Enhancing the Efficacy of Radiation Therapy: Premises, Promises, and Practicality

This special series of Journal of Clinical Oncology focuses on innovative approaches to enhancing the outcome of patients treated with radiation therapy. Articles by outstanding leaders in the field are included: Morris and Harari¹ address molecular targeted therapy plus radiation; Wang and Tepper² describe uses of nanotechnology for enhancing diagnosis, radiation targeting, and radiation cell killing; and Giaccia³ analyzes how molecular radiation biology can be applied in the clinic.

As Morris and Harari¹ point out, within the universe of molecular cancer therapeutics there is a dearth of clinical trials testing combined-modality systemic therapy plus radiotherapy (CMRT), by which we mean the administration of agents concurrently with radiation rather than sequentially before or after radiation. A key reason for this is that the development of CMRT is hampered by an approach to drug development that focuses almost exclusively on obtaining an initial US Food and Drug Administration–approved clinical indication for patients with metastatic disease that is refractory to standard therapy. Thus, the expense of developing CMRT and the potential for toxicity that might slow approval usually relegates radiation modifier development to drugs that are already approved for other indications. This not only limits the number of compounds that are investigated but also the time over which a company can achieve return on investment.

We understand this logic; however, we believe that this strategy might actually hurt potential return on investment for a number of reasons. First, developing a drug for use alone or in combination with other systemic agents, but not with radiation, does not fully develop the drug's clinical potential because it limits the patient population that could benefit. Second, each year there are drugs that reach clinical trials as systemic therapies but fail to improve outcomes and therefore do not receive approval. They could be repurposed as radiation modifiers to provide a route for US Food and Drug Administration approval, which would salvage the investment. Third, understanding of the molecular mechanisms of radiation response continues to improve, and there are now a number of attractive targets for which agents can be developed specifically for the purpose of CMRT, such as kinases that regulate the DNA damage response.⁴ Thus, there is a strong rationale for incorporating radiation therapy into early drug development. Moreover, we believe that the likelihood of success would be substantially increased if CMRT development originated from rational preclinical studies.⁵

In an effort to help frame the broad potential for enhancing radiation efficacy for those not familiar with the nuances, here we provide a short primer on three aspects of CMRT: premises, promises, and practicality.

Premises

There may be some misconceptions about what radiation therapy can bring to CMRT, and here we summarize certain key principles.

Spatially focused therapy.

Radiation can be delivered precisely to a specific target volume so that the amount of tissue receiving CMRT is limited. Recent technical advances allow intensity-modulated and image-guided radiation therapy to sculpt the high-dose region to the tumor or even subregions within the tumor while reducing high-dose regions involving normal tissue. This allows cancers in organs that were heretofore not believed to be candidates for curative dose radiation, such as the liver,⁶ to be effectively treated. However, this multiple-field approach with high-energy x-rays leads to more normal tissue receiving a low dose. Guidelines based on dose-volume relationships for normal tissues are being continuously refined,⁷ with anticipated benefits.

Classical radiation and chemotherapy biology.

So-called classical radiation biology includes essential radiation survival mechanisms, mathematical formulas that model the biologic effects of dose and fractionation, normal tissue injury models, and tumor microenvironment effects (primarily hypoxia). It is not dissimilar to classical chemotherapy including pharmacokinetics, dose equivalency such as area under the concentration-time curve and IC50 (half-maximal inhibitory concentration) for drug effect, and models of drug toxicity. Both include cell survival curves, but the difference in potency between chemotherapy and radiation is worth noting. Radiation survival curves usually plot dose (linear) versus surviving cells (log), and drug assays are usually dose (log) versus cell killing (linear).

This difference in potency is translated to the clinic, where active systemic agents are identified by achieving partial (approximately 90% of cells dead) or complete response (approximately 99% of cells dead), which is approximately equivalent to one or two logs of cell kill, respectively. For many human cancers, it is estimated that to eradicate one tumor, eight to 10 logs of tumor cells must be killed. Although this degree of cytotoxicity can be achieved with radiation therapy alone, in some tumors treated with radiation alone, some cells will still survive and lead to local recurrence.

