Advances in Radiation Therapy for Cancer

Advances in Radiation Therapy for Cancer

Following the introduction of monoclonal antibodies, signal transduction inhibitors, and other targeted agents beginning in the late 1990s, there is a common misconception that the use of older cancer therapies, such as radiation, is on the decline. On the contrary, an estimated 1.1 million patients were treated with radiation in 2009, representing an increase of 15% from 2007 according to a market research study published by IMV Medical Information Division[1].

The clinical application of radiation therapy in oncology, which uses high-energy radiation to shrink tumors and kill cancer cells, dates back to the early 1900s when radium was used to successfully treat a pharyngeal carcinoma in Vienna[2]. By the 1930s, fractionated X-rays were used to cure a group of patients with inoperable cancer of the larynx[3]. Today, radiation therapy remains a cornerstone of cancer treatment and is often used in combination with surgery and chemotherapy.

Consisting of X-rays, gamma rays, and charged particles, radiation can be delivered to a cancer patient using several techniques. These include using a machine outside of the body (external-beam radiation therapy), placing radioactive material in the vicinity of cancer cells (internal radiation therapy, or brachytherapy), and systemic radiation therapy using injected substances (radiopharmaceuticals) that travel in the blood to seek and destroy cancer cells. Of the three, external-beam radiation represents the most popular delivery option, with nearly one million patients treated annually[4].

Despite numerous medical and scientific advances following its clinical introduction more than a century ago, radiation therapy is an important and growing treatment option for breast, prostate, lung and other cancers. One study calculated the annual percentage of patients receiving radiation therapy between 1991 and 2002 and found that the fraction of breast and prostate cancer patients receiving radiation therapy rose from 26% to 51% and from 33% to 47%, respectively[5]. In fact, a recent journal article suggests that 52% of all cancer patients should receive radiation[6], with the American Cancer Society expecting approximately 1,596,670 new cancer cases to be diagnosed in 2011[7].

Regardless of how it is delivered to the patient, most types of radiation do not specifically attack cancer cells and therefore cause injury to normal tissues surrounding the tumor. Accordingly, the goal of radiation therapy is to maximize the dose delivered to tumor cells while minimizing exposure to normal, healthy cells. While conformal radiotherapy, intensity-modulated radiotherapy (IMRT), image-guided radiotherapy, and proton radiotherapy have allowed more precise targeting of the tumor; exposure to normal tissues and organs still limits the amount of radiation therapy that can be administered to a patient undergoing cancer treatment[8],[9].

It has been reported that increasing the effective ionizing radiation dose by just 10% would increase treatment effectiveness by 5–30%, depending on the type of cancer[10]. For instance, a randomized trial demonstrated that when men with early-stage prostate cancer were treated with high-dose (79.2 Gray equivalents) rather than conventional-dose (70.2 Gray equivalents) external radiation therapy, they were almost twice as likely to be free from disease relapse after 10 years and less likely to have required additional cancer therapy[11]. Many patients in the study still experienced disease relapse after 10 years (32% in the conventional-dose group, 17% in the high-dose group). This suggests that even higher doses of radiation could be more effective – if it weren’t for the significant side effects due to normal tissue damage.  These include urinary reactions, such as bleeding, irritation and pain, urinary frequency, urgency, and incontinence along with rectal complications that include diarrhea, frequent and painful stools, and bleeding.

The close proximity of tumors, normal tissues, and vital organs invariably requires radiation exposure to normal tissue margins that are potentially contaminated with microscopic disease. Therefore, improvements in targeting radiation to the tumor are unlikely to completely prevent side effects and it is expected that normal tissue exposure will remain the key dose limiting toxicity for therapeutic radiation. For example, radiation therapy directed to the chest is commonly employed to treat lung, esophageal, breast and lymphoma cancers. However, lung inflammation caused by radiation therapy, called radiation pneumonitis, is the most common dose-limiting complication of chest radiation[12].

Since the initial clinical application of radiation for the treatment of cancer, researchers have explored the use of radiation protecting compounds (radioprotectants) to defend normal tissues or minimize toxicity after radiation damage has occurred. This is an especially important consideration in escalating the dose of radiation with the aim of increasing overall survival. Early radioprotectant research may have been limited by a lack of consensus with respect to the best animal models, assessment tools, and end points for each of the organ systems considered to be most at risk after moderate radiation exposures[13].

