Combining Pinpoint Accuracy With the Benefits of Conventional Radiation Therapy

  • December 22, 2021
  • By Richard Saltus

    Soon after X-rays were discovered in 1895, doctors began using radiation to treat cancer. Today, about half of all cancer patients will receive radiation therapy at some point. While it can often be highly effective in shrinking tumors and alleviating cancer symptoms, radiation — high-energy beams of charged particles — administered from outside the body unavoidably damages some healthy tissues and can cause short- and long-term side effects.

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    To maximize the killing power of radiation and minimize side effects, scientists have developed ways of attacking cancer cells with radioactive drugs, known as radiopharmaceuticals, that are delivered through the bloodstream directly to the tumor. It's an ingenious strategy that potentially can reduce the risk of side effects by exclusively targeting tumor cells. In addition to attacking the main tumor, radiopharmaceutical drugs can also seek out and destroy small deposits of cancer cells that have spread to other areas of the body.

    Key elements of radiopharmaceutical drugs are radioisotopes (unstable atoms that emit radiation) that are guided by molecules such as monoclonal antibodies to bind to targets present on cancer cells but not normal cells. This brings the radioisotope directly to the tumor, where it acts by breaking the DNA double helix in the cancer cells. The potential of radiopharmaceutical therapy has sparked a surge of clinical trials and commercial activity. There is "an explosion of companies that are looking at different radiopharmaceutical agents targeting cancer," says Heather Jacene, MD, clinical director of nuclear medicine at Dana-Farber.

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    Just in the past few years, a handful of radiopharmaceutical drugs have been approved for clinical use. For example, radium-223 dichloride (Xofigo), which was approved in 2013 by the U.S. Food and Drug Administration (FDA), can be used to treat prostate cancer that has metastasized to the bones. Radium-223 dichloride is absorbed into the bones, and the radiation it emits kills cancer cells there. It does not cure cancer but helps to shrink bone metastases and relieve bone pain, and it may help people with metastatic prostate cancer live longer.

    Other radiopharmaceuticals have been approved for thyroid cancer, adrenal gland tumors, neuroendocrine tumors, and some types of non-Hodgkin lymphoma. Researchers are now designing and testing similar compounds for cancers including melanoma, lung cancer, colorectal cancer, and leukemia. Current radiopharmaceutical efforts are focused on radioisotopes that are linked to antibodies, peptides (building blocks of proteins), or small molecules that target specific proteins expressed on the surface of tumor cells.

    In 2018, the FDA approved the drug lutetium Lu 177-dotatate, or Lutathera, to treat certain gastrointestinal and pancreatic neuroendocrine tumors; Lutathera targets the somatostatin receptor present on the tumor cell surface. The approval was based on a phase 3 study that showed tumors took a longer time to progress in patients who receive Lu177-dotatate compared to those receiving standard therapy. The approval of Lu177-dotatate represents an important advance in the care of patients with neuroendocrine tumors. Moreover, it was hailed as a big step forward in the field. It showed that solid tumors could be effectively targeted with cell-killing radiation from radioisotopes linked to peptides that latched onto a cancer-specific target on tumor cells.

  • Advanced prostate cancer has been an early testing ground for radiopharmaceuticals. In 2020, the FDA approved a diagnostic drug that, when injected into the bloodstream, can be imaged by PET scanning to indicate the presence of PSMA-positive prostate cancer lesions in the tissues of the body. (PSMA, or prostate-specific membrane antigen, is a protein found in large amounts on prostate cancer cells.) The images can show whether prostate cancer has spread to other parts of the body.

    As an experimental treatment, researchers at the drug company Novartis developed a radiopharmaceutical drug called Lu177-PSMA-617 that targeted PSMA and was delivered via the bloodstream to men with advanced prostate cancer. Reporting on a phase 3 study in June 2021, the study team reported that the treatment improved the time it took for the cancer to progress and the overall time that patients were able to live with cancer.

