Management of Bone Metastases  
[Including Vertebral Metastases]

compiled/written by doctordee
June 2002


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Links
Introduction
Detection
Surgery -- Long Bones
Surgery -- Vertebral
Ablation
Radio Frequency Ablation [RFA]  
Cryoablation
Embolization
	Chemoembolization
	Radioisotope embolization
Bisphosphonates
Radiation
RadioIsotopes  
RadioTherapy   
Injections Into Tumors
Percutaneous Vertebroplasty
Percutaneous Intratumoral Injection Therapy   
Cytotoxic Injections [alcohol, chemotherapy agents, radioisotopes]
Hyperthermia
Other Systemic Treatment
	Chemotherapy	
	Hormonal


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PubMed/Medline Search-Click below:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20metastases%20treatment
This will give you the first page of 20 citations on the subject.  By using their toolbar, you can put limits on the search, obtain the complete set of abstracts for the search, increase to 200 citations OR abstracts per page, as well sort by date or author.

Furthermore, PubMed/Medline searches give you the site where the research or technique is done.  If you are considering undergoing a specialized procedure, a recent publication can give you a place that does it, as well as information about their results.

The Coleman Article [Management of Bone Metastases]-Click below:
http://theoncologist.alphamedpress.org/cgi/content/full/5/6/463
Coleman, R., The Oncologist, Vol. 5, No. 6, 463-470, December 2000 (c) 2000 AlphaMed Press 
[This is not a comprehensive article, but it does give some valuable information.]

Other useful links:

http://www.bonetumor.org

http://www.oncolink.com/
 
Pubmed All References - metastases and spine
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=metastases%20spine

Spinal Cord Tumor Information 
http://www.tbts.org/sctumors.htm

Lesions of the Spine  
http://www.cid.ch/TEACH/Db-te26.html
  
Proton Beam and Stereotactics - Can be used on Cervical Spine 
http://www.va.gov/hac/champva/policy/cvapmchap2/1c2s30.13.pdf
 
IMRT. There are a number of new techniques like stereotactic radiotherapy or Intensity Modulated Radiation Therapy that may be used.  
http://www.varian.com/onc/imr000.html
 
USC Neurosurgery Department
http://uscneurosurgery.com/
 
 
 
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INTRODUCTION

 "Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. ... The prognosis of these patients is generally poor and the treatment is primarily palliative: the intention is to relieve pain, prevent fractures, maintain activity and, if possible, to prolong survival. Besides analgesics the therapeutic options include local treatment with radiotherapy and/or surgery, and systemic treatment using chemotherapy, endocrine therapy, radioisotopes as well as bisphosphonates. Social and psychological supportive care is also very important. Radiotherapy plays an important role, but the other modalities such as bisphosphonates may also offer the same level of palliation, but their definite role has not been as clearly defined." http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9142968 &dopt=Abstract  
Nielsen OS.  Palliative treatment of bone metastases. Acta Oncol 1996;35 Suppl 5:58-60  PMID: 9142968 

Bone develops as a result of a balance between the bone cells that break down bone [osteoclasts] and the bone cells that build up bone [osteoblasts].  Tumor metastases in bone develop from interactions between the bone cells and the tumor cells, destroying the bone's ability to bear loads, initially in disruption of the bone structure and microfractures, but finally in total loss of bone integrity.  

Complications from bone metastases include bone pain, fractures, hypercalcemia [too high level of calcium in the blood, which causes weakness and can create kidney failure], and compression of the spinal cord.  Bone metastases can massively impair quality of life, and can themselves cause death.

Surgery, Radiation, and now Bisphosphonates are the current first line treatments of choice for stabilization, pain, and hypercalcemia respectively.  

Rib fractures and the collapse of vertebrae are most common.  Vertebral collapse results in loss of height, but if multiple and severe, in humpback and curved spine, which has a further effect in restriction of lung capacity.  The most disability, however, is caused by the fracture of a long bone or compression of the spinal cord.

Surgical intervention is the treatment of choice for unstable vertebrae or neurologic deficit, with the excision of the tumorous bone and stabilization of the spine. Surgery, Radiation, and now Bisphosphonates are the current first line treatments of choice for stabilization, pain, and hypercalcemia respectively.  
There are other treatment options available for those who cannot undergo surgery, of invaluable use in preventing, controlling, eradicating, or palliating metastatic bone tumors.  [And probably, whatever other treatment modality they choose, patients with bony LMS lesions should probably be on Bisphosphonates.   Ed.]

Surgical intervention, external beam radiotherapy, and systemic endocrine and chemotherapy treatments have been the classical methods of treatment of metastases to bone.  However, the opportunities for improving the management of metastatic bone disease have never been greater. Recent developments have occurred in all aspects of cancer management with improvements in skeletal imaging, reconstructive orthopedic surgery, and radiotherapy-particularly through the development of bone-seeking 
radiopharmaceuticals, new endocrine and cytotoxic treatments, and an increasing use of bisphosphonates to prevent and treat skeletal complications, as well as embolization, radio frequency ablation, percutaneous alcohol injection, percutaneous vertebroplasty, and new specific molecules based on cellular signaling mechanisms. 

        "Multimodal therapy of tumor patients with osseous metastases is an interdisciplinary task. 
        The surgical treatment requires optimal integration, in terms of timing and extent of the procedure, into the 
        overall treatment plan. In addition to surgery, modern therapeutic 
        approaches include systemic chemotherapeutic, hormonal and immunological 
        therapy, radiotherapy, and other drug therapy (i.e. bisphosphonates). We 
        use classical stabilization methods with plates and bone cement or 
        intramedullary nailing and also new implants with angular stability like 
        an internal fixator and modular endoprothesis systems in operative 
        therapy. Such stabilizing systems allow bridging of tumor defects in 
        almost all parts of the skeleton. The ultimate goal of any treatment and 
        especially of operative intervention is a mobile patient with little or 
        no pain and a good quality of life."  [10]

Surgery, Palliative Radiation, and now Bisphosphonates are the current first line treatments of choice for stabilization, pain, and hypercalcemia respectively.  It is this compiler's choice to include many possible treatment modalities, for situations where the usual and usually available modalities might not be effective.  Chemotherapy is best saved for inoperable metastases that are potentially life threatening, such as lung, liver, or brain.  

10: Haas NP, Melcher I, Peine R. Metastases compromising physical stability Chirurg 1999 Dec;70(12):1415-21         


Increasing Incidence of Vertebral Metastases
After survival time was prolonged because of the advent of doxorubicin, sarcoma patients started showing an increased incidence of brain metastases, as patients lived long enough for these metastases to seed and grow. [For more information on this, see the Brain Metastasis section of Metastatic Disease on this website.]
Coincident with improved overall cancer palliation during the past 2 decades has been an increasing incidence of clinically apparent bone metastases. Likewise, as survival time for LMS continues to increase, but without a cure and without effective control over tumor seeding and growth, the incidence of metastatic LMS to the spine might also increase.
References:
Fukutomi M, Yokota M, et.al. Increased incidence of bone metastases in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2001 Sep;13(9):1083-8
Harrington KD, Orthopedic surgical management of skeletal complications of malignancy. Cancer 1997 Oct 15;80(8 Suppl):1614-27



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DETECTION OF BONY METASTASES


Of 277 soft tissue sarcoma [STS] patients, 10% had metastases within an average period of 18.6 months from diagnosis.. The regional bones close to the primary tumour were affected in 46% of the patients with bony mets, and the axial bones in 64%.  STS metastatic bony lesions showed predominantly lytic changes, and approximately half of the lesions progressed to pathological fractures. [6]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9250736&dopt=Abstract


By Symptoms:  pain or fracture or neurologic deficit.

By Blood Tests:  elevated alkaline phosphatase, elevated bone isoenzyme of alkaline phosphatase, hypercalcemia [blood calcium levels too high].  Current research is aimed at trying to find good blood test markers that indicate bone resorption, and to differentiate metabolic from tumoral problems if possible.   Hopefully techniques would be developed that would allow evaluation of bone tumor response to treatment by a simple blood test.

By Imaging Techniques:
The main imaging techniques used to diagnose bone tumors are conventional radiography, CT, MRI, and isotope bone scan. Angiography is rarely used, but is helpful when a preoperative selective embolization is needed, or when complex vertebral surgery or vascular surgery is planned.

By Xrays:  lytic lesions, usually, 'holes' in bones.  For a lytic lesion to show on Xray, 50% of the bone matrix must be destroyed.  Xrays will not show early stage disease.  Conventional radiography is the screening examination of choice and is sufficient in several benign lesions not requiring treatment. Supplementary imaging studies are usually needed when radiographic findings are questionable and/or the lesion requires treatment. 

By Bone Isotope Scan: will show areas of increased bone activity-including inflammation, arthritis, and infection. It can be thus useful to depict lesion quiescence or activity and to stage any tumor that can metastasize to the skeleton. Bone scan is also helpful to show bone lesions when they are not visible on plain radiographs and can indicate the tumor response to preoperative chemotherapy. 

By MRI scan:  MRI is the scan of choice for depicting any bone tumor.  MRI beautifully shows the different tissues and compartments and it is particularly sensitive in depicting fat. Moreover, it can be repeated many times, even in pregnant women, because it needs no ionizing radiations and iodinated contrast; it is also free of artifacts in the patients with orthopedic devices that are usually nonferromagnetic. However, the execution of an adequate MRI requires experience and knowledge of bone pathologic conditions. 
While Bone Isotope Scans and PET scans are useful adjuncts to indicate strong suspicious of metastases to bone, it is the MRI which is the definitive examination to give clear delineation of the bone tumor and its extent.  No imaging method is without its difficulties, however, and sometimes the MRI cannot distinguish between different types of lesions; one notable situation is between a hemangioma [a noncancerous tumor of twisted blood vessels] and some neoplasms [often also highly vascular].  [Repeatedly on the LMS ACOR List, the MRI has shown the bone mets, despite negative Xrays and negative bone scans.  The scan of choice for detecting bone tumors is MRI.  Ed.]

By PET scan:  will show areas of increased metabolic rate, in bone and other organs, including inflammation, arthritis, and infection.  It is a new technique, and its specificity and reliability are still open to interpretation.  

By CT scan: CT best shows mineralized tissues and pulmonary metastases. It is also frequently used as a guide for needle biopsies. Not a good choice for bone studies. 