The term “radioprotectant” as used in this article refers to any agent that protects normal tissue against radiation-induced damage, whether administered before (prophylactic), during (mitigation), or after (therapeutic) exposure. To date, the only such prophylactic product to receive approval from the U.S. Food and Drug Administration (FDA) is Ethyol® (amifostine), which was originally discovered through the U.S. Army Research and Development Command’s Anti-radiation Drug Development Program.  This project was intended to search for ideal protective agents for use in a variety of radiation exposure scenarios, such as nuclear war and industrial accidents[14].

Subsequently developed for oncology indications by Pennsylvania-based biotechnology firm U.S. Bioscience, Ethyol is a prodrug that is converted in the body’s tissues to an active metabolite that can scavenge reactive oxygen species (ROS) generated by exposure to either chemotherapy or radiation therapy. By the early 1990s, Wall Street’s expectations for radioprotectants were high and the market value of U.S. Bioscience exceeded $1 billion. At the time, it was projected that 750,000 patients per year could benefit from Ethyol.

Ethyol was approved by the FDA in 1995 to reduce kidney damage associated with repeated chemotherapy (cisplatin) in patients with advanced ovarian cancer and non-small-cell lung cancer. The FDA extended the indication for use in 1999 to protect the salivary glands from radiation therapy used to treat head and neck cancer.

Unfortunately, Ethyol’s inconvenient administration via 15-minute or 3-minute intravenous infusion and unfavorable side effect profile greatly limited product acceptance. According to the prescribing information, nearly one-third of patients experienced Grade 3 or higher nausea/vomiting and nearly two-thirds of patients developed abnormally low blood pressure (hypotension) in the ovarian cancer study. While those toxicities were less common in the lower dose used in the head and neck cancer study, 17% of those patients still discontinued Ethyol due to adverse events.

Despite these severe limitations, MedImmune – now a member of the AstraZeneca (NYSE: AZN) group of companies – obtained Ethyol in 1999 through its acquisition of U.S. Bioscience in a transaction valued at nearly $500 million. In 2006, 2005 and 2004, MedImmune reported worldwide product sales for Ethyol of $87 million, $95 million, and $92 million, respectively.

Products with improved safety and ease of administration could significantly expand the annual market opportunity for radioprotectants beyond $100 million and renew investor interest in the field.  In this regard, a promising new class of investigational agents are entering early clinical development for oncology indications in parallel with leveraging government support as medical countermeasures for radiological/nuclear, biological, and chemical threats (see Table 1). There is an interest in developing and procuring such agents for national stockpiles, with U.S. funding primarily provided by the U.S. Department of Health and Human Services through the National Institute of Allergy and Infectious Diseases (NIAID) and Biomedical Advanced Research and Development Authority (BARDA).  As a further vote of confidence for the new class of radioprotectants, two +$100 million BARDA contracts to develop treatments for the pulmonary/lung and hematopoietic/bone marrow sub-syndromes of acute radiation syndrome (ARS) have been awarded to companies within the past year (see Table 1).

“The complexities of developing radioprotectant agents under conditions where there are few truly appropriate animal model(s) that will satisfy FDA requirements has limited interest and participation from both academia and industry,” said Jackie Williams, Ph.D., research professor of radiation oncology at the James P. Wilmot Cancer Center at the University of Rochester. “Nonetheless, despite these difficulties, several of these next-generation radioprotectants have demonstrated significant efficacy by ameliorating radiation-induced toxicities in animal studies and have been studied in Phase I clinical trials, to date without demonstrating the severe toxicities seen with Ethyol.”

For example, Aeolus Pharmaceuticals (OTCQB: AOLS) is developing AEOL 10150, a metalloporphyrin that scavenges ROS at the cellular level, mimicking the effect of the body’s own natural antioxidant enzyme superoxide dismutase (SOD). In two Phase I clinical trials, 37 patients with amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) received 3 mg to 75 mg of AEOL 10150 as a single daily injection, twice daily injection, or continuous infusion. No serious adverse clinical events were reported.

In addition, a total of 150 human volunteers have received single or double injections (2 to 50 micrograms intramuscularly) with Cleveland BioLabs’ (NASDAQ: CBLI) CBLB502, a Toll-like receptor 5 (TLR5) agonist designed to block stress-induced cell death in normal cells.  The primary adverse event reported to date with CBLB502 has been a transient flu-like syndrome.

