© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 59-63,
1998
© 1998 Oxford University Press
Clinical Overview: Issues in Kaposi's Sarcoma Therapeutics
* Affiliation of author: Clinical Immunology Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
Correspondence to: Susan E. Krown, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
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Abstract |
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 Top Abstract IntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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Four questions are posed that are critical to the development of improved therapeutic and prophylactic strategies for Kaposi's sarcoma (KS). 1) Can we predict who will develop KS? Accurate identification of high-risk factors for KS development is essential for the development of KS prophylaxis trials. 2) Can developing insights into KS pathogenesis be translated into improved therapeutic and/or new prophylactic strategies for patients at high risk? Several approaches are being developed that target new blood vessel development, inflammatory cytokines, and the viruses that are implicated in KS pathogenesis. 3) How does the improved prognosis for human immunodeficiency virus (HIV)-infected patients affect KS treatment strategy? Improved anti-HIV therapy has implications for the timing of KS therapy, the choice of therapeutic approaches, and the potential for adverse drug interactions. 4) How can we best evaluate benefits from KS treatment? More rigorous, standardized criteria are in development and will be essential not only for accurate documentation of objective tumor regression, but also for assessment of tumor-associated symptom relief in a quantitative, function-oriented way.
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Introduction |
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TopAbstractIntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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Tremendous progress has been made recently in identifying the factors that contribute to the development of Kaposi's sarcoma (KS), the most common cancer associated with human immunodeficiency virus type 1 (HIV-1) infections, but treatment of KS remains suboptimal. In reviewing the issues in KS management, the following four critical questions must be addressed as attempts are made to improve therapy and develop KS prophylaxis strategies over the next several years:
- Can we predict who will develop KS?
- Can developing insights into KS pathogenesis be translated
into improved therapy and/or new prophylactic strategies for
patients at high risk?
- How do the improved treatments and prognosis for HIV-infected
patients affect our overall KS treatment strategy?
- How can we best evaluate benefits from KS treatment?
These issues will be briefly discussed in the succeeding sections of this article.
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Prediction of KS Development |
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TopAbstractIntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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The ability to predict who will develop KS is critical for the development and interpretation of prophylaxis trials. The potential to intervene prior to the development of KS is an exciting new possibility, but some prophylactic strategies may involve the administration of drugs with toxic potential, so accurate identification of high-risk individuals is essential. Although we have known for a long time that, in developed countries, HIV-infected gay and bisexual men are most likely to develop KS, only a minority do so. In developed countries, however, it is often not appreciated that HIV-infected individuals from other transmission groups also show a marked increase in KS risk that has recently been estimated in the United States as 10 000 times greater than that in the age- and sex-matched general population (1). Therefore, sexual orientation and behavior alone are not sufficient to identify who will develop KS in the United States, and they are not relevant factors in other parts of the world, like Africa, where KS incidence is relatively high in both sexes and is not associated with male homosexuality.
Although human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) has not been established as the cause of KS (i.e., no published data show that the virus can transform and immortalize cells), the presence of HHV-8 infection has now been unquestionably linked to KS. There is, however, increasing evidence in patients with established KS that no single serologic assay detects evidence for HHV-8 infection in all patients (2,3), whereas certain methods detect antibodies in a substantial minority of unaffected, low-risk individuals (2,3). Clearly, therefore, the sensitivity and specificity of these tests need to be improved, and the relevant serologic responses must be identified. Studies are also needed to confirm whether antibody titer correlates with subsequent KS risk (4) and to evaluate whether detection or burden of HHV-8 DNA in cells adds predictive value to the serologic assays that are better suited to large-scale screening.
If we accept that not all individuals with evidence of HHV-8 infection are at equal risk for KS development, we also need to ask whether other factors interact with HHV-8 either to promote KS development or to protect against it. Those who treat KS have often observed sudden, rapid tumor progression around the time an opportunistic infection develops and improvement when the infection was treated, lending credence to the idea that excess production of inflammatory cytokines as well as increased HIV replication itself may stimulate KS growth. Also observed, on less frequent occasions, has been regression of KS lesions when active antiretroviral therapy was instituted (5). These observations in patients with established KS are the clinical counterpart to numerous laboratory observations predating the discovery of HHV-8 that implicated a wide range of cytokines, angiogenic factors, and HIV products in KS pathogenesis (6-9). We now need to look more closely at the role of these factors as codeterminants, with HHV-8, of future KS development. Within the AIDS Malignancy Consortium (AMC), a recently established, National Institutes of Health-supported multicenter trials group, active discussions are under way to design these predictive investigations and to use them to develop prophylaxis and natural history trials.
