While novel targeted and biological agents receive much attention as the future of cancer therapy, radiation therapy remains one of the three main cancer treatment modalities along with surgery and chemotherapy. Despite a start as early as 1895, radiation therapy continues to evolve and have wide utility for cancer treatment. In a review published in Science Translational Medicine, Stanley L. Liauw, MD, Philip P. Connell, MD, and Ralph R. Weichselbaum, MD, of the department of radiation and cellular oncology at the University of Chicago, review the recent advances in radiation oncology and talk about the ways to improve treatment.
Overall Function of Radiotherapy in Cancer Treatment
Surgery and radiotherapy are often done in combination or consecutively, and radiation therapy can also be a noninvasive alternative to surgery, particularly when organ preservation is necessary, such as with bladder or laryngeal cancer.
Low dose, punctate radiotherapy has been shown to selectively kill tumor cells while allowing normal tissue to recover. There is a window of dose and timing of radiotherapy that results in optimal tumor cell killing while allowing normal tissue to rebuild itself. A common regimen of radiotherapy is daily treatment about five times per week for a total of 6 to 8 weeks. Dosage is determined by “consideration to the unique relationship between the dose-response curves for the specific tumor and surrounding normal tissues, which vary widely for each clinical circumstance,” state Weichselbaum and colleagues.
Radiotherapy as a neoadjuvant treatment prior to surgery can make tumor resection easier. As an adjuvant therapy, radiotherapy serves to treat microscopic residual disease. Radiotherapy can also be combined with chemotherapy to act as “a radiosensitizer for the purpose of increasing local control,” state the authors. The use of each of these approaches varies depending on the type of cancer and the stage of disease.
Side Effects of Radiation Therapy
Short-term side effects of radiotherapy are due to the inhibition of self-renewal of normal tissue exposed to the radiation. This includes vascular damage, fibrosis, and other effects depending on the site of treatment. Long-term, radiation therapy can lead to secondary cancers due to acquired mutations in exposed cells.
Drugs in Development
One major challenge of radiotherapy is that some tissues are very radiation-sensitive but are found directly adjacent to the tumor. Prostate cancer, for example, has a relatively high cure rate with radiotherapy but because high doses and combination with hormonal therapy are required, the patient suffers significant side effects as a result of treatment. To bypass normal tissue toxicity, drugs that can sensitize just tumors to radiotherapy are needed. Such drugs could boost response rates and minimize unwanted side effects.
The types of drugs in development as radiation therapy sensitizers include inhibitors of double-stranded break repair as well as inhibitors of the DNA damage response. The hypothesis is that because radiotherapy results in DNA single-stranded and double-stranded breaks, adding an additional attack on the mechanisms that repair these types of damage will result in a one-two punch that will kill tumor cells. Normal cells, with intact damage response pathways and no genetic mutations that compromise repair, on the other hand, will be able to repair their genomes. Current targets in development include the MRN complex which functions in DNA double-stranded break repair as well as components of the homologous and nonhomologous recombination pathways of repair.
Poly (ADP-ribose) polymerase (PARP) inhibitors are currently in clinical trials in combination with both chemotherapy and radiotherapy for various solid tumors. PARP functions to repair DNA damage in the cell. Histone eacetylase (HDAC) inhibitors are also in early stages of development. HDACs generally facilitate a more compact higher-order DNA structure. Inhibiting these enzymes may thwart the ability of the cell to efficiently repair DNA, according to published research. Inducers of cell-cycle arrest are yet another approach that may result in more efficient tumor cell killing by sensitizing cells to radiation therapy–induced DNA damage. Several compounds that function to induce cell-cycle arrest are in early stage clinical trials. Many other targeted therapies are also in development that may enhance radiotherapy, including anti-angiogenesis therapies, immune modulators, and inhibitors of apoptosis, or programmed cell death.
Protecting Normal Tissue During Treatment
As cancer treatments get better, more patients are surviving longer and suffering from the side effects of radiotherapy. Radioprotecting drugs could allow higher, focused radiation on the tumor itself, while minimizing damage to normal tissue. Another type of therapy could be therapeutic agents that stimulate tissue-healing post-therapy. The main issue with developing these types of agents is to avoid protecting or stimulating tumor cells as well. Agents in development include sulfhydryl-containing compounds that can absorb the free radicals generated by radiation-induced ionization. Other radiotherapy protective drugs in development include cell-cycle arrest drugs as nondividing cells are less susceptible to radiation damage.
Identifying molecular predictors of response to radiotherapy is an active research effort. The authors suggest that caution should be taken especially when the analysis relies on a small biopsy sample that may not represent the full heterogeneity of the tumor.
Novel types of radiation therapy technology are also in development. Brachytherapy is a type of treatment the authors highlight as potentially outperforming external beam. Brachytherapy is currently limited to cancers with a well-defined area that can be accessed noninvasively, such as prostate, breast, cervical, and skin cancers. The high doses used with brachytherapy require fine technical skill since exposure of normal tissue can cause high toxicity.
The authors call for a more individualized approach to radiotherapy, for better ways to test potential predictive biomarkers, and for continued objective, evidence based decision-making.