Many studies suggest that the use of HAART can reduce the risk of developing AIDS-related infections. In those PHAs who develop the AIDS-related cancer called non-Hodgkin's lymphoma, the use of HAART combined with chemotherapy appears to prolong survival compared to the time when HAART was not available.
Although this news is promising, much work remains to be done in the field of AIDS-related cancer treatment. For instance, protease inhibitors are notorious for raising or lowering levels of other drugs in the blood. Little research has been done on how this class of drugs affects commonly used chemotherapy (or how chemo affects protease inhibitor levels). To begin to address some of these issues, research teams across the United States conducted a study on which we now report.
Researchers enrolled 63 HIV positive adults whose profile at the start of the study was as follows:
Chemotherapy was given in 21-day cycles, that is, subjects received intravenous chemotherapy on the first day of every cycle and then a "rest" for the remaining 20 days, after which another cycle began. The length of the cycles varied depending on the response to treatment.
The first 41 subjects received reduced or modified doses of intravenous chemotherapy called mCHOP as follows:
For the first five days of each cycle, subjects also received tablets of the anti-inflammatory drug prednisone 100 mg/day. To protect their bone marrow from the toxicity of chemotherapy, subjects received the bone marrow stimulant G-CSF (Filgrastim) on days 4 through 13 of each cycle.
The remaining 26 subjects received a standard CHOP regimen:
They also received prednisone and G-CSF in the dose and schedule as previously stated.
Subjects with tumours that spread to the brain/spinal cord also received cytarabine (Cytosar) 50 mg/week infused into their spinal cord during the first four weeks of the study to attack those tumours. All subjects received standard doses of the anti-HIV drugs indinavir (Crixivan), 3TC (Epivir, lamivudine) and d4T (Zerit).
Responses to chemotherapy can vary. Some people have a complete response and, for a time, all traces of the tumour disappear. We say "for a time" because cancer can recurr. Others have what's called a "partial response" where some tumours disappear while others remain. In some people the tumours don't shrink but they don't grow — this is called "stable disease." In still other cases, the tumours continue to grow despite the use of chemotherapy. Cancer doctors call this "progression." In some cases doctors are unable to assess the impact of chemotherapy because subjects develop other life-threatening complications and have to stop taking chemo; they may also leave the study or die.
Responses to chemotherapy over the short-term by subjects receiving low-dose chemo (mCHOP) were as follows:
Responses to high-dose chemo (CHOP) over the short-term were as follows:
It is important to note that about 63% of subjects who received the low-dose chemo had lymphoma with widespread tumours as compared to 35% in the high-dose group. This difference in the distribution of people with severe lymphoma likely affected the response to therapy since the fewer the tumours, the better the response. Given this distribution, it is perhaps not surprising that cancer recurred in the following proportion of subjects who developed a complete response in the short term:
On average, subjects who received mCHOP and had a complete response to chemo remained free from lymphoma for about nine months. The equivalent figure for subjects in the high-dose group has not been reached yet, but so far 80% of complete responders remain free from lymphoma one year after recovery.
The researchers examined possible reasons why some subjects developed a complete response. They looked at many factors including CD4+ count, viral load, severity of lymphoma and age, among others. They found that the only significant factor enabling a complete response was the use of high-dose chemo.
The following side effects were severe and occurred in the following proportion of subjects receiving low-dose chemo (mCHOP):
The following side effects were severe and occurred in the following proportion of subjects receiving high-dose chemo (CHOP):
The results of measurement of drug levels in the blood suggested that levels of the following drugs were higher than normal during the study:
Despite this, increased bone marrow damage was uncommon, likely because subjects used G-CSF. Indinavir levels were not significantly affected by chemotherapy. Subjects in both high- and low-dose chemotherapy groups had increased levels of CD4+ cells during the study, probably because they were using HAART. Viral load also decreased in both groups for the same reason.
What is unusual about this study is that only one subject developed a life-threatening complication (caused by a fungus). In contrast, many previous studies of chemotherapy for AIDS-related lymphoma reported the occurrence of a variety of opportunistic infections. This difference is probably because of the effect of HAART. All in all, results from this study point to a major change in the response to chemotherapy among HAART users who have lymphoma.
Doctors conducting future studies of HAART and chemotherapy may find it useful to monitor the level of anti-cancer drugs in the blood of subjects. This is because higher-than-normal levels of anti-cancer drugs can cause liver and bone marrow damage. Bone marrow damage was minimized in this study by the use of G-CSF.
REFERENCES
1. Vaccher E, Spina M, di Gennaro G, et al. Concomitant cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin's lymphoma. Cancer 2001;91:155-163.
2. Ratner L, Lee J, Tang S, et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. Journal of Clinical Oncology 2001;19(8):2171-2178.
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Copyright © 2001 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284 http://www.catie.ca.
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