20 Radiotherapy and Radiopharmaceuticals for Cancer Pain
The Massachusetts General Hospital Handbook of Pain Management
Radiotherapy and Radiopharmaceuticals for Cancer Pain
Thomas F. DeLaney
The report of my death was an exaggeration.
—Note to London Correspondent of the New York Journal, June 1897, Mark Twain (1835–1920)
I. General principles
II. Indications for radiation therapy
III. Goals of palliative treatment
IV. Radiation therapy for treatment of bone metastases
V. Hemibody irradiation
VI. Systemic radioisotopes
I. GENERAL PRINCIPLES
Pain is a frequent complication of cancer. It can be a presenting symptom of the disease, a sign of local recurrence of tumor after prior treatment, or a symptom of metastatic disease. Palliative radiation therapy has been a mainstay of nonsurgical cancer treatment since soon after the discovery of x-rays. Radiation, delivered either by external beam, implantation (placement of radioactive sources within the tumor), or systemic radiopharmaceutical, can be effective in the management of cancer pain. Radiation therapy can relieve pain related to either metastatic disease or symptoms from local extension of primary disease. This chapter will focus on the treatment of pain related to metastatic disease. It is worth emphasizing that radiation therapy can complement analgesic drug or other therapies and may enhance their effectiveness because it directly targets the cause of pain.
In principle, ionizing radiation is delivered to the tumor with the intent of reducing or eliminating viable cancer cells while maintaining normal tissue integrity. It is most commonly given as megavoltage external beam photons produced by a linear accelerator. Electrons, which have a more limited range in tissue defined by their energy, can also be produced by linear accelerators and can be very useful in the treatment of superficial tumors with the additional benefit of sparing normal tissues below the tumor. Systemically administered radiopharmaceuticals such as strontium-89 (89Sr) and samarium-153 (153Sm) have a role in the treatment of patients with symptomatic metastatic disease involving multiple bones, whereas iodine-131 (131I) is appropriate treatment for patients with metastatic thyroid cancers that are iodine avid.
Brachytherapy (implantation of radioactive sources into tumor) is a useful mode of radiation delivery because of the physical advantage of very high radiation doses given to the tumor compared to surrounding normal tissue and the biologic advantage of a low dose rate (which differentially spares normal tissue). Brachytherapy is usually used in the management of the primary tumor; it is less commonly used for palliation of metastatic disease.
External beam radiation is prescribed by absorbed radiation dose (the SI unit is the gray, 1 Gy is equal to 100 rads) per unit volume in a selected field. The total dose, the number of fractions given daily, and the volume of tissue irradiated are determined by considering the needs and likely benefit for each patient.
II. INDICATIONS FOR RADIATION THERAPY
The primary indications for radiotherapy in the management of cancer pain are listed in Table 1. These include bone pain due to metastases (with or without pathologic fracture), spinal cord compression, tumor infiltration of nerve plexus, blockage of hollow viscera, and reduction in space-occupying lesions (particularly cerebral metastases). Radiotherapy can also be very useful in palliation of bleeding from tumors, cough or dyspnea secondary to tumor invading the bronchus, and superior vena cava syndrome.
Table 1. Indications for palliative radiation therapy
The decision to use radiation therapy includes consideration of the type of neoplasm, relative effectiveness of available treatment modalities, prior treatment, extent of disease (single or limited versus multiple metastatic sites), the patient’s performance status and length of expected survival, and bone marrow reserve. The efforts of the radiation oncologist should be closely coordinated with those of other physicians and healthcare personnel. Patients with particularly difficult pain problems may benefit from presentation at a tumor board or other appropriate multidisciplinary conference to allow for input and discussion among the varying specialists with expertise in the management of cancer pain.
III. GOALS OF PALLIATIVE TREATMENT
The intent of palliative treatment is rapid and durable pain relief, ideally maintaining symptom control for the remainder of the patient’s life, with minimal associated morbidity. Radiation therapy can arrest local tumor growth that might otherwise lead to intractable pain, cord compression, airway obstruction, uncontrolled bleeding, or pathologic fracture. For some patients, the resultant elimination of or reduction in the need for narcotic pain medications can improve quality of life. Reduction in pain can also result in improvement in ambulation.
Treatment should be tailored to the patient’s clinical condition and overall prognosis. Patients with good performance status and a limited burden of metastatic disease near critical structures such as the spinal cord or brachial plexus may benefit by radiation treatment programs that give a higher total radiation dose delivered in multiple fractions. Although such a program may require more initial visits to the radiotherapy clinic, it is likely to result in more durable palliation in the patient with a longer life expectancy. In contrast, patients with widely metastatic disease and limited life expectancy should be considered for rapid, limited-fraction treatment courses.
