It has been known for at least 100 years that radiation can kill cancer cells, but its original mode of therapeutic deliveryin a beam via an external sourcerequires knowing the anatomic location of the tumor. Metastases can occur at multiple (and often unknown) sites. And even when the location of a tumor is known, innocent tissues in the line of fire can suffer collateral damage.
In contrast to this outside-in approach, targeted radiotherapysystemic administration of radioactive agents that home in on a particular tissue, antigen, or receptor typeproceeds from the inside out. Two such compounds, radiolabeled monoclonal antibodies to the CD20 antigenZevalin (ibritumomab tiuxetan; Biogen Idec) and Bexxar (tositumomab; Corixa and GlaxoSmithKline)are both now approved and in use for non-Hodgkin lymphoma (see News, Feb. 5, 2003, Vol. 95, No. 3, p. 189). Several other radiolabeled antibodies have been shown to be effective in early phase clinical trials as well as in preclinical studies.
"These agents are at least twice as potent as their parent antibodies," said Gerry DeNardo, M.D., emeritus professor of internal medicine, radiation oncology, and pathology at the University of California at Davis, who first began working with radiolabeled monoclonal antibodies more than two decades ago.
To be effective by themselves, therapeutic antibodies have to be potent and penetrating, and they need to kill only those cells that express large amounts of the target antigen. As a component of targeted radiotherapy, however, an antibody is merely a delivery vehicle. The attached radioisotopes do the killing, and their emissions penetrate tumors, reaching diseased cells that may or may not express the target antigen.
But antibodies are big. Smaller molecules travel better, penetrate tumor tissue better, and are excreted much more swiftly when released into circulation. Research efforts are now shifting to these smaller molecules to better exploit the effects of radioisotopes. Some of these newer radiopharmaceuticals, often conjoined with newly tamed radioisotopes, are doing a better job than their older counterparts of targeting cancer cells and providing pain relief, and some are even showing promise as therapeutic agents alone or in combination with other chemotherapy drugs.
Radiolabeled Peptide Receptor Ligands
Unlike classic steroid hormones, peptide hormones do not diffuse through cell membranes into the cytoplasm but instead bind to cell surface receptors. Many neuroendocrine tumors overexpress such receptors for growth-hormoneinhibiting hormone, or somatastatin, said Tom D'Orisio, M.D., an endocrinologist at the University of Iowa College of Medicine.
D'Orisio's clinic was the largest single recruiting center for a multinational phase II trial of Novartis's radiolabeled, long-lived somatastatin analog in 300 patients with fast-growing advanced somatastatin-receptorexpressing neuroendocrine tumors. The full results, which Novartis has submitted to the U.S. Food and Drug Administration in a bid for accelerated approval, are not yet published. But, D'Orisio said, "70% of the 40 patients we treated were clinically stable or improved," a strong outcome considering the disease's typical rapid progression in advanced stages.
Neuroendocrine tumors constitute a relatively small fraction of overall cancer cases, but the trial's success could herald expansion to more prevalent cancers. Meningiomas, some lymphomas, and tumors of the breast, prostate, colon, and lung have been known to overexpress at least one of the five known somatastatin-receptor subtypes.
Bone Seekers
Representatives of another class of radiopharmaceuticals readily bind to sites where new bone is being depositeda frequent reaction to the presence of a metastatic lesion. In adults, pronounced bone formation occurs almost exclusively at sites of metastases.
Many authorities describe bone pain palliation as, in DeNardo's words, "one of the most underutilized areas of cancer treatment." By some estimates, up to 70% of patients with advanced breast or prostate cancer have bone metastases, as do some 15% to 30% of patients with cancers of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney. "[Bone metastases] are the business end of the tumor, where the tumor exhibits the majority of its symptoms," said Chris Logothetis, M.D., chairman of the University of Texas M. D. Anderson Cancer Center's Department of Genitourinary Oncology. "Bone metastases also replace the marrow and cause anemia and thrombocytopenia, which becomes a huge problem." They also cause unrelenting pain.
