Metastasis to distant organs remains the major cause of mortality in cancer patients. This is most clearly presented in the SEER cancer statistics shown in Table 1. Despite ongoing efforts with new chemotherapeutics, small molecule inhibitors and biologics, patients with distant metastases continue to have a grim prognosis.
Table 1.
5-year survival by stage*
| Site | localized | distant |
|---|---|---|
| Breast | 99% | 30% |
| Colorectal | 90% | 14% |
| Lung | 56% | 5% |
| Ovary | 93% | 29% |
| Pancreas | 32% | 3% |
| prostate | 100% | 30% |
Radiopharmaceutical therapy (RPT) involves the use of pharmaceuticals that either bind specifically to tumors or accumulate by a broad array of physiological mechanisms indigenous to the neoplastic cells to deliver radiation preferentially to the targeted cells. RPT acts by delivering tumoricidal radiation to tumor cells; unlike external beam radiotherapy (XRT), the radiation is targeted by systemically administered pharmaceuticals that circulate throughout the body and deliver radiation to tumor cells. Since the range of the beta-particle radiation emitted by most RPT agents is on the order of a few mm, normal organs that do not concentrate the radiopharmaceuticals do not suffer radiation damage. Depending upon the amount of radioactivity administered, organs that are involved in the distribution or clearance of the agent are susceptible to toxicity. Accordingly, hematological and renal toxicity are of concern. Table 2 lists several of the RPT agents that are either, currently under commercial development, in commercially-sponsored clinical trials or that are already approved by the U.S. Food and Drug Administration.
Table 2 –
Abridged list of RPT agents that are on the market or under commercially-sponsored development
| RPT agent | Company | Indication |
|---|---|---|
| 89Sr-strontium chloride (Metastron)* | QBioMed | Bone pain palliation |
| 90Y-resin µspheres (SIR-Spheres)* | CDH Genetech/Sirtex | Hepatic malignancies |
| 90Y-glass µspheres (Thera Spheres)* | BTG | Hepatic malignancies |
| 131I-NaI* | Jubilant Draximage, Malklincrodt | Thyroid cancer |
| 131I-MIBG (Azedra)* | Progenics | Adrenergic+ tumors |
| 131I-aCD45 | Actinium Pharmaceuticals | BM transplant prep |
| 153Sm Lexidronam (Quadramet)* | Lantheus | Cancer bone pain |
| 153Sm-CycloSam | Oncolix/Isotherapeutics | Osteosarcoma |
| 166Ho-µspheres | Terumo | Hepatic malignancies |
| 177Lu-lutetium DOTATATE (Lutathera) | Novartis/AAA | Neuroendocrine tumors |
| 177Lu-aPSMA-R2 | Novartis/AAA | Prostate, tumor neovasc. |
| 177Lu -NeoBOMB1 | Novartis/AAA | Bombesin+ tumors |
| 177Lu -PSMA-617 | Novartis/Endocyte | Prostate, tumor neovasc. |
| 211At-aLAT-1 | Telixpharma | Multiple Meyeloma |
| 212Pb-antisomatostatin | OranoMed/Radiomedix | Somatostatin+ tumors |
| 212Pb-aTEM1 | OranoMed/Morphotek | TEM1+ tumors |
| 212Pb-aCD37 | OranoMed/NordicNanovector | Leukemia |
| 212Pb-PLE | OranoMed/Cellectar | Solid Tumors |
| 223Ra-dichloride (Xofigo)* | Bayer | Bone mets |
| 225Ac-aCD33 | Actinium Pharmaceuticals | Leukemia, MDS |
| 225Ac-aCD38 | Actinium Pharmaceuticals | Multiple Myeloma |
| 225Ac-FPX-01 | J&J/Fusion Pharma | NSCLC, pan-cancer target |
| 227Th-aCD22-TTC | Bayer | Lymphoma |
| 227Th-HER2-TTC | Bayer | HER2+ tumors |
| 227Th-MSLN-TTC | Bayer | Mesothelin+ tumors |
| 227Th-PSMA-TTC | Bayer | Prostate, tumor neovasc. |
FDA approved
Only 10 radionuclides are used in this list of 26 RPTs: five beta-particle emitters, 89Sr, 90Y, 131I, 153Sm, 177Lu and 5 alpha-particle emitters, 211At, 212Pb/212Bi, 223Ra, 225Ac and 227Th. Alpha-particle emitters are of increasing interest because they deposit energy along their track at a density that is 200 to 300 times greater than that of beta-particle emitters. Their 100-µm-range also confines the radiation dose delivered to the target region. The former leads to substantially greater cell kill per unit absorbed dose while the latter reduces toxicity to untargeted normal organs. The high energy deposition density (also referred to as linear energy transfer or LET) causes complex DNA double-strand breaks that are difficult to repair. As a result, the cell kill associated with alpha-emitters is impervious to most resistance mechanisms, including hypoxia. There is also evidence in patients and in pre-clinical studies that mutation- or pharmacologically-induced compromise of DNA double-strand break repair pathways can increase the potency of alpha-emitter-based RPT [1, 2].
As noted above, alpha-emitter-based RPT is highly potent. If some fraction of the targeting vehicle also accumulates in normal tissue, the high anti-tumor potency could also be accompanied by high toxicity. Unlike most systemic treatment of cancer, the biodistribution of RPT agents may be imaged in humans using nuclear medicine imaging modalities. These images may be used to evaluate the (radiation) absorbed dose delivered to tumors and normal tissues. Experience in external beam radiation therapy [3] has shown that absorbed dose [4, 5] is the best overall predictor of tissue toxicity and anti-tumor efficacy. Pharmacodynamics studies to elucidate mechanism and fate of the therapeutic agent are not as critical to RPT implementation as they are for chemotherapeutic and biologic agents. This is because RPT is a radiation delivery modality, and as noted above, there is a considerable experience regarding the effects of radiation. Accordingly, an imaging and dosimetry-driven approach to developing and implementing alpha-emitter RPT will avoid unexpected toxicity while also avoiding the largely empirical approach to determining the optimal amount of an RPT to administer to a given patient population. Precision medicine is generally defined in the context of assessing a patient’s genetic markers and the pathways involved in maintaining the cancer phenotype, then identifying the agents that specifically impact the “driver” pathway. In RPT, this paradigm may be implemented by incorporating quantitative imaging and dosimetry in early stage trials to assess the variability in biodistribution and dosimetry across a patient population and based on this decide whether the therapeutic gains in individual patient dosimetry warrant the logistical and economic hurdles involved in implementing an individual patient treatment-planning based approach to RPT delivery.
Footnotes
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Disclosures:
The author is a consultant for Bayer Pharmaceuticals, is on the scientific advisory board of Orano Med and is a founder of Radiopharmaceutical Imaging and Dosimetry, LLC (Rapid).
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