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Pathogenesis-Based Therapeutic and Prophylactic Strategies for KS |
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TopAbstractIntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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Several cytotoxic agents have been identified that can induce regression, albeit temporary, of established, advanced KS (10). At the National AIDS Malignancy Conference, the activity of two recent introductions to the therapeutic armamentarium, paclitaxel and vinorelbine, was described (11,12). Paclitaxel's ability to inhibit angiogenesis (13) may partially explain its apparent high activity and the relatively long duration of response it induces in patients with advanced, refractory disease. Although the introduction of these agents increases the options for treatment of aggressive, widespread KS, there is still a need for therapy that induces higher and longer-lasting response rates. There is also a perceived need on the part of many investigators to develop effective therapy that makes better "biologic sense." This sort of targeted approach, based on the rapidly growing but still incomplete knowledge of KS pathogenesis, has tremendous intellectual appeal and has inspired a variety of clinical trials. With some exceptions, the results thus far have been mostly quite limited. However, for a number of these approaches directed against the formation of new blood vessels, inflammatory cytokines, and the viruses implicated either indirectly or directly in KS pathogenesis, there are some glimmers of activity that merit a closer look.
Antiviral Strategies
Both HIV-1 and HHV-8 are potential targets for anti-KS therapy. Although HIV-1 infection is not a requirement for development or progression of KS, active infection with HIV-1 is associated with high levels of inflammatory cytokines implicated in the development of KS lesions (14,15). In addition, the HIV-1 Tat protein, which is released into the extracellular milieu by productively infected cells, also serves as a mitogen for KS-derived spindle cells in vitro and acts synergistically with growth factors and inflammatory cytokines to increase KS cell proliferation (8,9). It should not be surprising, therefore, that effective control of HIV-1 replication achieved through the use of highly active antiretroviral drug regimens has now been reported to induce KS regression in some patients (5) and to obviate the need for long-term maintenance chemotherapy in others (16). It is also possible that the improved KS response rates seen when nucleoside reverse transcriptase inhibitors are added to interferon alfa (17,18) may be partially attributable to the synergistic antiretroviral activity of these agents. Anecdotal reports that established KS regressed after treatment with foscarnet (19) and several studies that showed a decreased incidence of subsequent KS in patients treated with antiherpesvirus agents (20,21) suggest that, under some circumstances, inhibition of HHV-8 may also be of therapeutic or prophylactic value. However, none of the agents tested is specific for HHV-8 (the treatments were directed against cytomegalovirus and the studies were not designed to evaluate effects on HHV-8), so the mechanism of KS inhibition in these cases is entirely speculative. It is also possible that part of interferon's anti-KS activity may involve direct HHV-8 inhibition. Although this possibility has not been specifically tested, interferon has been shown to inhibit a closely related virus, Herpesvirus saimiri(22). Even if KS is the product of viral transformation, a consistent therapeutic effect of antiherpesvirus agents against established KS is probably unlikely, since the growth of transformed cells is often independent of the virus. It may be more plausible to envision a prophylactic role for such agents if they are administered prior to a putative transforming event.
Cytokine Inhibition Strategies
A number of proinflammatory cytokines whose production is reportedly increased in some patients with HIV infection have also been considered targets for KS therapy. Tumor necrosis factor (TNF) and interleukin 1 (IL-1) have each been shown to stimulate KS cell proliferation in vitro, either directly or through induction of interleukin 6 (IL-6) (6,7), and various agents that modify their production or action have either been tested in early clinical trials or proposed as candidate therapeutic agents. Of particular note are the retinoids, which are multifunctional agents among whose many attributes are down-regulation of both IL-6 receptors and IL-6 production in myeloma cells (23), and thalidomide, a specific inhibitor of TNF (24). One retinoid, 9-cis-retinoic acid, which interacts with both the retinoic acid receptor and the retinoid X receptor, has shown anti-KS activity when applied locally to KS lesions in gel form (25). The AMC is now testing this as a systemic, orally administered drug, and there are some early indications of anti-KS activity. In addition, Bernstein et al. (26) have recently presented preliminary evidence of anti-KS activity for an intravenously administered liposomal preparation of all-trans-retinoic acid. Preliminary clinical evidence from two studies (27,28) suggests that orally administered thalidomide may also have substantial anti-KS activity. Interferon alfa, which has demonstrated activity against KS in some patients (29), has been shown in clinical trials in normal volunteers and patients with chronic hepatitis to induce the production of the soluble TNF receptor and the IL-1 receptor antagonist (30,31), which are endogenous down-regulators of these KS stimulatory cytokines. Other potential candidate agents that target cytokines, but which have not yet been tested, include the soluble TNF receptor, the IL-1 receptor antagonist, and the matrix metalloproteinase inhibitor marimistat, which also possesses inhibitory activity against TNF convertase, an enzyme that converts TNF to its active form.