References: 
1. Campanacci M, Mercuri M, Gasbarrini A, Campanacci L. The value of imaging in the diagnosis and treatment of bone tumors Eur J Radiol 1998 May;27 Suppl 1:S116-22  
2. Krappel FA, Bauer E, Harland U. Efficacy of MRI--whole spine image in diagnosis of vertebral metastases--results of a prospective study. Z Orthop Ihre Grenzgeb 2001 Jan-Feb;139(1):19-25 
3. Woitge HW, Pecherstorfer M,  et.al.   Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res 1999 May;14(5):792-801
4. Griffith JF, Kumta SM.  Clinics in diagnostic imaging (25). Aggressive vertebral haemangioma. Singapore Med J 1997 May;38(5):226-30 
5. Savelli G, Maffioli L, Maccauro M, De Deckere E, Bombardieri E., Bone scintigraphy and the added value of SPECT (single photon emission tomography) in detecting skeletal lesions. Q J Nucl Med 2001 Mar;45(1):27-37
6. Yoshikawa H, Ueda T, Mori S, Araki N, Kuratsu S, Uchida A, Ochi T. Skeletal metastases from soft-tissue sarcomas. Incidence, patterns, and radiological features. J Bone Joint Surg Br 1997 Jul;79(4):548-52  PMID: 9250736 [PubMed - indexed for MEDLINE] 


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SURGICAL INTERVENTION -- LONG BONES


The chance of developing a fracture increases with the duration and extent of tumor growth in the bone. The development of a fracture is devastating. It is vital that patients are routinely assessed by a specialist orthopedic and/or spinal surgeon to advise on prophylactic surgery. "A pathological long-bone fracture in a patient with known metastatic bone disease is really a reflection of inadequate clinical management."[5] Orthopedic management should enable intervention prior to fracture, enabling a simpler and safer operation.

"Fractures are common through lytic metastases and weight bearing bones, the proximal femora being the most commonly affected sites... Although controversial, several radiological features have been identified which may predict imminent fracture. These include pain, the anatomical site of a lesion, its radiological characteristics, and its size. Although the intensity of bone pain is not directly associated with fracture risk, pain that is exacerbated by movement does appear to be an important factor, which predicts impending fracture. Radiographic assessment gives information on the size of a lesion and the extent to which the bone is destroyed. When less than one-third of the diameter of a long bone is affected, pathological fracture is relatively unusual, but above this amount and especially when more than 50% of the cortex is destroyed, the fracture rate increases markedly to approximately 80%. A practical scoring system incorporating the above factors has been described to give valuable guidance in the selection of patients for prophylactic fixation."  [8]


Prior to surgery, bone isotope scans, Xrays of the entire affected bone, and possibly also MRI scans of the area, should be done.  Other bony lesions will be seen, stabilized, and included in the field of irradiation.  A pathologic fracture from a second metastasis at the edge of a plate or nail fixation of the first metastasis, is much more difficult to treat.  "Providing the lesion is irradiated, there is no evidence to suggest that surgery increases the risk of disseminating tumor cells either locally or into the circulation. If the patient is not fit for surgery, then radiotherapy and nonweight-bearing is indicated." [5]
 

A fracture because of a bony metastasis [pathologic fracture] does not necessarily mean the patient is terminally ill.  But untreated pathologic fractures rarely heal: large areas of bone destruction may not leave enough tissue for repair, and radiotherapy also inhibits fracture healing.  So primary internal stabilization followed by radiotherapy is usually the treatment of choice, and the most likely path to restore mobility as well as relieve pain. [5.87]

"Coincident with improved overall cancer palliation during the past 2 decades has been an increasing incidence of clinically apparent bone metastases, and from these metastases subsequent pathologic fractures of the long bones, spine, and pelvis. Current techniques for surgical management of these fractures are extremely effective in alleviating pain and allowing patients to resume an ambulatory status, often without the need of external support. This, in turn, has significantly improved the quality of the remaining months or years of these individuals' lives. In fact, the long term survival of patients after their first long bone pathologic fracture from malignancy has more than tripled for the most common cancers (breast carcinoma, prostate carcinoma, lymphomas, and myelomas) during the past 25 years. Surgical techniques for stabilizing pathologic or impending fractures must be individualized for the area of involvement, the particular qualities of the bone involved, and the potential for involvement of adjacent soft tissue structures. Long bone fractures most commonly occur in the femur and humerus and are typically internally fixed by intramedullary devices that control impaction, distraction, and torquing stresses by the use of proximal and distal interlocking fixation. Such fixation must be able to withstand weight-bearing stresses on lower extremity long bones. Upper extremity pathologic fractures are often subjected to distractive forces inherent in lifting and pulling, but they are also subjected to heavy compressive forces, particularly in patients who require crutches or other devices to assist them in walking. Fixation of upper or lower extremity long bone fractures ordinarily may be accomplished with minimal blood loss or morbidity. In contrast, fractures or impending fractures involving the acetabulum necessitate extensive joint reconstruction, with inherent increased potential for morbidity and complications. For this reason, the anticipated prognosis for survival and mobility should be greater preoperatively for patients with acetabular fractures than for patients with fractures of either upper or lower extremity long bones. ... Ninety-six percent of patients experience good or excellent relief of pain after internal fixation of pathologic malignant long bone fractures. Eighty-four percent of patients with acetabular fractures experience good or excellent relief of pain after joint reconstruction. ... Patients with pathologic fractures from metastatic carcinoma of the breast had a mean survival of 24.6 months after surgical management of their fractures. There was a similarly encouraging improvement in the survival statistics for patients with other primary tumor types. Most malignant pathologic fractures of the pelvis, long bones, or spine are amenable to effective stabilization by the techniques described in this article. These techniques allow resumption of weight-bearing ambulation in all but a few patients, good or excellent relief of pain in the vast majority, and an enhanced anticipation of survival and improvement in quality of life." [87] 


PubMed/Medline search for more information: Click on link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=long%20bone%20metastases%20surgical




SURGICAL INTERVENTION -- VERTEBRAL METASTASES
The spine is the commonest site for skeletal metastases.  Sometimes the vertebrae are invaded by direct extension of a nearby tumor in the lung, neck, or abdomen.  Sometimes the metastases arrive at the vertebrae by means of blood-borne spread, from the primary, through the lung circulation, to the peripheral circulation.  The tumor might possibly also spread to the vertebrae via a "third circulation", the Batson plexus, a network of deep pelvic veins with rich anastomoses [connections] to the vertebral plexus [another network of veins].  [1, 2]  
Metastatic tumors destroy vertebrae so that they spontaneously fracture [called a "pathologic" fracture].  If the vertebral pieces move out of alignment, they can cause major damage to the spinal cord, resulting in paralysis of the lower body [paraplegia] or all four limbs [quadriplegia], depending upon where the fracture is.  Metastases in the spine can also cause symptoms from tumors growing into the spinal canal and pressing upon the spinal cord.   Due to advances in spinal surgery, effective help often can be provided to these patients. The extent and type of surgical intervention, however, must be carefully considered in each individual case.  [3, 4] 
"The development of back pain in a patient with cancer, associated with an abnormality on a plain spinal radiograph, should serve as a warning for the possible development of spinal cord compression. In this situation more than 60% of patients will have myelographic abnormalities or evidence of epidural disease on magnetic resonance imaging. The key to successful rehabilitation is early diagnosis, high-dose corticosteroids, rapid assessment, and urgent referral for both decompression and spinal stabilization or radiotherapy. Neurological recovery is unlikely if the spinal compression is not relieved within 24-48 h."  [5] http://theoncologist.alphamedpress.org/cgi/content/full/5/6/463


"Spinal instability is a cause of back pain in approximately 10% of patients with metastatic bone disease. This can cause excruciating pain, which is mechanical in origin. The patient is only comfortable when lying absolutely still and any movement reproduces severe pain. Consequently, the patient may not be able to sit, stand or walk even with the use of a spinal support. Because the pain is due to the instability, radiotherapy or systemic treatment will not relieve the pain. As with a pathological long-bone fracture, stabilization is required for pain relief. This involves major surgery, which may be associated with significant morbidity and mortality. There are several methods of spinal stabilization, but the posterior approach is technically easier and allows stabilization of a longer length of the spine. With careful selection of patients, excellent results can be obtained [6] 

Criteria for impending vertebral collapse have been described as:  "50-60% involvement of the vertebral body with no destruction of other structures, or 25-30% involvement with costovertebral joint destruction in the thoracic spine; and 35-40% involvement of vertebral body, or 20-25% involvement with posterior elements destruction in thoracolumbar and lumbar spine. ...  With respect to the timing and occurrence of vertebral collapse, there is a distinct discrepancy between the thoracic and thoracolumbar or lumbar spine. When a prophylactic treatment is required, the optimum timing and method of treatment should be selected according to the level and extent of the metastatic vertebral involvement. "[7]

