NEWS

Second Line Therapies Move to the Forefront in Colorectal Cancer

Mike Miller

After more than 30 years, a new standard of treatment for metastatic colorectal cancer may be close at hand, according to experts at the annual meeting of the American Society of Clinical Oncology in Atlanta, last month.

Two new drugs, CPT-11 (also known as irinotecan or CamptosarTM) and oxaliplatin (Eloxatine) — both of which have shown promise in a number of earlier studies — now appear to substantially improve the time to tumor progression when used in combination with the existing standard of care. Since the 1960s, patients with advanced colorectal cancer have received 5-fluorouracil, a drug that interferes with DNA and RNA synthesis, and more recently, in combination with leucovorin, a drug that helps 5-FU work more effectively.

By adding either of the two new drugs, however, investigators found that patients gained an extra 3 to 5 months of progression-free survival, although neither the quality of life nor overall survival was affected.

When questioned about the actual benefit to patients, Michael Gordon, M.D., Indiana University School of Medicine, Indianapolis, responded that "quality of life versus extension of life is a major question and is very dependent on the type of cancer." Because metastatic colon cancer has a high mortality rate with a life expectancy of less than 24 months, Gordon and other colorectal oncologists at ASCO pointed out, patients are "extraordinarily grateful" for just a few extra months when their tumors are quiescent.



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Dr. Michael Gordon

 
Multicenter Trial

Leonard Saltz, M.D., Memorial Sloan-Kettering Cancer Center, New York, presented data from a 666-patient, 3-year multicenter international trial with one of the new drugs, CPT-11. CPT-11 has been approved for use since the mid-1990s as a second-line therapy when combination 5-FU/leucovorin fails.

In 1996, Saltz and his co-investigators initiated a phase III trial comparing the standard therapy of 5-FU and leucovorin with two new drug modalities; either CPT-11 alone or CPT-11 with 5-FU and leucovorin. Saltz reported that the standard therapy showed a median time to tumor progression of 4.4 months, while the new drug combination with CPT-11 showed a 6.9 month time to progression. Overall survival was statistically similar, he said.

Jean-Yves Douillard, M.D., Ph.D., Centre R Gauducheau, St-Herblain, France, conducted a different phase III CPT-11 trial with 387 patients. "Our primary objective was to measure response rates, " he said, " and we saw a 49% rate with the new combination of CPT-11 with 5-FU and leucovorin, as opposed to a response rate of 31% percent with the standard therapy. Significantly in our study, we also saw a progression-free survival benefit."

Robert Mayer, M.D., Dana-Farber Cancer Institute, Boston, described results of the two CPT-11 trials as "extremely encouraging" and superior to existing therapy. Mayer noted that the dose schedules used in these trials show some benefit but also different toxicities, mainly increases in diarrhea.



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Dr. Robert Mayer

 
Trial results with oxaliplatin in combination with 5-FU and leucovorin were also presented at ASCO. Eric Van Cutsem, M.D., Ph.D., University Hospital, Gasthuisberg, Leuven, Belgium, said his smaller, 24-week, 173-patient study had a response rate of 11%, "which is nearly double [that of] the standard therapy," but median survival of 10 months was approximately the same for both groups of patients.

According to Mayer, the oxaliplatin trials are not as far along as the CPT-11 trials, so any recommendations for treatment must be viewed with caution. He said that there are unconfirmed reports of a 40% response rate from other oxaliplatin studies, which are "hopeful," but in need of corroboration.

Commenting on the progress that chemotherapy has made since the early 1960s, Mayer said that by the mid-1990s investigators realized that oral 5-FU had better outcomes than administering the drug intravenously, and also cost less. Mayer also said that by later in the 1990s, the 13% to 15% response rate for CPT-11 as a second-line therapy was encouraging. "Now we're beginning to find out how effective some of these therapies are in combination," he said.

Best Therapy?

Which drug or drug combination will emerge as the best therapy for late-stage colorectal cancer is still unclear. The National Cancer Institute is planning to launch a large, mulitsite, multi-arm study of a number of drug combinations including oxaliplatin and CPT-11 to see if, as has been suggested, there is a synergistic benefit. The trial will take a number of years to accrue and analyze.

Because late-stage colorectal cancers can involve liver metastases, which are often fatal, one of the other discussions at the ASCO meeting involved their treatment — a topic that received widespread media attention. Of the estimated 138,000 new cases of colorectal cancer expected to be diagnosed in 1999, at least 60% of patients will develop liver metastasis — only a small number of whom will respond to conventional chemotherapy

Hepatic Pump

Nancy Kemeny, M.D., Memorial Sloan-Kettering Cancer Center, New York, presented her research on hepatic arterial infusion. In this technique, a pump is placed under the skin to deliver chemotherapy directly to the liver as adjuvant therapy after resection of liver metastases from colorectal cancer. Patients treated with only systemic chemotherapy seldom live more than 2 years, according to Kemeny. But with hepatic arterial infusion, where the chemotherapy is delivered directly to the hepatic artery (the artery that provides the liver with the majority of its nutrient source), the 2-year survival outcomes were increased from 69% in the control group to 85%.

Kemeny said that back in the 1970s few of her patients lived much more than 2 years past the time of their original diagnosis. "To see an 85% survival rate after 2 years [now] is very exciting," she said.

Derek Raghavan, M.D., Ph.D., University of Southern California Norris Comprehensive Cancer Center, Los Angeles, who led a session on novel therapies, said Kemeny's work is intriguing because "it is about getting away from hackneyed standard methodologies."



             
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