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Indeed, like chemotherapy, strontium-89 is itself myelosuppressiveit suppresses bone marrow proliferation, according to Serafini. "Many patients developed significant cytopenia and didn't recover from it," he said. "Oncologists became disillusioned."
Pick Your Poison
In the late 1990s, the FDA approved Quadramet (samarium-153 lexidronam; Cytogen), a radiopharmaceutical consisting of samarium-153 chelated by a bone-seeking tetraphosphonate for bone pain palliation in cancer. Samarium-153 has a half-life of just under 2 days. The rapid depletion in residual radioactivity means that patients can move quickly into chemotherapy. It also means that those with diminished blood cell counts can, in short order, be given hematopoietic agents such as recombinant erythropoietin or granulocytemacrophage colony-stimulating factor without risking high mutation rates in newly burgeoning blood cells. "Strontium-89's effect is so sustained that you have to wait 3 months after administering it before you can start chemotherapy," said Logothetis. With Quadramet, the wait time shrinks to about 2 weeks.
Serafini led a large randomized phase III study of Quadramet in hormone-refractory prostate cancer, published in 1998, that demonstrated Quadramet's pain palliation efficacy. "In a single week, you could see patients improving," he recalled. At palliative doses, Quadramet's only apparent side effect is mild myelosuppression.
Furthermore, at the annual meeting of the Society of Nuclear Medicine in mid-June, an Italian group will present results suggesting that it is possible to capitalize on chemotherapy's radiosensitizing tendency. Combining Quadramet with chemotherapy in hormone-refractory prostate cancer yielded a median survival of 29 months, versus only 11 months when Quadramet and the other drugs were given more than 4 months apart. However, the study size was very small (30 patients).
Logothetis has pushed hard for expanded chemotherapy/radiopharmaceutical combination trials in prostate cancer, which he considers the ideal indication for establishing proof that bone-seeking radiopharmaceuticals can play a crucial role in prolonging patients' lives. Now, Logothetis's colleague at M. D. Anderson, Shi-Ming Tu, M.D., is gearing up to lead a dose escalation trial combining Taxotere (docetaxel; Aventis), which was just approved by the FDA for prostate cancer, with Quadramet. A similar study is under way at Johns Hopkins University in Baltimore. Results of another study at Northwestern University combining Quadramet with Taxol (paclitaxel; Bristol-Myers Squibb) were presented at the American Society of Clinical Oncology's annual meeting in early June.
Side Effect as Objective
There are times when bone-seeking radiopharmaceuticals' chief side effect, bone marrow suppression, may be beneficial.
Multiple myeloma is a bone marrow cancer known to be very susceptible to radiation treatment. Total-body irradiation was once a standard therapy but, as chemotherapy became increasingly routine in this indication, fell out of favor because of the two modalities' additive toxicity.
Multiple myeloma patients' lives can be prolonged by wiping out their diseased bone marrow with high-dose chemotherapy followed by an autologous transplant of their own previously harvested stem cells, said Gregory Wiseman, M.D., a Mayo Clinic oncologist and nuclear medicine specialist. But, he added, "even when patients have a very good response to a bone marrow stem-cell transplant, the disease tends to relapse and take almost every patient's life eventually" because the chemotherapeutic conditioning regimen prior to the transplant failed to kill every last myeloma cell.
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In a dose escalation trial for the same indication conducted last year at three U.S. centers, a similar agent called Skeletal Targeted Therapy or STR (holmium-166 DOTMP; NeoRx), which uses the radioisotope holmium-166 and a different chelating phosphonate, produced complete or near-complete complete remissions in 43% of the 83 evaluable subjects, said Sergio Giralt, M.D., the institutional principal investigator at M. D. Anderson. But, at higher doses, there were high rates of toxicity, mainly in the bladder and kidney, that manifested after the first 60 days of follow-up. Several patients died.
A planned multicenter phase III trial of STR, involving upwards of 200 subjects, will use a dose in the lower to midrange of the earlier-phase studyslightly less than two-thirds of the amount delivered to patients" bone marrow in the Mayo Clinic's Quadramet study. Moreover, he said, all subjects will be given continuous bladder irrigation to forestall the buildup of dangerous radioactivity levels in that organ.
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