Surgical intervention is the treatment of choice for unstable vertebrae or neurologic deficit, with the excision of the tumorous bone and stabilization of the spine.  "Coincident with improved overall cancer palliation during the past 2 decades has been an increasing incidence of clinically apparent bone metastases, and from these metastases subsequent pathologic fractures of the long bones, spine, and pelvis. Current techniques for surgical management of these fractures are extremely effective in alleviating pain and allowing patients to resume an ambulatory status, often without the need of external support. This, in turn, has significantly improved the quality of the remaining months or years of these individuals' lives. In fact, the long term survival of patients after their first long bone pathologic fracture from malignancy has more than tripled for the most common cancers (breast carcinoma, prostate carcinoma, lymphomas, and myelomas) during the past 25 years."  [87]
Generally, surgery is recommended, with tumor excision, and removal of tumorous parts or the entire vertebra.  It is recommended that surgery be done BEFORE there is major neurological deficit, as the results are much better.   "Surgical indications must be made at the first sign of deficit, regardless of the degree of compression present in the radiologic documentation, in order to avoid the transformation of reversible functional medullary changes into irreversible structural lesions."   [78]
Results of surgical excision of metastatic neoplastic disease and stabilization of the spine seem to be overwhelmingly positive.  Surgical intervention does prevent paraplegia, quadriplegia, and other neurologic deficit, as well as managing pain.  The surgical techniques are well developed, and hospitalizations are not long, but complications can occur, and hemorrhage is one of them.    Techniques vary, and can vary also with site of the tumor.  
Excisions dealing with LMS lesions should always be en bloc if it is at all possible.  That means that the tumor and its environs are removed in one resected piece, with wide margins.  There is no cutting into the tumor, or removing the tumor piecemeal.  [21, 30, 80, 111, 139]
"Embolization of vertebral metastases is a safe treatment prior to surgical resection. With appropriate monitoring, complications can be eliminated. The resulting devascularization allows for an aggressive resection of pathologic tissue."  As well as decreasing hemorrhagic complications.  [126]
"The spine is the commonest site for skeletal metastases. The majority of patients with spinal metastases can be managed conservatively, at least initially, but a significant number will develop complications, either neurological or mechanical, requiring surgical intervention. This paper emphasizes the need for a spinal surgeon to be involved early in the care of these patients...Post-operatively pain improved in 38 of the 42 patients (90%), the neurological deficit in 20 of the 29 patients with a deficit (69%) and the ambulatory ability in 25 of the 32 patients (78%) with very restricted mobility...: Identification of the cause of a patient's symptoms allows appropriate surgical intervention with favorable results." [36]
"Most spinal metastases can be managed conservatively. Those requiring surgical intervention present with progressive neurologic compromise, which requires decompression, or spinal instability, which requires stabilization. Constructs for internal stabilization of the spine must not be adversely affected by local postoperative irradiation. ... Eighty-two percent of patients with neurologic compromise secondary to vertebral malignancy improve at least one functional grade after decompression and stabilization, and 88% experience good or excellent relief of spinal pain with restoration of walking ability. Thirty-two percent survived for more than 2 years after spinal decompression and stabilization. Patients with pathologic fractures from metastatic carcinoma of the breast had a mean survival of 24.6 months after surgical management of their fractures. There was a similarly encouraging improvement in the survival statistics for patients with other primary tumor types. Most malignant pathologic fractures of the pelvis, long bones, or spine are amenable to effective stabilization by the techniques described in this article. These techniques allow resumption of weight-bearing ambulation in all but a few patients, good or excellent relief of pain in the vast majority, and an enhanced anticipation of survival and improvement in quality of life "[87]
Twenty-one patients between 39-71 years underwent reconstructive surgery for destructive spinal tumors. Tissue was removed with autogenous bone grafting with or without vertebral prosthesis resulting in early ambulation,  relief of pain, and neurological recovery reported in all.  There were no complications from surgery.  Surgical intervention is recommended where "reasonable longevity" is expected.  [17]
Surgical Complications:  In one study "90 patients underwent minimally invasive spinal surgery by thoracoscopic assistance as treatment for their anterior spinal lesions. A total of 30 complications were noted in 22 patients (24.4%). Two fatal complications occurred, resulting from massive blood transfusion in one case and postoperative pneumonia in another. Other nonfatal complications included four cases of transient intercostal neuralgia, three superficial wound infections, three cases of pharyngeal pain, two cases of lung atelectasis, two cases of residual pneumothorax, two cases of subcutaneous emphysema, one inadvertent pericardial penetration due to adhesion, one chylothorax that resolved after conservative management, one vertebral screw malposition, and one graft dislodgement that needed late revision surgery. Three patients required ventilatory support for longer than 72 hours. Five patients with spinal metastases had an estimated intraoperative blood loss of more than 2,000 ml. No injury to the internal organs or spinal cord was observed. There were four conversions to open procedures due to two cases of severe pleural adhesions and two poorly tolerated one-lung ventilation. At the latest follow-up, nine patients had died as a result of cancer dissemination. CONCLUSIONS: (a) Well-selected patients and attention to details are essential to optimizing surgical results. (b) A refined technique for less invasive tumor surgery has been developed. (c) Surgeons had better experience with the standard anterior spinal approach and showed no hesitation in converting to an open procedure when necessary. A procedure failure does not mean a treatment failure." [60] 
Children with vertebral metastases who are treated with chemo, radiation and laminectomy, and who survive longer than 2 months, will probably develop spinal deformity if spinal stabilization is not carried out. [155 ]

PubMed/Medline Search to obtain abstracts of references: Click on link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=vertebral%20metastases%20surgical   

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References:  Surgical Management of Vertebral Tumors

1.  Oetiker RF et.al. Ther Umsch, Palliative surgery for bone metastases ,2001 Dec;58(12):738-45
2. Fleming MP et.al. Arch Pathol Lab Med , Myelophthisis as a solitary manifestation of failure from rectal carcinoma. A Batson phenomenon? ,2000 Aug;124(8):1228-30
3. Sim FH et.al., Ann Acad Med Singapore Metastatic bone disease: current concepts of clinicopathophysiology and modern surgical treatment. 1992 Mar; 21(2):274-9
4. Sanguinetti C , et.al. Chir Organi Mov The surgical treatment of spinal cord compression caused by tumorous metastases. A review of 91 cases. 1998 Jan-Jun;83(1-2):113-25
5. Coleman R., The Oncologist, Vol. 5, No. 6, 463-470, December 2000, (c) 2000 AlphaMed Press.
6. Healey JH, Brown HK. Complications of bone metastases-surgical management." [Cancer 2000;88(suppl 12):2940-2951
7. Taneichi H, Kaneda K, Takeda N, Abumi K, Satoh S , Risk factors and probability of vertebral body collapse in metastases of the thoracic and lumbar spine. Spine 1997 Feb 1;22(3):239-45
8.  Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathological fracture. Clin Orthop   1989;249:256-264
17: Hussein AA, El-Karef E, Hafez M.   Eur J Surg Oncol 2001 Mar;27(2):196-9 Reconstructive surgery in spinal tumours. 
30: Boriani S, Bandiera S, Biagini R, et. al.
Chir Organi Mov 2000 Oct-Dec;85(4):309-35. The use of the carbon-fiber reinforced modular implant for the reconstruction of the anterior column of the spine. A clinical and experimental study conducted on 42 cases. 
31: Schulte M, Schultheiss M, et. al., Eur Spine J 2000 Oct;9(5):437-44, Vertebral body replacement with a bioglass-polyurethane composite in spine metastases--clinical, radiological and biomechanical results.  
36: Hatrick NC, Lucas JD, et.al., Radiother Oncol 2000 Sep;56(3):335-9, The surgical treatment of metastatic disease of the spine. 
37: Bilsky MH, Boland P, et. al., Spine 2000 Sep 1;25(17):2240-9,discussion 250, Single-stage posterolateral transpedicle approach for spondylectomy, epidural decompression, and circumferential fusion of spinal metastases. 
46: Merk H, Koch H, et. al. , Z Orthop Ihre Grenzgeb 2000 Mar-Apr;138(2):169-73, Implantation of a Harms titanium mesh cylinder for vertebral body replacement in spinal metastases. 
60: Huang TJ, Hsu RW, et. al., Complications in thoracoscopic spinal surgery: a study of 90 consecutive patients. Surg Endosc 1999 Apr;13(4):346-50
61: Giehl JP, Kluba T., Anticancer Res 1999 Mar-Apr;19(2C):1619-23, Metastatic spine disease in renal cell carcinoma--indication and results of surgery.  
63: Janusz W, Mosiewicz A, et. al., Neurol Neurochir Pol 1999 Mar-Apr;33(2):403-12, Metastatic tumors in vertebral canal, 
65: Okuyama T, Korenaga D, et. al., J Surg Oncol 1999 Jan;70(1):60-3, Quality of life following surgery for vertebral metastases from breast cancer.  
67: Villas C, Arriagada C, et. al., Rev Med Univ Navarra 1998 Oct-Dec;42(4):188-93,  Surgical treatment of vertebral metastasis. 70: Ther Umsch 1998 Jul;55(7):418-22 , Orthopedic aspects of vertebral metastases. Heini PF.   
72: Been HD, van Ooij A, Veraart BE, Slot GH.   Ned Tijdschr Geneeskd 1998 May 2;142(18):1009-15,  One hundred years of orthopedics in the Netherlands. IV. Spinal abnormalities.  
74: Dominkus M, Krepler P, Schwameis E, Kotz R Orthopade 1998 May;27(5):282-6, Surgical therapy of spinal metastases,  
76: Klekamp J, Samii H.  , Acta Neurochir (Wien) 1998;140(9):957-67 , Surgical results for spinal metastases. 
78: Sanguinetti C, Aulisa L, et.al., Chir Organi Mov 1998 Jan-Jun;83(1-2):113-25  The surgical treatment of spinal cord compression caused by tumorous metastases. A review of 91 cases. 
80: Boriani S, Biagini R, De Iure F, et.al., Chir Organi Mov 1998 Jan-Jun;83(1-2):53-64 Resection surgery in the treatment of vertebral tumors. 
81: Cappelletto B, Del Fabro P, Meo A., Chir Organi Mov 1998 Jan-Jun;83(1-2):167-76  Decompression and surgical stabilization in the palliative treatment of vertebral metastases. 
87: Harrington KD.   Cancer 1997 Oct 15;80(8 Suppl):1614-27 , Orthopedic surgical management of skeletal complications of malignancy. 
98:  Bauer HC.  J Bone Joint Surg Am 1997 Apr;79(4):514-22    Comment in: J Bone Joint Surg Am. 1998 Sep;80(9):1396. Posterior decompression and stabilization for spinal metastases. Analysis of sixty-seven consecutive patients. 
108: Olerud C, Jonsson B.  et.al., Acta Orthop Scand 1996 Oct;67(5):513-22  Surgical palliation of symptomatic spinal metastases. 
110: Sundaresan N, Steinberger AA, Moore F, et.al., J Neurosurg 1996 Sep;85(3):438-46, Indications and results of combined anterior-posterior approaches for spine tumor surgery. 
121: Onimus M, Papin P, et. al., Eur Spine J 1996;5(6):407-11, Results of surgical treatment of spinal thoracic and lumbar metastases. 
123:  Hosono N, Yonenobu K, et.al., Spine 1995 Nov 15;20(22):2454-62 Vertebral body replacement with a ceramic prosthesis for metastatic spinal tumors. 
124: Plotz W, Wicke-Wittenius S, et. al.,  Fortschr Med 1995 Nov 10;113(31):437-40 Vertebral replacement in palliative tumor therapy. Possible surgical procedures--significant improvement in quality of life. 
126: Breslau J, Eskridge JM.    J Vasc Interv Radiol 1995 Nov-Dec;6(6):871-5  Preoperative embolization of spinal tumors.  
129: Hosono N, Yonenobu K, Fuji T, Ebara S, et.al., Clin Orthop 1995 Mar;(312):148-59 Orthopaedic management of spinal metastases. 
139: Tomita K, Kawahara N, Baba H, Tsuchiya H, Nagata S, Toribatake Y. Total en bloc spondylectomy for solitary spinal metastases.  Int Orthop 1994 Oct;18(5):291-8 
151: Toma S, Venturino A, Sogno G, et.al., Clin Orthop 1993 Oct;(295):246-51 Metastatic bone tumors. Nonsurgical treatment. Outcome and survival.  
155: Freiberg AA, Graziano GP, et. al.  Metastatic vertebral disease in children. J Pediatr Orthop 1993 Mar-Apr;13(2):148-53

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Radio Frequency Ablation


RFA     Further information about RFA treatment is on the RFA page.

