This article by Cianfrocca and von Roenn is a welcome addition to the oncologic literature, as our knowledge of the pathogenesis and therapy of Kaposis sarcoma (KS) has expanded explosively during the past few years. There is little resemblance between the treatment options of 5 years ago and the much-improved interventions available today, especially with respect to chemotherapy.
Also, advances in the management of human immunodeficiency virus (HIV) infection (most importantly, the HIV-1 protease inhibitors) have affected the epidemiology, severity, and therapeutic responsiveness of KS, as well as the number and degree of comorbid conditions with which the oncologist must contend. Highly active antiretroviral therapy (HAART) has remarkably affected the incidence of KS and, in some regions of the country, has nearly eliminated the occurrence of new cases. However, it is unclear how long this caesura will last; it is disquieting that patients with resistance to antiretroviral drugs are being identified with increasingly greater frequency.
Usefulness of Interferon-Alfa Questioned
I do take minor issue with certain points made in this paper. The authors extensively discuss the use of interferon-alfa (Intron A, Roferon-A) in the treatment of KS. In my practice, I find the usefulness of this agent to be limited for the following reasons. First, the rate of response to this interferon in a patient with a CD4 cell count less than 200 to 300/mm³ is low enough to make this drug an unreliable choice. It remains to be seen whether concurrent HAART will increase the response rate in these patients (a concept currently under investigation by the authors in an AIDS-Related Malignancies Consortium study).
Second, the time to a clinically significant response to interferon-alfa is quite long, often in the range of 3 to 6 months. Thus, deeming this drug ineffective after less than 6 months of therapy probably indicates an inadequate trial.
Third, the toxicity profile of interferon-alfa is significant, with severe and often intolerable early side effects, such as fever, sweats and chills, malaise, and myelosuppression. Patients receiving this therapy also must contend with the nuisance of subcutaneous injections. Moreover, long-term toxicity after months of interferon-alfa therapy, such as extreme fatigue, major depression, severe neurologic compromise, and even psychosis, can be even more debilitating. Given the relatively mild toxicity of the currently available chemotherapeutic agents, such as liposomal doxorubicin(Drug information on doxorubicin) (Doxil), liposomal daunorubicin(Drug information on daunorubicin) (DaunoXome), and paclitaxel(Drug information on paclitaxel) (Paxene, Taxol), as well as their swifter and greater efficacy, most patients find chemotherapy to be preferable.
Advantages of Systemic Chemotherapy
Although radiation therapy was a mainstay of the therapy of KS a number of years ago, it is now used less frequently, also because of the better tolerability of chemotherapy. Other advantages of systemic chemotherapy over radiation include the prevention of new lesions developing outside of the radiation port, improved treatment of visceral disease, more reliable resolution of tumor-induced edema, and fewer complications of mucosal therapy, such as radiation-induced mucositis and xerostomia.
Two additional drugs have recently been reported to have activity in KS in phase II trials. Vinorelbine (Navelbine), a newer vinca alkaloid, was found to be effective in 28 patients as second-line therapy, with a 44% objective response rate. The most remarkable aspect of this trial is that this response rate was achieved in patients who had been heavily pretreated with chemotherapy, 97% of whom had received prior vincristine or vinblastine(Drug information on vinblastine) therapy. Since in vitro data suggest that prior therapy with vinca alkaloids may increase sensitivity to taxanes, vinorelbine may be a good choice in patients who have proved unresponsive to paclitaxel.
Docetaxel(Drug information on docetaxel) (Taxotere) is another compound that shows promise. It has recently been described as having an 80% response rate (including some complete remissions) in KS, with myelosuppression being the major toxicity. It remains to be seen whether this taxane will have any advantages over paclitaxel.
Improvements in Therapies Still Needed
There are still improvements to be made. These therapies are often given chronically over months to years to avoid relapse or progression; any improvement in toxicity profile (such as decreased alopecia and fatigue) or ease of administration (such as an orally bioavailable or nonmyelosuppressive compound that would obviate the need for clinic visits for infusions or blood counts) would markedly improve patients quality of life.
Another drawback to this new generation of therapies is their cost. At my center, drug costs of the liposomal anthracyclines or paclitaxel can run in excess of $1,500, and, with administration and other related costs, a cycle of therapy can cost as much as $2,000 every 3 or 4 weeks. Clearly, the improved tolerability and probable better efficacy of these new therapies come with a substantial price tag, and this must be factored into any determination of their potential utility.