CMRT can increase the number of logs of tumor cells killed to improve local control. Indeed, most clinical studies of CMRT versus radiation therapy alone show that the addition of the systemic agent has greater impact on improved local control than on decreased metastasis.⁸ The efficacy of an agent as a radiation modifier can be characterized by calculating a dose-modifying or dose-enhancement ratio from the effect of radiation with and without the drug using in vitro (clonogenic survival curve) and in vivo (tumor growth delay or TCD50: the dose required to cure [one half] the tumors) techniques. Although classical radiation and chemotherapy biology do not necessarily reveal molecular mechanisms, they remain highly relevant to translational CMRT by describing essential relationships of dose and schedule to optimize utility.

Radiation fractionation.

The dose per fraction and total number of fractions now have a wide range in clinical practice from the standard 1.8 to 2 Gy per day, 5 days per week schedule. Hypofractionation with a small number of doses of 7 to 20 Gy can be used to achieve high rates of local control for small tumors, whereas ablation of a small amount of normal tissue may not have a clinical impact. Whether the underlying biology is simply a higher equivalent dose or there are new biologic effects such as vascular damage that determine efficacy remains an area of active debate and research.^9,10 In either case, this is a novel opportunity for precision radiation therapy plus drug(s), possibly involving hypoxic cell sensitizers,⁹ among others.

Promises

Important concepts are emerging from the laboratory and clinic that provide new avenues for CMRT.

Charged particles.

Unlike x-rays, which deposit energy within a tumor and then into normal tissue as the beam exits the patient, proton radiation therapy delivers radiation to the target and then stops without irradiating distal normal tissue. Thus, in comparison to x-rays, proton radiation therapy can decrease the amount of normal tissue that receives low-dose radiation. Therefore, it is conceivable that concurrent systemic therapy may be better tolerated with protons than with x-rays. Protons are assumed to have an ability to kill tumor cells that is similar to that of x-rays, as a function of ionizing energy (dose) deposited. Carbon ion radiation therapy, which is available in Germany, Italy, and Japan, has biologic properties (called relative biologic effectiveness) that might offer additional advantages beyond protons in terms of providing a more potent effect in the tumor.¹¹ The improved dose distribution plus possible other advantages of heavy-particle therapy might provide particularly attractive opportunities for CMRT.

Molecular radiation biology.

Radiation is being defined by the molecular events it produces. The molecular changes vary based on dose size, fractionation, number of fractions, and underlying genetic background.¹² Thus, it may be possible to choose a radiation dose to produce the desired molecular changes for use in CMRT, that is, taking advantage of the radiation stress response and the cellular response and adaptation to it.^12,13

Novel drug activity and CMRT.

For most classical CMRT, the systemic agent has antitumor activity that is independent of radiation, although drugs that are used together with radiation are frequently administered in schedules that emphasize their radiation-sensitization properties and not necessarily their single-agent cell-killing characteristics (eg, weekly cisplatin). With newer, molecularly targeted agents (such as epidermal growth factor receptor inhibitors, as reviewed by Morris and Harari¹) and targets (such as mitochondria, discussed by Giaccia³), cell killing in the absence of radiation may not be necessary. Hypoxic sensitizers are another example of drugs that are not necessarily cytotoxic by themselves but work together with radiation therapy in the clinic.¹⁴

The molecular and biochemical ramifications of a specific mutation within a tumor can be extraordinarily complex. A mutation may lead to susceptibility for a drug alone or in combination with radiation, but there can be heterogeneity in efficacy and toxicity for CMRT among drugs that target a specific pathway, for example, poly (ADP-ribose) polymerase inhibitors.^15,16 In selecting a radiation modifier for a particular signaling pathway, studying a few potential drugs in that class may help to identify the best combination and possibly reveal a mechanism that was not predicted by the putative mechanism of action.

Immunologic effects.

Radiation can stimulate an immunologic response.^17–19 The use of radiation as part of immunotherapy is of intense interest on the basis of vaccine studies^20,21 and the striking demonstration of the abscopal effect with radiation plus immune modulation.²² Damage produced in one cell can induce changes in its neighbors, a concept called nontargeted or bystander effects.^23,24 The impact on clinical response is a subject of debate; however, understanding the effect of radiation on the different normal tissues within and near the tumor (stroma, endothelial cells, immune cells) and also possibly at a distance may well enable both the delivery of higher doses and unique targets for treatment.