Radiofrequency thermal ablation (RFA) is a new minimally invasive treatment for localized cancer, which can be done percutaneously.  "Minimally invasive surgical options require less resources, time, recovery, and cost, and often offer reduced morbidity and mortality, compared with more invasive methods "  It is safe, simple, and effective. [8, 1, 2, 6, 7]  RFA can ablate inoperable painful metastatic spinal tumors, and relieve pain, relieve or prevent neurologic deficit, and ablate the tumor so there is no further tumor growth. [9]

"Image-guided, local cancer treatment relies on the assumption that local disease control may improve survival. Recent developments in ablative techniques are being applied to patients with inoperable, small, or solitary liver tumors, recurrent ... renal cell carcinoma, and neoplasms in the bone, lung, breast, and adrenal gland. ... Recent refinements in ablation technology enable large tumor volumes to be treated with image-guided needle placement, either percutaneously, laparoscopically, or with open surgery. Local disease control potentially could result in improved survival, or enhanced operability." [8] 

Consensus indications for use of RFA in oncology are currently ill-defined, despite widespread use of the technique.  "More rigorous scientific review, long-term follow-up, and randomized prospective trials are needed to help define the role of RFA in oncology."  [8] 


More Information:
Pubmed search for Radio Frequency Ablation on Bone.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20radio%20frequency%20ablation
              

References:
              1: Radiology 1992 Apr;183(1):29-33   Ablation of osteoid osteomas with a percutaneously placed electrode: a new procedure. Rosenthal DI, Alexander A, Rosenberg AE, Springfield D. PMID: 1549690 [PubMed - indexed for MEDLINE] 
              2: J Bone Joint Surg Br 2001 Apr;83(3):391-6  Percutaneous radiofrequency ablation in osteoid osteoma. Lindner NJ, Ozaki T, Roedl R, Gosheger G,  Winkelmann W, Wortler K.   PMID: 11341426 [PubMed - indexed for MEDLINE] 
              3: Radiol Med (Torino) 2001 Nov-Dec;102(5-6):329-34  [Percutaneous radio-frequency ablation of osteoid osteoma: technique and preliminary results] [Article in Italian] Gallazzi MB, Arborio G, Garbagna PG, Perrucchini G, Daolio PA. PMID: 11779979 [PubMed - indexed for MEDLINE] 
              4: Radiology 2001 Nov;221(2):463-8 Primary treatment of chondroblastoma with percutaneous radio-frequency heat ablation: report of three cases.Erickson JK, Rosenthal DI, Zaleske DJ, Gebhardt MC, Cates JM. PMID: 11687691 [PubMed - indexed for MEDLINE]
  5: J Bone Joint Surg Am 1998 Jun;80(6):815-21  Percutaneous radiofrequency coagulation of osteoid osteoma compared with operative treatment. Rosenthal DI, Hornicek FJ, Wolfe MW, Jennings LC, Gebhardt MC, Mankin HJ. PMID: 9655099 [PubMed - indexed for MEDLINE] 
              6: Eur Spine J 1998;7(5):422-5     High-frequency radio-wave ablation of osteoid osteoma in the lumbar spine.  Osti OL, Sebben R. PMID: 9840478 [PubMed - indexed for MEDLINE]
              7: Radiology 1995 Nov;197(2):451-4  Osteoid osteoma: percutaneous radio-frequency ablation. Rosenthal DI, Springfield DS, Gebhardt MC, Rosenberg AE, Mankin HJ. PMID: 7480692 [PubMed - indexed for MEDLINE]
	 8. Cancer 2002 Jan 15;94(2):443-51  Percutaneous tumor ablation with radiofrequency. Wood BJ, Ramkaransingh JR, Fojo T, Walther MM, Libutti SK. 
Diagnostic Radiology Department, Special Procedures Division, National Institutes of Health Clinical Center, Bethesda, Maryland 20892, USA. bwood@nih.gov 
PMID: 11900230 [PubMed - indexed for MEDLINE] 
      9. Dietrich H.W. Gronemeyer,M.D. et.al  The Cancer Journal Vol.8, No.1, Institute of MicroTherapy and the Department of Radiology and Microtherapy, University of Witten/Herdecke, Germany. EFMT Development and Research Center for Microtherapy in Bochum, Germany.

        
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Cryoablation

"The technological advances which have caused renewed interest in cryosurgery are the development of intraoperative ultrasound to monitor the therapeutic process and the development of new cryosurgical equipment designed to use supercooled liquid nitrogen. The thin, highly efficient probes, available in several sizes, can be placed in diseased sites via endoscopy or percutaneously in minimally invasive procedures. The manner of use is to place the probe in the desired location in the diseased tissue with ultrasound guidance. If required by the size or location of the tumor, as many as five probes can be inserted and cooled to -195 degrees C simultaneously. The process of freezing is monitored by ultrasound which displays a hypoechoic (dark) image when the tissue if frozen. Rapid freezing, slow thawing, and repetition of the freeze/thaw cycle are standard features of technique." [1]
"The cases selected for cryosurgery are generally those for which no conventional treatment is possible.  ... Diverse tumors [in sites] such as the brain, bronchus, bone, pancreas, kidney, and uterus, have ... been treated in small numbers by cryosurgery. Judging from this experience, further expansion in the use of cryosurgical techniques seems certain." [1] 
1. Cryobiology 1997 Jun;34(4):373-84
Minimally invasive cryosurgery--technological advances. 
Baust J, Gage AA, Ma H, Zhang CM. 
Center for Cryobiological Research State University of New York, Binghamton 13902, USA. 
PMID: 9200822 [PubMed - indexed for MEDLINE] 

For more information, click on the pubmed search:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=cryoablation%20bone%20cancer





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Embolization

 
Embolization requires snaking a catheter [ a long narrow tube] into the small arteries feeding a tumor, and then injecting particles into that small artery.  The particles clog up the arteries, and clots form.  This robs the tumor of its blood supply, so it can die.  It also cuts off possible areas of bleeding if used preoperatively in hypervascular tumors.  Operating on very vascular tumors usually means there is heavy bleeding, because the area becomes very vascularized with a high blood flow.  So embolization can either directly attack a tumor so that it dies back, and stops eroding bone, or it can be used to decrease blood flow to the area, allowing cleaner removal of tumor with less blood loss.
''The technique of selective embolization has been in use for years in the treatment of vascular anomalies, severe hemorrhage and benign or malignant tumors, notably renal cell cancer vertebral metastases. Because this technique is relatively easy to perform and can offer immediate relief of symptoms, it is an attractive option for patients with hypervascular vertebral metastases with signs of spinal cord compression. Selective catheterization of the arteries feeding the metastases is performed, followed by infusion of polyvinyl alcohol particles.  Embolization results in rapid resolution of neurological symptoms, sometimes within hours. The therapeutic effect lasts from months to years. Embolization of hypervascular vertebral metastases is a palliative therapeutic option that may offer rapid relief of symptoms.''[44]
Embolization can also stop tumors from bleeding spontaneously.  "Embolization therapy is reported in three patients bleeding from metastatic carcinoma of the breast. Two had life threatening hemorrhage from sternal erosion;.... The third patient had intermittent bleeding of extensive fungating axillary and anterior chest wall metastases. Autologous clot alone was used in the first case with immediate cessation of bleeding and transient neurological symptoms secondary to back flow of thrombus into the vertebral artery were noted. The second and third patients received Oxycel-Ivalon and Gel-foam respectively; bleeding ceased and no complications were noted." [15]
Embolization alone can often reduce metastatic spinal cord compression, so surgical decompression is either not necessary or can be postponed. [7,11, 12]
Massive perioperative hemorrhage is often associated with surgery for vertebral metastases. Preoperative embolization reduces operative blood loss so that  hypervascular tumors may be removed safely after embolization.  The resulting devascularization allows for an aggressive resection of pathologic tissue [4,5,6,8,18,57,72,87] 
Access to PubMed Search & Obtaining Abstracts of the Medical Journal Articles:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20metastasis%20embolization
Chemoembolization
 Chemoembolization [also called transcatheter arterial embolization] consists of embolization, as described above, with specific catheterization of the artery or arteries supplying the tumor.  But the embolization is with gelatin sponge particles, which are impregnated with chemotherapy agents.  Thus the chemo agents remain in contact with the tumor at higher concentrations than would be possible systemically.  Doxorubicin is one of the agents frequently used this way.  This modality can be combined with RFA hyperthermia, and/or radiotherapy. [22]  For more information about chemoembolization and transcatheter arterial embolization [T.A.E.] see the section under Liver Metastases.
        

Radioisotope Embolization  [Theraspheres]

This would be a technique whereby the selective catheterization of tumor-supplying arteries would result in embolization of the arteries with either glass beads or resin impregnated with Yttrium-90. This would result in the radiation being discharged locally in the tumor.  Currently this technique is only under investigation for treatment of liver metastases, not bone metastases.   However, it would seem to lend itself to treatment of bone metastases.   For more information, see the Liver Metastasis section of this website.

The question of whether Theraspheres [glass beads] or resinous beads are used may be decided by whether the radioisotope remains within the delivery system or whether it leaches out into the systemic circulation.  Whether the presence of the glass or resin will prevent subsequent RFA treatment of the area, or the presence of the Yttrium-90 prevent use of other agents subsequently is not known.  