IV. RADIATION THERAPY FOR TREATMENT OF BONE METASTASES
For a single site or a limited number of sites of bony metastatic disease, external beam radiation therapy is appropriate and may relieve symptoms for an extended period of time. For patients with symptomatic bony disease at multiple sites, it is more appropriate to institute analgesics along with available systemic chemotherapy or endocrine therapy and bisphosphonates. If symptoms persist, consider systemic radiopharmaceuticals, localized external radiotherapy to the most symptomatic areas, or hemibody irradiation.
Most patients referred for palliation of metastatic bone pain have primary tumors of the highest overall incidence—namely, breast, prostate, or lung. Eighty percent to 90% of these patients experience pain relief, and it is complete in 50%. The majority of patients experience some pain relief within 10 to 14 days after the start of therapy. Seventy percent of patients have pain relief by 2 weeks after the completion of treatment. Ninety percent have relief within 1 to 3 months. Pain relief after radiation therapy is durable in 55% to 70% of patients.
Although it has been supposed that tumor shrinkage is responsible for this pain relief, the exact mechanism is poorly understood. Patients often experience pain relief at radiation doses that are well below that necessary to induce a complete regression of tumor.
Several small studies did not report any clear differences in overall response rates among patients with different tumor tissue types. A large, randomized study by the Radiation Therapy Oncology Group (RTOG), however, that examined different radiation fractionation schemes reported a higher percentage of complete pain relief in patients with breast and prostate primary tumors compared to patients with lung and other primary tumors. Sites of metastases do not correlate with the degree of pain relief. Severe and frequent pain is a poor prognostic feature. A sudden increase in pain during treatment should raise concern about a pathologic fracture, and appropriate radiographs and orthopedic evaluation should be performed.
Radiation affects both tumor cell and adjacent normal osteoclasts and osteoblasts. The presence of tumor, however, is a greater threat to the structural integrity of bone than the adverse effects of radiation on bone healing. Bone reossification often occurs following tumor eradication. Seventy-eight percent of osteolytic lesions treated in one study recalcified, and another 16% showed no further progression after radiation therapy.
Evaluation of patients with bone metastases includes the use of bone scintigraphy, which is more sensitive than skeletal radiography except in patients with purely lytic (osteoclastic) disease such as myeloma. Bone scintigraphy also detects many initially asymptomatic metastases, some of which may subsequently become symptomatic. Abnormal areas on a bone scan of long bones should be examined by skeletal radiographs to determine if there are areas of significant lytic disease that should be radiated or orthopedically stabilized to prevent pathologic fracture. Lytic lesions that are 2.5 cm or more in weight-bearing bones or have lysis of at least 50% of cortical bone may require orthopedic fixation. Magnetic resonance imaging (MRI) should be used in patients with bone pain and normal bone scans and radiographs. MRI of the spine is appropriate in patients with suspected spinal cord compression. In such patients, at least a sagittal midline scout view of the entire spine should also be obtained to rule out the occasional second site of spinal cord compression.
The radiation therapy ports are planned using data from the history and physical examination, bone scan, skeletal films, computed tomography and MRI scans, and a review of any prior radiation therapy fields. Soft-tissue masses, most often associated with bony metastases to the vertebral bodies or pelvis, must be included in the radiotherapy fields. The distribution of bone marrow must be considered, especially in patients receiving chemotherapy.
There is considerable debate about the optimal total dose, fraction size, and duration of treatment for metastatic lesions in bone. In patients with metastatic cancer in whom life expectancy is limited, quick and effective treatment with minimal morbidity is desired. One of the most commonly employed fractionation schemes, 3000 cGy in 10 fractions over 2 weeks, has been compared in a number of recent studies to shorter treatment schedules. An RTOG study randomized 759 patients to one of five treatment schedules that ranged from 4 days to 3 weeks in overall duration: 2000 cGy in four fractions, 1500 cGy in five fractions, 2000 cGy in five fractions, 3000 cGy in 10 fractions, or 4050 cGy in 15 fractions. No significant difference in response was seen. An independent re-analysis of the data, however, noted that the protracted fractionation schemes were more likely to provide complete relief and cessation of opioids. In other randomized trials, there is no clear advantage for the longer, multiple-fraction regimens when compared to shorter or single-course regimens. Three large European randomized studies compared 800 cGy in one fraction with 3,000 cGy in 10 fractions (Royal Marsden Hospital, 288 patients), with 2,000 cGy in five fractions or 3,000 cGy in 10 fractions (Bone Pain Trial Working Party, 765 patients), or with 2,400 cGy in six fractions (Dutch Bone Metastasis Study, 1,171 patients). No difference was seen with respect to pain relief, time to its achievement, duration of relief, or toxicity. Re-treatment was given more frequently in the single-fraction arms, which may in part be related to physician willingness to re-irradiate an area that had received the lower prior radiation dose. An ongoing trial in the United States is underway to validate these results.
