Radiation

Radiation therapy for hormone refractory prostate cancer patients, may be beneficial for reducing or eliminating pain or, in some circumstances, reducing or eliminating a tumor. At this stage of prostate cancer, the disease is systemic and not localized. Still, there may be 1 or 2 spots of bone metastases that can be irradiated or there might be a soft tissue metastasis that can be irradiated.

What will be discussed here is radiation primarily for pain relief, in the form of intensity modulated radiation therapy(IMRT) or 3-D conformal radiation therapy(3DCRT) and the radiopharmaceuticals such as Strontium-89(⁸⁹SR) or Samarium-153(¹⁵³SM) - sometimes called injectable radioisotopes.

External beam radiation in the forms of IMRT, RT and 3DCRT are all be used for a local “spot” radiation therapy, such as to a soft tissue tumor or 1 to a few bone metastases. The radiopharmaceuticals find application for the pain of bone metastases where the number of sites make direct radiation impractical.

Caution: any form of radiation can impact the bone marrow and reduce its ability to manufacture blood cells. This could cause a situation where chemotherapy would not be possible due to the low blood levels. There can potentially be a problem with VEGF. Be sure you understand the risks and benefits of radiation before undergoing treatment.

See Toxicities and Patient Guidelines.

External-beam radiation is primarily for localized areas of tumor. For spinal cord compression, it is the most appropriate form of treatment(1). Dosing is usually done in 10-15 fractions and can be used with injectable radioisotopes. Re-treatment of the same area is usually not possible. EBRT can be used for controlling individual bone lesions, reducing pain in 80% of patients and also reducing the risk of fracture. Treatment of one bone metastasis has little risk, but as more and more bone metastases are treated using EBRT, the greater the toxicity(to bone marrow.)

An article in Current Oncology Reports by Oliver Sartor, (12) provides some guidelines regarding when to use radiopharmaceuticals and when not to use them(contraindicated). The tables below summarize those recommendations:

Prostate cancer metastases form in bone some 90% of the time. These bone lesions cause considerable pain and discomfort. There are 3 radioactive pharmaceuticals that are FDA-approved, but only for palliation of painful bone metastases. These are strontium-89 (Metastron®), samarium-153 lexidronam (Quadramet®) and phosphorus-32. For patients with multiple painful bone metastases, these agents may be appropriate since they all target multiple sites simultaneously.(2) These agents work by localizing in the metabolically active bone surrounding osteoblastic lesions and delivering high-dose radiation therapy to those sites without affecting normal tissue(except for the impact on bone marrow.) They follow the metabolic pathways of phosphorus or calcium.

Strontium-89(Metastron®).⁸⁹Sr was FDA approved in 1993 and has since demonstrated pain reduction in 60% - 80% of patients with metastatic lesions to bone from several tumor types. ⁸⁹Sr is a pure beta-emitter(an electron) with a half-life of 50.6 days and is used by the body in an osteoblastic(bone building) process similar to that of calcium.(3) The radioisotope is preferentially deposited in areas of tumor in bone -- more so that in normal bone and particularly when coordinated to a chloride molecule.

⁸⁹Sr chloride (Metastron®, Amersham International plc) has been shown to relieve pain at doses of 30 to 40 mCi/kg. Approximately 80% of patients with metastatic prostate cancer experience some degree of pain relief, and 10% to 15% experience complete relief. Pain relief occurs after 2 to 4 weeks of therapy and peaks at 4 to 12 weeks.(2) The most common toxicity associated with ⁸⁹Sr is thrombocytopenia, and platelet counts may decrease 50% or more below pretreatment levels.(4) Leukocyte counts are also reduced. Platelet and leukocyte counts reach their nadir(lowest value) typically in 5-7 weeks after treatment. Three months after treatment, these counts should be about 80% of their pre-treatment levels.

Samarium-153(Quadramet®. Samarium-153 is both a beta particleand a gamma ray emitter with a half-life of 46 hours. Since gamma rays are emitted, a gamma camera can be used to also obtain a bone scan. ¹⁵³Sm is approved for relief of osteoblastic bone pain in cancer patients. Approximately 80% of treated patients experienced pain relief, with duration of pain relief between 2 and 17 weeks.(2) As with strontium-89, thrombocytopenia is the most common toxicity. Platelet counts can decrease 40% to 50% with the nadir at 3 to 5 weeks.

