HOUSTON‘‘We appear to be approaching a ceiling for benefits of
cytotoxic chemotherapy in advanced non-small-cell lung cancer (NSCLC). All
recent randomized studies have had similar results, and there has been no clear
efficacy benefit from nonplatinum combinations or triplets. Certainly for
advanced disease and even for early disease, where metastases kill most
patients, a paradigm shift is needed, and that shift will probably be to
targeted therapy that works against specific biologic pathways," said Roy
S. Herbst, MD, PhD. Dr. Herbst is assistant professor of medicine and chief of
the Section of Thoracic Oncology at the University of Texas M.D. Anderson
Cancer Center in Houston, Texas.
"Initially, these agents were classified as cytostatic agents, as
opposed to the current cytotoxic drugs and were thought not to produce
single-agent responses. Recent data suggest a low but real single-agent
response for some of them," Dr. Herbst said. The main categories now under
active study are signal transduction or cell-cycle inhibitors, angiogenesis
inhibitors, gene therapy, vaccines, and receptor-targeted therapy.
Perhaps More Specific
Dr. Herbst said that the hope is that agents aimed at biological pathways
will be even more specific for the tumor cell than for normal cells and
therefore less toxic. "The hope is that these agents could be used for
longer periods, used for maintenance therapy, and used to prevent or keep in
check metastatic disease," he said. "In lung cancer, we can think
about integrating these agents with current therapy at all stages of disease.
In the earliest premalignancy stage, they may be useful as preventive agents.
In localized disease, where there is still 40% recurrence in stage I disease,
we might think about surgery, radiotherapy, then a biological as maintenance
therapy. In locally or regionally advanced disease, after the best response we
might try to prevent recurrence with a biologic agent. In the advanced setting,
where we do not cure anyone, perhaps we could prolong survival by using a
Dr. Herbst suggested that the new paradigm for lung cancer treatment will
involve surgery and radiation combined with chemotherapy and biologic therapy
for distant metastases. "In almost all cases they are synergistic,"
he said. "This will be directed at preventing recurrence and keeping
metastases in check."
Major issues regarding new molecular therapies include identification of the
target and determining whether the target is important in NSCLC and whether
screening for overexpression of the target is necessary. "It also helps to
know the mechanism of action and whether there are surrogate markers for drug
response that can be used in phase I trials," Dr. Herbst said.
New trial designs are also needed. "You don’t want to dose these
biologic agents to the maximum tolerated dose but to the biologically effective
dose," Dr. Herbst said.