Rising to the Occasion: Radionuclide Therapy

First-order treatment of cancer typically involves chemo and/or radiation therapy and surgical intervention, but radionuclide therapies offer some advantages for select patients by delivering a very intense dose sequestered to affected tumor sites. These are the therapies currently available and in clinical trials, with a few novel compounds waiting for validation in the wings.

There is a wide variety of radionuclide therapies available for oncologic use and for benign disease such as overactive thyroid or as a radiation synovectomy for arthritis. Radionuclide therapies are fashioned into targeted treatments by either localized injection, by minimally invasive radioembolization and, in the case of radioimmunotherapy, by labeling the radionuclide with antibodies that zero in on physiological processes unique or augmented in tumors.

The mainstays

In oncology, one of the most commonly used radionuclide therapies is radioactive iodine, or I-131. This is used most commonly for thyroid malignancy. Other well-known mainstream therapies include strontium-89 (Sr-89) and samarium-153 ethylenediaminetetramethylene phosphonic acid (Sm-153 EDTMP), both of which have an affinity for bone and are used in palliation treatments for metastatic prostate and breast cancers. Radioembolization with yittrium-90, or Y-90 microspheres, also has been gaining traction, especially in the case of inoperable hepatocellular carcinoma or liver metastases.

More recently, radiolabelled monoclonal antibody therapies have been getting more play, including I-131 MIBG (metaiodobenzylguanidine), which is currently used in the treatment of phaechromocytoma and neuroblastoma, as well as non-Hodgkin’s lymphoma. MIBG can be used in non-therapeutic imaging, but with radioactive iodine it can target and kill tumor cells that metabolize norepinephrine.

Another radiolabelled monoclonal antibody therapy is I-131 with anti-CD45 antibody for the treatment of advanced acute myeloid leukemia or myelodysplastic syndrome. Previous studies using this type of radioimmunotherapy focused on older patients, but one study showed a significant benefit for patients under 50. Estimated survival at one year for 15 patients who underwent treatment was approximately 73 percent (Biol Blood Marrow Transplant. 2014 May 20. pii: S1083-8791(14)00299-7).

Netting neuroendocrine tumors

Grace Kong, MBBS, a nuclear medicine physician at the Centre for Cancer Imaging, Peter MacCallum Cancer Centre in East Melbourne, Australia, presented a study on PRRT (peptide receptor radionuclide therapy) for the treatment of neuroendocrine tumors during the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2014 Annual Meeting in St. Louis. 

In Kong’s study, PRRT is taken a step further to become peptide receptor chemo-radionuclide therapy (PRCRT). This therapy is especially beneficial for patients with NETs who exhibit high-somatostatin receptor expression. Patients in the study had undergone at least three courses of treatment with lutetium-177 and the drug DOTA-Octreotate (Lu-Tate), which is prescribed for inoperable patients. High-somatostatin receptor expression marks especially aggressive tumors and is associated with poor survival. To make it PRCRT, the researchers added a radio-sensitizing chemotherapy (5FU) in 63 out of the 68 patients. As a result, 72 percent survival at two years was representative for a majority of patients. In fact, more than half of patients were still alive after five years from the point of administration of PRCRT.

“Lu-Tate [PRCRT] has been shown to be highly effective in patients with progressive NET with high somatostatin receptor expression,” says Kong. “Based on our recent results and other published studies, PRCRT should be considered and incorporated as a treatment option for clinical use in suitable patients with NET.”

I-131 MIBG has been applied in dose-intensified treatment for palliation and stabilization of disease in advanced carcinoid tumors, as well. In one retrospective study of 31 patients with neuroendocrine tumors, I-131 MIBG was associated with limited toxicity and stable disease in 80 percent of patients with a median time to progression of 34 months (J Nucl Med. 1 Dec 2013 vol. 54 no. 12 2032-2038).

An increasing number of studies have been looking at DOTATATE and DOTATOC for the treatment of neuroendocrine cancer. “There are hopes that Lu-177 or Y-90 labeled DOTATATE or DOTATOC may be approved for treatment of neuroendocrine tumors,” says Hossein Jadvar, MD, PhD, an associate professor of radiology and of biomedical engineering at the University of Southern California (USC). The ability to image and track therapies is a distinct value. “In the case of NETs, there can be theranostic pairs such as Ga-68 DOTATATE and Lu-177 DOTATATE.”

