Patients who receive treatment for Kaposi’s sarcoma (KS) consisting of pegylated liposomal doxorubicin with potent antiretroviral therapy have a low rate of relapse, according to a retrospective Spanish study published in the August 1st edition of Clinical Infectious Diseases. Most of the relapses that did occur happened in the first twelve months after chemotherapy was finished. But the investigators found that there was a high rate of lymphoma in their patients, and they speculate that this could have been due to infection with HHV-8 and severe immune suppression.
The introduction of effective HIV treatment in the late 1990s led to a dramatic and sustained fall in the amount of KS seen in richer countries. But cases of this AIDS-defining cancer are still seen.
Treatment with pegylated liposomal doxorubicin and antiretroviral therapy for Kaposi’s sarcoma has a response rate of 70%. However there is little information on the rate of relapse and longer-term survival in patients who receive this treatment.
Spanish investigators therefore looked at the medical records of 98 patients who received this treatment in two clinical trials between 1997 and 2002.
Nearly all these patients (96%) were men, all were white and the median age was 40 years. Median CD4 cell count was low at just 150 cells/mm3 and median viral load was a little under 16,000 copies/ml. Tests for HHV-8, the herpes virus associated with KS and some other cancers, were conducted on 69 patients, and 52 individuals (75%) had positive results.
A total of 16% of patients had the least severe stages of KS and 17% the worst. Visceral KS was present in 29 patients.
All the patients were receiving potent antiretroviral treatment.
Pegylated liposomal doxorubicin was provided in a median of nine treatment cycles. A complete response was observed in 48 patients, a partial response in 27, and no response in 13. A total of seven patients died whilst receiving therapy, and three patients did not complete treatment.
Of the 75 patients with a complete or partial response, 61 had data available for the investigators’ examination. The median period of follow-up since the last dose of anti-KS therapy was 50 months. A relapse was observed in eight patients (14% per year), and five of these relapses occurred in the first year after stopping chemotherapy.
Patients experiencing a relapse were more likely to have had more serious forms of KS, and had lower CD4 cell counts at the end of follow-up (316 cells/mm3 vs. 488 cells/mm3, p = 0.07), but this difference was not statistically significant. They also had smaller increases in their CD4 cell count compared to baseline (23 cells/mm3 vs. 248 cells/mm3, p = 0.018).
Long-term toxicity associated with pegylated liposomal doxorubicin therapy was only detected in one patient, and this consisted of ventricular dilation (increase in size of the heart muscles) and mild dysfunction some three years after receiving 20 cycles of treatment with the drug.
In statistical analysis, the investigators found that the only factor associated with relapse was severity of KS at diagnosis (OR, 6.2; 95% CI. 1.2 – 3.0). There was also a trend for a greater rate of relapse amongst patients with lower CD4 cell counts at the end of follow-up (every 100 cell/mm3 decrease in CD4 cell count OR, 1.4; 95% CI, 0.9 – 1.7).
But despite this low rate of relapse, 29 patients died during a median of 29 months of follow-up after receiving the first dose anti-KS therapy. This meant there was a mortality rate of 15% per year. Nine patients died whilst receiving treatment, nine died in the first year after the completion of therapy, with the other twelve patients dying subsequently.
Only three deaths were associated with progression of KS, and eight deaths were attributed to infectious complications.
The investigators also reported “an unexpectedly high rate of tumour-related death” amongst the other 18 patients with nine cases of other cancers diagnosed. This included seven patients with some form of lymphoma. The rate of lymphoma death was 2.3% per year.
CD4 cell count at the end of follow-up was the only factor associated with survival (p = 0.02). The investigators note that all the patients with lymphoma were HHV-8-positive. They write: “it is…known that having had a tumour is a predisposing factor for the development of a second tumour; this risk can be higher in immunosuppressed patients who harbour an oncogenic [cancer-causing] virus, such as HHV-8.”
An accompanying editorial states that the high incidence of lymphoma in this study is a warning of “the importance of avoiding excessive exposure to chemotherapeutic drugs that could favour the development of non-Hodgkin’s lymphoma or other neoplasms in populations that are at risk of developing such complications.” (Anthracyclins, the class of drugs to which doxorubicin belongs, have been associated with an increased risk of non-Hodgkin's lymphoma and leukaemia in patients treated for a variety of cancers.)
The authors suggest that milder forms of KS in HIV-positive patients should be treated with antiretroviral therapy alone. They only recommend therapy with liposomal-like drugs for severe cases of KS.
Martin-Carbonero L. et al. Long-term prognosis of HIV-infected patients with Kaposi’s sarcoma treated with pegylated liposomal doxorubicin. Clin Infect Dis 47: 410 – 417, 2008.
Dupin N. et al. Treatment of Kaposi’s sarcoma in the highly active antiretroviral therapy era. Clin Infect Dis 47: 418 – 420, 2008.