Download Kaposi`s Sarcoma - World Health Organization

KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
KAPOSI’S SARCOMA
Executive Summary
Kaposi’s sarcoma (KS) is the most common tumor in HIV-infected individuals in Africa (1).
However, it was relatively common in South Africa before the HIV/AIDS epidemic with an
incidence of 5 per 100,000 individuals being at risk of developing it (2). After the advent of
HIV/AIDS, the incidence increased dramatically ( 3). In Kenya, a study by Onyango et al (2004)
at Kenyatta National Hospital showed that mucocutaneous KS had a relative frequency of 2 to
5% of all malignancies with a male to female ratio of 2:1.
KS is a vascular tumor which arises in multifocal sites. The skin is most commonly involved,
though virtually any organ, except perhaps the brain can be involved. It exists in four forms –
classic, equatorial Africa endemic, secondary to iatrogenic immunosuppression, and HIV/AIDSrelated forms.
The classic form occurs in older men of Mediterranean or Jewish background. It presents with a
few cutaneous lesions on the lower limbs and has an indolent nature. The equatorial Africa form
occurs in all age groups (endemic KS). It is usually aggressive in nature, affecting both adults
and children. The form associated with immune suppression post organ transplantation was first
noted in renal transplant recipients and has been described in other transplant recipient patients.
HIV-1 associated KS (epidemic form) is an aggressive form which presents with cutaneous
and/or visceral lesions. It has been noted that highly active antiretroviral therapy (HAART) alone
improves the outcome of HIV associated KS (4,5). In South Africa, addition of chemotherapy to
HAART achieve higher KS response over 12 months as compared to HAART alone (6).
Patients with aggressive forms of KS are commonly treated with paclitaxel or doxorubicin (or
liposomal doxorubicin), bleomycin and vinblastine or vincristine (ABV). The ABV regimen has
been shown to give better response rates than BV (Bleomycin, vinblastine / vincristine) alone
(6,8). This regimen was however not very popular because of toxicity (8) Gemcitabine
monotherapy has been suggested as an alternative option in patients previously treated with ABV
(9).
Paclitaxel, with response rates ranging from 59%-71% when given without HAART (12,13), is
considered the most attractive agent since it is effective and tolerable over long-term
administration especially when combined with growth factors (13,14). Paclitaxel for this reason
should be added to the essential medicines list.
Liposomal daunorubicin (Dauno Xsome) and pegylated liposomal doxorubicin (Doxil) are
popular in high-income countries because of a better toxicity profile, and have similar efficacy as
ABV though no studies support its superiority when compared to ABV or doxorubicin (8,10).
1 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
These agents are more costly, and without clear proved incremental benefit over other regimens,
are not being recommended for including in the EML.
Alpha interferon and radiotherapy have also been used in the management of AIDS-associated
KS. Their use has been limited by the toxicity profile. Rapamycin was noted to be safe in HIV
infected individuals with KS and can in some cases induce tumor regression (11).
Public Health Relevance
Kaposi’s sarcoma is a relatively rare cancer worldwide. GLOBOCAN estimated 44,247 new
cases and 26,974 deaths worldwide in 2012 (22). 2012 data shows 40,874 of new cases in less
developed regions and 3,373 new cases in more developed regions. The African continent is
disproportionately affected, where 37,509 (85%) of all cases occur. Men are approximately 2
times more at risk for developing Kapsosi’s sarcoma than women worldwide.
Kasposi’s sarcoma has four classifications, based on varying clinical characteristics and risk
factors (23). Classic Kasposi’s sarcoma affects elderly, immunocompetent individuals of
Mediterranean or Eastern European descent. It is a slow-progressing and relatively benign form
of the cancer. Endemic or African Kaposi’s sarcoma is most common in Central and Eastern
Africa and primarily affects adults. Iatrogenic Kaposi’s sarcoma is found in populations with
compromised immune systems, primarily in patients who have received organ transplants.
