Templates by BIGtheme NET

AIDS-RELATED KAPOSI’S SARCOMA: MANIFESTATIONS AND MANAGEMENT STRATEGIES WITH HAART AND ADJUVANT THERAPIES

Download File

Amanari Ogeonye  Charles FWACS [1], Umanah Ivy Nneka  FMCPath [2]

[1]Consultant Plastic Surgeon, Dept. of Surgery, University of Uyo Teaching Hospital, Uyo
[2]Consultant Pathologist, Dept. of Pathology, University of Uyo Teaching Hospital, Uyo

ABSTRACT
AIDS-related Kaposi sarcoma varies widely from a few mucocutaneous lesions to more florid ones with life threatening visceral involvement. Highly active antiretroviral therapy (HAART) has radically improved the outcome of this disease, and is pivotal to any treatment of the tumour. Late disease will require adjuvant chemotherapy for some duration to induce remission. Less expensive chemotherapy regimens may be needed in sub Saharan Africa heavily burdened with the disease and poverty. Various biologic agents are undergoing clinical trials at different stages and may prove useful in controlling the disease when combined with HAART and chemotherapy.

KEY WORDS
Kaposi sarcoma; AIDS; Antiretroviral therapy; Management.

INTRODUCTION
Kaposi sarcoma (KS), a multifocal tumour comprised mostly of cells of endothelial origin with a unique spindled shape, was first described by Moritz Kaposi, a Hungarian dermatologist, in 1872.[1] Although KS can present is any of the four clinicopathologic  forms/types,[1,2] AIDS-related Kaposi sarcoma (AIDS-KS), is an aggressive, epidemic type of Kaposi sarcoma and the most common presentation of KS first described in young homosexual or bisexual men with HIV as part of the AIDS epidemic in 1981.[2] Highly active antiretroviral therapy (HAART) is an integral part of the treatment of AIDS-KS and has reduced its morbidity and mortality, with adjuvant therapies mostly reserved for late disease. In sub Saharan Africa, management is more complicated due to poor access to HAART and effective adjuvant therapy. In this review, we look at the clinical manifestations of AIDS-related Kaposi sarcoma (AIDS-KS), the various strategies available for its management, and treatment challenges in sub-Saharan Africa.

CLINICAL MANIFESTATIONS
The manifestation of AIDS-KS can vary from a slowly progressive disease to an aggressive and life threatening one, with those patients not on HAART having a graver prognosis[3]. In more developed countries, the disease is generally more common in males affecting a much higher percentage of homosexual or bisexual men than heterosexual ones[4] while in Africa, although still more common in men, more women and children are affected[5]. Early AIDS-KS may appear as a subtle macular mucous or cutaneous lesion and subsequently develops into plaques and then nodules.[6,7] The lesions often become numerous and may involve the lymph nodes and visceral organs like the gastrointestinal tract, the lungs and the liver and there may be associated lymphoedema. Lesions can ulcerate, become painful, or invade deeper structures like the bone.[8,9] Visceral organ involvement rarely leads to symptoms.[10] That notwithstanding, gastrointestinal lesions could cause odynophagia, vomiting, abdominal pain, intestinal obstruction or bleeding. Pulmonary lesions may be an asymptomatic finding on a radiograph or manifest as cough, breathlessness, haemoptysis or chest pain. Pulmonary involvement could lead to death directly from the disease, though most patients with AIDS-KS die of opportunistic infection.[4]

Article4-TABLE

Extracutaneous lesions have been described in certain atypical locations like the musculoskeletal system, the heart, the nervous system, even developing within wounds and blood clots.11 In a study of 49 young homosexual men with AIDS-KS in North America in 1983, Krigel et al reported that 63% had widely distributed, innumerable skin lesions, 27% had localised or fewer than five skin lesions, and 8% had no skin lesions, and 61% had generalised lymphadenopathy and 43% had one or more gastrointestinal tract lesions.[12] Oral cavity lesions are frequent in this disease, occurring in about 20% of patients with AIDS-KS.[13] The AIDS Clinical Trial Group (ACTG) Oncology Committee published a group staging system for the evaluation of AIDS-KS based on the extent of the tumour, severity of immunodeficiency, and systemic illness variables.[14] A subsequent prospective study of 294 patients enrolled in ACTG therapeutic trials for AIDS-KS in the United States (US) showed that each of these three variables was independently associated with survival.[15] The staging system is as shown in Table 114

