CHICAGO-Capecitabine (Xeloda) research continues to bring to light new combinations of agents in the treatment of metastatic breast cancer, and to test the combination of capecitabine(Drug information on capecitabine)/ radiation therapy in the treatment of other solid tumors. A series of symposia sponsored by Roche and held in conjunction with the 39th Annual Meeting of the American Society of Clinical Oncology explored the use of capecitabine, a tumoractivated oral fluoropyrimidine, in various treatment regimens. Essence of Radiosensitization Edgar Ben-Josef, MD, of The Karmanos Cancer Institute and Wayne State University in Detroit, explained how radiosensitization can be used to control gastrointestinal (GI) malignancies without increasing the complication rate. "This is the essence of radiosensitization. We want to achieve a therapeutic gain. And, for effective radiosensitization, I can't overemphasize the importance of not increasing toxicity," Dr. Ben-Josef said. Forty years ago, early work with fluorouracil(Drug information on fluorouracil) (5-FU) showed that combining ineffective chemotherapeutic doses and ineffective radiation doses could result in cures in 30% of tumors in animal models of cancer. Subsequent research revealed the importance of correct timing. For example, to be effective, 5-FU must be in the tissues within 8 hours after radiotherapy, Dr. Ben-Josef explained. Dr. Ben-Josef reported his findings comparing 5-FU and capecitabine and testing a capecitabine/radiotherapy combination in prostate cancer cell lines. "5-FU adds nothing to radiation," he said, "but capecitabine adds an important synergistic effect." To summarize the phase III data on capecitabine vs 5-FU in metastatic colon cancer, the response rate with capecitabine was 25% compared to 16% with 5-FU. The time to progression for both agents was equivalent, as was survival. But according to Dr. Ben-Josef, "there are clearly fewer grade 3/4 toxicities with capecitabine." Advantage in Lowering Doses A study among 32 patients with a variety of malignancies in the GI tract found that the capecitabine/radiotherapy combination had an advantage in older patients. The median age of the patients in the study was 67 years, but patients up to 84 years were included. Dr. Ben-Josef said, "Because this combination of capecitabine and radiotherapy is well tolerated, you can treat patients you might not otherwise consider for aggressive treatment, either because they have comorbidities or due to their advanced age." The treatment regimen started with capecitabine 1,250 mg/m2 bid, but it was reduced to 625 mg/m2 bid. The median dose, and the one most commonly used, was 800 mg/m2 bid, 5 days a week with radiotherapy. In a phase I study, there were no dose-limiting toxicities at this dose. Results from the laboratory indicate that with capecitabine there is effective radiosensitization at much lower doses than the maximum tolerated dose (MTD). "This is the situation that we face with most chemotherapeutic agents today," Dr. Ben-Josef said. "For substantial tumor responses, we have to accept fairly high complication rates, and therefore the paradigm has been to push the dose to the MTD, to operate just below the MTD. It doesn't make sense now to work in the region of the MTD. The therapeutic gain is much higher at lower doses. So I submit that with newer, tumor-selective drugs we need to start working with a new paradigm: to identify the minimum effective dose (MED), then operate a notch above this minimum. Then we can explore the full potential of the drug being investigated." Metastatic Pancreatic Cancer Current trials using capecitabine to treat inoperable and metastatic pancreatic cancer were reviewed by Robert Fine, MD, Columbia University, New York. Pancreatic cancer has a poor response rate to chemotherapy (ASCO abstracts 1129 and 1517). "The mechanisms of drug resistance are very important for understanding why these tumors are so resistant," Dr. Fine said. "First, to kill these cells, we have to exploit biochemical synergisms, and lab data show that if you achieve a biochemical synergy between drugs being used, you can overcome some mechanisms of drug resistance. Second, with synergistic chemotherapy you can significantly lower the chemotherapy concentrations and still kill the same number of cells-more is not always better. So you add finesse to what the oncologist wants to achieve: shrink the tumor without hurting the patient. Third, you want to target pathways for p53 independent apoptosis because 75% to 80% of all pancreatic cancer tumors have mutant p53-tumor cells in pancreatic cancer patients are not going to die through the classic p53-dependent apoptotic pathways." The Finesse of Oncology Echoing Dr. Ben-Josef's description of the importance of synergism in combination therapies, Dr. Fine said, "You want to reduce doses without sacrificing efficacy- this is what I call the finesse of oncology. Dr. Fine's goal in treating pancreatic cancer is to induce p53-independent apoptosis. "The gist of our work is that we found in human pancreatic cancer cell lines, gemcitabine(Drug information on gemcitabine) (Gemzar), docetaxel(Drug information on docetaxel), and 5-FU produce synergistic cell-kill. When we used this synergism, we were able to reduce the doses by 50% and still kill the same number of tumor cells." "And for simplicity of administration, we used capecitabine. We gave 42 metastatic patients 750 mg/m2 of