Questions and Answers

Following the formal presentations at this conference, the floor was thrown open to questions from the audience. Following are selected questions and answers that were deemed of particular clinical relevance.

Strontium-89 Calibration

· Question: If you plan to give a patient a 4 mCi dose of Sr-89, how do you advise the physicist to prepare the dose?

· Answer: Dr. Porter--Most clinicians use the reference dose and date recorded on the label to determine the dosage at the time of administration. However, the NRC regulations listed in the Federal Register require that any radioisotope dose in excess of 10 mCi must actually be measured. Although this currently applies only to gamma-emitters, the NRC has set forth a proposal that all alpha and beta emitters also require internal measurements, indicating that proper records must be maintained. This is extremely important to those of us involved in Sr-89 therapy.

The current definition of misadministration are: The wrong patient, route, or dose (by greater than 20% of the prescribed dosage).

The problem encountered in Sr-89 calibration is the difficulty measuring the bremsstrahlung (radiation arising from an interaction between beta particles and surrounding atomic nuclei) to the beta radiation, the minor Sr-89 gamma component of 909 KeV (1%), and the variation in the Sr-85 contamination (gamma component, 514 KeV). In addition, the wall thickness and type of container used imposes more variability. For example, with a level of Sr-85 contamination typically between 0.1 and 0.2%, the difference in the calibrated response can be 27%, exemplifying the importance of accurately detailed contamination levels from the manufacturer for each batch of Sr-89.

Therefore, a new radiopharmaceutical rule was proposed by the NRC/NIST in October 1993. It states that all alpha- and beta-emitting radiopharmaceutical dosages must be measured by direct assessment of activity using a combination of measurements and calculations, except for unit dosages obtained from a manufacturer or preparer licensed pursuant to 10 CFR 32.72 or equivalent state requirements. A recognized preparer of pharmaceuticals can be a hospital or licensed regional pharmacy. Clearly, assaying dosages will soon become more complicated.

Durability of Strontium

· Question: What is the durability of strontium for pain relief and how often can you readminister Sr-89 if pain recurs?

· Answer: Dr. Porter--Several studies have indicated that the duration of the pain response is approximately three to 4 months. If hematologic parameters are not significantly altered, the patient can be retreated. In patients who are not hematologically compromised, I often retreat a second time with 3 or 4 mCi doses without notable problems. However, I am more hesitant to administer Sr-89 a third time.

The Problem of Extravasation

· Question: We have treated ten patients with strontium and one developed signs of extravasation. Have any of you experienced this problem and should there be instructions or cautions regarding possible extravasation for this agent?

· Answer: Dr. Porter--I believe it depends on how the strontium is administered. Did you use a butterfly in the vein? If so, that could be the problem. Butterfly infusion is not recommended.

· Dr. McGowan--I believe that Sr-89 can be safely administered subcutaneously without concern about extravasation. Since physiologically it will be handled as calcium, I would not be concerned about an Adriamycin-like toxicity.

· Comment from an oncologist in the audience--Our staff consists of well- trained chemotherapy nurses who follow the usual precautions. Despite this, one patient who developed edema after treatment with strontium was treated with heat in the emergency room, worsening the condition. After 6 or 7 hours, I saw this patient, applied ice and the edema disappeared in 2 or 3 days. Fortunately, there was no skin desquamation or ulcer formation.

· Dr. Porter--There is probably less of an extravasant reaction with Sr-89 than with infusion of cytotoxic chemotherapeutic agents, due to the dose, the infusion rate, and the fact that the skin has a high tolerance for radiation. For preventive measures, one should not infuse with a butterfly in a vein. It is more desirable to infuse Sr-89 into a running I.V. of saline. This provides a dilutional effect, avoiding the theoretical risk of a cardiac incident, since strontium is very similar to calcium (although, to my knowledge, there have been no cardiac incidents due to Sr-89 therapy). Secondly, this mode of administration insures the patency of the infusion.

The Use of Centerlines

· Question: Do you have any recommendations on using centerlines, since strontium is a calcium analog?

· Answer: Dr. Porter--I would be relatively cautious about using an untested centerline.

Medicolegal Questions

· Question: Do Board-certified radiation oncologists have reason to be concerned over medicolegal liabilities for administering radioactive agents, as opposed to a Board-certified radiologist?

· Answer: Dr. Porter--I would actually assume the opposite, since our profession is a patient-treating specialty. Strontium-89 is clearly not a diagnostic tool. It is a therapy, which has to be integrated with other available therapies and the extent of disease progression. The training accepted for radiation oncology by the ACGME (Accreditation Committee for Graduate Medical Education) expects us to have an understanding of isotopes. In some ways, this particular point in our training has been abrogated. If radiopharmaceuticals are to become standard in prostate cancer therapy, it behooves us to attain and retain such expertise.

Who Administers Iodine?

· Question: Who prescribes and administers radioiodine in the United States?

· Answer: Dr. McGowan--In our jurisdiction in Canada, it is almost exclusively administered by the radiation therapist.

· Dr. Stone--At our institution, endocrinologists and nuclear medicine physicians are involved. It is prescribed by the endocrinologists.

