ANSTO's radioisotope subsidiary Australian Radioisotopes (ARI) produces and markets a drug called Quadramet based on the reactor-produced radioisotope samarium-153 (Sa-153). It is used for the palliation of skeletal metastases (i.e. secondary tumours) arising from primary tumours elsewhere in the body (usually the prostate).

ANSTO/PPK's Draft EIS on the proposed new reactor in Australia (p.5-15) lists Sa-153 among the “most significant” isotopes which would be produced using a new reactor.

Quadramet may be a useful addition to the arsenal of treatment options - but it is just one of a range of palliative treatments for skeletal metastases. The various radioisotopes used for this purpose all have some advantages and disadvantages over one another; but overall they appear to be roughly equivalent in terms of palliative effect, side-effects and other parameters. And radioisotope treatments are not front-line treatments anyway. Certainly Quadramet is no wonder-drug, despite claims from ANSTO/ARI that it represents the "next generation" of treatments and a qualitative advance over the most common radioisotope currently used, strontium-89 chloride (Metastron). It may be possible to import Quadramet despite its short half life. Despite the best efforts of ANSTO/ARI, and the subsidisation of ARI by ANSTO (and indirectly by tax-payers), there is no guarantee that Quadramet will secure a significant market share.

Given these points, Quadramet does not lend weight to the case for a new reactor in Australia.

Quadramet is radioactive samarium-153 complexed with EDTMP (ethylenediaminetetra methylenephosphonic acid).

Patients receiving Quadramet generally experience onset of pain relief within one week of treatment according to ARI. According to a 1997 article by Ben-Josef and Porter, in the Annals of Medicine, relief occurs within 7-14 days of treatment. This relatively rapid relief gives Quadramet a minor advantage over strontium-89 chloride (Metastron), which usually begins having a palliative effect about 10-20 days after administration.

According to ARI, relief of pain may persist for four months or longer with Quadramet. This may be true but it is worth considering that strontium-89 chloride (Metastron) is effective for approximately 2-3 radioactive half-lives. Is Quadramet really effective for up to 60 half lives as ARI's claim suggests? According to Ben-Josef and Porter, median duration of palliation is 2.6 months for Quadramet, not four months or longer as ARI claims.

According to ARI, at least 500 people each year develop painful skeletal metastases from a variety of primary tumours (esp. prostate, breast or lung) which cannot be treated or have ceased to respond to treatment using drugs or external radiotherapy. Question: do 500 people develop skeletal metastases, or does the 500 figure refer specifically to patients for whom alternative treatments are not available? Generally, how many patients might benefit from the use of Quadramet? According to ARI, the expected market may be over $500 000 annually.

A survey of 816 members of the American Society for Therapeutic Radiology revealed that strontium-89 chloride is the most common radioisotope used for skeletal metastases from prostate cancer. In fact strontium-89 chloride accounted for 99% of all use of radioisotopes for this purpose. (Question: in the USA, Europe etc., is strontium-89 chloride licensed as a palliative for metastases only from the prostate, or from other primary tumours as well?) The US Food and Drug Authority approved the general marketing of Quadramet in March 1997. It will be interesting to see if Quadramet is taken up in the USA to any significant degree.

There have been some overseas studies of samarium-153, although it has been the subject of considerably less study than strontium-89 chloride and phosphorus-32. Evidently overseas studies involved 453 patients. In Australia, very small clinical trials have been carried out at the Royal Brisbane Hospital (9 patients) and the Peter MacCallum Cancer Institute in Melbourne (10 patients). According to the 1997 article by Ben-Josef and Porter, "Clinical experience with samarium-153 is still limited."

Even without a reactor in Australia, it should be possible for Australian doctors and patients to have access to Quadramet, despite its relatively short half-life of 47 hours. Nycomed Amersham said in its RRR Submission that "possible supply solutions could be found using Pacific Basin or European reactors as appropriate." ARI says that its production of Quadramet will allow Australians "and people in the near geographic region to have reliable access to Quadramet." This, by implication, acknowledges that importing Quadramet into Australia could be an option. There are unconfirmed reports from ANSTO staff members that Sa-153 (either the Sa-153 isotope alone, or perhaps Sa-153 EDTMP).

According to Ben-Josef and Porter, samarium-153 results in overall pain relief in 74% of patients treated. This is similar to other radioisotopes such as strontium-89 chloride (Metastron), rhenium-186, and phosphorus-32.