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References for this Section:
4: Breslau J, Eskridge JM. Preoperative embolization of spinal tumors. J Vasc Interv Radiol 1995 Nov-Dec;6(6):871-5
5: Mori K, Yamada S, Kosaka A, et. al., A case of liver metastases from leiomyosarcoma in the chest wall which was made resectable by chemoembolization.  Gan To Kagaku Ryoho 1997 Sep;24(12):1741-4
6: Griffith JF, Kumta SM. Clinics in diagnostic imaging (25). Aggressive vertebral haemangioma. Singapore Med J 1997 May;38(5):226-30 
7: Ikejiri K, Furuyama M, Muranaka T, Anai H, Takeo S, Sakai K, Saku M, Yoshida K. Carcinoma of the thyroid manifested as hyperthyroidism caused by functional bone metastasis. Clin Nucl Med 1997 Apr;22(4):227-30 
8: Olerud C, Jonsson B. Surgical palliation of symptomatic spinal metastases. Acta Orthop Scand 1996 Oct;67(5):513-22
11. O'Reilly GV, Kleefield J, Klein LA, Blume HW, Dubuisson D, Cosgrove GR. Embolization of solitary spinal metastases from renal cell carcinoma: alternative therapy for spinal cord or nerve root compression. PMID: 2928919 [PubMed - indexed for MEDLINE] 
12: Taki Y, Yamaoka Y, Takayasu T, Ino K, Shimahara Y, Mori K, Morimoto T, Ozawa K. Bone metastases of hepatocellular carcinoma after liver resection.  J Surg Oncol 1992 May;50(1):12-8 
15: Harrington DP, Barth KH, Baker RR, Truax BT, Abeloff MD, White RI Jr. Therapeutic embolization for hemorrhage from locally recurrent cancer of the breast. Radiology 1978 Nov;129(2):307-10 
18: Bilsky MH, Boland P, Lis E, Raizer JJ, Healey JH. Single-stage posterolateral transpedicle approach for spondylectomy, epidural decompression, and circumferential fusion of spinal metastases. Spine 2000 Sep 1;25(17):2240-9,discussion 250 
22: Nagata Y, Mitsumori M, Okajima K, Mizowaki T,et.al., Transcatheter arterial embolization for malignant osseous and soft tissue sarcomas. II. Clinical results.Cardiovasc Intervent Radiol 1998 May-Jun;21(3):208-13 
44: Smit JW, Vielvoye GJ, Goslings BM, Embolization for vertebral metastases of follicular thyroid carcinoma.  J Clin Endocrinol Metab 2000 Mar;85(3):989-9457: Berkefeld J, Scale D, Kirchner J, Heinrich T, Kollath J., Hypervascular spinal tumors: influence of the embolization technique on perioperative hemorrhage. AJNR Am J Neuroradiol 1999 May;20(5):757-63  
72: Taniguchi T, Ohta K, Ohmura S, Yamamoto K, Kobayashi T. Perioperative management for total en bloc spondylectomy--the effects of preoperative embolization and hypotensive anesthesia Masui 2000 Feb;49(2):168-71 
87: Choi IS, Tantivatana J. Neuroendovascular management of intracranial and spinal tumors. Neurosurg Clin N Am 2000 Jan;11(1):167-85


Further References Obtained from a Review Article

  1.. Luessenhop AJ, Kachmann R, Shevlin W. 1965 Clinical evaluation of artificial embolization in the management of large cerebral arteriovenous malformations. J Neurosurg. 23:400. 
  2.. Gomes AS, Busuttil RW, Baker JD, Oppenheim W, Machleder HI, Moore WS. 1983 Congenital arteriovenous malformations. The role of transcatheter arterial embolization. Arch Surg. 118:817-825.[Medline] 
  3.. Dawson RC, Joseph GJ, Owens DS, Barrow DL. 1998 Transvenous embolization as the primary therapy for arteriovenous fistulas of the lateral and sigmoid sinuses. Am J Neuroradiol. 19:571-576.[Abstract] 
  4.. Hekster RE, Luyendijk W, Tan TI. 1972 Spinal-cord compression caused by vertebral haemangioma relieved by percutaneous catheter embolisation. Neuroradiology. 3:160-164.[Medline] 
  5.. Hekster RE, Endtz LJ. 1987 Spinal-cord compression caused by vertebral haemangioma relieved by percutaneous catheter embolisation: 15 years later. Neuroradiology. 29:101.[Medline] 
  6.. Guibaud L, Herbreteau D, Dubois J, et al. 1998 Aneurysmal bone cysts: percutaneous embolization with an alcoholic solution of zein-series of 18 cases. Radiology. 208:369-373.[Abstract] 
  7.. Ravina JH, Herbreteau D, Ciraru-Vigneron N, et al. 1995 Arterial embolisation to treat uterine myomata. Lancet. 346:671-672.[Medline] 
  8.. Gold RE, Grace DM. 1975 Gelfoam embolization of the left gastric artery for bleeding ulcer: experimental considerations. Radiology. 116:575-580.[Abstract] 
  9.. Valavanis A. 1986 Preoperative embolization of the head and neck: indications, patient selection, goals, and precautions. Am J Neuroradiol. 7:943-952.[Abstract] 
  10.. Casasco A, Herbreteau D, Houdart E, et al. 1994 Devascularization of craniofacial tumors by percutaneous tumor puncture. Am J Neuroradiol. 15:1233-1239.[Abstract] 
  11.. Smith TP, Gray L, Weinstein JN, Richardson WJ, Payne CS. 1995 Preoperative transarterial embolization of spinal column neoplasms. J Vasc Interv Radiol. 6:863-869.[Abstract] 
  12.. Barton PP, Waneck RE, Karnel FJ, Ritschl P, Kramer J, Lechner GL. 1996 Embolization of bone metastases. J Vasc Interv Radiol. 7:81-88.[Abstract] 
  13.. Gellad FE, Sadato N, Numaguchi Y, Levine AM. 1990 Vascular metastatic lesions of the spine: preoperative embolization. Radiology. 176:683-686.[Abstract] 
  14.. Hess T, Kramann B, Schmidt E, Rupp S. 1997 Use of preoperative vascular embolisation in spinal metastasis resection. Arch Orthop Trauma Surg. 116:279-282.[Medline] 
  15.. O'Reilly GV, Kleefield J, Klein LA, Blume HW, Dubuisson D, Cosgrove GR. 1989 Embolization of solitary spinal metastases from renal cell carcinoma: alternative therapy for spinal cord or nerve root compression. Surg Neurol. 31:268-271.[Medline] 
  16.. Sundaresan N, Choi IS, Hughes JE, Sachdev VP, Berenstein A. 1990 Treatment of spinal metastases from kidney cancer by presurgical embolization and resection. J Neurosurg. 73:548-554.[Medline] 
  17.. Sun S, Lang EV. 1998 Bone metastases from renal cell carcinoma: preoperative embolization. J Vasc Interv Radiol. 9:263-269.[Abstract] 
  18.. Wallace S, Chuang VP, Swanson D, et al. 1981 Embolization of renal carcinoma. Radiology. 138:563-570.[Abstract] 
  19.. Chuang VP, Soo CS, Wallace S. 1981 Ivalon embolization in abdominal neoplasms. Am J Roentgenol. 136:729-733. 
  20.. Wallace S, Charnsangavej C, Carrasco CH, Bechtel W. 1984 Infusion-embolization. Cancer. 54:2751-2765.[Medline] 
  21.. Tadavarthy SM, Moller JH, Amplatz K. 1975 Polyvinyl alcohol (Ivalon)-a new embolic material. Am J Roentgenol Radium Ther Nucl Med. 125:609-616.[Medline] 
  22.. Camille RR, Leger FA, Merland JJ, Saillant G, Savoie JC, Riche MC. 1980 Recent advances in the treatment of bone metastases from cancer of the thyroid (author's translation). Chirurgie. 106:32-36.[Medline] 
  23.. Ripp GA, Wendth AJJ, Vitale P. 1977 Metastatic thyroid carcinoma of the mandible mimicking an arteriovenous malformation. J Oral Surg. 35:743-745.[Medline] 
  24.. Monteil JP, Houlbert D, Saliba N, Despreaux G, Tran BH. 1985 Cranial and cervical metastases of vascular nature in thyroid cancer. Apropos of 2 cases. Ann Otolaryngol Chir Cervicofac. 102:53-57.[Medline] 
  25.. Yamasoba T, Kikuchi S, Sugasawa M, Higo R, Sasaki T. 1994 Occult follicular carcinoma metastasizing to the sinonasal tract. ORL J Otorhinolaryngol Relat Spec. 56:239-243.[Medline] 
  26.. Chuang VP, Wallace S, Swanson D, et al. 1979 Arterial occlusion in the management of pain from metastatic renal carcinoma. Radiology. 133:611-614.[Abstract] 
  27.. Hermanek P, Sobin LH. 1992 Thyroid gland (ICD-OC73). TNM classification of malignant tumors, 4th ed, 2nd rev. International Union Against Cancer. Berlin: Springer Verlag; 35-37. 
  28.. Goslings BM. 1975 Proceedings: effect of a low iodine diet on 131-I therapy in follicular thyroid carcinomata. J Endocrinol. 64:30P. 
  29.. Schlumberger M, Challeton C, De Vathaire F, et al. 1996 Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med. 37:598-605.[Abstract] 
  30.. Pelikan DM, Lion HL, Hermans J, Goslings BM. 1997 The role of radioactive iodine in the treatment of advanced differentiated thyroid carcinoma. Clin Endocrinol (Oxf.).47 :713-720. 
  31.. Rockwell S. 1997 Oxygen delivery: implications for the biology and therapy of solid tumors. Oncol Res. 9:383-390.[Medline] 



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BISPHOSPHONATES


Usually bone metastases are lytic lesions, ones in which the bone is destroyed and replaced with tumor tissue. Lytic lesions imply an increase in osteoclastic bone cell activity.  Tumor cells within the bone marrow space can secrete substances [paracrine factors] that stimulate osteoclast function, resulting in osteolysis [bone destruction].  Also, bone cells can release cytokines and growth factors, which might can encourage tumor growth.

Bisphosphonates, a class of drugs that inhibit osteoclast activity, are useful in preventing and/or inhibiting the growth and symptoms of lytic bone metastases, as well as preventing and treating generalized osteoporosis [sometimes caused by chemotherapy agents] in cancer patients.

 " All bisphosphonates are characterized by a phosphorus-carbon-phosphorus (P-C-P)-containing central structure, which promotes their binding to the mineralized bone matrix, and a variable R' chain which determines the relative potency, side effects, and probably also the precise mechanism of action. Following administration, bisphosphonates bind avidly to exposed bone mineral around resorbing osteoclasts leading to very high local concentrations of bisphosphonate in the resorption lacunae (up to 1,000 µM). On release from the bone surface, bisphosphonates are internalized by the osteoclast, where they cause disruption of the biochemical processes involved in bone resorption [9]. Bisphosphonates also cause osteoclast apoptosis, with the appearance of distinctive changes in cell and nuclear morphology. Although the molecular targets responsible for promoting this apoptosis are unknown, the bisphosphonates have recently been shown to inhibit enzymes of the mevalonate pathway which are ultimately responsible for events that lead to the post-translational modification of GTP-binding proteins such as Ras. Recent studies also suggest that bisphosphonates may have direct apoptotic effects on tumor cells [10, 11]. "  [Coleman, R. The Oncologist, Vol. 5, No. 6, 463-470, December 2000 (c) 2000 AlphaMed Press ]


USE OF BISPHOSPHONATES 


Bisphosphonates for Hypercalcemia of Malignancy
Hypercalcemia is a common complication of malignancy.  Focal bone destruction by tumor cells, generalized bone destruction by substances secreted by the tumor, and impairment of kidney function may all contribute to high blood calcium levels. Intravenous bisphosphonates are now established as the treatment of choice for hypercalcemia. Seventy to ninety percent of patients will achieve normocalcemia resulting in relief of symptoms and improved quality of life [12] 


Bisphosphonates for Bone Pain
Radiotherapy is the treatment of choice for localized bone pain but many patients have widespread poorly localized, nonmechanical bone pain while others 
will experience recurrence of pain in previously irradiated skeletal sites. The bisphosphonates provide an alternative treatment approach to the management of 
these patients. [13-15].