The following are guidelines for treatment fractionation. It is expedient to give single-fraction irradiation to the debilitated patient with a very short life expectancy. Single large fractions, however, to some sites such as the abdomen and brain may not be well tolerated acutely. Hence, each radiation oncologist must consider the site of disease, the patient’s performance status and social situation, and any normal tissue in the treatment field when deciding on a treatment regimen. Patients with one or few sites of metastases who have a good performance status and a primary disease that responds well to systemic therapy may live for many years after irradiation for bony pain. Large fractions that are known to produce more late effects in normal tissue must be used with considerable caution in these patients, especially when radiation fields include the brain, spinal cord, kidneys, or significant portions of the liver or bowel.
At the same time, these patients may survive long enough to have problems with recurrent tumor in involved bony sites that have not been radiated to sufficiently high doses. Patients with bony metastases producing spinal cord compression are not suitable for single-fraction treatment because of the obvious neurologic risks of recurrent tumor in this site.
It has been difficult to demonstrate a clear dose–response relationship in treatment of bone metastases, often because the groups studied have been heterogeneous, with different tissue types and survival times after treatment. Arcangeli from Italy reported a higher frequency of complete pain relief when doses of 4,000 cGy or more were employed.
Hence, in patients with good performance status, limited metastatic disease, and long expected survival after palliative irradiation, doses of at least 4,000 cGy with conventional fractionation are recommended. For patients whose expected survival is short, a high dose is less important, as they will not live long enough to manifest recurrent tumor.
V. HEMIBODY IRRADIATION
Sequential hemibody irradiation has been utilized for patients with diffuse, widely disseminated bony metastases. It is designed to avoid repeated trips to the hospital for multiple courses of irradiation. It results in complete relief of pain in 21% and partial relief in 77% of patients; most of those treated have had breast, prostate, or lung cancer. Pain control is achieved rapidly, with improvement noted within 2 days among half of the patients experiencing pain relief. Kuban reported good palliation with hemibody irradiation in patients with disseminated prostate cancer. Palliative effects were maintained until death in 82% of the patients treated to the upper half of the body and 67% of patients treated to the lower half.
For hemibody radiation, 600 cGy of irradiation is delivered to upper body and 800 cGy to lower body. Patients treated for metastases of the upper body are usually hospitalized for a day, hydrated, and premedicated with antiemetics and corticosteroids. Mid- and lower-body therapy patients are premedicated as outpatients to minimize nausea and vomiting.
In one large study of hemibody irradiation by the RTOG, there were no fatalities related to treatment. Treatment to the lower and mid body were well tolerated, with severe nausea and vomiting, diarrhea, or hematologic toxicity occurring in 2%, 6%, and 8% of patients, respectively. Upper-body treatment with partial lung shielding induced severe nausea and vomiting, fever, or hematologic toxicity in 15%, 4%, and 32% of the patients, respectively. Hematologic complications are worse in patients who have received prior chemotherapy or who receive the treatment with low peripheral blood counts. Fractionated hemibody irradiation (2,500 to 3,000 cGy in 9 to 10 fractions) has been reported to yield more durable pain relief by a group from Memorial Sloan-Kettering without any increase in complications.
VI. SYSTEMIC RADIOISOTOPES
Several systemically administered radiopharmaceuticals have been used to palliate pain caused by multiple osseous metastases. 131I can provide pain relief in patients with well-differentiated thyroid carcinoma, with bone scan evidence of response in 53% of patients. 89Sr and 153Sm-ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) are used to treat patients with sclerotic metastases (metastatic prostate cancer and other selected cases).
Patient selection is important. Relative indications include bone metastases causing pain that is not controlled by analgesics or arising in a narcotic-intolerant patient, absence of soft-tissue masses, osteoblastic lesions, multiple metastatic sites, and tumor that is refractory to hormonal treatment or chemotherapy. Because of the limited penetration of the beta emissions delivered by systemic radioisotopes, radioisotope therapy is not appropriate for patients with spinal cord compression, who instead should be treated with external beam radiation. As radioisotopes can depress the marrow and are cleared by the kidneys, significant thrombocytopenia, neutropenia, or renal impairment are also relative contraindications. Urinary incontinence, which presents a radiation safety hazard, is also a contraindication.
