Despite early findings over recent years that seem to support the normalization model, before this year, no clinical studies had described the effects of VEGF blockade on chemotherapy drug uptake by tumors in humans.2 Now, the first such study, by researchers in the Netherlands, appears to challenge the widely accepted normalization model. Contrary to expectation, the new study found that VEGF blockade can impair rather than improve the delivery of chemotherapy drugs to tumors.2 The researchers used positron emission tomography (PET) to track radiolabeled docetaxel in patients with NSCLC. Surprisingly, they found that administering bevacizumab before docetaxel significantly reduced the perfusion and influx rate of taxane to tumors, an effect that lasted 4 days.2

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“The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors,” the authors reported.2 “These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of antiangiogenic drugs.”

New randomized, controlled clinical trials are needed to identify the optimal schedule for bevacizumab plus cytotoxic chemotherapy, and animal studies may prove instrumental in identifying the molecular mechanisms explaining her team’s findings, lead author Astrid Van der Veldt, MD, of the VU Medical Center in Amsterdam, told Oncology Nurse Advisor.

“The authors should be congratulated for performing this study and examining a very important question about anti-VEGF treatment in human tumors,” Jain, a pioneer of the normalization model, told Oncology Nurse Advisor. “There has been a relative dearth of translational studies examining the physiological effects of anti-VEGF treatment in cancer patients, largely due to logistical difficulties—and more such studies are urgently needed to shed further light on this important question.”

Previous clinical and preclinical animal studies that seemed to support the normalization model of VEGF blockade and improved tumor drug uptake, may have yielded misleading results because they tracked tumor perfusion using radiolabeled glucose (using FDG PET tumor imaging), rather than radiolabeled chemotherapy drugs, Van der Veldt suspects.

“The kinetics of 18F-FDG are fundamentally different from those of anticancer drugs, as 18F-FDG reflects glucose metabolism,” she explained.

“This is an interesting and important study that contradicts much of the previous literature … and has significant clinical and translational implications,” said Professor Timothy Cripe, MD, PhD, Director of Hematology/Oncology and Bone Marrow Transplant at Nationwide Children’s Hospital, Columbus, Ohio.

The new findings need to be further explored and validated, Cripe and Jain both emphasized. The new study is preliminary and exploratory, Jain told Oncology Nurse Advisor, and timing of VEGF blockade is not the only consideration.

“There are a large number of variables that can modulate the effects of anti-VEGF therapy on drug delivery,” Jain said. “The most important of these is dose. A lower dose could normalize vessels and improve drug delivery, whereas a higher dose could reduce both perfusion and drug delivery. The question of an appropriate [VEGF blockade] dose is a complete black box in the setting of human tumors and the results of this study should be interpreted with caution.”

“It would have been better if the authors had compared a larger group of patients and tested several doses in this study, and compared changes in perfusion with the treatment outcome—response rate, progression-free survival, [or] overall survival,” Jain said.

And while the new study found statistically significant impairment of tumor drug uptake, these may not prove to be clinically significant, Cripe argued. “The effects of combined therapy on the tumor microenvironment might offset the effects of loss of drug delivery, so that in the end schedule might not matter,” he said.