NEWS

Treating the Most Intractable Cancers Progresses Slowly

Tom Reynolds

Among the most dreaded diagnoses in medicine are cancers that have defied decades of scientific effort to find effective therapies. Nearly all cancer patients are offered some sort of treatment, and for the vast majority, standard therapies exist. But for the most intractable diseases — including certain cancers of the brain, kidney, liver, pancreas, and skin — current treatments offer little survival benefit and virtually no chance of cure.

As always, there is hope on the horizon — vaccines and immunotherapies, improved surgical techniques, targeted radiation beams and implants, and novel chemotherapy agents and delivery systems.

And the situation is improved from a decade ago when there were a half-dozen or so cancers with no standard treatment at all, said Scott Saxman, M.D., of the National Cancer Institute's Cancer Therapy Evaluation Program.



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Dr. Scott Saxman

 
"For example, 10 years ago a placebo-controlled trial of certain types of lung cancer would have been perfectly reasonable," because available treatments lacked proven efficacy. "That's no longer true," he said. "There are chemotherapies that are considered standard. They're not great — the survival advantage is only a few months — but now a placebo trial would not be tenable in that disease."

Whether ethical or not, trials using placebo are seldom performed, Saxman added, because patients with serious disease, not surprisingly, resist the possibility of assignment to a best supportive care group. "It's very difficult to get patients to participate in placebo-controlled trials even in malignancies where the standard therapy may never have been shown to improve outcome," he said. "Patients want to feel like they're getting something."

Late stage liver cancer is one of the few remaining malignancies with no accepted systemic treatment. "There is no standard therapy for advanced metastatic liver cancer," according to NCI's Physicians' Data Query database. Half the patients in a 1985 Radiation Therapy Oncology Group trial showed responses to external beam radiation therapy followed by radiolabeled polyclonal antiferritin antibody, "but it is a localized treatment and does not address the question of systemic disease," PDQ notes, recommending that patients with advanced liver cancer enroll in clinical trials.

Role for Sex Hormones

Laboratory studies have suggested that sex hormones may be involved in liver carcinogenesis, and a few trials of anti-androgens and anti-estrogens have been conducted. Placebo-controlled trials of tamoxifen in liver cancer are under way in Europe and Singapore. But in a January 1998 review in the European Journal of Cancer, researchers at the National Tumor Institute in Milan reported that "there is, as yet, no definitive evidence that endocrine treatment favorably affects the outcome of patients with hepatocellular carcinoma."

At the University of Chicago Cancer Research Center, Sridhar Mani, M.D., is conducting a phase II trial to test the drug dolastatin-10 in patients with metastatic or recurrent tumors of the liver, bile duct, or gallbladder. This agent is the product of a mollusk called a sea hare, which uses the poison to ward off predators. In patients, it blocks cell division by interfering with microtubules.

In some cancers, treatments have become the de facto standard despite a lack of solid evidence for benefit. For instance, although interleukin 2 is approved for renal cell cancer and melanoma, it has not been shown in a randomized trial to improve outcome. In fact, said Saxman, a randomized trial in Europe using IL-2 showed no survival benefit in patients with renal cell cancer. "Would a placebo-controlled trial be reasonable in that disease? I think probably yes," he said. "Is it possible to do that? I think the answer in the United States is no, from a patient acceptance point of view."

In a study published in the April 30, 1998, New England Journal of Medicine, French investigators compared IL-2, interferon alfa 2a, or both in metastatic renal cell carcinoma patients. Patients treated with both cytokines had a greater response rate and a significantly longer progression-free survival time than patients receiving one or the other. But no differences were seen in overall survival, and the authors wrote that they "cannot conclude that the combined treatment provided a significant advantage."

No Placebo Arm

Saxman said this trial has been criticized for not including a placebo arm. In fact, although the authors note that "there is no standard treatment for metastatic renal cell carcinoma," they considered it inadvisable to use a placebo because some patients have shown tumor regression with cytokine therapies.

The problem is that without placebo-controlled trials, it is difficult to firmly establish a treatment's efficacy in the face of no standard therapy. For instance, IL-2 is also approved for treatment of melanoma, although no randomized trials have been done to show its efficacy. Instead, the studies relied on historical controls, a weaker method that may be subject to bias. "One of the criticisms," Saxman said, "is how do we know IL-2 really has efficacy and this isn't just a selection bias?"

Brain tumors are another group of cancers that are notoriously difficult to treat, and one of the most intractable is glioblastoma multiforme, said Stuart A. Grossman, M.D., of Johns Hopkins University, Baltimore. Grossman is the project leader for the nine-institution alliance known as New Approaches to Brain Tumor Therapy, one of two NCI-funded brain tumor consortia created to develop new treatments for adults with primary brain tumors. NABTT conducts phase I and II trials, serving as an early testing ground for promising new compounds.



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Dr. Stuart A. Grossman

 
"Standard treatments for brain tumors have been around for decades, and they don't work very well at all," said Grossman. "We're trying to come up with different ways of treating patients." In testing new agents both from NCI and from pharmaceutical companies, NABTT investigators design their trials carefully to maximize the chances of uncovering the drugs' benefits. For example, they are testing new agents on newly diagnosed glioblastoma patients who have had no prior radiotherapy or chemotherapy, so they may have less drug resistance than previously treated patients. Patients get periodic brain scans and are put on standard radiotherapy if their tumors progress.

"If a drug doesn't work in this group of patients, it probably won't work at all, so you don't have to play around with it for years," said Grossman. Paclitaxel and 9-aminocamptothecin showed minimal efficacy against glioblastoma, but an ongoing trial is testing another agent, a synthetic mitotic inhibitor known as CI-980.

Another important principle in NABTT trials is dose escalation. The investigators discovered that anti-convulsant drugs their patients were taking revved up their detoxifying liver enzymes, reducing the bioavailability of the anti-neoplastic drugs. Glioblastoma patients therefore required much higher doses of paclitaxel, for instance, to reach the blood levels and toxicities seen in other cancer patients. After seeing a similar effect for 9-aminocamptothecin, the researchers built in a dose escalation component to their trials of CI-980 and CPT-11.

"Both of those drugs look like they will also require much higher doses in patients with brain tumors than in other patients," Grossman said. In fact, he added, in most previous chemotherapy trials against brain tumors, patients may have been underdosed for this reason, meaning the drugs were not given a fair chance and some that failed may be worth retesting.

For patients with recurrent high-grade astrocytoma, another poor-prognosis brain tumor, NABTT is conducting a dose-escalation trial of Gliadel polymer wafers made by Guilford Pharmaceuticals in Baltimore. These are implanted in a brain cavity after tumor resection, where they deliver controlled doses of the drug BCNU. The wafers are approved by the Food and Drug Administration at a concentration of 3.9% BCNU. But because animal studies suggested a higher dose might work better, NABTT researchers have steadily escalated the dose and are about to begin testing wafers containing 28% BCNU in hopes of improving clinical efficacy.



             
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