Infection with the virus HHV-8 (human herpes virus-8) can cause a disease called Kaposi's sarcoma (KS). Signs of this disease are the growth of KS lesions on the skin; as well, lesions can merge, particularly inside the body, around lymphatic vessels. This can cause fluid build-up, swelling and pain. In some cases, particularly when KS affects important organs such as the lungs, it can become life threatening.

Many options for the treatment of KS are available, from standard chemotherapy drugs to vitamin A-type creams (Panretin, alitretinoin). Recently, liposomal forms of chemotherapy such as Caelyx (liposomal doxorubicin) and Daunoxome (liposomal daunorubicin) have become available. These are supposed to be more active than their original formulations. However, none of these drugs cures KS.

What allows KS to flourish is a weakened immune system. The use of highly active antiretroviral therapy (HAART) has helped to reverse the course of KS in many PHAs who respond to therapy. However, in some PHAs, HAART alone may not be sufficient for managing KS. Researchers at several clinics across the U.S. have recently published the results of a clinical trial of the drug paclitaxel (Paxene, Taxol) in the treatment of PHAs with KS. This drug seems to be useful but, like all chemotherapy, can have serious side effects.

Study details

Researchers enrolled 107 HIV positive subjects who had the following profile when they began the study:

• 100% male
• average age – 38 years
• average CD4+ count – 41 cells
• 81% had 25 or more KS lesions
• 36% had KS in their lungs or gastrointestinal tract
• 52% had fluid build-up or swelling
• 82% had previously experienced a life-threatening illness or had the following signs/symptoms when they entered the study – fevers, night sweats, unintentional weight loss, fatigue
• at least 8% of subjects had previously received chemotherapy for KS
• about 44% were using a protease inhibitor (PI) as part of their treatment

The brand of paclitaxel used in this study was Paxene. The drug was given intravenously every two weeks at a dose of 100 mg per square metre of skin over the course of three hours. Taking the following drugs before each dose of Paxene helped to reduce hypersensitivity reactions:

• Decadron (dexamethasone) – 10 to 20 mg
• Tagamet (cimetidine) – 300 mg
• Gravol (diphenhydramine) – 50 mg

If subjects developed blood/bone marrow, liver or kidney toxicity, the next dose of Paxene could be either delayed or reduced to 75 mg/m2 .

Results — Response to therapy

Responses to Paxene were as follows:

• In four subjects, all lesions and associated complications cleared for at least four weeks.
• In 56 subjects, some lesions shrank or disappeared as did signs/symptoms such as swelling, fluid build-up and pain.
• Overall, 56% of subjects showed some form of positive response to therapy while 46% did not.
• Response to therapy was promising both in subjects with internal and external KS lesions.
• Similarly, response to therapy was not different in subjects who had more than 200 CD4+ cells from those with fewer cells.
• On average, subjects took about six weeks to respond significantly to therapy and this response lasted for about nine months.
• Half the subjects remained alive two years after entering this study.

Effect of protease inhibitors

While use of PIs did not affect the response to Paxene, it did appear to do the following:

• delay the spread of new lesions
• prolong the length of Paxene's anti-cancer effect
• prolonged survival

Side effects

Although Paxene had benefits, it caused a range of side effects in the following proportion of subjects:

• diarrhea – 67%
• fever – 66%
• weakness – 65%
• hair loss – 62%
• nausea – 48%
• rash – 47%
• headache – 34%

Perhaps the most dangerous side effect was Paxene's impact on the bone marrow. Sixty-five percent of subjects developed less-than-normal levels of the infection-fighting white blood cells called neutrophils. In 44% of these subjects, the decrease was severe, while in 54% it was life threatening. Not surprisingly, four subjects died from Paxene-related side effects.

Infections

During chemotherapy, about 53% of all subjects developed AIDS-related infections. The most common were as follows:

• CMV (cytomegalovirus) eye infections – 12%
• PCP (Pneumocystis carinii pneumonia) – 6%
• MAC (Mycobacterium avium complex) – 3%
• fungal infection of the brain – 2%

Despite the side effects associated with Paxene, on some measures quality of life improved, probably because lesions disappeared from the faces of subjects and pain was decreased because swelling was reduced.

In this study, Paxene had significant anti-KS activity in a population of severely affected and ill subjects. Exposure to many previous types of chemotherapy did not result in any apparent cross-resistance to Paxene. The drug did cause significant side effects, as is common with many chemotherapy regimens. PHAs exposed to Paxene require careful monitoring. Paxene is now being tested in the U.S. as an initial treatment for KS. Paclitaxel is licensed in North America as a treatment for breast, lung and ovarian cancers.

REFERENCE

Tulpule A, Groopman J, Saville MW, et al. Multicenter trail of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 2002 Jul 1;95(1):147-54.

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