A new study questions the maximum-tolerated-dose approach in cancer.
A new study has raised questions about the maximum-tolerated-dose (MTD) paradigm in cancer. Using a breast cancer xenograft model, researchers from the Lee Moffitt Cancer Center took advantage of low-dose chemotherapy to apply brakes to a tumor’s resistance mechanism, rather than trying to destroy the tumor with a much higher dose—as is the norm with MTD. The observations from this research, published in Science Translational Medicine, suggest adapting to living with cancer might not be too radical an approach.
The pitfalls of chemotherapy are well known—the treatment kills drug sensitive cells in a widely heterogeneous population of tumor cells, and leaves the resistant cells to proliferate as soon as treatment stops. To counter this phenomenon, the researchers at Moffitt designed a study that would adapt the chemotherapy dose based on how each tumor responds, with the goal of stabilizing the tumor by maintaining a population of the chemosensitive cells that would regulate the resistant cells.
MCF-7 estrogen receptor—positive and MDA-MB-231/luc triple-negative breast cancer cells were grown in mouse mammary fat pads and were treated with paclitaxel. Tumor response was monitored using magnetic resonance imaging (MRI). Using higher doses in the initial phase to plateau tumor growth, the authors treated the animals with progressively smaller doses of chemotherapy. The strategy resulted in nearly 60% to 80% of animals presenting a continued decline in tumor size without the need for drug treatment. MRI and histological analysis of the tumor found less necrosis and increased vascular density, which the authors write may be a result of vascular normalization. The increased vascular density lets more drug to be delivered to the tumor, which in turn allows for lowering of the drug dose.
An important point raised by the authors is the accurate measurement of tumor volume during treatment. Clinical trials usually perform cross-sectional imaging, which cannot determine tumor volume unlike an MRI.
“We have explored a flexible treatment strategy, which varies the drug dosing and scheduling to maintain a persistent population of sensitive cells and reduce the proliferation of resistant populations. Our results suggest that this adaptive therapeutic strategy can be adapted to clinical imaging and can result in prolonged progression-free survival in breast cancer,” the authors conclude.