AIDs-Kaposi’s sarcoma develops in populations infected with HIV-AIDS. In Western countries,
AIDS-KS is most commonly found in HIV-infected men who have sex with men. In certain
African countries with high rates of HIV, AIDS-KS affects men and women proportionately, and
there is also a high incidence in children (23).
Requirements for diagnosis, treatment, and monitoring
Diagnostics:
First and foremost is the clinical picture of erythematous violaceous cutaneous lesions that can
be macular, patch, plaque, nodular or exophytic. The lesions can be solitary, localized or
disseminated. This in the background of HIV/AIDS should alert the physician to the diagnosis of
KS. The presence of local/regional lymphoedema almost gives away the diagnosis. However
tissue confirmation is mandatory before instituting any form of therapy.
Local punch biopsy or rarely, excision biopsy are all that are required for a skin biopsy. Lymph
node excision can also be done in predominantly nodal lesions. Endoscopic biopsies may be
required for lesions presenting solely in visceral lumens. Tissues should be subjected to
pathologic examination by an experienced histopathologist.
Testing:
Any patient with a diagnosis of Kaposi’s sarcoma must have HIV test done. Positive cases must
have differential lymphocyte counts and where possible HIV viral load. Quite often the patients
2 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
are anemic, or thrombocytopenic, or neutropenic. Complete blood counts must be assayed.
Various forms of kidney injury also occur; therefore renal function studies must be carried out.
Liver function tests and coagulation assays should also be carried out. Cardiac function
assessment should be carried out because the anthracycline doxorubicin, whether pegylated or
not, is a key agent in the management of this disease, with the attendant risk of cardiotoxicity.
Patients with HIV/AIDS commonly have concurrent opportunistic infections including
tuberculosis, and opportunistic tumors including aggressive subtypes of B cell lymphomas. Their
coexistence greatly alter the treatment approaches, therefore appropriate imaging should be
carried out as indicated.
Solitary asymptomatic, nonulcerated patch lesions can just be managed with appropriate
combination antiretroviral therapy. Surgical excision may have a role if lesions are raised and/or
symptomatic, though this is controversial, since there is a tendency for new lesions to spring up
from the excision wound edges. Locoregional lesions can be managed appropriately with
radiation.
Administration and Care of Patients:
Clinical needs include the ability to manage patients with HIV who are on antiretroviral therapy,
and the issues surrounding that treatment. Facilities need to be adept at managing additional
services for HIV-positive patients, including following of CD4 counts, organ function, and
management of HIV related infectious complications. Management of cytopenias related to HIV
and cytotoxic agents is paramount.
In regard to management of KS, clinical assessment skills are required.
For the administration of the regimens described, there is the need for safe and effective
ordering, preparation and administration of parenteral chemotherapy as listed. Care and skill in
the administration of vesicants such as vincristine and doxorubicin is needed. Specifically
clinical and laboratory assessment are required, as well as the infrastructure to deliver parenteral
chemotherapy. Management of potential allergic reactions to taxanes, bleomycin and other
drugs are required. Skills in management of potential lung toxicity from bleomycin is also
required. Skills in management of potential neuro-toxicity from vincristine and taxanes is
needed.
3 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Overview of Regimens
The following tables include basic information on administration and dosing for a Basic
Regimen and an Advanced Regimen, and exclude ancillary medications pertaining to the
management of side effects. For the therapeutic regimens considered, treatment duration is based
on clinical judgment.
