutte Contre Le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM Study). Oncologist. 2012;1213-1220.

6.Doxorubicin [package insert]. New York, NY: Pfizer Inc.; December 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=00634b2b-4e48-4178-8877-28582af894ad&type=display. Accessed September 1, 2022.

7.Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995;13:1537-1545.

8.Dacarbazine [package insert]. Parsippany, NJ: Teva Pharmaceuticals USA Inc., February 2020; https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=26e91082-7698-4680-beab-07c47802f0f9&type=display. Accessed September 1, 2022.

9.Omura GA, Major FJ, Blessing JA, et al. Randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer. 1983;52:626-632.

10.Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34:786-793.

11.Antman K, Crowley J, Balcerzak SP, et al. An Intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11:1276-1285.

12.Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: A Southwest Oncology Group Study. J Natl Cancer Inst. 1991;83:926-932.

13.Ifosfamide [package insert]. Deerfield, IL: Baxter International, Inc; July 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=91e433a9-6800-43a6-ac13-a49a04a5aecd&type=display. Accessed September 1, 2022.

14.Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11:1269-1275.

15.Grobmyer SR, Maki RG, Demetri GD, et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15:1667-1672.

16.Epirubicin [package insert]. New York, NY: Pfizer, Inc.; August 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0a03c798-a652-4895-b29c-3b521a89ba42&type=display. Accessed September 1, 2022.

17.Nielsen OS, Dombernowsky P, Mouriden H, et al. Epirubicin is not superior to doxorubicin in the treatment of advanced soft tissue sarcomas. The experience of the EORTC Soft Tissue and Bone Sarcoma Group. Sarcoma. 2000;4:31-35.

18.Eribulin [package insert]. Nutley, NJ: Eisai, Inc.; December 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=31ce4750-ded5-4a0b-95e9-f229fa6bc822&type=display. Accessed September 1, 2022.

19.Schöffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes [published correction appears in Lancet Oncol. 2015 Sep;16(9):e427]. Lancet Oncol. 2011;12(11):1045-1052. doi:10.1016/S1470-2045(11)70230-3

20.Schöffski P, Maki RG, Italiano A, et al. Randomized, open-labe, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI). J Clin Oncol. 2015;33(18)(suppl).

21.Look KY, Sandler A, Blessing JA et al. Phase III trial of gemcitabine as second-line chemotheraoy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study. Gynecol Oncol. 2004;92(2):644-647.

22.Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, et al. Randomized phase II study comparing gemcitabine plus dacarba versus dacarbazine alone in patients with previously treated soft tissue sarcoma: A Spanish Group for Research on Sarcomas Study. J Clin Oncol. 2011;29:2528-2533.

23.Vinorelbine [package insert] Schaumburg, IL: Sagent Pharmaceuticals; April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=10a70995-e04d-4044-b1dc-c9aa27460397&type=display. Accessed September 1, 2022.

24.DiLeo P, Morgan JA, Zahrieh D, et al. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial. Cancer. 2007;109(9):1863-1869.

25.Sutton G, Brunetto VL, Kilgore L, et al. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol. 2000;79:147-153.

26.Van Oosterom AT, Mouridsen HT, Nielsen OS, et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer. 2002;38:2397-2406.

27.Liposomal Doxorubicin (Doxil) [package insert]. Deerfield, IL: Baxter Healthcare Corp.; August 2019. https://www.baxter.com/sites/g/files/ebysai746/files/2019-11/Doxil%20Product%20Insert%2020%20mg.pdf. Accessed September 1, 2022.

28.Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: A study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37:870-877.

29.Sutton G, Blessing J, Hanjani P, et al. Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol. 2005;96:749-752.

30.Pazopanib (Votrient) [package insert]. East Hanover, NJ: Novartis Phamaceuticals Corp.; December 2021. https://www.novartis.com/us-en/sites/novartis_us/files/votrient.pdf. Accessed September 1, 2022.

31.van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886.

32.Temozolomide [package insert]. Princeton, NJ: Sandoz Inc.; November 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5d529b2d-d182-4d3d-a65d-613af39e254f&type=display. Accessed September 2022.

33.Anderson S, Aghajanian C. Temozolomide in uterine leiomyosarcomas. Gynecol Oncol. 2005;98(1):99-103.

34.Garcia del Muro X, Lopez-Pousa A, Martin J, et al. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. 2005;104(8):1706-1712. doi:10.1002/cncr.21384

35.Trabectedin (Yondelis) [package insert]. June 2020. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/YONDELIS-pi.pdf. Accessed September 1, 2022.

36.Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793. doi:10.1200/JCO.2015.62.4734

37.Entrectinib (Rozlytrek) [package insert]. South San Francisco, CA: Genentech USA, Inc. July 2022. https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf. Accessed September 1, 2022.

38.Larotrectinib (Vitrakvi). [package insert]. Stamford, CT: Loxo Oncology, Inc. March 2021. https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf. Accessed August 22, 2022.

39.Niraparib (Zejula) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; June 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Zejula_Capsules/pdf/ZEJULA-CAPSULES-PI-PIL.PDF. Accessed September 1, 2022.

40.Olaparib (Lynparza) [package insert]. AstraZeneca Pharmaceuticals. March 2022. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/00997c3f-5912-486f-a7db-930b4639cd51/00997c3f-5912-486f-a7db-930b4639cd51_viewable_rendition__v.pdf. Accessed August 22, 2022.

41.Pan M, Ganjoo K, Karam A. Rapid Response of a BRCA2/TP53/PTEN-Deleted Metastatic Uterine Leiomyosarcoma to Olaparib: A Case Report. Perm J. 2021; 25:20.251. doi:10.7812/TPP/20.251

42.Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; August 2022. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed August 31, 2022.

43.Rucaparib (Rubraca) [package insert]. Boulder, CO: Clovis Oncology, Inc.; June 2022. https://clovisoncology.com/pdfs/RubracaUSPI.pdf. Accessed September 1, 2022.

44.Fulvestrant (Faslodex) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; August 2020. FASLODEX PRESCRIBING INFORMATION (den8dhaj6zs0e.cloudfront.net). Accessed September 1, 2022.

(Revised 9/2022; NCCN Uterine Neoplasms Guidelines) © 2022 by Haymarket Media, Inc.