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

 

References


[1] IMV’s Radiation Therapy Census Database and Market Summary Report at www.imvinfo.com

[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.

Bayer’s Bold New Bet Fails to Rain on Spectrum Pharmaceuticals

Despite recent progress and the availability of novel therapies, radiation is still an effective tool in the war against cancer – as it has been for more than a century.  The original and still predominant mode of administration is via external methods wherein a radiation source is directed at the intended target or region. Unfortunately, this “outside in” approach has the drawback of causing collateral damage to healthy organs and tissues that lie on either the path between the source and the target or beyond the intended target on the “exit” pathway.

In the 1990s, the U.S. Food and Drug Administration [FDA] cleared for marketing the first intravenously delivered, particle emitting radionuclides for the treatment of pain arising from the spread of cancer to bone. Termed Systemic Targeted Radionuclide Therapy (STaRT), this new approach offered the promise of selectively irradiating disease sites while sparing normal tissue. Metastron® [strontium-89 chloride injection] was introduced in 1993 and Quadramet® [samarium-153 EDTMP] was later introduced in 1997.

In 2003, the FDA cleared for marketing two different radioactive labeled monoclonal antibodies for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma [NHL].  Both of these STaRT products utilize monoclonal antibodies that target an antigen expressed by certain normal and malignant B-cell lymphocytes.  However, Zevalin® [ibritumomab tiuxetan] employs yttrium-90 as its therapeutic payload, while Bexxar® [tositumomab] uses iodine-131.

Despite great promise and STaRT’s established safety and efficacy, a July 14, 2007, article in the New York Times stated that only 10% of patients who are suitable candidates for the drugs ever receive treatment.  Spectrum Pharmaceuticals, Inc. (SPPI) reported that U.S. sales of Zevalin were $11.4 million in 2008; while a similar non-radioactive product Rituxan® [rituximab] is a top-selling cancer drug by Genentech and Biogen Idec, Inc. (BIIB), with reported U.S. sales of $ 2.6 billion in 2008.

The lack of commercial success for existing STaRT products may be due to a mixture of clinical and commercial factors, including the following:

  • Clinical considerations
    • Half-life, or the amount of time required for a given amount of radionuclide to lose 50% of its strength or activity
      • In general, a half-life of 10 days or less is considered optimal, as longer half-lives may create waste management issues and clinically, are more likely to show toxicity problems.
    • Particle range
      • Higher particle ranges may result in greater damage to surrounding normal tissue, leading to side effects such as myelosuppression.
    • Specificity
      • Some radionuclides, such as strontium-89, have general disease-targeting properties, while others are conjugated to antibodies or other carriers to reach the intended target.
  • Commercial considerations
    • Production
      • Radioisotopes utilized for STaRT are produced commercially in nuclear reactors, cyclotrons or linear accelerators, and radionuclide generators, the selection of which can impact the cost-effectiveness of manufacturing.
    • Shipment
      • Radionuclides that have very short half-lives or that require extensive shielding as a result of high-energy gamma ray emissions [eg, iodine-131] create logistical issues for shipment and handling and may even require a local production unit close to the treatment center.
    • Administration
      • Marketers often assume that oncologists’ decisions about therapy are driven purely by the scientific data.  While medical oncologists are the key prescribing audience for marketed STaRT therapies, most aren’t licensed to administer radiopharmaceuticals – resulting in patient referrals to radiation oncologists and/or nuclear medicine physicians.  Therefore, these physicians may not be economically incentivized to prescribe products that they are not paid to administer.
    • Reimbursement
      • Reimbursement by the Centers for Medicare and Medicaid Services [CMS] and private insurance carriers is critical to the commercial success of any product.  In a letter by GlaxoSmithKline plc (GSK) to CMS regarding changes to the Hospital Outpatient Prospective Payment System [HOPPS], the company indicated that the proposed 2008 payment rate for Bexxar “results in a reimbursement rate that is approximately 50% below hospitals’ actual acquisition cost for the therapy.”

While some commercial considerations, namely administration and reimbursement, still need to be addressed, “next-generation” STaRT product candidates appear to address many historical clinical considerations and could ultimately fulfill the promise of this therapeutic class.

For example, Algeta ASA (OSE: ALGETA) is developing Alpharadin, the first in a new class of STaRT therapies based on the alpha-emitting radionuclide radium-223. Phase 2 studies in patients with hormone-refractory prostate cancer [HRPC] have already demonstrated that Alpharadin can prolong patient survival, improve quality of life and offer a benign safety profile.  A Phase 3 trial is underway to confirm Alpharadin’s efficacy and safety as a targeted treatment for bone metastases in patients with HRPC.

Radium-223 appears to offer the perfect mix of clinical characteristics (see table 1 for a comparison of STaRT products).  It has an 11.4 day half life, which is significantly shorter than the 50.6 day half-life for strontium-89, but not too short to create logistical issues with shipment.  Further, radium-223 has an extremely short particle range of 0.04 millimeters, which is equal to approximately 2-10 cell diameters.  This likely explains Alpharadin’s benign toxicity profile.

Table 1: comparison of STaRT products

Year Introduced Product Indication Radioisotope Half-life Max Particle Range in Tissue
1993 Metastron® Treatment of bone pain arising from cancer Strontium-89 50.6 days 8.00mm
1997 Quadramet® Samarium-153 1.9 days 3.00mm
2003 Bexxar® Treatment of non-Hodgkin’s lymphoma Iodine-131 8.0 days 2.00mm
2003 Zevalin® Yttrium-90 2.7 days 12.00mm
Phase 3 trial underway Alpharadin Treatment of bone metastases in hormone-refractory prostate cancer Radium-223 11.4 days 0.04mm

Lending credibility to the future of next-generation STaRT products, Algeta today announced an $800 million global agreement with Bayer AG for the development and commercialization of Alpharadin.  In view of the fact that Bayer currently markets Zevalin outside of the U.S., this news could be interpreted as either good or bad news for investors betting on an acquisition of Spectrum Pharmaceuticals.