Standard Regimen
Paclitaxel
Paclitaxel
Paclitaxel
Intravenous infusion
Intravenous infusion
100 mg/m2 q 2 wks
135 mg/m2 q 3 wks
Alternative Regimens (if paclitaxel is not available or not tolerated) Vincristine: 6 cycles
Vincristine
Bolus intravenous
1.4 mg/m2 q 2 wks
Vincristine/Bleomycin: 6 cycles
Vincristine
Bolus intravenous
Bleomycin
Bolus intravenous
1.4 mg/m2 q 2 wks
10 iu/m2 q 2 wks
ABV for HIV-positive Patients: 6 cycles
Vinblastine
Bolus intravenous
Bleomycin
Bolus intravenous
Doxorubicin
Intravenous infusion
6 mg/m2 q 2 wks
10 iu/m2 q 2 wks
25 mg/m2 q 2 wks
ABV for HIV-negative Patients: 6 cycles
Vinblastine
Bolus intravenous
Bleomycin
Bolus intravenous
Doxorubicin
Intravenous infusion
6 mg/m2 q 3 wks
10 iu/m2 q 3 wks
50 mg/m2 q 3 wks
Note: The liposomal doxorubicin preparations are acceptable for treatment of Kaposi’s
sarcoma, and in some patients have a favorable toxicity profile, but are no more efficacious
than the regimens described above, and considerably more costly, therefore we are not
recommending that it be added to the EML.
4 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Review of Benefits and Harms
Benefits
In high-income countries where patients with HIV/KS are likely to present with disease that is
not widespread, response rates ranging between 22% - 80% have been reported with combined
antiretroviral therapy alone (4,5,15,16). This situation is highly unlikely to hold for low-income
countries where patients present with bulky, advanced disease (6). In a South African study
patients on combined antiretroviral therapy and chemotherapy fared better than patients on
combined antiretroviral therapy alone(6). Krown and colleagues in New York also noted that it
was extremely rare for patients with extensive, poor risk KS to respond to HAART alone (17).
The treatment of HIV KS is basically palliative and complete remission is not a realistic goal.
Various treatment regimens are available with differing response rates and toxicity profiles.
Paclitaxel, with response rates ranging from 59%-71% when given without HAART (12,13), is
considered the most attractive agent since it is effective and tolerable over long term
administration especially when hematopoietic growth factor support is incorporated (13,14,).
Harms and Toxicity Considerations
Common
Patients with KS treated with paclitaxel commonly experience alopecia, myelosuppression
including neutropenia, anemia and thrombocytopenia, and mild peripheral neuropathy.(13)
Paclitaxel administration requires premedication with glucocorticoids and antihistamines to
reduce the risk of infusion reactions.
Vinca alkaloids including vincristine and vinblastine are associated with a high incidence of
neurotoxicity, typically manifesting as sensory neuropathy, which is usually reversible.(18) This
neuropathy also reduces GI transit time leading to constipation specifically with vincristine and
vinblastine, which may warrant prophylaxis.(19)
Serious
Myelosuppression with paclitaxel, PLD and/or vinblastine can be severe and may lead to an
increased risk of opportunistic infection or other serious infection in this patient population.
(10,13)
Bleomycin is associated with rare but potentially serious cases of pulmonary fibrosis. (10,21)
The risk of toxicity is dose-dependent (increasing with cumulative doses above 400 units) and
therefore bleomycin dosed in the regimens above has very little risk of this adverse effect.
Doxorubicin/PLD can lead to long term cardiomyopathy when cumulative doses exceed
450mg/m2. This risk is dose-dependent and at the doses delivered with regimens here (<300
mg/m2), the risk is small.(10,20) This information has been kept in for comprehensiveness,
however PLD is not recommended for addition to the List of Essential Medicines.
5 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Systematic Reviews
Gbabe OF et al. Treatment of severe or progressive Kaposi’s sarcoma in HIV- infected adults
(Review). Cochrane Reviews. 2013:1–76.
Background: Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the
second most common cancer in HIV-infected patients worldwide. Since the introduction of
highly active antiretroviral therapy (HAART), there has been a decline in its incidence.