· Comment from the audience--In Australia, a radiation oncologist is licensed for external beam radiotherapy, radiopharmaceutical therapy, and the use of seed sources. For a fee, we are licensed to use all three modalities.

· Dr. Poulter--It is variable in our cities. Sometimes it is administered by nuclear medicine physicians and sometimes by radiation oncologists. Proper training is the vital issue with radioiodine handling.

· Dr. Porter--I agree.

· Dr. Poulter--I would like to make a comment related to this matter. In my experience, nuclear medicine physicians are not sufficiently trained to make therapeutic judgements for metastatic bone disease. They must be made more familiar with alternative therapy options. The administration of the radiopharmaceutical is not the only issue. The appropriateness of Sr-89 treatment must be determined by those with experience in treating metastatic disease.

· Comment from the audience--There are really two factors that must be considered. There is the licensing to prescribe/order the radiopharmaceutical and the licensing by the NRC to administer it. I believe that in the United States, radiation oncologists cannot administer radioactive substances unless they have 30 hours of radioimmunoassay experience and a Board license. Is that correct?

· Dr. Porter--No. Each state actually has different criteria that determine whether a physician is properly credentialed. Some hospitals even have their own criteria and process. The NRC approves the license if you were Board- certified in radiation oncology, nuclear medicine, or radiology before a certain year. In addition, there is no limitation concerning the radiopharmaceuticals you are licensed to administer.

However, the NRC apparently requires dose calibration by the clinician and most dose calibrators do not have Sr-89 settings. The setting must be established with the first Sr-89 shipment, relying on the accuracy of the manufacturers calibration. There is currently no standard or requirements for the physician to take measurements for a pure beta emitter, but they are forthcoming and we must develop this expertise.

Toxicities From

Hemibody Irradiation

· Question: Dr. Poulter, are there significant toxicities associated with hemibody radiotherapy as it is administered today?

· Answer: Dr. Poulter--In the early days, the major lethal toxicity associated with hemibody radiation was radiation pneumonitis. To the best of my knowledge, correcting for lung transmission and limiting the dose to 700 cGy has eliminated that problem. There were no cases of pneumonitis in the RTOG 8206 study.

In terms of hematologic toxicities, there are decreases in platelets and white blood cell counts, but this reverses spontaneously without treatment. I suspect that this effect could actually be ameliorated by growth factors allowing sequential radiation treatments or higher doses in fractionated therapy. However, with fractionation, organs such as the liver and kidney become dose limiting and shielding must be adopted, making the protocol rather complex.

A Rising PSA Post-Treatment

in an Asymptomatic Patient

· Question: How do you treat a patient with a rising PSA after radiotherapy or surgery if they are asymptomatic and the bone scan is negative?

· Answer: Dr. Stone--The question of when to start treatment is an area of much controversy. Recent data demonstrate that hormonal therapy most benefitted patients with minimal disease, typical of those with solid tumors. Early treatment with the best therapy yields the best response. The more difficult case is the patient who relapsed and failed radiation therapy, radical prostatectomy and chemotherapy. The PSA values of these patients often increase slowly and there is no real consensus concerning the best time to start hormonal therapy in these patients.

The Crawford Study consisted of patients with confirmed D1 or D2 disease and significant disease as determined by bone scan or chest x-ray. These patients were not treated due to their rising PSA values, so there is no information on the survival benefit of treating these relapsers with hormonal therapy.

Failing patients are often anxious about the disease progression and want active treatment. If the patient is sexually active, I typically wait until the acid phosphatase level is clearly above normal before starting treatment. If the acid phosphatase is normal, the bone scan is normal and the PSA is slowly increasing, I do not usually recommend therapy. My criteria to initiate hormonal therapy is an acid phosphatase level consistently above normal or a rapidly accelerating PSA (increases of ten or more increments at 3-month evaluation periods).

What Role for the Bisphosphonates?

· Question: Dr. Logothetis, do you include lymph node involvement in the V1-V2 staging system for prostate cancer that you showed? Also, what is the role of the bisphosphonates, APD, etc, in the management of bone metastases?

· Answer: Dr. Logothetis--Since very few patients were referred to us because of nodal metastases, that parameter was not included in the staging system. Subsequently, we have modified the system to include node involvement. Originally, nodal metastases were considered a null variable, since it was assumed all patients had nodal disease prior to bone metastases. In the new modification, there is an N-positive category preceding the 01-02 category and some of these patients are now receiving systemic therapy.

Empirically, the bisphosphonates seem to relieve some symptoms. The results are not dramatic and there is not much organized data that is tumor specific for prostate cancer. Theoretically, the bisphosphonates should work better in lytic disease vs blastic disease.

· Dr. McGowan--Although metastases due to advanced prostatic cancer are often blastic, there is usually accelerated osteolysis, an indication for the use of bisphosphonate treatment. I agree that there is currently limited clinical data evaluating their usefulness for this disease. Two Medical Research Council studies were planned, consisting of patients with and without metastases and addressing the use of bisphosphonate adjuvant treatment.