MANAGEMENT STRATEGIES
The current concept in the management of AIDS-KS involves an optimised standard regimen by a team experienced in treating HIV and Kaposi sarcoma.[16] HAART has led to a marked reduction in the incidence, morbidity and mortality of AIDS-KS.[17,18] The aim of treatment is symptom palliation, tumour shrinkage, and prevention of disease progression.[19] Although treatment may lead to reduction in skin, mucosal and visceral lesions with alleviation of the associated symptoms, there is no data available to show this improves survival.[20] Treatment strategy should be based on the stage of the disease, and also include prophylaxis and treatment of opportunistic infections, in addition to HAART and antitumor treatment.[4] According to the AIDS Clinical Trial Group,  many good risk patients may respond well to HAART alone, while poor risk patient will require an additional treatment modality to HAART such as chemotherapy which could be discontinued on disappearance of lesions.[21]

HAART
HAART is associated with a decrease in the incidence of AIDS-KS and reduction in the size and number of its lesions therefore patients with AIDS-KS should first of all be placed on HAART due to its benefits. The response to HAART ranges from 20 to 80%, with worse outcome in patients with more advanced tumour, and patients that were not on HAART before developing the tumour.[22]  Though there are few studies available on the efficacy of various HAART regimens, experimental studies may favour use of protease inhibitor containing regimens.[23]  In early disease, HAART alone may be sufficient as treatment. A meta-analysis found that 81% of patients without advanced AIDS-KS showed a complete response to HAART, while only 5 cases of response to HAART alone were documented in literature among persons with more advanced AIDS-KS.[23] In patients with more advanced disease, it is therefore expedient to combine HAART with adjuvant therapy.

Local therapy
A few localized AIDS-KS lesions can be amenable to surgical excision, cryotherapy, or electrodessication.[4] Intralesional vinblastine injection has also been found to be very effective.24 A phase III randomized double-blind trial on the efficacy and safety of topical application of 0.1% Alitretinoin in cutaneous AIDS-KS showed that it is beneficial, with an overall patient response rate of 37%.[25] The study also showed it was generally well tolerated. Local radiation therapy at doses of at least 20Gy is very effective, especially when targeted at localized skin and oral mucosal lesions.[26]  At fractions of 8Gy, effective treatment of skin lesions can be achieved with fewer adverse reactions.[27]

Systemic cytotoxic chemotherapy
Systemic chemotherapy is utilized for bulky, symptomatic, more aggressive, or life threatening lesions.[21] Various studies have been done on the use of anthracyclines, taxanes, vinca alkaloids, bleomycin, and etoposide as single agents, or in combination, for the treatment of AIDS-KS.Three of these agents, pegylated liposomal doxorubicin, liposomal doxorubicin, and paclitaxel have been approved by the Food and Drug Administration (FDA)  based on their clinical efficacy and reasonable side effects profile.[18] In several randomized control studies, patients showed much better response rates (vs. for pegylated liposomal doxorubicin or liposomal daunorubicin (45%–60% ), compared to the combination of doxorubicin, bleomycin, and vincristine (20%–25%).[28] The liposomal anthracyclines also showed a more acceptable toxic profile. As an adjunct treatment to HAART in the treatment of AIDS-KS, pegylated liposomal doxorubicin and paclitaxel used as single agents showed response rates near 50%.[29] Not much has been done to evaluate the effectiveness of these preferred agents in treating AIDS-KS in sub-Saharan Africa where the burden of this disease is greatest, probably due to the unavailability of these drugs.
A recent study comparing bleomycin/vincristine to vincristine monotherapy as treatment for AIDS- KS among 449 patients starting HAART in Malawi showed improved tumour response in 53% of the patients on bleomycin/vincrisine as opposed to 29% of those on vincristine alone.[30]  Nearly all the patients (98%), however, showed only a partial response.

