Epidemic, or acquired immunodeficiency (AIDS)-related, Kaposis sarcoma (KS) ushered in the AIDS epidemic in the early 1980s among the male homosexual population in the epicenters of New York City, Los Angeles, and San Francisco. As a medical oncologist who has been involved in the systemic treatment of this disease since the beginning of the epidemic, I feel that we have almost come "full circle."
A little over a year ago, I had no idea that an article on epidemic KS, such as this one by Cianfrocca and von Roenn, possibly would soon be mainly of historical interest. With the advent of aggressive, effective combination antiretroviral therapy resulting in complete suppression of the human immunodeficiency virus (HIV), advanced epidemic KS requiring systemic treatment is being seen less and less.
This article is an excellent review of the treatment of epidemic KS. It also covers the pathogenesis of epidemic KS, describing the role of HIV and the KS-associated herpesvirus (KSHV). The article does not place adequate emphasis, however, on the role of complete suppression of HIV in changing the natural history of epidemic KS.
The authors refer to the poster presentation of Dr. Matt Volm and myself at the 1997 American Society of Clinical Oncology (ASCO) meeting. We documented that the institution of aggressive combination antiretroviral therapy in patients with epidemic KS and the resultant fall of HIV RNA to an undetectable level (as determined by polymerase chain reaction [PCR]) permit the discontinuation of chronic chemotherapy of epidemic KS. This has been described by others[Drs. Jamie von Roenn, Susan Krown, Lawrence Kaplan, personal communications, May 1997] but has not yet been reported in the literature. The pathogenesis of epidemic KS involving both HIV and KSHV, as described in this article, provides an explanation for our observations.
As noted in the article, antibody to KSHV is found in male homosexuals prior to the development of KS. A study by Goa and colleagues using specimens from the Multicenter AIDS Cohort Study demonstrated that 52% of patients seroconverted to KSHV positivity 13 to 103 months before the clinical appearance of KS. As HIV replication increases over time with resultant immunosuppression, epidemic KS becomes apparent and progresses.
The authors describe the role of HIV in the pathogenesis and proliferation of epidemic KS. Suppression of HIV directly removes these effects, thereby resulting in clinical regression of epidemic KS. Reversing the immunosuppression also indirectly affects epidemic KS, eliminating the environment conducive to its proliferation.
With suppression of HIV using effective triple-combination antiretroviral therapy, a decrease in associated opportunistic infections and deaths has been noted as the immune system is reconstituted.[2-4] Most likely for the same reasons, epidemic KS regresses in that same environment. I predict that the incidence of epidemic KS will decline dramatically as more statistics are gathered.
In their description of the clinical manifestations of pulmonary KS, the authors make no mention of the use of CT as a useful diagnostic procedure. In my experience, and in the literature, a CT scan of the chest, using fine cuts and high resolution with no intravenous contrast, can be most helpful in establishing the diagnosis. A reading radiologist who is familiar with this disease is necessary. In the appropriate clinical setting, there is no need for the more time-consuming and troublesome thallium-gallium scan to make the diagnosis of pulmonary KS noninvasively.
Indeed, over the years, documenting and monitoring "measurable disease" have been major problems in the management of patients with epidemic KS in the setting of clinical trials, as discussed by the authors. However, I would caution that it is difficult, if not impossible, to use bidimensional measurements when following these lesions for response. This is due to the fact that there may be no change in the bidimensional measurements as the lesions respond to treatment, but rather, a decrease in intensity of color and a flattening. Indeed, bidimensional measurements of some lesions increase as they respond and flatten. Reproducible photographs of indicator lesions and areas of the body are of utmost importance in following mucocutaneous epidemic KS for response to therapy.
To the authors discussion of local therapy, I would add that more caution is needed with regard to the use of radiation therapy for lesions of the oral cavity. At New York University Medical Center, radiation was abandoned as a form of local therapy very early in the epidemic due to the severe mucositis seen.[6,7] The authors also make no mention of the unacceptable toxicity seen when radiation is used to treat lesions on the plantar aspect of the feet--a practice that was also abandoned at our institution early on.
With respect to treatment of systemic epidemic KS with interferon-alfa (Intron A, Roferon-A), the higher recommended doses quoted at the time of the initial FDA approval of the drug for epidemic KS are no longer appropriate. Dr. Susan Krown has noted that, in the early years, interferon-alfa was used in these high doses as an oncologic antiproliferative agent. The drug was rarely tolerable at these doses. The observation, initially made by Dr. Krown, that very low doses of interferon-alfa (as low as 1 MU/d) in combination with a single nucleoside analog, eg, didanosine(Drug information on didanosine) (ddI [Videx]), were very active in suppressing epidemic KS, is consistent with the pathogenesis of epidemic KS, as described in the article.
The cumulative toxicity of bleomycin(Drug information on bleomycin) (Blenoxane) is not limited to pulmonary fibrosis. More of a problem with higher cumulative bleomycin doses is Raynauds phenomenon, which has also been described in young men with testicular cancer treated with this drug. I personally have seen gangrenous fingers as a result of this toxicity of bleomycin.
I do agree with the authors that the most appropriate first-line chemotherapeutic agents for epidemic KS are the newer liposomal anthracyclines, liposomal daunorubicin(Drug information on daunorubicin) (DaunoXome) and liposomal doxorubicin(Drug information on doxorubicin) (Doxil), due to their activity and their relative lack of cumulative toxicity compared with the more standard chemotherapeutic agents. For the same reasons, paclitaxel(Drug information on paclitaxel) (Paxene, Taxol) would be my choice for therapy in patients whose disease progresses after treatment with the liposomal agents. I have found that a lower dose of paclitaxel, 80 mg/m² given every 14 days, produces a very nice response with minimal toxicity besides myelosuppression--sometimes with no alopecia (unpublished data).
There is no question that aggressive, triple-combination antiretroviral therapy including a potent protease inhibitor is now the cornerstone of therapy for epidemic KS. Indeed, in patients with advanced disease on presentation, "debulking" with either chemotherapy or interferon-alfa and triple antiretroviral therapy may be necessary, to be followed by continued "maintenance" antiretroviral therapy. The efficacy of this approach will be determined by the appropriate clinical trials. There may be a small percentage of epidemic KS cases that are no longer under the control of HIV. Such cases represent a true malignancy that still requires aggressive ongoing chemotherapy.
In conclusion, I would like to stress just how important it is that the oncologist treating patients with epidemic KS give full consideration to the underlying illness when treating this tumor.