89Sr is a bone-seeking calcium analog incorporated by osteoblasts into new bone. It is a beta (electron) emitter with a 1.46-megavolt (MeV) maximum energy, a physical half-life of 50.6 days, and a penetration range in tissue of 4 to 6 mm. It has no significant gamma emissions, so it cannot be imaged. Patients give off very little radioactivity into the environment and most can thus be treated as outpatients. Unbound 89Sr is eliminated in the urine within 2 days. 89Sr has been well studied in prostate and breast cancer, but it can be used for osteoblastic metastases from other primary tumors. Moderate or greater pain relief has been documented in approximately 80% of patients with prostate or breast cancer, with complete relief in approximately 10% to 30%. Pain relief is not usually seen until 2 to 3 weeks after injection. The recommended dose of 89Sr is approximately 4.0 mCi (60 to 80 µCi/kg). Strontium can be retained in metastatic bone for up to 90 days. The dose delivered to tumor depends on disease burden; it is estimated to be 800 to 2,000 cGy in patients with diffuse disease, or 3,000 to 10,000 cGy with a limited or moderate tumor burden.
When evaluated in a placebo-controlled phase III trial as an adjuvant therapy in patients treated with external beam radiation, 89Sr did not affect the degree of pain relief at the index lesion, but a greater proportion of patients in the 89Sr group were able to discontinue analgesics (17.1% versus 2.4%), remained free of new painful bone metastases at 3 months (58.7% versus 34%), and had a longer time to further radiation therapy (35.3 versus 20.3 weeks).
Toxicities that can result from 89Sr include thrombocytopenia, neutropenia, and, hemorrhage. In the adjuvant trial cited earlier, grade 3 thrombocytopenia was seen in 22.4% and grade 4 in 10.4% of the 89Sr group, resulting in the need for platelet transfusions in 5.2%. This compares with 1.7% patients with grade 3 and 1.7% with grade 4 thrombocytopenia in the placebo group who did not require any platelet transfusions. Hemorrhage occurred in 14.9% of the 89Sr patients and in 5.2% of the control patients. Grade 3 neutropenia was seen in 10.4% and grade 4 in 1.5% of the patients in the 89Sr arm and in none of the control patients. Occasional patients have a pain flare several days after administration. This may be a good prognostic indicator according to some investigators. Some patients have reported a flushing sensation, often facial, but this is self-limited.
153Sm-EDTMP is a therapeutic agent composed of radioactive 153Sm and the tetraphosphonate chelator EDTMP. It has recently been approved for use as a systemic radiopharmaceutical. The recommended dose is 1 mCi/kg. The agent has an affinity for bone and accumulates in osteoblastic regions of bone. Its physical half-life of 1.9 days results in higher rates of dose delivery than 89Sr, which typically translates into a more rapid onset of action and more rapidly reversible toxicity. Its 0.81-MeV maximum energy beta emission is lower than that of 89Sr, yielding a lower penetration in tissue of 2 to 3 mm and theoretically less marrow toxicity. It also has a gamma emission, which allows imaging with a gamma camera to document accumulation of isotope at affected sites. Treatment efficacy seems similar to that of 89Sr, with a risk of marrow toxicity that is approximately half that reported for 89Sr.
It is easy for pain specialists treating patients with pain due to cancer to forget the powerful effects of radiation therapy in reducing pain and treating various other symptoms (see Table 1). Radiation is effective not only to shrink the primary tumor but also for soft-tissue metastases and for widespread bone metastases. Radiation therapy can be palliative as well as curative. The building of a good working relationship between pain physicians and radiation oncologists contributes greatly to the effective management of cancer pain.
Anderson PR, Coia L. Fractionation and outcomes with palliative radiation therapy. Semin Radiat Oncol 2000;10:191–199.
Ashby M. The role of radiotherapy in palliative care. J Pain Symptom Manage 1991;6:380–388.
McEwan AJB. Use of radionuclides for the palliation of bone metastases. Semin Radiat Oncol 2000;10:103–114.
McQuay HJ, Collins SL, Carroll D, Moore RA. Radiotherapy for the palliation of painful bone metastases. Cochrane Database Syst Rev 2000;2:CD001793.
Ratanatharathorn V, Powers WE, Moss W, Perez CA. Bone metastasis: Review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys 1999;44:1–18.
Rose CM, Kagan AR. The final report of the expert panel for the Radiation Oncology Bone Metastasis Work Group of The American College of Radiation Oncology. Int J Radiat Oncol Biol Phys 1998;40:1117–1124.
Arcangeli G, Giovinazzo G, Saracino B, et al. Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration. Int J Radiat Oncol Biol Phys 1998;42(5):1119–26.
Kuban DA, Delbridge T, el-Mahdi AM, Schellhammer PF. Half-body irradiation for treatment of widely metastatic adenocarcinoma of the prostate. J Urol 1989;141(3):572–4.