However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients. Objectives: To
assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the
advantages of different chemotherapy regimens in HAART and HAART naive HIV infected
adults with severe or progressive Kaposi's sarcoma. Selection Criteria: Randomised trials and
observational studies evaluating the effects of any chemotherapeutic regimen in combination
with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons
between different chemotherapy regimens. Data Collection and Analysis: Two review authors
assessed the studies independently and extracted outcome data. We used the risk ratio (RR) with
a 95% confidence interval (CI) as the measure of effect. We did not conduct meta-analysis as
none of the included trials assessed identical chemotherapy regimens. Main Results: We
included six randomised trials and three observational studies involving 792 HIV-infected adults
with severe Kaposi's sarcoma. Seven studies included patients with a mix of mild to moderate
(T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of
participants with severe Kaposi's sarcoma disease. Studies comparing HAART plus
chemotherapy to HAART alone showed the following: one trial comparing HAART plus
doxorubicin, bleomycin and vincristine (ABV) to HAART alone showed a significant reduction
in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100
participants); there was no statistically significant reduction in mortality and no difference in
adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART
alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution
inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR
0.49; 95% CI 0.16 to 1.55, 129 participants). Studies comparing HAART plus chemotherapy to
HAART plus a different chemotherapy regimen showed the following: one trial involving 49
participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on
HAART showed no difference in disease progression. Another trial involving 46 patients and
comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no
participants with progressive Kaposi's sarcoma disease in either group. Studies comparing
different chemotherapy regimens in patients from the pre-HAART era showed the following: in
the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference
with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95%
CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178
participants and comparing oral etoposide versus ABV demonstrated no difference in mortality
in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a
higher median survival time in the ABV group; there was also a non-statistically significant
reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to
179.29, 24 participants). An additional non-randomised study showed a non-statistically
significant overall mortality benefit from liposomal doxorubicin as compared to conservative
6 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
management consisting of either bleomycin plus vinblastine, vincristine or single-agent
antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality
of evidence can be described as moderate quality. The quality of evidence was downgraded due
to the small size of many of the included studies and small number of events. Authors’
Conclusions: The findings from this review suggest that HAART plus chemotherapy may be
beneficial in reducing disease progression compared to HAART alone in patients with severe or
progressive Kaposi's sarcoma. For patients on HAART, when choosing from different
chemotherapy regimens, there was no observed difference between liposomal doxorubicin,
liposomal daunorubicin and paclitaxel.
Additional reviews supporting the use of paclitaxel in HIV KS can be found in:
•
•
•
•
•
Yarchoam R, and Little RF. Immunosuppression-related malignancies. In: DeVita VT Jr,
Lawrence TS, Rosenberg SA. Cancer: Principles and Practice of Oncology. Wolters
Kluwer Lippincotts, Williams and Wilkins, 8th Edition, pp2404-2407.
Aboulafia D. AIDS-related malignancies: Non-Hodgkin’s lymphoma and Kaposi’s
sarcoma. In: ASC0-SEP. Medical oncology self-evaluation program 2007, pp 283-286.
Ayoro OC. A study to determine the influence of chemotherapy on outcomes of AIDSassociated muco-cutaneous Kaposis’ sarcoma at Kenyatta National Hosipital. Masters of
Medicine Dissertation, University of Nairobi, 2014.
Schwarz RA. Kaposi sarcoma treatment protocols. Medscape April 16, 2013.
Krown SE, et al. Letters to the editor: Stage-stratified approach to AIDS-related Kaposi’s
sarcoma: Implications for resource-limited environments. J Clin Oncol 2014;32:25122513.
Recommendations
The reviewers recommend the incorporation of Kaposi’s sarcoma treatment options into the
WHO Model List of Essential Medicines. All medicines are already listed in the WHO’s 2013
List of Essential Medicines.
Additions proposed for Section 8.2 of the EML
None
7 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
References
1. Whitby D, Howard MR, Tenant-Flowers M, et al. Detection of Kaposi’s sarcoma associated
herpesvirus in peripheral blood of HIV infected individuals and progression to Kaposi’s
sarcoma. Lancet 1995, 346: 799-802.
2. Cook-Mozaffari P, Newton R, Baral V, et al. The geographical distribution of Kaposi’s
sarcoma and of lymphomas in Africa before the AIDS epidemic. Br J Cancer 1998, 78:152128.