The bullish case is that Bayer is making a fresh $800 million investment in the field of STaRT, which could lend support to a consolidation of Zevalin marketing rights by Bayer.  However, the bear case is that Algeta has already demonstrated in vivo the potential of linking alpha-emitting radionuclides to existing monoclonal antibodies, including rituximab, which could ultimately pose quite a competitive threat to earlier-generation STaRT products like Zevalin.  In view of recent 52-week highs for Spectrum Pharmaceticals, however, it appears for now that investors are opting for the bullish thesis.

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Disclaimer: This article contains the author’s own opinions, and none of the information contained therein constitutes a recommendation that any particular security, portfolio of securities, transaction, or investment strategy is suitable for any specific person. To the extent any of the information contained in the article may be deemed to be investment advice, such information is impersonal and not tailored to the investment needs of any specific person.

Spectrum Pharmaceuticals to Benefit from FDA Action on Zevalin?

According to the American Cancer Society [ACS], non-Hodgkin lymphoma [also known as non-Hodgkin’s lymphoma, NHL, or sometimes just lymphoma] is a cancer that starts in cells of the lymph system, which is part of the body’s immune system.  NHL is the fifth most common cancer in both men and women in the United States [not counting skin cancers].  In 2009, the ACS estimates that there will be nearly 66,000 new cases of NHL in the United States and that about 20,000 people will die from the disease.  In general, the overall 5-year relative survival rate for people with NHL is 65%, and 10-year relative survival is 54%.

By 2003, the U.S. Food and Drug Administration [FDA] had approved two radioactive labeled monoclonal antibodies for the treatment of patients with “relapsed” or “refractory”, low-grade or follicular B-cell NHL.  Refractory NHL is disease that never responded or has stopped responding to standard therapies.  Relapsed NHL is disease that has returned after successful initial treatment.

Both products utilize monoclonal antibodies that target an antigen expressed by certain normal and malignant B-cell lymphocytes [CD20] combined with the killing power of radiation to eradicate tumor cells.  Zevalin® [ibritumomab tiuxetan] by Spectrum Pharmaceuticals, Inc. (SPPI) in the United States and Bayer Schering Pharma ex-United States employs yttrium-90 as its therapeutic payload, while Bexxar® [tositumomab] by GlaxoSmithKline (GSK) uses iodine-131.

In April 2008, the European Commission extended the marketing authorization for Zevalin in Europe to include first line consolidation therapy for patients with NHL.  The decision by the European Commission to expand Zevalin’s indication was based on data from the pivotal Phase 3 First-Line Indolent Trial [FIT] demonstrating that the addition of Zevalin significantly prolonged the median progression-free survival time from 13.5 months [control arm] to 37 months [p<0.0001].  The data were presented for the first time at the 49th Annual Meeting of the American Society of Hematology [ASH] in December 2007.

In November 2008, the FDA accepted and granted priority review status for Spectrum Pharmaceuticals’ supplemental Biologics License Application [sBLA] for expanded use of Zevalin as a first line consolidation therapy for patients with NHL.  A Prescription Drug User Fee Act [PDUFA] target date of July 2, 2009 has been established by the FDA for a decision regarding the Zevalin sBLA, although PDUFA dates appear to be a moving target with the agency nowadays.

Assuming the sBLA is approved, which appears likely based on the European Commission decision, Spectrum Pharmaceuticals stated that Zevalin’s addressable patient population would increase by approximately 18,000.  At an approximate cost of $25,000 per treatment, the additional market for Zevalin would be worth $450 million.  Not bad.

Unfortunately, despite the fact that both Zevalin and Bexxar have been demonstrated as safe and effective treatments for patients with relapsed or refractory NHL for years, it has been reported that fewer than 10% of patients who are candidates for the products ever receive them.  Recall the aforementioned statistic regarding NHL relative survival rates, indicating that a significant number of patients experience relapsed or refractory NHL.  According to Spectrum Pharmaceuticals, Zevalin’s annual sales in the United States were a mere $11.4 million in 2008.

Therefore, while an expanded indication for Zevalin is nice, the fact that the product has yet to penetrate the market indication afforded approximately five years ago implies that there are other obstacles to the product’s success.  For example, while medical oncologists are the key prescribing audience for Zevalin and Bexxar, most aren’t licensed to administer radiopharmaceuticals – resulting in patient referrals to radiation oncologists and/or nuclear medicine physicians in the hospital setting.  This may provide an economic incentive to medical oncologists to exhaust all non-radioactive options, such as chemotherapy, before referring NHL patients to receive products that will not improve their bottom line.  Sad but true, this and other factors were discussed in my opinion editorial for Oncology Business Review [OBR] back in September 2007 titled “Radiopharmaceuticals Need a Jump-STaRT.”

Spectrum Pharmaceuticals’ stock has been strong as of late – but perhaps more a result of Russell Investments adding Spectrum Pharmaceuticals to the Russell Global®, the Russell 3000® and the Russell 2000® Indexes.  For investors, significantly improved sales of Zevalin in future quarters will be much more important to Spectrum Pharmaceuticals than near-term approval of the sBLA.

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Disclaimer: This article contains the author’s own opinions, and none of the information contained therein constitutes a recommendation that any particular security, portfolio of securities, transaction, or investment strategy is suitable for any specific person. To the extent any of the information contained in the article may be deemed to be investment advice, such information is impersonal and not tailored to the investment needs of any specific person.