Biologic treatment
Biologic agents studied in the treatment of AIDS-KS include interferon alpha-2a and interferon alpha-2b, bevacizumab, thalidomide, matrix metalloproteinase inhibitors like COL-2, and interleukin 12.[31-38] The interferon alphas were among the first biologic agents used in the treatment of AIDS-KS following trials in the 1980s before the advent of HAART.[4] Little is known about how they suppress AIDS-KS lesions although this may be linked to the antiproliferative and immunomodulatory properties.
In two separate studies amongst AIDS-KS patients, the interferon alphas showed response rates of 33-45% and 3-33% at high and low doses respectively, depending on the extent of the disease, earlier treatment with chemotherapy, history of opportunistic infections, CD4 count,  beta-2-microglobulin level, and the presence of circulating interferon.[31,32] There was significantly more toxicity in the patients given high doses. This high dose monotherapy is rarely given today; rather the drug is given in combination with other antiretroviral drugs.[2] High dose monotherapy is also associated with other morbidites such as neutropenia and the response is quite slow, maximal after 6 months hence it is not advisable for rapidly progressive symptomatic AIDS-KS. Bevacuzimab is a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), a factor known to contribute to the pathogenesis of Kaposi sarcoma. A phase II study of bevacuzimab in AIDS-KS patients showed a response in 5 out of 16 patients who did not improve with HAART and chemotherapy.[33] Thalidomide is another therapeutic agent which is known to inhibit angiogenesis associated with tumour progression, partially by inhibiting fibroblast growth factor. When administered to a 14 year old girl with AIDS-KS oral ulcers, thalidomide was associated with regression of the lesions, disappearance of the KS-associated herpes virus DNA from the blood, and a reduced viral load in the AIDS-KS tumour sample.[34] COL-2, a topical MMP inhibitor showed 44% response in a clinical trial but with poor tolerance by patients.[35] Matrix metalloproteinases (MMPs) help angiogenesis by breaking down extracellular matrix. Although they are involved in wound healing, MMPs can be associated with malignant tumours, and are expressed in KS.[36,37] Interleukin-12 enhances type I T-cell responses and exhibits anti-angiogenic effects.38 A phase I pilot study of interleukin 12 showed 71% partial or complete response in 24 patients with AIDS-KS whose tumour was progressing while on HAART.[38]

Antiviral therapy
Antiviral medication targeting Kaposi sarcoma associated herpes virus with cidofor has not been demonstrated to be effective by itself in the treatment of AIDS-KS.39,40

CONCLUSION
The aggressive progression of AIDS-KS demands early and prompt diagnosis of the disease with its varied manifestations, and the immediate commencement on HAART and, where necessary, as in late disease, effective adjuvant treatment. In sub-Saharan Africa, there is difficulty in readily accessing these expensive medication therefore more research is needed to discover a more affordable yet and equally effective treatment strategy.