3. Del Maso L, Serraino D, Franceschi S. Epidemiology of AIDS related tumours in developed
and developing countries. Eur J Cancer, 2001, 37:1188-1201.
4. Dupin N, Rubin de Cervens V, Gorin I, et al.The influence of HAART on AIDS-associated
KS. Br J Dermatol 1999; 140:875-81.
5. Mosam A, Uldrick TS, Shaik F, et al. An evaluation of the early effects of a combination
antiretroviral therapy programme on management of AIDS-associated Kaposi’s sarcoma in
Kwa Zulu Natal, South Africa. Int J STD AIDS 2011; 22(11):671-73.
6. Mosam A, Shaik F, Uldrick TS, et al. A randomized controlled trial of HAART and
chemotherapy in therapy-naive patients with HIV-associated Kaposi’s sarcoma in South
Africa. J Acquir Immune Defic Syndr 2012, Mar 19(e-published ahead of print).
7. Gill PS, Rarick M, McCutchan JA, et al. Systemic treatment of AIDS-related Kaposi’s
sarcoma: results of a randomized trial. Am J Med 1991; 90: 427-33.
8. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin
versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J Clin
Oncol 1996;14:2353-64
9. Makombe SD, Harries AD, Yu JK, et al. Outcomes of patients with Kaposi’s sarcoma who
start antiretroviral therapy under routine programme conditions in Malawi. Trop Doct 2008
38:5
10. Stewart J, Jablonowski H, Goebel FD, et al. Randomized comparative trial of pegylated
liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related
Kaposi’s sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin
Oncol 1998;16:683-91.
11. Krown SE, Roy D, Lee JY, et al. Rapamycin with antiretroviral therapy in AIDS-associated
Kaposi’s sarcoma: An AIDS Malignancy Consortium Study. J Acquir Immune Defic Syndr
2012 Apr 15; 59(5):447-54.
12. Seville MW, Lietzau J, Pluda JM, et al. Treatment of HIV-associated Kaposi’s sarcoma with
paclitaxel. Lancet 1995;346:26-8
8 KAPOSI’S SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
13. Gill PS, Tulupe A, Espina BM, et al. Paclitaxel is safe and effective in the treatment of
advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 1999;17:1876-83.
14. Saville MW, Lietzan J, Pluda J et, al. A phase ll trial of Paclitaxel (Taxol) in patients with
HIV-associated Kaposi’s sarcoma. AIDS Res Hum Retrovirol 1994; 10(suppl.): S103.
15. Aversa SM, Cattelan AM, Salvagno L, et al. Treatment of AIDS-related Kaposi’s sarcoma.
Crit Rev Oncol Hematol2005;53:253-265.
16. Cattelam AM, Calabro MI, De Rossi A, et al. Long-term outcome of AIDS-related Kaposi’s
sarcoma during highly active antiretroviral therapy. Int J Oncol 2005;27:779-85.
17. 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;22:399-402.
18. Lee EQ, Wen PY. Overview of neurologic complications of non-platinum cancer
chemotherapy. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA, 2014.
19. Krishnamurthi SS. Enterotoxicity of chemotherapeutic agents. In: UpToDate, Post TW (Ed),
UpToDate, Waltham, MA, 2014.
20. Floyd J, Morgan JP. Cardiotoxicity of anthracycline-like chemotherapy agents. Post TW
(Ed), UpToDate, Waltham, MA, 2014.
21. Gilligan TD. Bleomycin-induced lung injury. In: UpToDate, Post TW (Ed), UpToDate,
Waltham, MA, 2014
22. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide,
2012. www.globocan.iarc.fr. Accessed 5 November 2014.
23. Sarid R and Calabro ML. Kaposi’s Sarcoma-Associated Herpesvirus: Epidemiology,
Biological Characteristics and Pathogenesis. Viral Infections of Humans 2014: 897-931
9