Randomized controlled trials of intravenous pamidronate, clodronate, ibandronate, and zoledronate have all demonstrated bone tumor pain relief.  None of the oral preparations alone have been shown to reduce bone tumor pain.  Both sclerotic and lytic lesions respond to the bisphosphonates.  Bone tumor pain seems to be linked to the rate of bone resorption.   Patients with bony tumors and high rates of bone resorption respond poorly to bisphosphonates.  Following bone resorption markers will probably become important in evaluation the effects of bisphosphonate treatment.  [13, 16, 17]



Bisphosphonates as Adjunctive Therapy in Metastatic Bone Disease

Trials of bisphosphonates delayed disease progression in bone, and maintained quality of life and a reduction in pain and use of analgesics in treatment of breast cancer and multiple myeloma.  The research questions now are when to start treatment, optimal duration of treatment, and predicting those patients most likely to benefit.  Bisphosphonates may confer a small increase in survival time in the under 50 breast cancer group, and in myeloma patients receiving salvage chemotherapy. [1, 13-26]

 
"We are still lacking good data from randomized trials of the role of bisphosphonates for other tumor types affecting bone. Osteoclast stimulation is a consistent finding in all tumor types, even those associated with predominantly sclerotic metastases, and certainly acute pain relief is seen in prostate cancer. However, at the present time long-term bisphosphonate use cannot be justified outside clinical trials until more evidence from the current trials is available." [12] 

 
"At present clodronate, usually given orally, and infusions of pamidronate are the two most widely used bisphosphonates in oncology. However, a small percentage (<5%) of an oral dose of clodronate is absorbed, and for some patients the size and number of capsules required limit compliance, while infusions of pamidronate are costly, time-consuming and place additional demands on already overworked intravenous therapy units. The development of more potent bisphosphonates could be expected to simplify treatment and possibly improve the therapeutic effectiveness of bisphosphonate therapy." [12] 


"Zoledronate is the most potent bisphosphonate in clinical development, and in in vitro systems has around 100-1,000 times the potency of pamidronate." [27,28]

"Ibandronate is another highly potent amino-bisphosphonate which is licensed in Europe for the treatment of hypercalcemia of malignancy, and in late clinical 
development for both the treatment of metastatic bone disease, and the prevention and treatment of osteoporosis. "  An oral form has been developed. [14,29]


Bisphosphonates for Treatment of Osteoporosis

Many patients with cancer are at increased risk of osteoporosis. This is a problem in women with uterine LMS, for whom there questions about the safety of hormone replacement therapy.  Chemotherapy can also precipitate osteoporosis.   Osteoporosis can be treated OR prevented with bisphosphonates.  [30]



Bisphosphonates for Prevention of Bone Metastases

There have been conflicting results in clinical trials testing whether bisphosphonates prevent bone metastases. [31-33]  Proving adjuvant effectiveness for bisphosphonates will need large randomized trials. Zoledronate, clodronate, and ibandronate are currently under investigation.   Significant positive results in preventing bone metastasis, added to the known effects of bisphosphonates on protecting bone mass, would make adjuvant treatment with bisphosphonates routine. 
However, until results prove a benefit for their use, bisphosphonates  cannot be used adjuvantly except for the prevention  or treatment of osteoporosis.  [37]


"The optimum time in the course of the disease to start bisphosphonates remains uncertain, but once treatment is initiated, patients should continue to receive 
bisphosphonate treatment for as long as the skeleton is the dominant site of metastases. Bisphosphonates may also prevent, or at least delay, the development of skeletal metastases and will prevent treatment-induced osteoporosis, but their routine use in early breast cancer cannot be recommended until the completion of 
confirmatory trials."[37] 



OTHER OSTEOCLAST INHIBITORS 

 
"In recent years much has been learned about the signaling mechanisms between osteoblasts and osteoclasts and the control of bone metabolism in cancer. Osteoprotogerin (OPG) is a member of the tumor necrosis factor receptor superfamily which is a natural inhibitor of osteoclast production and activity. OPG acts as a decoy receptor binding with OPG-ligand, the natural stimulator of osteoclast maturation that is produced in large quantities by the osteoblast [34]. OPG has recently been shown to inhibit cancer-induced bone destruction and reduce skeletal pain in mice [35], and a synthetic version is now entering phase I trials in cancer patients. If the effects on bone resorption that have been seen in normal volunteer testing (Amgen-data on file) are confirmed in a cancer population, this long-acting subcutaneous preparation could be of great importance in the future. "[37]



PubMed/Medline Search for more information and references: Click on link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20metastases%20bisphosphonates
 

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References:  Bisphosphonates


1. Theriault RL, Lipton A, Hortobagyi GN et al. Pamidronate reduces skeletal   morbidity in women with advanced breast cancer bone lesions: a randomized,   placebo-controlled trial. Protocol 18 Aredia Breast Study Group. J Clin Oncol   1999;17:846-854.

2 Hortobagyi GN, Theriault RL, Porter L et al. Efficacy of pamidronate in   reducing skeletal complications in patients with breast cancer and lytic bone   metastases. Protocol 19 Aredia Breast Study Group. N Engl J Med   1996;335:1785-1791.[Abstract/Full Text] 
  
9 Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer   1997;80(suppl 8):1652-1660.[Medline] 

10  Yoneda T, Michigami T, Yi B et al. Use of bisphosphonates for the treatment of   bone metastasis in experimental animal models. Cancer Treat Rev   1999;25:293-299.[Medline] 
 
11 van der Pluijm G, Lowik C, Papapoulos S. Tumour progression and angiogenesis   in bone metastases from breast cancer: new approaches to an old problem.   Cancer Treat Rev 2000;26:11-27.

12  Coleman RE. Pamidronate disodium in the treatment and management of hypercalcaemia. Reviews in Contemporary Pharmacotherapy 1998;9:147-164

13 Body JJ, Bartl R, Burckhardt P et al. Current use of bisphosphonates in   oncology. International Bone and Cancer Study Group. J Clin Oncol   1998;16:3890-3899.[Abstract] 
  
14 Body JJ, Lichinitser MR, Diehl IE et al. Double-blind placebo controlled trial   of ibandronate in breast cancer metastatic to bone. Proc Am Soc Clin Oncol   1999;18:575a. 
  
15 Berenson JR, Lipton A, Rosen LS et al. Phase I clinical study of a new   bisphosphonate, zoledronate (CGP-42446), in patients with osteolytic bone   metastases. Blood 1998;88(suppl 1):586a. 
  
16 Vinholes JJ, Purohit OP, Abbey ME et al. Relationships between biochemical and   symptomatic response in a double-blind trial of pamidronate for metastatic   bone disease. Ann Oncol 1997;8:1243-1250.  
17 Coleman RE. Biochemical markers of malignant bone disease. In: Rubens RD,   Mundy GR, eds. Cancer and the Skeleton. London: Martin Dunitz, 2000:137-150. 
  
18 Body JJ, Coleman RE., Piccart M. Use of bisphosphonates in cancer patients.   Cancer Treat Rev 1996;22:265-287.[Medline] 
  
19 Paterson AHG, Powles TJ, Kanis J et al. Double-blind controlled trial of oral  clodronate in patients with bone metastases from breast cancer. J Clin Oncol   1993;11:59-65.[Abstract] 
  
20 Lahtinen R, Laakso M, Palva I et al. Randomised, placebo controlled   multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group.   Lancet 1992;340:1049-1052.[Medline] 

21  McCloskey EV, Maclennan ICM, Drayson M et al. A randomised trial of the effect   of clodronate on skeletal morbidity in multiple myeloma. Br J Haematol   1998;100:317-325.[Medline] 
  
22 Conte PF, Mauriac L, Calabresi F et al. Delay in progression of bone   metastases treated with intravenous pamidronate: results from a multicentre   randomised controlled trial. J Clin Oncol 1996;14;2552-2559.[Abstract] 
  
23 Hultborn R, Ryden S, Gunderson S et al. Efficacy of pamidronate on skeletal   complications from breast cancer metastases. A randomised prospective double   blind placebo controlled trial. Acta Oncol 1996;35(suppl 5):73-74. 
  
24 Berenson JR, Lichtenstein A, Porter L et al. Long-term pamidronate treatment   of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol   1998;16:593-602.[Abstract] 

 25  Lipton A, Demers L, Curley E et al. Markers of bone resorption in patients   treated with pamidronate. Eur J Cancer 1998;34:2021-2026.[Medline] 
  
26 Lipton A, Theriault RL, Hortobagyi GN et al. Pamidronate prevents skeletal   complications and is effective palliative treatment in women with breast   cancer and osteolytic bone metastases: long-term results of two randomised,   placebo-controlled trials. Cancer 2000;88:1082-1090.[Medline] 
  
27 Body JJ, Lortholary A, Romieu G et al. A dose-finding study of zoledronate in   hypercalcaemic cancer patients. J Bone Miner Res 1999;14:1557-1661.[Medline] 
  
28 Major P, Lortholary A, Hon J et al. Zoledronic acid is superior to pamidronate   in the treatment of tumor-induced hypercalcamia: a pooled analysis. Proc Am   Soc Clin Oncol 2000;19:604a. 
  
29 Coleman RE, Purohit OP, Black C et al. Double-blind, randomised,   placebo-controlled study of oral ibandronate in patients with metastatic bone   disease. Ann Oncol 1999;10:311-316.[Medline] 
  
30 Saarto S, Blomqvist C, Valimaki M et al. Chemical castration induced by   adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes   rapid bone loss which is reduced by clodronate: a randomised study in   premenopausal patients. J Clin Oncol 1997;15:1341-1347.[Abstract] 
  
31 Powles TJ, Paterson AHG, Nevantaus A et al. Adjuvant clodronate reduces the  incidence of bone metastases in patients with primary operable breast cancer.   Proc Am Soc Clin Oncol 1998;17:468a. 
  
32 Diel I, Solomayer E-F, Costa SJ et al. Reduction in new metastases in breast   cancer with adjuvant clodronate treatment. N Engl J Med   1998;339:357-363.[Abstract/Full Text] 
  
33 Saarto T, Blomqvist C, Virkkunen P et al. No reduction of bone metastases with  adjuvant clodronate treatment in node-positive breast cancer patients. Proc Am   Soc Clin Oncol 1999;18:128a. 
  
