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Mesothelioma Clinical Trials Information
Mesothelioma Clinical Trial Summary
The risk of a cancer patient dying from an experimental
treatment while participating in a phase 1 clinical trial decreased about
tenfold between 1991 and 2002, according to a study led by researchers from
Harvard Medical School.
During the same period, response rates to treatment (as measured by tumor
shrinkage) also decreased, though by a much smaller amount. Researchers suggest
that both these trends may be explained in part by the emergence of new targeted
cancer drugs that are less toxic and that often work by stopping tumor growth
rather than by shrinking tumors.
Clinical Trials Background
Phase 1 of mesothelioma clinical trials are the earliest studies of new
treatments in people. The goals of a phase 1 trial are usually to find out
whether an experimental treatment is safe in people and to establish the best
dose to test in larger studies.
Participation in phase 1 of mesothelioma clinical trials can involve significant
risks and uncertain benefits. Because the experimental treatment has not been
previously tested in people, little is usually known about its possible adverse
effects. What’s more, patients who enroll in phase 1 trials of new cancer
treatments typically have advanced disease that is no longer responding to
conventional treatment. Past estimates have suggested that only about five
percent of participants benefit from the treatment they receive in a phase 1
trial.
However, the conduct of phase 1 trials has changed in recent years, raising the
question of whether they have become safer or perhaps more beneficial for
participants. The current study was an effort to look into that question.
The Study of Mesothelioma Clinical Trials
Researchers reviewed data from 213 phase 1 trials involving 6,474 cancer
patients. The mesothelioma clinical trials were selected from those submitted
for presentation at the annual meeting of a major cancer society between 1991
and 2002. Each clinical trial tested a single experimental drug – either a
conventional drug (called cytotoxic), which kills both normal and cancer cells,
or a so-called targeted drug, which aims more directly at cancer cells, leaving
most normal tissue alone. Targeted drugs tend to cause fewer side effects
(called “adverse” or “toxic” reactions).
The investigators looked at the “toxic death rate” - that is, how many patients
died from the adverse effects of the experimental drug. They also looked at how
many patients responded to treatment, using the standard definition of response:
tumor shrinkage of more than 50 percent. The study team was led by Thomas G.
Roberts, Jr., M.D., of Harvard Medical School in Cambridge, Mass.
Clinical Trial Results
A total of 231 patients (2.1 percent) died while they were enrolled in a phase 1
trial included in the study. Of these, 35 deaths (0.54 percent of all the
patients involved in the 213 trials) were caused by the experimental drug.
The toxic death rate declined from 1.1 percent during the first four years
covered by the study (1991 to 1994) to 0.06 percent during the last four years
(1999 to 2002). Thus, the chance that a patient would die from the experimental
treatment was at least 10 times greater during the first four years studied than
during the last four years. Patients treated with targeted drugs were one-fourth
as likely to die from the treatment as patients treated with cytotoxic drugs.
A total of 243 patients (3.8 percent) responded to the mesothelioma treatment
according to the traditional definition of “response” - that is, their tumors
shrank by more than half. Overall, the response rate declined from 6.2 percent
during the first four years covered by the study to 2.5 percent during the last
four years. Thus, patients were less than half as likely to respond to treatment
(as measured by tumor shrinkage) during the last four years studied (1999 to
2002) as during the first four years (1991 to 1994).
However, note the researchers, this does not necessarily mean the later trials
were less beneficial to participants. Tumor shrinkage may not accurately reflect
the beneficial effect of targeted drugs. Many targeted drugs stop the tumor from
growing rather than cause the tumor to shrink. For this reason, the researchers
suggest that the time it takes a tumor to start growing again (“time to
progression”) might be a better measurement of the benefit of targeted drugs.
The authors suggest three possible reasons for the decline in treatment-related
deaths over the study period.
Almost half (47 percent) of the trials included in the study involved targeted
drugs, which tend to have fewer adverse effects than conventional cytotoxic
drugs.
Supportive care for cancer patients improved over the study period. For example,
new and better drugs were introduced to combat severe nausea and infections,
common side effects of conventional cancer treatment.
Oversight of cancer clinical trials became more stringent, resulting in more
careful scrutiny of patients prior to enrollment. Thus, patients with a higher
risk of dying from experimental treatment were less likely to be enrolled in a
phase 1 clinical trial.
Clinical Trial Limitations
The mesothelioma researchers looked at only those phase 1 trials that tested a
single experimental drug. They did not look at trials in which an experimental
drug is added to standard therapy, a common practice in cancer clinical trials.
They also excluded trials in which patients received radiation therapy in
addition to an experimental drug. Including these trials in the analysis might
have found a higher rate of toxic death.
In addition, the trial results selected for inclusion in the review had all been
published in medical journals. This may have resulted in “publication bias,”
because studies with unfavorable outcomes are less likely to be published, say
the authors of an accompanying editorial, Eric X. Chen, M.D., Ph.D., and Ian F.
Tannock, M.D., Ph.D., of the University of Toronto in Canada.
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