REFERENCES

  1. Douglas JL, Gustin JK, Moses AV, Dezube BJ, Pantanowitz L. Kaposi Sarcoma Pathogenesis: A Triad of Viral Infection, Oncogenesis and Chronic Inflammation. Transl Biomed. 2010; 1(2): 172.
  2. Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men–New York City and California. MMWR Morb Mortal Wkly Rep 30 (25): 305-8, 1981. Centre for Disease Control (CDC).
  3. Sullivan RJ, Pantanowitz L, Dezube BJ. Targeted therapy in Kaposi sarcoma. BioDrugs. 2009 ;23(2): 69–75.
  4. National Cancer Institute, (2014). Kaposi Sarcoma Treatment (PDQ®). [online] Available at: http://www.cancer.gov/cancertopics/pdq/treatment/kaposis/HealthProfessional/page1/AllPages#1 [Accessed 15 Oct. 2014].
  5. Mbulaiteye SM et al. Spectrum of cancers among HIV-infected persons in Africa: the Uganda AIDS-Cancer Registry Match Study. Int J Cancer 2006;118(4):985-90
  6. Wilson D et al (ed). South African Handbook of HIV Medicine. Cape Town, Oxford University Press Southern Africa, Chapter 19, 2002.
  7. Radu O, MD; Pantanowitz L. Arch Pathol Lab Med. Vol 137, 2013: 289-294
  8. Sissolak G, Mayaud P. AIDS-related Kaposi’s sarcoma: epidemiological, diagnostic, treatment and control aspects in sub-Saharan Africa. Trop Med Int Health. 2005;10(10):981-92.
  9. Master SP, Taylor JF, Kyalwazi SK, Ziegler JL. Immunological studies in Kaposi’s sarcoma in Uganda. Br Med J 1970:1(5696):600-2
  10. Aidsmap.com, (2014). HATIP #102, 28th February 2008 – Kaposi’s sarcoma: a clinical review. [online] Available at: http://www.aidsmap.com/Kaposis-sarcoma-a-clinical-review/page/1262264/#item1262274 [Accessed 15 Oct. 2014].
  11. Pantanowitz L, Dezube BJ. Kaposi sarcoma in unusual locations.BMC Cancer. 2008;8:190.
  12. Krigel RL, Laubenstein LJ, Muggia FM: Kaposi’s sarcoma: a new staging classification. Cancer Treat Rep 1983; 67 (6): 531-4.
  13. Flaitz CM et al: Kaposi’s sarcoma associated herpesvirus-like DNA sequences (KSHV/HHV-8) in oral AIDS-Kaposi’s sarcoma: a PCR and clinicopathologic study.Oral Surg Oral Med Oral Pathol Oral Radiol and Endod 1997;83:259-264.
  14. Krown SE, Metroka C, Wernz JC: Kaposi’s sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1989;7(9): 1201-7.
  15. Krown SE, Testa MA, Huang J: AIDS-related Kaposi’s sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 15 (9): 3085-92, 1997.
  16. Antman K, Chang Y. Kaposi’s sarcoma. 2000; NEJM  vol 324, no.14, pp 1027-1038.
  17. Olweny CL, Borok M, Gudza I, Clinch J, Cheang M, Kiire CF, Levy L, Otim-Oyet D, Nyamasve J, Schipper H. Treatment of AIDS-associated Kaposi’s sarcoma in Zimbabwe: results of a randomized quality of life focused clinical trial. Int J Cancer. 2005; 113:632–639.
  18. Sullivan, R., Pantanowitz, L., Casper, C., Stebbing, J. and Dezube, B. (2008). HIV/AIDS: Epidemiology, Pathophysiology, and Treatment of Kaposi Sarcoma–Associated Herpesvirus Disease: Kaposi Sarcoma, Primary Effusion Lymphoma, and Multicentric Castleman Disease. Clinical Infectious Diseases, [online] 47(9), pp.1209-1215. Available at: http://dx.doi.org/10.1086/592298 [Accessed 15 Oct. 2014].
  19. Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, Di Trolio R, De Placido S, Dezube BJ. Management of AIDS-related Kaposi’s sarcoma. Lancet Oncol. 2007;8(2):167–176.
  20. Safai B: Kaposi’s sarcoma and acquired immunodeficiency syndrome. In: DeVita VT, Hellman S, Rosenberg S, eds.: AIDS: Etiology, Diagnosis, Treatment and Prevention. 4th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 295-318
  21. Krown SE: Highly active antiretroviral therapy in AIDS-associated Kaposi’s sarcoma: implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi’s sarcoma. J Clin Oncol 2004;22 (3): 399-402.