One interesting study by Y. Menda et al (5), found that repeated treatments of samarium-153 lexidronam of 1mCi/kg over 28 months(11 doses) produced only transient decreases in leukocycte and platelet counts and proved the efficacy and safety for repeated treatments.

Sartor et al(6), at the 2001 ASCO meeting, also administered multiple 1.0 mCi/kg doses of Sm-153-lexidronam whenever painful bone metastases reoccurred. There were 15 prostate cancer patients and 3 breast cancer patients. Doses administered ranged from 2-11/patient. The mean administered dose was 81 ± 17 mCi (range 52–113 mCi) and the median interval between doses was 133 days (range 55–595 days). White blood cells(WBC) and platelets(PLT) transiently decreased by about 50% with a median time to nadir of 4-5 weeks for both WBCs and PLTs. This was true regardless of how many times Sm-153-lexidronam was given. Recovery was generally by week #8. There was one case of grade 4 toxicity of WBCs or PLTs after 3 doses.

Phosphorus-32. Seldom used -- ⁸⁹Sr and ¹⁵³Sm are considered safer agents.

Rhenium-186. While not an approved treatment, a double blind, placebo controlled trial was run and the results presented at ASCO 2001(abstract # 2416) that using strict pain assessment criteria, Rh-186 had a significantly greater improvement in pain relief over the placebo.

S. Tu et al(7), combined strontium-89 and chemotherapy. 103 patients first received 2-3 cycles of ketoconazole/doxorubicin alternating with estramustine/vinblastine. 72 patients who were clinically stable or responders to the initial chemotherapy we randomly assigned to receive either doxorubicin + strontium-89 or just doxorubicin, every week for 6 weeks. Complete resolution of pain was had by the 49 patients who had bone pain to start with. Survival was better for the 36 patients who received the combination of Sr-89 + doxorubicin(median 27.7 months - 4.9-37.7 range) versus the 36 patients who received doxorubicin alone(median 16.8 months - 4.4-34.2 range).

W. Ackerley et al(8), in a multi-institutional study (not randomized), looked at the combination of estramustine(emcyt), vinblastine and strontium-89.

- PSA response rate (a decline of ≥ 50% in PSA for at least 6 weeks) was 48%(21 patients)

It appears that the combination of strontium-89 + doxorubicin used by Tu et al is superior to strontium-89 + emcyt + vinblastine. A potentially even better combination would be to combine taxotere with samarium-153. Emcyt could also be added to the taxotere.

A somewhat sobering assessment of radiopharmaceuticals for treatment of painful osteoblastic metastases is the paper by EB Silverstein et al(10). The authors note that bone pain can be ameliorated 50-80% of the time, but there is no way to know who will or will not respond, nor which of the several radiopharmaceuticals is the most efficacious or the safest. They note that toxicity includes mild-to-moderate pancytopenia and an occasional brief flare of pain. They recommend avoiding treating patients with disseminated intravascular coagulation, because treatment with the radiopharmaceuticals may predispose the patient to thrombocytopenia. In spite of these toxicities, they indicate that treatment may be repeated about every 8- to 12-weeks, depending on the time it takes for normal leukocytes and platelet counts to be reestablished.

pancytopenia - the decrease in all the formed(cellular) elements of the circulating blood, decreased platelet, white blood cell and red blood cell count.

thrombocytopenia - the decrease in the number of platelets in the blood; decreased platelets increases the potential for bleeding and decreases the ability to form an adequate blood clot.

platelets - these are disc shaped structures(the thrombocytes) found in the circulating blood. They have a role in coagulation; platelets prevent bleeding and are important in blood clot formation as a result of injury.

disseminated intravascular coagulation (DIC) - this is widespread blood clotting, possibly caused by metastatic cancer or its treatment. See article on blood clots.

