Showing Normalization by Anti-Angiogenic Drugs in Patients
To test the normalization concept in human tumors, we began a clinical trial in rectal carcinoma patients at Massachusetts General Hospital (MGH) in Boston. This phase I trial was led by my colleague Chris Willett, who was a professor in radiation oncology when I started this trial. Today he's the chairman of radiation oncology at Duke University in Durham, N.C. This was the first trial that showed how anti-angiogenic therapy might work in patients, and it formed the basis of an ongoing phase II trial at MGH and Duke.
Avastin, the anti-angiogenic therapy we used, is an antibody against vascular endothelial growth factor (VEGF). We gave the patients Avastin monotherapy [Avastin alone with no other therapy], waited about two weeks and then collected blood and urine samples. We measured the pressure inside these tumors, imaged them using two different imaging technologies, and also collected tumor biopsies to learn about the response of tumors to Avastin. Then, the patients received continuous infusion of the chemotherapy drug 5-FU and external-beam radiation therapy along with Avastin every two weeks. At the end of the combined chemo-radiation and Avastin therapies, we waited seven more weeks and then the residual tumor was resected surgically.
To gain further insight into vascular normalization and to identify surrogate and predictive markers of anti-angiogenic therapy, we are doing similar trials at Massachusetts General Hospital in tumors of different types, including glioblastoma, head and neck, and ovarian cancer. For each trial, we are using a number of imaging methods, and collecting blood, urine and tumor biopsies whenever possible. (The status of each of these trials is available on the MGH Cancer Center website.)
What was unique about our first clinical trial was that in all the previous phase III trials with Avastin, it was always given in combination with chemotherapy right from day one. We gave the chemotherapy later, which allowed us to learn about the biology of patients’ tumor vessels in response to Avastin alone. Up until then we had no idea what Avastin alone was doing to the blood vessels of a patient's tumor.
This dose-escalation phase I clinical trial was sponsored by the NCI. After completing the studies in the first six patients at a 5-milligram dose of Avastin, the dose was doubled to 10 milligrams, which led to toxicity, so we had to stop the trial at that point. (We are now doing a phase II trial in which we’ve gone back to testing Avastin at a lower dose of 5 milligrams.) Here I will summarize the results of the phase I trial in rectal carcinoma patients.
Our work of 15 to 20 years has shown that tumors have very high fluid pressure inside them. This high pressure—referred to as the interstitial hypertension—is a barrier to drug delivery and is a result of abnormality in tumor vessels. I had hypothesized that vascular normalization would be able to reduce this pressure. We had shown this in tumors in mice. And we saw the same thing in the patients in our first Avastin clinical trial. So this was consistent with our mouse studies.
During the trial, we also wanted to learn more about the normalization process. A CT scan with contrast showed that the number of a tumor’s blood vessels, after one dose of Avastin, was reduced by 50 percent. So then we asked: All right, are the remaining vessels “normalized”? And if so, how normal are they? Or, if they are abnormal, are they as abnormal as when we started out?
To answer some of these questions, we utilized positron emission tomography (PET) to measure the uptake of a glucose-like molecule. We found that after one dose of Avastin, the blood supply was reduced by half, but the PET signal did not go down. Actually, it did not change—indicating that the remaining, presumably normalized blood vessels were functioning better than what we started with. We saw this in 11 out of 11 patients, which included six patients on a 5 milligram dose of Avastin and five on a 10 milligram dose. These data provided the first evidence for vascular normalization in cancer patients and were published in Nature Medicine in 2004 and the Journal of Clinical Oncology in 2005.