capecitabine twice daily. The result was a complete response rate of 9.5% and a partial response rate of 47%. Also, 74% had a clinical benefit response," Dr. Fine reported. GTX Regimen and Variation "We used an apoptotic assay with a human pancreatic cancer cell line. We found that 5-FU and gemcitabine killed a small number of tumor cells, and docetaxel kills a few more. But if you put them together, you get this powerful synergism. That experiment led to the regimen that we refer to as GTX." The GT-X regimen consists of capecitabine 500 to 750 mg/m2 twice daily for 14 days. After 4 days, patients receive gemcitibine 750 mg/m2 over 75 minutes and low-dose docetaxel (Taxotere) 30 mg/m2 over 30 minutes. It is a 2-week regimen with the third week off, and responses are evaluated after three cycles. In the case of GTX failure, Dr. Fine then separated the administration of the drugs. This was based on lab experiments showing resistance to GTX was due to cytokinetic cell cycle resistance. The same three drugs that had just failed were used again, but this time in a sequential manner. This modified regimen is referred to as sequential GT-X. Dr. Fine comments, "This is a very easy treatment for the patient. The dose is about 60% to 75% of the GTX doses. In a preliminary study of 10 patients who failed GTX, there was one complete response and two partial responses of their metastatic disease. Four other patients achieved stable disease. Median duration of stable disease was 5.5 months. Three patients did not respond. There were no grade 2 or higher toxicities," he explained. "The GTX regimen is based on in vitro synergisms and equal activity in mutant and wild type p53 PC cells," Dr. Fine said. "The toxicity profile is favorable. Lower doses still kill tumor cells. Response rates are promising in the advanced state, and further studies are warranted to ascertain the true clinical benefit," Dr. Fine concluded. Metastatic Breast Cancer A phase III study of capecitabine plus bevacizumab(Drug information on bevacizumab) (Avastin) in metastatic breast cancer was discussed by Kathy Miller, MD, of Indiana University Medical Center, Indianapolis (ASCO abstract 766). "For the past 2 to 3 decades, it has been known that tumor growth is dependent of angiogenesis. This discovery generated an investigation as to what factors stimulate or inhibit blood vessel growth. Vascular endothelial growth factor (VEGF) is one of the most potent stimulators of angiogenesis, and this finding led to explosive growth in the development of agents that inhibit VEGF signaling. One of the earliest agents was bevacizumab, a humanized monoclonal antibody directed against VEGF itself. It recognizes all of the VEGF isoforms, and it has activity in monotherapy," Dr. Miller explained. In heavily pretreated breast cancer patients, about 9% of patients have an objective response to bevacizumab monotherapy, Dr. Miller reported, and an additional 10% are without progression at 22 weeks. This finding led to a phase III trial for patients with prior anthracycline or taxane therapy for metastatic breast cancer, or who had a relapse within 12 months of completing anthracycline and taxanecontaining adjuvant therapy. The study had 462 patients who were well balanced for demographics and all of the prognostic factors that might influence progression-free survival and overall survival. Three-quarters of the patients had visceral disease, so it was a difficult patient population. Both capecitabine and bevacizumab toxicity mirrored what was seen in earlier trials. Response Was Increased But Not the Duration Response rates, as evaluated by investigators or by a blinded review facility, nearly doubled, but there was no difference in duration of response. Therefore the progression-free survival data are not much different between the two treatment arms (4.17% for capecitabine, 4.86% for capecitabine plus bevacizumab). There was no improvement in median progression- free survival. "When we measure median progression free survival, we measure the median," Dr. Miller stressed. "Response rates of 10% to 20% do not drive median progression- free survival. That is driven by the 80% to 90% of patients who did not respond to therapy. Time to response shows the time the patient is in response to therapy. If the patient never responded, the patient has a time of 0. In this study, at each time point, the patients who are given the combination therapy are doing slightly better, but most of that benefit is early in the treatment. By the third time point, most of the excess responses gained by the combination arm are lost. So, there are excesses, but they are short-lived. And without that, you will never see an improvement in the time to progression," Dr. Miller explained. VEGF Expression Matters "VEGF expression does matter, but probably not in the way that most people would have predicted, " Dr. Miller said. "Basically, this was a negative study because it was powered to look at differences in median progression-free survival, and there were no differences, but in my mind it is a critical proof of concept study, and it really validates the importance of antiangiogenic therapy. That conclusion is because of the clear increase in objective response rate while taking into account that this was a very difficult patient population," she continued. "Our challenge now is to take advantage of that activity so we can get even greater benefit for our patients," Dr. Miller concluded.