    "It is impressive because it is targeted therapy, and most other prostate cancer drugs aren't targeted," said Mary-Ellen Taplin, MD, a prostate cancer specialist and chair of the Executive Committee for Clinical Research at Dana-Farber. "I am thrilled to have another option for patients who are in need of effective treatments." Taplin says the added survival benefit — about four months on average — "shows that this treatment, while effective, can be improved upon to bring more benefit to our patients." This radiopharmaceutical drug could show more advantages in patients with earlier stages of the disease or as part of combination therapy. These approaches are being studied actively in clinical trials.

    Using a radioactive substance that can be imaged to locate a cancer in the body, coupled with another radiotherapeutic drug to treat it is known as theranostics.

    "The field of theranostics has seen substantial growth recently with the approval of several new agents," said Ross Berbeco, PhD, the director of medical physics research in Radiation Oncology. "At Dana-Farber Cancer Institute and Brigham and Women's Hospital, it is emerging as a potentially important addition to our cancer treatment options."

    Jacene, who is also assistant chief of nuclear medicine molecular imaging at Brigham and Women's, says several trials of radiopharmaceuticals are underway at Dana-Farber. She says clinical trials may be suggested by medical oncologists in treatment centers or in nuclear medicine. "In either instance, together the treatment center team and our nuclear medicine team evaluate the proposal to determine if it is something that fits within our portfolio and makes scientific sense." Through this approach, Dana-Farber participated in a pivotal phase 3 study that led to the approval of Lu177-dotatate, as well as the phase 3 study of Lu177-PSMA-617.

    One recently opened trial is a phase 1 study that uses an alpha-particle-emitting isotope drug to target IGF-1R (the insulin-like growth factor-1 receptor) on solid tumor cells, including prostate, colorectal, and adrenocortical cancers. "You have to get imaged first, and if your tumor has a high enough level of IGF-1R you can go onto the next phase getting treated," explains Jacene. "If it's there, we can treat it."

    Another trial is testing a combination of radium-223 dichloride and cabozantinib, a targeted inhibitor drug, in patients with advanced kidney cancer that has metastasized to bones.

    In collaboration with Jennifer Chan, MD, MPH, director of the program in carcinoid and neuroendocrine tumors at Dana-Farber Brigham Cancer Center, the nuclear medicine team is participating in a cancer cooperative group clinical trial for patients with neuroendocrine tumors. The patients receive the radiopharmaceutical Lu177-dotatate, along with triapine, a drug that primes cancer cells to be more responsive to radiation. Researchers expect combinations of radiopharmaceutical and other types of drugs, such as targeted kinase inhibitors and immunotherapy agents, to be potentially more effective than radiopharmaceutical agents alone.

    Despite the potential and advantages of radiopharmaceutical treatment, the field is still in its early days. It has been tested in only a few of the many types of cancer that exist, and much remains to be explored in terms of targets that can be attacked with radioactive substances.

    Another challenge that researchers are grappling with is dosimetry — calculating how much of a radioactive drug to give to an individual patient and for how long. Jacene says that greater study of dosimetry should help personalize therapy for patients. In addition, the need for large numbers of specialized practitioners and staff qualified to handle and administer radiopharmaceuticals imposes limits on how widely the treatments will be used in the near future.

    "I think, and truly hope, the field continues to grow, but right now it's mainly major medical centers and academic sites that are set up to use radiopharmaceutical therapy," Jacene says. However, she says, the field is becoming better known and this extends to patient groups as well.

    "I attended a prostate cancer support group last month and I was asked extremely important and tough questions [about the therapy] for 30 minutes," Jacene says.

    To stimulate research and collaboration on promising new radiopharmaceuticals, the National Cancer Institute (NCI) in 2019 launched the Radiopharmaceutical Development Initiative, headed by Charles Kunos, MD, PhD, of NCI's Cancer Therapy Evaluation Program. He predicts that this new targeted approach, while it won't eliminate conventional radiation therapy, "is going to transform radiation oncology in the next 10 to 15 years."