34 Kong Y-Y, Yoshida H, Sarosi O et al. OPGL is a key regulator of  osteoclastogenesis, lymphocyte development and lymph-node organogenesis.   Nature 1999;397:315-323.[Medline] 
  
35 Honore P, Luger NM, Sabino AC et al. Osteoprotogerin blocks bone   cancer-induced skeletal destruction. Skeletal pain and pain-related   neurochemical re-organisation of the spinal cord. Nat Med 
  2000;6:521-528.[Medline  

36 van Holten-Verzantvoort AT, Bijvoet OLM, Cleton FJ et al. Reduced morbidity from skeletal metastases in breast cancer patients during long term bisphosphonate (APD) treatment. Lancet 1987;ii:983-985.

37. The Coleman Article [link and the citation] http://theoncologist.alphamedpress.org/cgi/content/full/5/6/463
The Oncologist, Vol. 5, No. 6, 463-470, December 2000 (c) 2000 AlphaMed Press  
Management of Bone Metastases     Robert E. Coleman   e-mail: r.e.coleman@sheffield.ac.uk.

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~~~~~~~~~~~~~~~~~~~~~~~~~~~

RADIOISOTOPES


Radioisotope Use In Cancer Metastatic to Bone
Radiosensitization
Strontium-89
Samarium-153
Rhenium-186
Phosphorus-32
Comparisons of RadioIsotopes
References

Radioisotope Use In Cancer Metastatic to Bone
        Bone pain is a common symptom in disseminated malignancy and may be difficult to manage effectively.  Pain caused by multiple bone metastases is treated by non-steroidal anti-inflammatory drugs and opioid-containing analgesics. Radiation is also of proven benefit for palliation of painful bony tumors.  There is growing interest in the therapeutic potential of bone-seeking radiopharmaceuticals that selectively irradiate the bone metastases while sparing healthy surrounding tissue. The radioisotope would be present in a higher concentration for a longer period of time at the tumor.   The response rate is roughly 70 to 80% of the patients treated. Pain relief may last for between 1 and 6 months, with the option of multiple treatments.  Response to additional treatments may not be as good as initial response. The prognosis of the disease is, however, usually not affected.[25,26] Patients with a positive bone scan using technetium 99m methylene diphosphonate (Tc-99-MDP) are eligible for treatment.  Although we can predict nonresponders, we cannot predict responders; however, patients with a better performance scale may have a better chance of pain relief. [120]

For patients with symptomatic widespread bone metastases, options include bisphosphonates or radiotherapy.  There are two forms of systemic radiotherapy available: hemibody irradiation and intravenous injection of radionuclides. Studies have shown the combination of either focal irradiation and hemibody irradiation or focal irradiation and the injection of strontium (89) prolongs the pain-free duration of the patients. [125]
               

Phosphorus-32, strontium-89, samarium-153 EDTMP, rhenium-186 HEDP and tin-117m DTPA have all been used effectively for bone pain palliation. [15,20,21,25,53,120] Each of these agents and/or radionuclides has specific advantages and disadvantages; however, the ideal agent for bone pain palliation has not yet been identified. [20,38,120] Systemic radionuclide therapy has two major advantages: 
(i) It addresses all sites of involvement; and  
(ii) 	      Selective absorption limits normal tissue dose. As a result, toxicity is reduced and the therapeutic ratio 
                  increased. 

It is also particularly useful when external beam therapy options have been exhausted, and normal tissue tolerance has been reached.  Prophylactic administration of systemic radionuclides for clinically occult metastases might delay their appearance [prostate cancer]. Often the isotope works better with a radiosensitizer [e.g. low dose cisplatin] , allowing for longer effectiveness, decreased growth and/or slowed progression of disease.  When the effect of the radioisotope wears off, and pain returns, repeat injections can be given, with repeat response [but it may not be so effective as initial response.]  Radioisotopes can also be used as part of a multi-modality approach, with significant chemotherapy.  Research is also indicated to compare treatment with radioisotopes and bisphosphonates, and to see whether they might work well together.  [9,51]

Pain palliation with bone-seeking radiopharmaceuticals is an effective and cost-effective management tool in patients with advanced cancer metastatic to bone. Strontium-89 (Metastron) and samarium-153-EDTMP (Lexidronam) are licensed for use in patients in the United States. Patients with a positive bone scan using technetium 99m methylene diphosphonate (Tc-99-MDP) are eligible for treatment, and indications and contraindications for use are now well defined. Evidence now suggests that the radiopharmaceuticals can reduce pain and analgesic requirements, improve quality of life, reduce lifetime radiotherapy requirements and management costs, and may slow the progression of painful metastatic lesions. Retreatment is possible and effective. 

Although sarcomas are relatively radioresistant, the total focal dose may be VERY high IF the tumor preferentially takes up the radioisotope. A very high dose might delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing osteoblastic tumors. [4,6,49]  

However, also because of their uptake in bone, treatment or repeated treatment of bone tumors by radioisotopes often results in myelodysplasia.  The bone marrow is exposed to radiation in higher doses and for longer periods by bone seeking radioisotopes.  A very high local dose can also cause bone marrow damage, so patients with extensive bone marrow invasion of tumor should be watched carefully as they are at high risk. [126]

  Use of radioisotope treatment repeatedly, or concomitantly with, or additionally to chemotherapy or radiation puts patients at high risk of bone marrow failure.  Stem Cell Harvesting and Autologous Re-Transfusion is a process that should be considered prior to instituting treatment in this case. [6] Other than myelodysplasia, the early side effect profile is negligible.[4]   Late effects [long term permanent damage] are not completely known, but are probably related to bone marrow damage and new primary cancers.  Skeletal doses of this order of magnitude are also known to be osteosarcomogenic [49,107] and probably leukemogenic [121] in humans when given as Strontium-90 injections.  

Generally, toxicity the flare phenomenon and myelosuppression, especially white cells and platelets--treatments should not be given to patients with suspected disseminated intravascular coagulation [can cause severe, life-threatening platelet loss]. [15,20,23,50, 120]   The Society of Nuclear Medicine's bone pain treatment procedure guideline states that patients referred for bone palliation should be screened for disseminated intravascular coagulation before therapy. [PMID: 10551466] 

Without Stem Cell conservation and re-transfusion, radioisotope treatment of LMS bone lesions might result in myelodysplasia after only one treatment, because of previous chemotherapy having been given in the usual very high dosage range that LMS requires.   Therefore, it might limit further chemotherapy.  
Surgery remains the treatment of choice. When surgery is not possible, then irradiation of the tumor, and possibly radioisotope treatment, might be used for palliation.  However, Stem Cell Harvesting and Autologous Retransfusion should be considered if radioisotope treatment of bone lesions is adopted. [3,4,6]  Radioisotopes seem to work best in prostate and breast cancer secondaries.  Although there is sometimes a response from other, lytic, cancers, the best responses come from these groups.  [117]
              

Radioisotope treatment is palliative, not curative, and might limit future chemotherapy treatments.



Pubmed search link:  Treatment of bone cancer with radioisotopes.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20radioisotope%20cancer%20treatment



About Radiosensitization

Intravenous outpatient radiopharmaceuticals have proven effective in treating pain associated with multiple osteoblastic bony metastasis from prostate or breast cancer. Radiosensitizers such as idoxyuridine incorporate into the DNA and increase the susceptibility of the cancer cell to radiation damage. Hypoxic cell sensitizers (such as metronidazole, misonidazole, SR 2508, and Ro-038799) increase oxygen to the cancer hypoxic cells and promote damage of the DNA, thus preventing cell repair. [Otto SE. J Intraven Nurs 1998 Nov-Dec;21(6):335-7. PMID: 10392098 ] 
              
This study reports on two preliminary experiences with low-dose platinum compounds, carboplatin and cisplatin, as radiosensitizers in Strontium-89 therapy.  No clinically significant adverse effects or myelosuppression by platinum compounds were observed. In carboplatin study a pain response was observed in 74% of the evaluable patients. The pain response in the patients treated with 89Sr and carboplatin was clearly and significantly superior to that seen in the patients treated with 89Sr alone, whereas survival was only marginally better in the combined treatment group.  In the cisplatin study a pain response was observed in 83% of the evaluable patients. 
CONCLUSIONS: Low-dose platinum compounds seem to enhance the effects of 89Sr radioisotope therapy on pain from bone metastases without relevant hematological toxicity.  [Sciuto R, Festa A, et. al., Clin Ter 1998 Jan-Feb;149(921):43, PMID: 9621488 ]

        
About Strontium-89

To date, the best studied and most commonly used radionuclide is strontium-89. Its efficacy as first line therapy or as adjuvant to external beam radiotherapy has been documented.  

        "Strontium-89 is a pure beta-emitting radioisotope, a chemical analogue of calcium, and it is therefore avidly concentrated by areas of high osteoblastic activity. Selective uptake and prolonged retention at sites of increased bone mineral turnover provide precise bone lesions targeting. 89Sr chloride (commercialised as Metastron) is typically administered in a single 150 MBq parenteral dose. Its radioactive  emission poses very little radioprotection concerns. Overall, studies show pain relief in up to 80% of patients, of whom 10 to 40% became effectively pain free. The mean duration of palliation was 3-4 months.  The mechanism of pain relief is controversial; it is probably, but not only, related to the absorbed dose in the tumor and bone. There is no clear dose-response relationship. The only reported toxicity is temporary myelosuppression. WBC and platelets should be monitored at least on a weekly basis until they return to baseline. It seems that only patients with a reasonably good general condition stand to benefit from this treatment. In conclusion, systemic radionuclide therapy using 89Sr represents a feasible, safe, effective, well tolerated and cost-effective palliative treatment in patients with refractory bone pain." [118]


Because Sr-89 is a beta-emitting radionuclide with a long physical half-life (50.5 days), precautions should be taken by the caretaker(s) against Sr-89 contamination from the patient's blood or excretions, particularly if the patient is incontinent. PMID: 7545083

Pubmed search link:  Treatment of bone cancer with strontium-89.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20strontium-89%20cancer%20treatment


About Samarium-153 


"Samarium-153-EDTMP is a 1:1 complex of radioactive Samarium-153 and a Tetraphosphonate [ethylenediamine-tetramethylene phosphonic acid (EDTMP)]. Samarium Sm-153-EDTMP has a high affinity for skeletal tissue and concentrates by chemiabsorption in areas of enhanced metabolic activity, where it associates with the hydroxyapatite crystal. Samarium-153 Lexidronam         [Quadramet (R)] has been approved for routine use by the FDA. This agent offers several advantages over other agents used for palliating bone pain. Due to its half-life of 46 hours and its beta emissions, a high dose rate can be delivered to regions adjacent to enhanced osteoblastic activity over a short period of time with little residual long term activity being left in the bone marrow. ... In addition, because it also emits a 103 keV gamma ray which makes it suitable for imaging and assessment of biodistribution, dosimetric applications are possible in the future."[11]