  22. Cattelan AM, Calabro ML, De Rossi A, et al. Long-term clinical outcome of AIDS-related Kaposi’s sarcoma during highly active antiretroviral therapy. Int J Oncol. Sep 2005;27(3):779-85.
  23. Casper C, Wald A. The use of antiviral drugs in the prevention and treatment of Kaposi sarcoma, multicentric Castleman disease and primary effusion lymphoma. Curr Top Microbiol Immunol 2007;312:289–307.
  24. Epstein JB, Lozada-Nur F, McLeod WA, et al.: Oral Kaposi’s sarcoma in acquired immunodeficiency syndrome. Review of management and report of the efficacy of intralesional vinblastine. Cancer 1989;64 (12): 2424-30.
  25. Bodsworth NJ, Bloch M, Bower M, et al.: Phase III vehicle-controlled, multi-centered study of topical alitretinoin gel 0.1% in cutaneous AIDS-related Kaposi’s sarcoma. Am J Clin Dermatol 2001;2 (2): 77-87.
  26. Cooper JS, Steinfeld AD, Lerch I: Intentions and outcomes in the radiotherapeutic management of epidemic Kaposi’s sarcoma. Int J Radiat Oncol Biol Phys 1991;20 (3): 419-22.
  27. Berson AM, Quivey JM, Harris JW, et al.: Radiation therapy for AIDS-related Kaposi’s Sarcoma. Int J Radiat Oncol Biol Phys 1990;19 (3): 569-75
  28. Northfelt DW, Dezube BJ, Thommes JA, et al.: 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 16 1998 (7): 2445-51.
  29. Cianfrocca M, Lee S, Von Roenn J, et al.: Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy. Cancer 2010;116 (16): 3969-77.
  30. Mwafongo, A., Rosenberg, N., Ng’ambi, W., Werner, A., Garneau, W., Gumulira, J., Phiri, S. and Hosseinipour, M. (2014). Treatment Outcomes of AIDS-Associated Kaposi’s Sarcoma under a Routine Antiretroviral Therapy Program in Lilongwe, Malawi: Bleomycin/Vincristine Compared to Vincristine Monotherapy. PLoS ONE, [online] 9(3), p.e91020. Available at: http://dx.doi.org/10.1371/journal.pone.0091020 [Accessed 16 Oct. 2014].
  31. Real FX, Oettgen HF, Krown SE: Kaposi’s sarcoma and the acquired immunodeficiency syndrome: treatment with high and low doses of recombinant leukocyte A interferon. J Clin Oncol 1986;4 (4): 544-51.
  32. Groopman JE, Gottlieb MS, Goodman J, et al.: Recombinant alpha-2 interferon therapy for Kaposi’s sarcoma associated with the acquired immunodeficiency syndrome. Ann Intern Med 1984;100 (5): 671-6.
  33. Uldrick TS, Wyvill KM, Kumar P, et al.: Phase II study of bevacizumab in patients with HIV-associated Kaposi’s sarcoma receiving antiretroviral therapy. J Clin Oncol 2012;30 (13): 1476-83.
  34. Soler RA, Howard M, Brink NS, Gibb D, Tedder RS, Nadal D. Regression of AIDS-related Kaposi’s sarcoma during therapy with thalidomide. Clin Infect Dis 1996;23:501-5.
  35. Dezube BJ, Krown SE, Lee JY, Bauer KS, Aboulafia DM. Randomized Phase II Trial of Matrix Metalloproteinase Inhibitor COL-3 in AIDS-Related Kaposi’s Sarcoma: An AIDS Malignancy Consortium Study. J Clin Oncol 2006;24(9):1389–1394.
  36. Benelli R, Adatia R, Ensoli B, Stetler-Stevenson WG, Santi L, Albini A. Inhibition of AIDS-Kaposi’s sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy. Oncology research 1994;6(6): 251-7
  37. Blankaert D, Simonart T, Van Vooren JP, Parent D, Liesnard C, Farber CM, et al. Constitutive release of metalloproteinase-9 (92-kd type IV collagenase) by Kaposi’s sarcoma cells. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jul 1;18(3):203–9.
  38. Little RF, Pluda JM, Wyvill KM, et al.: Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma. Blood 2006;107 (12): 4650-7.
  39. Little RF, Merced-Galindez F, Staskus K, et al. A pilot study of cidofovir in patients with Kaposi sarcoma. J Infect Dis 2003;187:149–153.
  40. Grundhoff A, Ganem D. Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis. J Clin Invest 2004;113:124–136.