Vascular sarcoma

Section editor
	Elizabeth J. Davis, MD Vanderbilt University Nashville, TN ejdavis25

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Guidelines

ESMO

• Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2014) PubMed

NCCN

• NCCN Guidelines - Soft Tissue Sarcoma
• NCCN Guidelines - AIDS-related Kaposi Sarcoma

Angiosarcoma, all lines of therapy

Bevacizumab monotherapy

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Regimen

Study	Evidence
Agulnik et al. 2013	Phase II

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. Agulnik M, Yarber JL, Okuno SH, von Mehren M, Jovanovic BD, Brockstein BE, Evens AM, Benjamin RS. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013 Jan;24(1):257-63. link to original article contains verified protocol PubMed

Paclitaxel monotherapy

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Regimen

Study	Evidence
Penel et al. 2008 (ANGIOTAX)	Phase II

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15

Supportive medications

• Dexamethasone (Decadron) 8 mg IV once per day on days 1, 8, 15, prior to Paclitaxel (Taxol)
• Cimetidine (Tagamet) 200 mg IV once per day on days 1, 8, 15, prior to Paclitaxel (Taxol)
• Dexchlorpheniramine (Polaramine) 5 mg IV once per day on days 1, 8, 15, prior to Paclitaxel (Taxol)
• "Standard antiemetics (mainly Metoclopramide (Reglan)) were prescribed as clinically indicated by the treating physician"

28-day cycle for 6 cycles

References

1. ANGIOTAX: Penel N, Bui BN, Bay JO, Cupissol D, Ray-Coquard I, Piperno-Neumann S, Kerbrat P, Fournier C, Taieb S, Jimenez M, Isambert N, Peyrade F, Chevreau C, Bompas E, Brain EG, Blay JY. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008 Nov 10;26(32):5269-74. Epub 2008 Sep 22. link to original article contains verified protocol PubMed

Kaposi sarcoma, all lines of therapy

ABV (Vinblastine)

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ABV: Adriamycin (Doxorubicin), Bleomycin, Vinblastine

Regimen

Study	Evidence
Laubenstein et al. 1984	Non-randomized

Chemotherapy

• Doxorubicin (Adriamycin)
• Bleomycin (Blenoxane)
• Vinblastine (Velban)

References

1. Laubenstein LJ, Krigel RL, Odajnyk CM, Hymes KB, Friedman-Kien A, Wernz JC, Muggia FM. Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol. 1984 Oct;2(10):1115-20. link to original article PubMed

ABV (Vincristine)

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ABV: Adriamycin (Doxorubicin), Bleomycin, Vincristine

Variant #1, 10/15/1

Study	Evidence	Comparator	Comparative Efficacy
Gill et al. 1996	Phase III (C)	Liposomal daunorubicin	Seems not superior

Gill et al. 1996 described doses but did not clearly say in the paper when these drugs were given, but this schedule is assumed based on the Northfelt et al. 1998 ABV regimen. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Doxorubicin (Adriamycin) 10 mg/m² IV once on day 1
• Bleomycin (Blenoxane) 15 units IV once on day 1
• Vincristine (Oncovin) 1 mg IV once on day 1

Supportive medications

• "No routine premedication was established by the protocol, but it could be provided at the discretion of the investigator"

14-day cycle for at least 2 cycles until complete remission

Variant #2, 20/10/1

Study	Evidence	Comparator	Comparative Efficacy
Northfelt et al. 1998	Phase III (C)	Pegylated liposomal doxorubicin	Inferior ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Doxorubicin (Adriamycin) 20 mg/m² IV once on day 1
• Bleomycin (Blenoxane) 10 mg/m² IV once on day 1
• Vincristine (Oncovin) 1 mg IV once on day 1

Supportive medications

• "Colony-stimulating factors (CSFs) were prescribed at the discretion of the investigators."