Another paper by A. Paszkowski et al(11) discusses disseminated intravascular coagulation in more detail. The authors note that mild thrombocytopenia typically recovers in 3-4 months following Sr-89. However, subclinical DIC is said to exist in 10-20% of advanced prostate cancer patients. Treating those patients with radiopharmaceuticals, may cause severe bone marrow depressions, due to their increased risk level. This can happen even with a normal platelet level. The Society of Nuclear Medicine has a bone pain treatment procedure guideline which recommends screening for DIC before therapy.

Patient Guidelines. There are several things that patients and their families need to be both aware of and things to do in regards to radiation therapy in any form. These are:

1. WA writes, "I had SR 89 and it greatly relieved pain and it caused the only bone met fade I ever had. I had very little platelet, RBC, or WBC deterioration and they quickly recovered."

2. Robert Young at www.phoenix5.org discusses his trial that was to test if Quadramet could be used to forestall the onset of bone pain, but insufficient enrollment led to early termination of the trial. He still had 3-4 treatments: see http://www.phoenix5.org/clinical/clinicalmain.html. He had 3 bone scans during the trial that appear to show an improvement in his bone metastases. The three bone scans are January 2001, March 2002 and October 2002. See http://www.phoenix5.org/essaysry/rvycj0320BoneScan.html

3. RB, who at one point had Sm-153, relates that in fighting pain and consequently rushing to "do something" resulted in an unnecessary injection of the Sm-153. It is a good message in that it points out the need for careful identification of the source(s) of pain and then choosing the best method of treating it. You can read about his experience here.

1.Catton CN, Gospodarowicz MK: Palliative radiotherapy in prostate cancer. Semin Urol Oncol 15:65-72, 1997.

2. Olson KB, Pienta KJ. Pain management in patients with advanced prostate cancer. Oncology. 1999;13:1537-1546.

4. Kalkner KM, Westlin JE, Strang P. Strontium-89 in the management of painful skeletal metastases. Anticancer Res. 2000;20:1109-1114.

5. Y Menda, DL Bushnell, RD Williams, S Miller, and MO Thomas: Efficacy and safety of repeated samarium-153 lexidronam treatment in a patient with prostate cancer and metastatic bone pain. Clin Nucl Med, September 1, 2000; 25(9): 698-700.

6. Oliver Sartor, David Bushnell, Robert Reid, Donald Quick: Repeated Administration of Sm-153-Lexidronam in the Treatment of Painful Bone Metastases. ASCO 2001, abstract # 1036.

7. Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, Daliani D, Papandreou CN, Smith TL, Kim J, Podoloff DA, Logothetis CJ: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial; Lancet. 2001 Feb 3;357(9253):326-327. The full text is available at Lancet www.thelancet.com/journal. The link to the issue with this article in it is http://www.thelancet.com/journal/vol357/iss9253/contents

8. Akerley W, Butera J, Wehbe T, Noto R, Stein B, Safran H, Cummings F, Sambandam S, Maynard J, Di Rienzo G, Leone L: A multiinstitutional, concurrent chemoradiation trial of strontium-89, estramustine, and vinblastine for hormone refractory prostate carcinoma involving bone. Cancer 2002 Mar 15; 94(6):1654-1660.

9. ASCO 2001 #2416 Efficacy of Rhenium-186-Hedp in Prostatic Cancer Patients with Metastatic Bone Pain: a Placebo Controlled Study. bernard antoni zonnenberg, sju han, suzy tan, bert derksen, john de klerk, peter van rijk, university medical centre utrecht, utrecht, Netherlands.

10. EB Silberstein, L Eugene, and SR Saenger: Painful osteoblastic metastases: the role of nuclear medicine. Oncology (Huntingt), February 1, 2001; 15(2): 157-63; discussion 167-70, 174. Where all of the radiopharmaceuticals can result in brief pain flares and thrombocytopenia, but treatment can be repeated in 8-12 week intervals depending on the return of blood counts.

11. AL Paszkowski, DJ Hewitt, and A Taylor Jr: Disseminated intravascular coagulation in a patient treated with strontium-89 for metastatic carcinoma of the prostate. Clin Nucl Med, November 1, 1999; 24(11): 852-4.

12. Oliver Sartor, Radioisotopic Treatment of Bone Pain from Metastatic Prostate Cancer, Current Oncology Reports 2003, 5:258-262.