Patients with multifocal metastases from visceral cancers, primarily breast and prostate, have long had their symptoms palliated with radiopharmaceuticals. These patients typically suffer marked decreases in quality of life as a result of pain, which has been described as "deep nonspecific ache rising in intensity as the disease progresses, incident pain on movement (allodynia), which renders patients virtually immobile, and spontaneous pain that can be severe." Patients generally progress from NSAIDs to opioids, and then to more advanced, systemic palliation therapies.
Mechanism of action, side effects, range, and safety considerations. While discrete sites of metastasis can be amenable to external beam radiotherapy for the palliation of pain, diffuse bony metastatic disease requires agents that preferably localize to bone, have limited toxicity but long enough half-lives to kill tumor cells, have favorable pharmacokinetic properties, and are safe to handle. To date, phosphorus-32, strontium-89 (Metastron), samarium-153 (Quadramet), rhenium-186, and rhenium-188 have all been used in this setting. 32P was noted early on to cause marked bone marrow suppression and thus is not used or approved for clinical use. The beta particles (which consist of electrons) emitted by these radioisotopes cause the destruction of malignant cells through DNA damage and the induction of apoptosis. They have a relatively low, linear energy transfer (LET) radiation that tracks 2.5 to 11 mm. The limited range of these particles minimizes danger to healthcare personnel, but the deceleration of beta particles as they pass through shielding (eg, lead) can result in the formation of more dangerous, high-energy x-rays. In addition to emitting beta particles, 153Sm, 186Re, and 188Re also decay to gamma photons, allowing for external monitoring of radionuclide biodistribution after administration. Bone marrow suppression, primarily in the form of thrombocytopenia and leukopenia, is the most common side effect seen with clinical use. 89Sr and 153Sm are FDA-approved for the palliation of bone pain associated with metastasis, while 186Re and 188Re are still considered experimental.
Strontium-89. The therapeutic benefit of 89Sr was first established in 1942 by Pecher, who administered 3 doses over 5 months to a patient with advanced prostate cancer metastasized to bone. The patient was noted to have an excellent clinical and radiographic response. Since that time, many observational and randomized controlled trials examining the use of 89Sr have been published. Strontium sits below calcium in the periodic table, and it thus follows the path of calcium in the human body and localizes to areas of bone where calcium turnover is the greatest. In general, although subjective pain scales and definitions of responders differ between many of these studies, published reports have largely demonstrated that the palliative effect of 89Sr is substantial (absolute risk reduction for achieving pain relief, 0.321; 95% CI, −0.035 to 0.678) and not secondary to a placebo effect. Comparison of 89Sr and local external beam radiation showed similar response rates but no difference in overall survival.
Samarium-153. 153Sm was approved by the FDA in 1997 for palliation of pain from cancer metastasized to bone. The radioactive element is chelated to ethylenediaminetetramethylene phosphonic acid to form 153Sm-EDTMP. This compound is cleared renally within 6 hours of intravenous administration. The element itself has a half-life of 1.9 days, but it is cleared from the blood with a t1/2 of 5.5 minutes. Although its mechanisms of targeting bone are not completely understood, 153Sm preferentially accumulates and associates with hydroxyapatite crystals in areas of high bone turnover. Examinations of metastatic lesions have noted concentrations of 153Sm that are five times those seen in normal tissue, thus exposing these tumors to greater amounts of radiation and protecting healthy tissues. The range of emitted beta particles from 153Sm is only 0.5 to 3 mm, shorter than that for beta particles from 89Sr.
Multiple observational studies have reported improvements in pain scores for patients with bony metastases from CRPC. Phase II randomized controlled trials have demonstrated that higher doses of 153Sm-EDTMP (37 megabecquerel/kg) were more effective than lower doses (18.5 megabecquerel/kg) or placebo at lowering pain scores and reducing analgesic use.[30,31] A phase III randomized controlled trial randomly assigned patients to receive either radioactive 153Sm-EDTMP or nonradioactive 152
Sm-EDTMP. The investigators noted significant reductions in analgesic use in the active treatment group at 4 weeks, 9% of complete responders had a greater than 50% reduction in serum prostate-specific antigen (PSA), and myelosuppression accounted for the majority of side effects. Sartor et al also demonstrated that 153Sm-EDTMP can be safely redosed in patients after loss of analgesic effect.