14-day cycle for up to 6 cycles

References

1. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, Rarick MU, Myers AM, Shepherd F, Sawka C, Pike MC, Ross ME. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-64. link to original article contains verified protocol PubMed
2. Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, Kaplan LD, Du Mond C, Mamelok RD, Henry DH. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998 Jul;16(7):2445-51. link to original article contains verified protocol PubMed

Bevacizumab monotherapy

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Regimen

Study	Evidence
Uldrick et al. 2012	Phase II

Chemotherapy

• Bevacizumab (Avastin) as follows:
  • Loading: 15 mg/kg IV once as a loading dose; start regular therapy 7 days later after this loading dose
  • Cycle 1 onwards: 15 mg/kg IV once on day 1

Supportive medications

• "Antihypertensive therapy was initiated for systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg persisting for more than 1 week or for systolic blood pressure greater than 210 mmHg or diastolic blood pressure greater than 120 mmHg at any time."
• "HIV-positive patients with CD4 count of less than 200 cells/µL received Pneumocystis jiroveci prophylaxis."
• "Mycobacterium avium prophylaxis was considered if CD4 count was less than 75 cells/µL."
• Patients with HIV/AIDS continued HAART
• Filgrastim (Neupogen) "used as clinically indicated"

21-day cycles

References

1. Uldrick TS, Wyvill KM, Kumar P, O'Mahony D, Bernstein W, Aleman K, Polizzotto MN, Steinberg SM, Pittaluga S, Marshall V, Whitby D, Little RF, Yarchoan R. Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. J Clin Oncol. 2012 May 1;30(13):1476-83. Epub 2012 Mar 19. link to original article contains verified protocol link to PMC article PubMed

Daunorubicin liposomal monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Presant et al. 1993	Phase II
Gill et al. 1996	Phase III (E-RT)	ABV	Seems not superior

Note: Gill et al. 1996 stopped treatment if CR was achieved.

Chemotherapy

• Daunorubicin liposomal (DaunoXome) 40 mg/m² IV over 30 to 60 minutes once on day 1

Supportive medications

• "No routine premedication was established by the protocol, but it could be provided at the discretion of the investigator"

14-day cycles

References

1. Presant CA, Scolaro M, Kennedy P, Blayney DW, Flanagan B, Lisak J, Presant J. Liposomal daunorubicin treatment of HIV-associated Kaposi's sarcoma. Lancet. 1993 May 15;341(8855):1242-3. link to original article PubMed
2. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, Rarick MU, Myers AM, Shepherd F, Sawka C, Pike MC, Ross ME. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-64. link to original article contains verified protocol PubMed

Doxorubicin pegylated liposomal monotherapy

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Variant #1, q2wk

Study	Evidence	Comparator	Comparative Efficacy
Stewart et al. 1998	Phase III (E)	BV	Superior ORR
Northfelt et al. 1998	Phase III (E)	ABV	Superior ORR

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 20 mg/m² IV over 30 minutes once on day 1

Supportive medications

• "Colony-stimulating factors (CSFs) were prescribed at the discretion of the investigators."

14-day cycle for up to 6 cycles

Variant #2, q3wk

Study	Evidence
Harrison et al. 1995	Phase II (RT)

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 20 mg/m² IV once on day 1

21-day cycles

References

1. Harrison M, Tomlinson D, Stewart S. Liposomal-entrapped doxorubicin: an active agent in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1995 Apr;13(4):914-20. link to original article contains protocol PubMed
2. Stewart S, Jablonowski H, Goebel FD, Arasteh K, Spittle M, Rios A, Aboulafia D, Galleshaw J, Dezube BJ; International Pegylated Liposomal Doxorubicin Study Group. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. J Clin Oncol. 1998 Feb;16(2):683-91. link to original article contains protocol PubMed
3. Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, Kaplan LD, Du Mond C, Mamelok RD, Henry DH. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998 Jul;16(7):2445-51. link to original article contains verified protocol PubMed

Etoposide monotherapy

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Variant #1, 8 cycles

Study	Evidence	Comparator	Comparative Efficacy
Hosseinipour et al. 2018 (REACT-KS)	Phase III (C)	As-needed Etoposide	Seems not superior

