Broader Implications of a Stage-Guided Stratified Therapeutic Approach for AIDS-Related Kaposi's Sarcoma

Abstract

Kaposi sarcoma (KS) remains the most common illness in people living with HIV (PLWH), although its incidence has declined dramatically since the introduction of combination antiretroviral therapy (cART). Unlike most malignancies that are staged using the TNM system, which takes into account tumor size and extent of spread, staging for AIDS-related KS must account for the presence of other AIDS-related effects, such as the severity of immunosuppression and presence of opportunistic infections. The AIDS Clinical Trials Group (ACTG) staging system considers three factors, notably, the extent of the tumor (T), the status of the immune system as measured by the CD4 count (I), and the extent of systemic illness. Each factor is further subgrouped into either good risk (0) or poor risk. T0 disease is defined as KS that is limited to the skin but without edema or ulceration, lymph node disease, or flat palatal lesions. T1 disease is defined as the presence of tumor-associated edema or ulceration, or extensive oral/GI KS or other non-nodal visceral lesions. Although this system has helped to clinically categorize patients, until now there has been no clear, universally adopted treatment algorithm that is based on disease stage. As with other HIV-associated malignancies, the challenge for health care professionals treating AIDS-related KS has revolved around the ability to effectively treat without causing the patient further immunocompromise and, if possible, to concomitantly reconstitute the immune system. Therefore, it is not surprising that the introduction of cART has led to a remarkable improvement in median overall survival (OS) of affected patients, which was less than 18 months in the pre-cART era. In addition to improving prognosis and time to disease progression in KS, cART can lead to lesion regression, and this applies to both protease inhibitor and non-nucleoside reverse transcriptase inhibitor– based regimens, the major categories of antiretroviral regimens. However, the resolution of KS with cART usually follows the recovery of cellmediated immunity in the host and can therefore be a slow process over several months, complicated in some instances, for example, by an immune reconstitution inflammatory syndrome. Furthermore, there is the complex paradox of how best to treat patients already receiving cART who have maintained a high CD4 count and low viral load, but who still develop KS. In the pre-cART era, chemotherapy was the mainstay of treatment for suitable patients with AIDS-related KS, and this has remained the major therapeutic modality despite the advent of cART in 1996. In the pre-cART era, chemotherapy was adopted as an accepted treatment modality in AIDS-related KS on the basis of the results of a number of clinical trials that assessed the efficacy and safety of combination regimens. In one study, 18 consecutive patients with socalled disseminated KS received a six-drug regimen of doxorubicin, vinblastine, bleomycin (ABV), dactinomycin, vincristine, and dacarbazine, with a partial or complete response observed in 13 individuals. Opportunistic infections were the most common cause of death. Another study compared the use of recombinant interferon alpha or ABV/dactinomycin, vincristine, and dacarbazine in the 18 consecutive patients with disseminated disease, and responses were similar in the two groups and were comparable with the results of earlier trials. Subsequent studies in the preand post-cART era have provided strong evidence in support of the use of single-agent anthracyclines or taxanes, particularly pegylated liposomal doxorubicin (PLD) and paclitaxel. In a study reported in 1998, Northfelt et al randomly assigned 258 patients with advanced AIDS-related KS to receive either PLD (20 mg/m) or ABV every 14 days for six cycles. PLD was more effective and less toxic than ABV (overall response rates, 45.9% v 24.8%; P .001). In 2010, Cianfrocca et al reported a study comparing paclitaxel with PLD in patients with advanced AIDS-related KS and demonstrated comparable response rates (56% v 46%; P .49), median progression-free survival of 17.5 v 12.2 months (P .66), and 2-year survival rates of 79% v 78% (P .75), although paclitaxel was associated with more grade 3 to 5 toxicity (84% v 66%; P .077). PLD has thus become the current standard first-line therapy for advanced disease in many centers in the developed world, with paclitaxel reserved as a second-line agent. However, this is not the case in less developed countries, where HIV remains endemic. Given the complexity of the ACTG staging system, there is no clear international consensus on what constitutes advanced disease, and therefore, no clear algorithm exists to determine which patients should receive cART alone and which should receive cART plus chemotherapy, or chemotherapy alone, given that interactions between protease inhibitors and chemotherapy may lead to worse neutropenia. In the article that accompanies this editorial, Bower et al answer these issues in part for the first time and present an elegantly JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 5 FEBRUARY 1