Practicality

Certain concepts and tasks need to be considered and implemented in moving from the laboratory to the clinic.

More is not always better.

Combining two or more drugs that each work with radiation in the clinic will not necessarily further improve outcome. This empirical approach was tested in a randomized trial for patients with head and neck cancer in which radiation therapy was combined with cisplatin with or without epidermal growth factor receptor inhibition. The two-drug CMRT was no more effective than cisplatin alone but produced more toxicity.²⁵ This lack of enhanced effect may be a result of both agents helping the same group of patients, or may result from enhancement in some patients and detriment in others, with no overall benefit to complex interaction among the treatments.⁵ Results such as this indicate the need for preclinical testing of the standard-of-care drugs plus radiation to which the novel agents are added. Moreover, preclinical experiments of CMRT should be performed in complementary preclinical model systems, such as patient-derived xenografts and genetically engineered mouse models of cancer. Genetically engineered mouse models not only serve as a model system that can mimic the response of human cancers to CMRT, but can also be used to dissect the mechanisms of tumor response to radiation alone or to CMRT,²⁶ potentially identifying novel targets.

Tumor heterogeneity effects.

The cellular and molecular heterogeneity within tumors during tumor evolution before treatment is becoming better understood, and clinical outcomes can be adversely affected by one or all of the following: de novo resistance, selection of resistant cells, and adaptive and induced changes during treatment.^27–29 This may limit the efficacy of targeted therapy alone but can provide an opportunity for CMRT. Although similar adaptation/selection may affect CMRT, achieving local control may be enhanced by combining the targeted therapy with radiation, which may kill the resistant cells by independent mechanisms. Interrogating the tumor before and during therapy, preferably before resistance has occurred, may guide the selection of agents to combine with radiation.¹² This is being studied by serial biopsy with validated molecular biomarkers^30,31 and/or serial imaging to provide a rational approach to adapting therapy.

Importance of preclinical studies and biomarkers.

Proper preclinical studies are needed, as suggested by recent workshops.^32–34 Given the time and steps required for the drug development process, it is wise to begin this process earlier. Moreover, given the range of expertise needed, preclinical studies are best accomplished through collaboration among academic investigators and pharmaceutical companies. Clinical trials are now using (requiring) biomarkers to establish pharmacodynamic efficiency (hitting the target, so to speak) and then to understand treatment response.^30,31 Radiation-induced DNA damage markers such a γH2AX and repair enzymes, for example, could be particularly informative for CMRT.

Analyzing success, failure, and reproducibility.

Understanding the results of null trials is proper science. On the basis of a critical review of six null CMRT studies,³⁴ further detailed review led to the conclusion that preclinical models should include standard-of-care treatments. The problem of reproducibility of preclinical studies from academic laboratories has received much needed attention.^35,36 On the basis of that information and the so-called null trials workshop, the Radiation Research Program is completing a detailed study of the methodology used in preclinical radiation modifier studies (H.B. Stone, personal communication, July 2014). There are also ongoing efforts to improve transparency of preclinical research³⁷ and possibly to have the National Institutes of Health validate key results.³⁸

In conclusion, the molecular era of oncology offers a plethora of opportunities for improved tumor eradication with CMRT: there are new concepts to exploit, drugs can be repurposed and the use for others can be expanded, and development can be improved through both classical approaches in radiation and drug development and also newer approaches using clinically relevant preclinical models. Radiation should be considered a drug that has the ability to deliver biologic changes in a spatially focused volume and which may also enhance systemic effects of treatment, such as immune modulation. Given the investment in drug development, considering CMRT as wise incremental cost, both early in drug development and for repurposing drugs, has outstanding value in terms of dollars invested and, in particular, patients who can benefit.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org.

AUTHOR CONTRIBUTIONS

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

C. Norman Coleman

No relationship to disclose

Theodore S. Lawrence

No relationship to disclose

David G. Kirsch

Stock or Other Ownership: Lumicell

Consulting or Advisory Role: Lumicell

Research Funding: Lumicell

Patents, Royalties, Other Intellectual Property: Lumicell