In the Sydney Morning Herald, an ARI spokesperson said Quadramet will cut treatment costs. Quadramet is believed to cost about $1600-1800 per dose. Perhaps Quadramet will cut treatment costs, but this should not be assumed in the absence of unambiguous data. Also, data on cost-per-dose can be misleading. For example strontium-89-based Metastron costs about $3000/dose, more than Quadramet, but strontium-89 is longer-lasting, and patients receiving strontium-89 can be treated on an out-patient basis whereas hospitalisation may be required with Quadramet in order to isolate the patient and thus avoid radiation exposure to family, friends etc. (strontium-89 does not emit gamma radiation but Quadramet does).

The report which recommended Medicare funding for Quadramet can be found on the internet:
- Medicare Services Advisory Committee, Samarium153-lexidronam for bone pain due to skeletal metastases
August 1999, <http://www.health.gov.au/haf/msac>

ARI's operations are heavily subsidised by ANSTO (and thus the government and thus tax-payers) - this will undoubtedly improve the prospects for Quadramet. A proper comparison of the costs of Quadramet vis a vis strontium-89 chloride and other treatments would be useful.

Unconfirmed reports suggest that ANSTO/ARI is selling Quadramet at a price below the Medicare rebate fee, whereas there is no such price differential for Sr-89-based Metastron. Does this mean that there is a financial incentive for doctors/clinics/hospitals to use the ANSTO/ARI product? Should the Medicare rebate for Quadramet be reduced to more closely reflect the market price - or should ANSTO/ARI's price for Quadramet better reflect the massive government/tax-payer subsidisation of ANSTO and the subsidisation of ARI by ANSTO? It is notable that Nycomed Amersham - which imports strontium-89 chloride (Metastron) into Australia - enjoys no such government/tax-payer largesse.

ARI says Quadramet provides improved pain relief to patients with metastatic cancer from breast, prostate, lung, and possibly other (primary) cancers. Quadramet has been licensed for use to treat metastases from a range of primary cancers although the quantity and quality of the data-base upon which this licensing decision was made is open to question (information on prostate secondaries is more solid).

ARI says Quadramet is the "next generation" advance from strontium-89 chloride and that strontium-89 chloride is only effective against secondaries arising from primary prostate cancer. The rhetoric about Quadramet being a "next generation" treatment is twaddle. The concept of Quadramet is ingenious in that it is both a palliative and a radiotracer (allowing imaging) at one and the same time - it emits beta radiation for palliation and gamma radiation for imaging. But I believe other radioisotopes combine these functions, although strontium-89 chloride does not (it is only a palliative not a radiotracer). However ingenious the capacity to combine functions, my understanding is that it makes little if any difference in terms of patient monitoring and management, pain relief, etc.

ARI's claim that strontium-89 chloride (Metastron) is only effective against secondaries arising from primary prostate cancer is incorrect. Strontium-89 chloride (Metastron) can be used to treat secondaries from a variety of primary tumour sites. For example Ben-Josef and Porter say this about strontium-89 chloride: "limited experience in patients with metastatic breast cancer suggests similar efficacy. In one retrospective review 25 of 28 patients were reported to obtain moderate or good relief of pain." Currently strontium-89 chloride is only licensed as a treatment for prostatic secondaries in Australia, but R&D is ongoing and a growing range of uses can be expected.

Side-effects of Quadramet:
- myelosuppression (decreases in white blood cell and platelet levels). These changes are only rarely clinically significant according to ARI.
- excretion is primarily or exclusively through the renal system yet "no data are available on the use of Quadramet in patients with renal impairment" according to ARI.
- Quadramet may cause foetal harm
- safety and effectiveness in children below the age of 18 years have not been established (beware of attempts to evoke images of cancer-riddled kiddies!)
- one patient with rapidly progressive prostate cancer and evidence of disseminated intravascular coagulation developed thrombocytopenia and experienced a fatal cerebrovascular accident four weeks after receiving Quadramet. (Note: this is one death yet trials in Australia have only involved 19 patients to date.)
- flare reactions (worsening of pain) occurred in a small number of patients who received Quadramet, but were "usually" mild, transient, self-limiting and controllable with analgesics according to ARI. According to Ben-Josef and Porter, a flare of pain occurs in 12% of patients with samarium-153.
- it might be useful to compare the possible iatrogenic effects of radiation from Quadramet with alternative radioisotope treatments. I do not have the data to make these comparisons. For Quadramet, the effective dose equivalent is about 11.43 mSv/37 MBq (37 MBq/kg is the recommended dose).

According to ARI, Quadramet should not be given concurrently with chemotherapy or external beam radiation therapy, because of the potential for additive effects on bone marrow. Perhaps strontium-89 has an advantage since it can be used as an adjunct or alternative to external beam radiotherapy.