Angiogenesis Inhibitory Strategies
A large number of strategies aimed at the inhibition of angiogenesis have been proposed. Some of these approaches have not yet been tested clinically, but candidate agents are already in development. These include, for example, inhibitors of matrix metalloproteinases, enzymes that facilitate capillary budding and invasion (32), agents targeted at distinctive endothelial cell surface molecules present on proliferating tumor-associated vasculature (33,34), and agents that interfere with angiogenic polypeptide signal transduction (35).
Agents utilizing other approaches have been tested with mixed results. For example, the fumagillin analogue TNP-470 has been studied in two phase I trials in patients with KS, yielding a few partial tumor responses in one study (36) and a significant reduction in tumor-associated edema in some patients (37). Several heparin-binding compounds that are thought to inhibit angiogenesis by blocking basic fibroblast growth factor (bFGF) receptor binding have also been studied in phase I trials, and while the high hopes and expectations for these agents have not been realized, evidence for biologic activity has been observed. For example, in some patients treated with tecogalan, a significant reduction in KS-associated edema was seen (38), perhaps signifying an important biologic effect. Interferon alfa and thalidomide are also capable of acting as angiogenesis inhibitors: Interferon inhibits bFGF gene expression and production in certain human tumor cell lines (39) and also inhibits endothelial cell motility, whereas thalidomide (in addition to its inhibitory effects on TNF production) may inhibit angiogenesis by multiple mechanisms, including inhibition of bFGF-induced vascular proliferation, intercellular adhesion, basement membrane formation, and overall vascular maturation (40). The relative success of interferon alfa in controlling KS and possibly also thalidomide—although it is probably too early to comment on thalidomide's usefulness—may be a function of the sheer multiplicity of their potential targets and suggests that some of the other agents with more restricted targets may be successful in controlling KS only when used as part of combination regimens directed at multiple steps in the development of KS lesions. It is disappointing, therefore, to see that the further development of a number of these agents is not being pursued, at least partially, because of their apparent lack of substantial efficacy as single agents. However, as discussed by Judah Folkman at this conference, it may be that newer agents such as angiostatin (41) or endostatin (42) will be far more active than some of those already shown to have only marginal single-agent activity.
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Effect of Improved HIV Therapy on KS Treatment Strategy |
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TopAbstractIntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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Patients with HIV infection are surviving longer as a result of improved antiretroviral therapy. These advances in HIV management are likely to benefit patients at all stages of HIV infection, including those with KS. The prospect of managing KS over a period of many years, rather than over a much shorter time period, raises several new questions and challenges that will need to be addressed when devising therapeutic plans and designing new therapeutic trials:
- When in the course of KS should treatment begin and with which
approaches or agents? Controversy about this issue preceded the
introduction of HIV protease inhibitors, and the apparent
benefits of state-of-the-art antiretroviral therapy on KS in some
patients have made definition of the optimum KS treatment
strategy even more complex.
- A corollary of the first question is: Has more effective anti-HIV
therapy rendered the need to find better KS therapy obsolete?
Alternatively, are we merely in a "honeymoon" period
that will end—as most honeymoons do—with increasing
numbers of patients becoming affected by KS later in the course
of their infection?
- If we assume that the honeymoon will end, we need to ask: Will
better control of HIV and its nonmalignant complications allow
pathogenesis-based strategies to work better, and should this
prompt a re-examination of some agents that were considered
ineffective in the era before protease inhibitors?
- We also need to ask: Will better control of HIV and its
complications also lead to higher response rates, longer response
durations, or a reduced need for maintenance therapy in patients
on standard KS therapies?
- Will the increasingly complex drug regimens of HIV-infected
patients lead to untoward interactions with anti-KS therapies?
Recently, for example, D. Scadden (personal communication, 1997)
observed severe toxicity from paclitaxel when a patient who had
been tolerating the drug well while on lamivudine, stavudine, and
indinavir was switched to a combination of delavirdine,
didanosine, and saquinavir. The metabolism of many cytotoxic
agents is dependent on hepatic enzymes whose activity may be
induced or inhibited by protease inhibitors and non-nucleoside
reverse transcriptase inhibitors. Interferon alfa may also
inhibit certain cytochrome P450 enzymes (43), potentially affecting the metabolism of certain
protease inhibitors. These potential drug interactions will be
studied in several upcoming trials in patients with KS.
