Discussion

June 2, 1996
Oncology, ONCOLOGY Vol 10 No 6, Volume 10, Issue 6

Dr. Safai: Dr. Abrams, I am not convinced that the apparent drop in KS incidence is real. I see many referred patients who have developed KS, but whose KS has never been reported, since it was not the initial presentation of HIV infection. In many cases, the lesions are not even biopsied.

Discussion

Dr. Safai: Dr. Abrams, I am not convinced that the apparentdrop in KS incidence is real. I see many referred patients whohave developed KS, but whose KS has never been reported, sinceit was not the initial presentation of HIV infection. In manycases, the lesions are not even biopsied.

Dr. Abrams: That is true, Dr. Safai, but it is still myclinical impression that there were many more cases of KS earlierin the epidemic. Since people develop KS while their CD4 countsare still relatively high, I have always wondered whether thatmight have been an earlier manifestation of immune deficiency,plus the contribution of the KS cofactor. With safer sexual practices,transmission of that cofactor could have declined so that peopledo not develop KS until later in the progression of HIV. Clinically,I feel that we are seeing fewer patients with KS, that those patientshave more advanced immune damage, and that their KS is more dangerousthan the indolent cases we used to see.

Dr. Safai: I am not disputing that there is a trend towarddecreasing incidence of KS. I just doubt that it is as steep asthese numbers seem to suggest. In many cases I have seen, if thepatient is relatively well and has only a few KS lesions, theKS is not reported. My next question is, if nitrites cause KS,why was there not more KS before the HIV epidemic?

Dr. Haverkos: Perhaps because the key element is some kindof interaction between HIV and one or more cofactors. This isa multifactorial tumor that probably requires both factors totrigger whatever cellular mechanism is involved.

Dr. Abrams: Dr. Safai, I am interested in the questionof whether KS metastasizes. Early on, we realized that patientswith minimal KS who presented with their first episode of Pneumocystispneumonia would sometimes have increases in their KS lesions.What do you think is happening in such cases?

Dr. Safai: I think that it is either a flare or a proliferationof an existing tumor or the development of a new tumor at a differentsite. This is not true metastasis, which means that the cell oforigin travels through the body, lodges in a new site, and beginsto proliferate. This does not happen in KS, and therefore it doesnot metastasize in the same way that melanoma metastasizes.

Dr. Abrams: Perhaps an opportunistic infection adds furtherinsult to the immune system or increases cytokine production.

Dr. Safai: We would like to investigate that, Dr. Abrams,but there are so many other infections in AIDS patients that sortingout the cytokine picture is very difficult. Frankly, I suspectthat what is involved is not really immunosuppression, but immunedysregulation, which allows the overproduction of cytokines thatcause the proliferation of the endothelial cell. Monocytes probablyalso play a role, since they are capable of secreting cytokinesand are under the control of the immune system. Cytokine releasemay increase in response either to iatrogenic immune suppressionor to amyl nitrite or some other factor. The ultimate questionis, what is the cytokine that drives the KS cell, and does itgo up or down when we block the immune system with prednisoneor cyclophosphamide?

Dr. Abrams: We have all feared that steroids would causethe appearance or progression of KS in AIDS patients, but I cannotremember seeing KS flares in patients on steroids for idiopathicthrombocytopenia purpura or for respiratory compromise associatedwith Pneumocystis pneumonia. Dr. Safai, is this really an issuein our patients with HIV-related disease?

Dr. Safai: Probably not. In 20 years at Memorial Sloan-Kettering,I saw very few cases of KS arising in patients treated with immunosuppressivetherapy. Furthermore, I have not seen or heard of any HIV-infectedperson who developed KS after steroid treatment.

Dr. Abrams: One final comment with regard to the edemayou described. Our house staff has frequently worked up patientswho have unilateral lower extremity edema, but few KS lesions,searching for deep-vein thrombosis or a pelvic mass, and thesecases are invariably negative. Unilateral edema, particularlyin the lower extremities, may appear much out of proportion tothe extent of KS lesions on the extremity.

Dr. Abrams, after your initial approach, when the patient developsprogressive KS lesions, what is your second-line therapy?

Dr. Abrams: Oral etoposide is a useful salvage therapy,particularly since by the time the patient develops this kindof progression, there are often venous access problems that makean oral formulation desirable. There are problems with myelotoxicity,however.

Dr. Safai: Dr. Abrams, we have had similar problems toyour's in developing a reproducible staging classification forKS. To some extent, this probably just reflects some of the specialcharacteristics of this disease.

Dr. Abrams: It certainly hampers our ability to interpretand compare data, Dr. Safai. Moving on to research on DaunoXome,could you please explain, Dr. Chew, why, if the plasma area underthe curve is so high with DaunoXome and the half-life is so long,there is so little toxicity?

Dr. Chew: Apparently because there is so little releaseof free drug into the circulation. The plasma drug levels reflectlevels of the liposome-encapsulated drug. This translates intomore drug delivered to tumor cells and less delivered to myocardium,hair follicles, bone marrow, gastrointestinal mucosa, and othertissues.

Dr. Safai: Why do you think there is more tumor concentrationof this drug in the liposomal form than as free drug?

Dr. Chew: I believe there is probably active tumor endocytosisof the liposomal particles, which then breaks down and releasesfree daunorubicin inside the tumor cell.

Dr. Abrams: Dr. Gallo, your comments about gamma interferon'srole may explain some results we observed in an early trial. Weconcluded that interferon-g was contributing to a more rapid declinein our AIDS patients.

Dr. Gallo: In terms of KS, interferon-g appears to be themost important of the inflammatory cytokines released by activatedT-cells. It is the most potent at inducing activated spindle cells,so I would predict that giving exogenous interferon-g would makematters worse for an HIV-infected patient.

Dr. Haverkos: I am interested in your suggestions aboutinflammatory cyto-kine levels possibly being higher in homosexualmen than in intravenous drug users. However, we have been followingcohorts of homosexual men and, of injection drug users in severalcities, and we find very few differences in immunologic measuresof disease progression between these two groups.

Dr. Gallo: Intuitively, I am amazed at that, but it doespoint out the need for more studies. As you know, assaying cytokinesis extremely difficult. The available assays are often less thanideal, and turnover rates are very high. In addition, local productionof cytokines may be most important, which could be even more difficultto measure. However, if this urine neopterin assay holds up, weshould start measuring it in the urine of homosexual men vs IVDUs.

Dr. Abrams: Dr. Gallo, what is your general feeling aboutwhere AIDS research is going?

Dr. Gallo: I have the same "down" feeling manyresearchers have with regard to progress in vaccine research andto responding to the AIDS crisis in the developing world. I thinkwe are in desperate need of inspiration right now-not just AIDSpatients, but also AIDS researchers. However, I have just theopposite feeling about the status of KS research. We are beginningto really understand the underlying processes, and if researchersand clinicians work closely together over the next year or two,I think we will solve the problem of how to manage HIV-relatedKS.

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