Strontium-89 chloride, marketed as Metastron by Nycomed Amersham, has a half life of 50.5 days. This half life is more than ample for importation. It has been imported into Australia for some years. According to Nycomed Amersham (personal communication, 1998), importation has been very reliable, with only one delay in the past few years.

Strontium-89 chloride:
- effective for an average of six months (range 4-15 months) - longer than Quadramet (median duration of palliation for Quadramet = 2.6 months according to Ben-Josef and Porter).
- proven pain palliation after conventional therapies have failed
- proven palliation for hormone refractory patients
- proven delay in new sites of pain
- no neurological toxicity reported
- may reduce or eliminate the need for dose escalation of narcotic analgesics
- effective from 10-20 days after administration
- can be used as adjunct or alternative to external beam radiotherapy for palliation of pain secondary to prostatic carcinoma at the stage of hormone therapy failure
- pain relief in over 70% of patients, complete freedom from pain in over 20%.

Side effects of strontium-89 chloride:
- suppression of white blood cells and platelets, but rarely associated with clinical sequelae and this is generally manageable
- another possible side-effect is exacerbation of pain within first few days after administration - a temporary effect which can be controlled with analgesics.

According to Ben-Josef and Porter: "To date, the best studied and most commonly used radionuclide is strontium-89. Large, prospectively randomized clinical trials have demonstrated its efficacy as a first-line therapy or as an adjuvant to external-beam radiotherapy. It is particularly useful when external-beam therapy options have been exhausted, and normal tissue tolerance has been reached."

Rhenium-186. Complexed to a bone-seeking phosphonate, HEDP. Half life 89.3 hours, which is sufficient to allow importation. Some gamma radiation so patient requires initial isolation to protect the public, hospital staff, and family. Effective for up to two months. Proven pain palliation after conventional therapies have failed. Pain palliation for hormone refractory patients not proved. Delays in appearance of new sites of pain not proven. Rhenium-186 HEDP has been studied in a small number of patients with metastatic cancer of prostate, breast, colon and lungs. 75-80% patients experienced pain relief, most often within two weeks. Duration of palliation = average five weeks (shorter than Quadramet or Metastron). Efficacy of Re-186 has been confirmed in a double-blind cross-over comparison with placebo. Myelosuppression as with some other radioisotopes (including Quadramet and Metastron). Also like other radioisotopes, pain flare occurs in 10% of patients but is resolved within one week.

Phosphorus-32. The second most studied radioisotope after strontium-89. Many human studies have been carried out with phosphorus-32. Subjective decrease in pain occurs in 60-80% of patients. Rapid pain relief. Half life 14 days, ample for importation.

Holmium-166 and dysprosium-165 are other radioisotopes which may have some use in the palliation of secondary skeletal tumours, but I'm not sure. Another radioisotope, which definitely is used for palliation of skeletal metastases, is Sn-117m DTPA (half life 13.6 days).

Non-radioisotope treatments:
- hormonal manipulation (for secondaries arising from prostate cancer), which can include surgical orchidectomy and drugs that depress testosterone or inhibit its action. Hormone manipulation is usually effective and rapid. However about 25% of patients fail to respond to hormonal manipulation, and the majority of responding patients will escape from hormonal control and develop progressive, usually symptomatic disease.
- according to Ben-Josef and Porter, the "vast majority of patients can be managed successfully with external beam radiotherapy." However according to Prof. Dr. Debruyne, local radiotherapy can be used but is "only effective for well-defined metastatic sites and it usually unmasks further sites of pain".
- according to Ben-Josef and Porter, "cytotoxic chemotherapy can effectively relieve pain." However according to Debruyne, "cytotoxic chemotherapy has not been very beneficial because of the lack of effective drugs and their substantial side-effects".
- perhaps the differences of opinion on the above two points are because Ben-Josef and Porter are discussing skeletal metastases in general, whereas Debruyne is specifically talking about skeletal metastases from prostate cancer.
- analgesics and narcotics (such as morphine) are used, but often with significant side-effects.

Linacs ?

Iodine seeds for prostate cancer and/or secondaries ?

Australian Radioisotopes (ARI), "Guidelines for the use of Quadramet under the special access  scheme".

Australian Radioisotopes (N.R. Wood and J. Whitewell), "Australian Manufacture of Quadramet".

Nycomed Amersham, document on strontium-89 chloride (Metastron), includes summary from Debruyne.

Edgar Ben-Josef and Arthur T. Porter, "Radioisotopes in the Treatment of Bone Metastases", Annals of Medicine, Vol.29, pp.31-35, 1997.

Leigh Dayton, "Radioactive drug to be mass-produced locally", Sydney Morning Herald, 14 October 1997.