Radium chloride, the new star

When it comes to imaging advanced prostate cancer, there are beta-emitting radionuclide therapies and now more and more clinicians are looking to alpha-emitters and namely radium-223, or Ra-223, for the treatment of symptomatic castration-resistant prostate cancer with bone metastases.

Radium-223 was approved by the FDA for this application in May 2013. While Sr-89 and Sm-153 emit beta particles, radium-223 emits alpha particles, which have very specific advantages.

“Ra-223 has a complex decay scheme in which four alpha-particles are generated during each decay, resulting in high energy deposition (28.2 MeV), with 95 percent of the energy from the alpha emissions,” wrote Neeta Pandit-Taskar, MD, nuclear medicine physician and director of the nuclear medicine training program at Memorial Sloan Kettering Cancer Center in New York City, and colleagues in a recent study. “The high linear energy transfer of alpha-radiation results in a greater biologic effectiveness than beta radiation, as well as generation of double-strand DNA breaks, and gives rise to cytotoxicity that is independent of dose rate, cell cycle growth phase, and oxygen concentration” (J Nucl Med. 1 Feb 2014 vol. 55 no. 2 268-274).

Pandit-Taskar presented her research during the SNMMI 2014 Annual Meeting in a special session on alpha-radionuclide therapy in bone. Molecular Imaging Insight was able to listen in.

“It has a favorable half-life—neither too long nor too short and the tissue penetration is much less, so that the bone marrow gets less dose,” she explains. For the presented study, the surface-to-red matter rate was 1.6 for Sr-89, 1.4 for Sm-153 and 10.3 for Ra-223, proving the much higher dose to the surface of bone for the alpha-emitter vs. the beta-emitter therapies. The half-life of Ra-223 is approximately 11.4 days, which allows for extensive deposition at the site of tumors. In addition to pain palliation, Ra-223 has been shown to extend overall survival, as well, she says.

Even though it is only approved for advanced prostate cancer, it could one day be approved for advanced breast and other cancers, if validated in more clinical trials. 

An even newer newcomer

Scandium-44 (Sc-44) and Sc-47 based theranostics are gaining some interest but at the time of this printing, its use remains in preclinical imaging studies. One such study published in July indicated that Sc-47 cm10 showed strong binding to folate receptors and was taken up successfully into experimental tumor models. In vivo SPECT/CT imaging also was successful. Results of the study showed pronounced delay in tumor growth in mouse models and a more than 50 percent increase in survival time. These potential therapies and imaging agents also are appropriate for imaging with PET (J Nucl Med. 17 Jul 2014 jnumed.114.141614).

Current challenges

The use of radionuclide therapies is contingent on supply of medical isotopes and a shortage can have a detrimental impact on patient treatment. In addition, physicians as well as patients need to be educated about the availability of these treatments to improve their accessibility and use. The third and most daunting limiting factor is the very slow and painstaking process that every therapy needs to go through to achieve regulatory approval—not just once, but for every unique clinical application of the drug. And then there are issues of accurate dosimetry for each of them. But the given sample of therapies seems to be rising to the occasion.

“Challenges of targeted radiopharmaceutical development include maximizing the amount of radionuclide delivered to the tumor and minimizing normal organ doses,” says Kong. “Ongoing research and improved understanding of tumor biology is important to provide increasing selection of tumor cellular targets, and advances in radiochemistry are providing new diagnostic and therapeutic options. Together with greater understanding of radiobiology, improving individual dosimetry in prediction of radiation dose to tumor and normal tissues, and combining radionuclide therapy with drugs that can enhance the efficacy of radiation, the range of diseases amenable to this approach will likely further increase.”

A collaborative effort

Kong goes on to stress that collaboration between institutions and regulatory agencies is key to improving access and the induction of more of these therapies into general clinical use. Jadvar, the 2014-15 SNMMI president-elect, agrees.

“This area is rapidly expanding and there is much interest in targeted therapies,” he says.  A special joint workshop of the National Cancer Institute and SNMMI was held in April 2013 and another is planned for October 2014 on campus at the National Institutes of Health. Molecular Imaging will continue to cover this important topic.