Comparisons of various beta emitters. Multiple studies have performed head-to-head comparisons of different beta particle–emitting radionuclides reviewed here. No clinically significant differences in pain, analgesic usage, or performance status have been noted. Recommendations to date have maintained that clinician or patient preference, ease and safety of handling, pharmacokinetics, and cost remain the primary determinants of which therapy should be used. There have been shortages in supplies of radionuclides in recent years, and this may pose some limitations on the choice of radiopharmaceutical.
Beta emitters in combination with chemotherapy and bisphosphonates. Although beta particle–emitting compounds have shown mixed data with regard to PSA response rates after therapy, researchers have investigated combinations of these radioactive, bone-targeted therapies with chemotherapeutic drugs and/or bisphosphonates to determine whether any synergistic effects might be seen. Several have hypothesized that the radiation might sensitize tumor cells to further damage by chemotherapeutic agents. A phase II trial randomly assigned patients to chemotherapy either with or without 89Sr. Overall survival improved considerably in the combination arm compared with chemotherapy alone (28 vs 17 months). Another phase II trial examined the combination of docetaxel(Drug information on docetaxel) and 153Sm-EDTMP in men with bone metastases from CRPC: PSA response was seen in 77%, pain response was seen in 69%, and the combination was well tolerated. The primary endpoint was PSA progression–free survival, which was 6.4 months, with all patients ultimately relapsing. Median survival was 29 months.
In summary, these agents offer palliation of pain and can reduce opioid use. While the radiation produced by these compounds is cytotoxic, PSA response is not the primary indicator of effect, and no study has shown these compounds by themselves to affect overall survival. They are relatively well tolerated, with the most common side effect being myelosuppression that is reversible. These drugs may be re-dosed for continued effect, and combinations with other accepted treatments for metastatic CRPC may provide synergistic effects. Given the concerns regarding radiation safety of clinical personnel and patients, they should always be administered in special facilities by qualified personnel.
External beam radiation therapy
Bony metastasis of primary cancers results in considerable morbidity for patients, primarily causing pain, neurologic and functional sequalae, and hypercalcemia. External beam radiotherapy has been a mainstay of palliation and treatment for these lesions, but the exact mechanism of action is not well defined. The doses required to provide pain relief are far less than those required to destroy tumorous lesions, implying effects on bone homeostasis and alteration of signaling pathways involved in bone turnover. Palliative goals of external beam radiotherapy include improvement in quality of life through pain reduction, prevention of further bone destruction, maintenance of the functional capacity of the patient, and prevention of neurologic sequalae, particularly in metastases to the spinal column.
Most studies report complete or partial pain relief in 70%, with 40% to 60% of those reporting partial relief. Onset of relief is variable, ranging from as soon as 48 hours after therapy to 4 weeks. Focal therapy can treat single lesions confirmed by imaging and correlated with patient symptoms. Considerations of site, surrounding tissues, margin, performance status, and current hematologic parameters should be taken into account when making decisions regarding treatment volume and dosing. Hemibody radiation should be considered in patients with multiple metastases. One trial compared local radiation to local radiation plus hemibody radiation. Development of new, symptomatic lesions was similar between the two groups, but time to progression was significantly longer in the combination group (12.6 vs 6.3 months).
The optimum dose and timing of delivery has been a hotly contested issue, but a meta-analysis showed no significant differences between the different schedules. A review of 12 randomized trials on the duration of pain relief and median overall survival by Ratanatharathorn et al largely concluded that no patients had durable responses that lasted the remainder of the life of the patient and that higher doses trended to the greatest pain relief. With respect to the cost-benefit ratio of a single-fraction dose (4 to 8 Gy) vs multifraction higher doses of radiotherapy (30 to 45 Gy total), this meta-analysis concluded that while the former does provide some relief in a large percentage of patients, the higher-dose fractionated regimens were much better. In the United States, a survey of radiation oncologists showed that most employ 30 Gy in 10 fractions.