- Do we need to be more concerned about the long-term consequences
of chemotherapy for KS? There has been a recent trend toward the
earlier use of chemotherapeutic agents like Doxil and DaunoXome.
These drugs are well tolerated by most patients and rarely induce
hair loss, nausea, or vomiting (44,45),
making many patients and perhaps even some physicians view them
as something other than chemotherapy. Now that the life span of
some patients with advanced KS may be measured in years, however,
we need to be more concerned about the development of secondary
cancers and other late complications of cytotoxic agents.
- Have we gone as far as we can go with standard chemotherapeutic
agents? Currently, few new cytotoxic agents are considered as
candidates for testing in KS. The results of studies using
combinations of several active drugs, such as the recently
completed AIDS Clinical Trials Group (ACTG) comparison trial of
Doxil alone or combined with bleomycin and vincristine (46) suggest that we may have reached a
point of diminishing returns, where responses are not
significantly increased but quality of life is diminished.
Therefore, it is more important than ever to develop targeted,
pathogenesis-based therapeutic strategies for KS.
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Methods to Evaluate Benefits From KS Treatment |
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TopAbstractIntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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In order to measure the benefits of treatment for KS, it is necessary to document not only whether tumor regression has occurred, but also whether the patient is better and has shown tangible benefits that extend beyond tumor shrinkage. This is true for any tumor but may be especially so for KS, which may not always be directly life-threatening but may adversely affect quality of life by causing pain, disfigurement, or functional disability. The standardized methods of evaluation and criteria for response, developed and later refined by the Oncology Committee of the ACTG (47), were an improvement over the vague and varied criteria used previously. However, these evaluation and response criteria have been criticized because of difficulties in the ability to reproduce and document lesion counts and measurements, the lack of standardized assessments of hard-to-measure visceral disease and edema, and the failure of the criteria to capture the clinical benefits such as pain relief, improvement in disfiguring lesions, and functional improvements induced by successful KS therapy.
Some of the problems with the ACTG criteria have stemmed from the failure of some investigators to consistently perform the repeated lesion counts and lesion measurements that were required to document response, but there is also general agreement that more rigorous standards of documentation are desirable. Feigal et al. (48) have described the joint efforts of the National Cancer Institute, the Food and Drug Administration, and the AMC to strengthen the process by which KS therapy is evaluated. This will include documentation not only of lesion size, character, and number in the skin and visceral sites, but also of physician and patient assessment of tumor-associated symptom relief in a function-oriented, quantitative way. Rigorous collection of the varied types of documentation required for these assessments will be tedious and time consuming but is an essential step in making effective therapy widely available to patients.
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Summary and Conclusions |
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TopAbstractIntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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Several challenges must be met in order to improve the therapy of AIDS-associated KS over the coming years. The opportunity now exists to consider strategies to prevent KS development, but more sensitive and specific methods are needed to accurately identify those patients at highest risk. Increased knowledge of the biology of KS now permits the development of therapeutic strategies that target critical elements in KS pathogenesis. To some extent, these sorts of approaches have already been applied with some moderately successful examples; however, opportunities are expanding as a more sophisticated understanding of the complex processes involved in KS development unfolds and as an increasing number of agents are developed that influence specific pathogenetic targets. The introduction of highly active antiretroviral therapy now presents the opportunity to manage KS over a period of many years. Although more successful anti-HIV therapy may lead to fewer patients affected by KS or to a decrease in KS severity, it is also possible that longer survival with HIV infection may be associated with an increase in KS incidence over time. These possibilities raise important yet unanswered questions about optimum treatment strategies, the long-term consequences of cytotoxic chemotherapy, and the potential for adverse drug interactions as treatment regimens become more complex. Rigorous standards are needed to accurately measure the benefits of KS therapy, so that safe and effective new agents can be expeditiously introduced into clinical practice. Methods now exist to measure changes in tumor size and number, but development of quantitative scales to evaluate functional status, pain, and quality of life presents a more difficult challenge in the drug development process.
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TopAbstractIntroductionPrediction of KS DevelopmentPathogenesis-Based Therapeutic...Effect of Improved HIV...Methods to Evaluate Benefits...Summary and ConclusionsReferences |
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