Chemotherapy

• Etoposide (Vepesid) 50 mg PO once per day on days 1 to 7

14-day cycle for up to 8 cycles

Variant #2, indefinite

Study	Evidence
Evans et al. 2002	Phase II

Chemotherapy

• Etoposide (Vepesid) 50 mg PO once per day on days 1 to 7

14-day cycles

References

1. Evans SR, Krown SE, Testa MA, Cooley TP, Von Roenn JH. Phase II evaluation of low-dose oral etoposide for the treatment of relapsed or progressive AIDS-related Kaposi's sarcoma: an AIDS Clinical Trials Group clinical study. J Clin Oncol. 2002 Aug 1;20(15):3236-41. link to original article contains verified protocol PubMed
2. REACT-KS: Hosseinipour MC, Kang M, Krown SE, Bukuru A, Umbleja T, Martin JN, Orem J, Godfrey C, Hoagland B, Mwelase N, Langat D, Nyirenda M, MacRae J, Borok M, Samaneka W, Moses A, Mngqbisa R, Busakhala N, Martínez-Maza O, Ambinder R, Dittmer DP, Nokta M, Campbell TB; A5264/AMC-067 REACT-KS Team. As-needed vs immediate etoposide chemotherapy in combination with antiretroviral therapy for mild-to-moderate AIDS-associated Kaposi sarcoma in resource-limited settings: A5264/AMC-067 randomized clinical trial. Clin Infect Dis. 2018 Jul 2;67(2):251-260. link to original article PubMed

Interferon alfa-2a monotherapy

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Regimen

Study	Evidence
de Wit et al. 1988	Phase II

Immunotherapy

• Interferon alfa-2a (Roferon-A)

References

1. de Wit R, Schattenkerk JK, Boucher CA, Bakker PJ, Veenhof KH, Danner SA. Clinical and virological effects of high-dose recombinant interferon-alpha in disseminated AIDS-related Kaposi's sarcoma. Lancet. 1988 Nov 26;2(8622):1214-7. link to original article PubMed

Interferon alfa-2b monotherapy

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Regimen

Study	Evidence
Volberding et al. 1987	Phase II (RT)
Lane et al. 1988	Non-randomized (RT)

Immunotherapy

• Interferon alfa-2b (Intron-A)

References

1. Volberding PA, Mitsuyasu RT, Golando JP, Spiegel RJ. Treatment of Kaposi's sarcoma with interferon alfa-2b (Intron A). Cancer. 1987 Feb 1;59(3 Suppl):620-5. link to original article PubMed
2. Lane HC, Kovacs JA, Feinberg J, Herpin B, Davey V, Walker R, Deyton L, Metcalf JA, Baseler M, Salzman N, Quinnan G, Fauci AS. Anti-retroviral effects of interferon-alpha in AIDS-associated Kaposi's sarcoma. Lancet. 1988 Nov 26;2(8622):1218-22. link to original article PubMed

Paclitaxel monotherapy

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Regimen

Study	Evidence
Saville et al. 1995 (CA139-174)	Phase II (RT)

Chemotherapy

• Paclitaxel (Taxol) 135 mg/m² IV over 3 hours once on day 1

21-day cycles

References

1. CA139-174: Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH, Humphrey RW, Feigal E, Steinberg SM, Broder S, Yarchoan R. Treatment of HIV-associated Kaposi's sarcoma with paclitaxel. Lancet. 1995 Jul 1;346(8966):26-8. link to original article contains protocol PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Noy et al. 2005	Phase III (C)	IM862	Seems to have superior TTP

No active antineoplastic treatment.

References

1. Noy A, Scadden DT, Lee J, Dezube BJ, Aboulafia D, Tulpule A, Walmsley S, Gill P. Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi's sarcoma in a phase III trial, but demonstrates sustained, potent effect of highly active antiretroviral therapy: from the AIDS Malignancy Consortium and IM862 Study Team. J Clin Oncol. 2005 Feb 10;23(5):990-8. Epub 2004 Dec 14. link to original article PubMed

Pomalidomide

Regimen

Study	Evidence
Polizzotto et al. 2016	Non-randomized

Chemotherapy

• Pomalidomide (Pomalyst) 5 mg PO once per day for days 1-21
  • Dose adjustment to 3 mg allowed if 5mg dose is not tolerated

Supportive medications

• Aspirin 81 mg PO once per day (unless contraindicated)

References

1. Polizzotto MN, Uldrick TS, Wyvill KM, Aleman K, Peer CJ, Maldarelli F, Goncalves PH, Figg WD, Steinberg SM, Yarchoan R. Pomalidomide for symptomatic Kaposi's Sarcoma in people with and without HIV infection: A Phase I/II Study. J Clin Oncol. 2016 Dec;34(34):4125-4131 link to original article PubMed