In view of the fact that radiation therapy remains a cornerstone of cancer treatment, the development of novel agents that protect normal tissue against the effects of ionizing radiation represents a large market opportunity and unmet medical need. Concerns over radiation exposure following industrial accidents, such as Japan’s Fukushima nuclear reactors, along with the threat of terrorist attacks only adds to the growing importance of developing safer and more effective radioprotective agents.

Table 1. Select companies developing radioprotectants for both oncology and bio-defense “dual use” indications

Company Product Lead Oncology Indication Stage Gov’t Support
Aeolus Pharmaceuticals (OTCQB: AOLS) AEOL 10150 Lung cancer Phase I planned* Awarded BARDA contract to develop treatment for the pulmonary/lung sub-syndrome of ARS fully valued at $118 million over 5-year period
Cellerant Therapeutics (private) CLT-008 Reduce chemotherapy induced neutropenia in high-risk leukemia Phase I/II Awarded BARDA contract to develop treatment for the hematopoietic/bone marrow sub-syndrome of ARS fully valued at $153 million over 5-year period
Cleveland BioLabs, Inc. (NASDAQ: CBLI) CBLB502 Reducing severity of mucositis and enhancing efficacy of radiotherapy for head and neck cancer Phase I planned, studies in 150 healthy volunteers completed Funded in collaboration with U.S. Department of Defense (DoD) for hematopoietic/bone marrow sub-syndrome of ARS
Onconova Therapeutics, Inc. (private) Ex-RAD® (ON 01210.Na) Reducing urinary and rectal complications from radiotherapy in prostate cancer Phase I studies in 52 healthy volunteers completed with subcutaneous administration, IND for oral formulation accepted by FDA in 2011 Funded in collaboration with DoD

* Note: The product has already been tested in 37 patients with ALS in Phase I trials



[1] IMV’s Radiation Therapy Census Database and Market Summary Report at

[2] Advances in radiotherapy and implications for the next century: a historical perspective. Connell PP, Hellman S. Cancer Res. 2009 Jan 15;69(2):383-92.

[3] Cancer of the Larynx — Five-Year Results, with Emphasis on Radiotherapy. Wang CC, O’Donnell AR. N Engl J Med 1955; 252:743-747.

[4] Can radiation risks to patients be reduced without reducing radiation exposure? The status of chemical radioprotectants. Mettler FA Jr, Brenner D, Coleman CN, Kaminski JM, Kennedy AR, Wagner LK. AJR Am J Roentgenol. 2011 Mar;196(3):616-8.

[5] Evaluation of trends in the cost of initial cancer treatment. Warren JL, Yabroff KR, Meekins A, Topor M, Lamont EB, Brown ML. J Natl Cancer Inst. 2008 Jun 18;100(12):888-97. Epub 2008 Jun 10.

[6] The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Delaney G, Jacob S, Featherstone C, Barton M. Cancer. 2005 Sep 15;104(6):1129-37. Erratum in: Cancer. 2006 Aug 1;107(3):660.

[7] American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society; 2011.

[8] Radioprotectors and mitigators of radiation-induced normal tissue injury. Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Oncologist. 2010;15(4):360-71. Review.

[9] Targeting the TGF-beta1 pathway to prevent normal tissue injury after cancer therapy. Anscher MS. Oncologist. 2010;15(4):350-9.

[10] Strategies to improve radiotherapy with targeted drugs. Begg AC, Stewart FA, Vens C. Nat Rev Cancer. 2011 Apr;11(4):239-53.

[11] Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09. Zietman AL, Bae K, Slater JD, Shipley WU, Efstathiou JA, Coen JJ, Bush DA, Lunt M, Spiegel DY, Skowronski R, Jabola BR, Rossi CJ. J Clin Oncol. 2010 Mar 1;28(7):1106-11. Epub 2010 Feb 1.

[12] Radiation-induced lung injury: Strategies for reducing damage while optimizing therapeutic dosage. Wiebe E, Rodrigues G. Oncology Exchange Vol. 5 No. 2 April 2006.

[13] Animal models for medical countermeasures to radiation exposure. Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser AK, Kirsch DG, Macvittie TJ, Mason KA, Medhora MM, Moulder JE, Okunieff P, Otterson MF, Robbins ME, Smathers JB, McBride WH. Radiat Res. 2010 Apr;173(4):557-78.

[14] History and development of radiation-protective agents. Weiss JF, Landauer MR. Int J Radiat Biol. 2009 Jul;85(7):539-73.

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