Targeted Therapies: New Spin on an Old Concept?

ORLANDO—Evolving targeted therapies for metastatic colorectal cancer hold promise for greater therapeutic efficacy and improved quality of life for patients, according to Edward H. Lin, MD, assistant professor of medicine, Division of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center. Speaking at an industry-sponsored symposium held in conjunction with the ASCO meeting, Dr. Lin discussed the general concepts of targeted therapy and reviewed several treatments under investigation.

"Targeted therapy is an ‘old concept’ in the context of new knowledge about carcinogenicity," Dr. Lin said. "Even 5-FU [fluorouracil], capecitabine [Xeloda], and irinotecan [CPT-11, Camptosar] are targeted therapies in a way. Now, Gleevec [imatinib mesylate] acting with c-KIT and Iressa [investigational] acting through the EGFR mechanisms are just another way of delivering molecularly targeted therapies."

Two misconceptions about targeted therapies are that they are merely cytostatic and that they are less toxic, Dr. Lin noted. "These agents are not exactly cytostatic. They can clearly induce tumor apoptosis as well as tumor deaths," he said. "We clearly need to validate their molecular targets, know their mechanism of action, and really try to modulate and reverse cancer hallmarks, such as angiogenesis, with these targeted agents."

Targeted therapies do have their own characteristic toxicities, Dr. Lin added, such as hand-foot syndrome with capecitabine and skin rash with EGFR inhibitors. But their important advantages are improved delivery, especially oral delivery, and improvements in the therapeutic index.

"Certainly, the pharmaceutical companies recognize that the future direction is oral-based chemotherapy," he said. "And many of the new chemotherapies—Iressa, COX-2 inhibitors, and Gleevec—are oral based."

Oral delivery is convenient and allows flexibility for patients and their caregivers, especially for those who work or want to travel, he said. It per-mits flexible dose adjustment and allows treatment to be easily tailored to each patient’s toxicities. Oral delivery is economical and is an efficient use of resources.

Dr. Lin pointed to HAART [highly active antiretroviral therapy] being used to treat HIV disease as a model of what can be achieved with these types of therapies. "We really should be drawn to the fact that the HAART therapy in HIV disease is an enormous success story," Dr. Lin said. "Many of these patients have returned to a normal quality of life, with essentially every-3-month follow-up."

The downside of oral treatment involves compliance issues, problems with dose verification, the need for more extensive patient education, and concerns about overdosing. Reimbursement issues for community oncologists also need to be addressed.

Dr. Lin pointed to his group’s results with the combination of capecitabine and the COX-2 inhibitor celecoxib (Celebrex), two agents that can be considered targeted therapies.

In their retrospective study of 67 patients with metastatic colorectal cancer, the researchers found that patients taking a capecitabine/celecoxib combination had less hand-foot syndrome and diarrhea than did patients on capecitabine alone.

Disease stabilization rates also were higher with the combination therapy: 62.5% for patients on capecitabine and celecoxib vs 22.8% for those taking capecitabine alone.

Overexpression of COX-2

Dr. Lin noted that 80% of colorectal tumors overexpress COX-2 and that the enzyme is involved in all stages of carcinogenesis, including metastasis. He added that COX-2, thymidine phosphorylase (TP), and various other factors are prognostic indicators for colorectal cancer and somehow should be integrated into the treatment paradigm for the management of metastatic colorectal cancer.

Inhibiting COX-2 expression reduces polyp formation in familial adenomatous polyposis, helps control tumor-related pain, and induces apoptosis in in vitro assays.

"We believe that capecitabine is activated through TP, which is also an important angiogenic enzyme, and through TS [thymidine synthase], also active through possible thrombospondin pathways that ultimately affect tumor angiogenesis," he said. "COX-2 may, in fact, act upstream of the VEGF pathways that ultimately also may affect tumor angiogenesis. Thus, it makes sense to proceed with the capecitabine/celecoxib combination."

Dr. Lin’s group is in the process of activating a phase II trial of capecitabine/celecoxib that will focus on tumor response. The capecitabine dose is 1,250 mg/m² twice a day on days 1 to 14 in a 21-day cycle. The celecoxib dose has been raised to 400 mg twice a day every day. "Previously we were looking only at hand-foot syndrome," he said. "If you are looking at tumor response, the party line is to go with 400 mg twice a day, which is generally, very well tolerated."