       
Samarium-153 ethylene diamine tetramethylene phosphonate [Samarium-153-EDTMP] is a beta particle and gamma ray emitting, bone-seeking radiopharmaceutical, and can provide therapeutic irradiation to osteoblastic [not osteoclastic or lytic] bone metastases [Osteoblasts are the bone cells that makes new bone]. It has been useful as an adjunct when treating some bony tumors with irradiation and polychemotherapy.  By itself, it is useful as a palliative agent for bone pain, and sometimes might slow development of metastases or slow tumor growth.  When the effect wears off, retreatment is possible. [3,4,6,37,39,47,49,56,59,60]


Benefit of Samarium-153 treatment in LMS is unknown, and unlikely to be more than palliative.  [3,4,6,37] Liver function tests were abnormal in some patients. [33]  
   

Pubmed search link:  Treatment of bone cancer with samarium-153.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20samarium-153%20cancer%20treatment


About Rhenium-186      

  
In connection with our work on the development of 186Re-tetra-phosphonates with optimum properties for use in bone pain palliation, a novel cyclic tetraphosphonate derivative has been synthesized, complexed with 186Re and evaluated with promising results. The ligand consists of a cyclic array of tetra-aminomethylphosphonate groups. Biodistribution studies of the complex were performed. The results suggest the suitability of the complex for further evaluation in higher animals for bone pain palliation. [124]

        


Pubmed search link:  Treatment of bone cancer with rhenium-186.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20rhenium-186%20cancer%20treatment



About Phosphorus-32

Can palliate pain and decrease tumor osteoblastic activity. It is given intravenously, and can be given repeatedly.  White count and platelet suppression can occur. [108]

Pubmed search link:  Treatment of bone cancer with phosphorus-32.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20phosphorus-32%20cancer%20treatment




Some Comparisons


Strontium-89 and external beam hemibody and local radiotherapy

There was no significant difference in median survival.  All treatments provided effective pain relief; improvement was sustained to 3 months in 63.6% after hemibody radiotherapy compared with 66.1% after strontium-89, and in 61% after local radiotherapy compared with 65.9% in the strontium-89 group. Fewer patients reported new pain sites after strontium-89 than after local or hemibody radiotherapy (p < 0.05).   Radiotherapy to a new site was required by 12 patients in the local radiotherapy group compared with 2 after strontium-89 (p < 0.01), although there was no significant difference between hemibody radiotherapy (6 patients) and strontium-89 (9 patients) in this respect.  Platelets and leukocytes fell by an average 30-40% after strontium-89.[122]

89Sr appears as effective a treatment option as HBI. Response is most likely with either approach when patients have a good         performance status and a limited extent of disease. [123]


Strontium-89 and Samarium-153 
There is probably no difference in response rates between samarium-153 and strontium-89 radioisotopes as measured by the effect on pain or in the time to progression. [26]

Strontium-89, Radiation, and Bisphosphonate
Local radiotherapy completely prevents the incidence of secondary bone mets in PROSTATE cancer, (89)Sr leads to an important decrease in this complication and olpadronate induces a significant, albeit smaller decrease in the incidence of SCC. [109]      
              

Strontium-89 and Rhenium-186-HEDP
        "Retreatments showed significantly P<0.01) worse responses (48% levels 3+4), in comparison to first RTBM. "
        "Duration of palliation was 5.0+/-3.5 months, and was longer in cases of excellent response, in first RTBM, in patients with limited metastases and when 89Sr was used. Better responses were found in cases of limited skeletal disease, under good clinical conditions, when life expectancy exceeded 3 months, and in radiologically osteoblastic or mixed bone         lesions. The only statistically significant predictive factor was life expectancy (P<0.001). Flare phenomenon (14.1% of cases) did not correlate with the response. Haematological toxicity (mild to moderate in most cases) mainly affected platelets, and was observed in 25.5% of cases overall and in 38.9% of retreatments. RTBM did not seem to prolong life, though in some cases scintigraphic regression of bone metastases was observed. The two radiopharmaceuticals did not show any statistically significant differences in palliative efficacy and toxicity, either in first RTBM or in retreatments."   [109]
       

          "The global response rate was 84% for 89Sr and 92% for 186Re-HEDP. The onset of pain palliation appeared  significantly earlier in Rhenium group. The duration of pain relief ranged from two months to 14 months (mean of 125 days with a median value of 120 days) in Group A and from one month to 12 months (mean of 107 days with a median value of 60 days) in Group B (p = 0.39).  A moderate hematological toxicity was apparent in both groups. Platelet and white blood cell counts returned to baseline levels within 12 weeks after 89Sr administration and 6 weeks after 186Re-HEDP administration [significant]. CONCLUSIONS: Both 89Sr and 186Re-HEDP are effective and safe in bone pain palliation in breast cancer with the latter showing a significantly faster onset of pain relief." [110]

Strontium-89, Rhenium-188, and Rhenium-186-HEDP 
All three radiopharmaceuticals were effective in pain palliation. The various radionuclides had no significant difference in the pain relief or bone marrow impairment. [119]


Samarium-153 and Rhenium-186

The level of the long-lived radioisotope impurity burden in 153Samarium appears low enough not to pose a problem, and was almost two orders of magnitude lower than that of 186Rhenium [Samarium-153 one hundredth of the long-lived radioactive impurity load carried by Rhenium-186].  This is a notable overall advantage of 153Sm over the use of 186Rhenium. [5]




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        Hua Xi Yi Ke Da Xue Xue Bao. 1995 Jun;26(2):155-9. Chinese.
        PMID: 7490021 [PubMed - indexed for MEDLINE]

              64: Serafini AN.

        Current status of systemic intravenous radiopharmaceuticals for the 
        treatment of painful metastatic bone disease.
        Int J Radiat Oncol Biol Phys. 1994 Dec 1;30(5):1187-94. Review.
        PMID: 7525518 [PubMed - indexed for MEDLINE]

              65: Ahonen A, Joensuu H, Hiltunen J, Hannelin M, Heikkila J, 
              Jakobsson M, Jurvelin J, Kairemo K, Kumpulainen E, Kulmala J, et 
              al.

        Samarium-153-EDTMP in bone metastases.
        J Nucl Biol Med. 1994 Dec;38(4 Suppl 1):123-7.
        PMID: 7543288 [PubMed - indexed for MEDLINE]

              66: Porter AT, Ben-Josef E, Davis L.

        Systemic administration of new therapeutic radioisotopes, including 
        phosphorus, strontium, samarium, and rhenium.
        Curr Opin Oncol. 1994 Nov;6(6):607-10. Review.
        PMID: 7827173 [PubMed - indexed for MEDLINE]

              67: Jiang CY, Zhu BL, Zhang YJ.

        [The value of Sm-153-EDTMP for treatment of metastatic bone pain and 
        improving quality of life]
        Zhonghua Zhong Liu Za Zhi. 1994 Mar;16(2):118-21. Chinese.
        PMID: 7523052 [PubMed - indexed for MEDLINE]

              68: Schott ME, Schlom J, Siler K, Milenic DE, Eggensperger D, 
              Colcher D, Cheng R, Kruper WJ Jr, Fordyce W, Goeckeler W.Related 
              Articles

        Biodistribution and preclinical radioimmunotherapy studies using 
        radiolanthanide-labeled immunoconjugates.
        Cancer. 1994 Feb 1;73(3 Suppl):993-8.
        PMID: 8306291 [PubMed - indexed for MEDLINE]

              69: Porter AT, Davis LP.

        Systemic radionuclide therapy of bone metastases with strontium-89.
        Oncology (Huntingt). 1994 Feb;8(2):93-6; discussion 96, 99-101.
        PMID: 8167090 [PubMed - indexed for MEDLINE]


              72: Bayouth JE, Macey DJ, Kasi LP, Fossella FV.

        Dosimetry and toxicity of samarium-153-EDTMP administered for bone pain 
        due to skeletal metastases.
        J Nucl Med. 1994 Jan;35(1):63-9.
        PMID: 7505819 [PubMed - indexed for MEDLINE]

              73: Collins C, Eary JF, Donaldson G, Vernon C, Bush NE, Petersdorf 
              S, Livingston RB, Gordon EE, Chapman CR, Appelbaum FR.Related 
              Articles

        Samarium-153-EDTMP in bone metastases of hormone refractory prostate 
        carcinoma: a phase I/II trial.
        J Nucl Med. 1993 Nov;34(11):1839-44.
        PMID: 8229221 [PubMed - indexed for MEDLINE]


              75: Eary JF, Collins C, Stabin M, Vernon C, Petersdorf S, Baker M, 
              Hartnett S, Ferency S, Addison SJ, Appelbaum F, et al.Related 
              Articles

        Samarium-153-EDTMP biodistribution and dosimetry estimation.
        J Nucl Med. 1993 Jul;34(7):1031-6.
        PMID: 7686217 [PubMed - indexed for MEDLINE]

              76: Goeckeler WF, Stoneburner LK, Kasi LP, Fossella FV, Price DR, 
              Fordyce WA.

        Analysis of urine samples from metastatic bone cancer patients 
        administered 153Sm-EDTMP.
        Nucl Med Biol. 1993 Jul;20(5):657-61.
        PMID: 8358352 [PubMed - indexed for MEDLINE]

              77: Holmes RA.

        Radiopharmaceuticals in clinical trials.
        Semin Oncol. 1993 Jun;20(3 Suppl 2):22-6. Review.
        PMID: 7684861 [PubMed - indexed for MEDLINE]

              79: Lewington VJ.

        Targeted radionuclide therapy for bone metastases.
        Eur J Nucl Med. 1993 Jan;20(1):66-74. Review.
        PMID: 7678397 [PubMed - indexed for MEDLINE]

              81: Farhanghi M, Holmes RA, Volkert WA, Logan KW, Singh A.Related 
              Articles

        Samarium-153-EDTMP: pharmacokinetic, toxicity and pain response using an 
        escalating dose schedule in treatment of metastatic bone cancer.
        J Nucl Med. 1992 Aug;33(8):1451-8.
        PMID: 1378887 [PubMed - indexed for MEDLINE]

              82: Sandeman TF, Budd RS, Martin JJ.

        Samarium-153-labelled EDTMP for bone metastases from cancer of the 
        prostate.
        Clin Oncol (R Coll Radiol). 1992 May;4(3):160-4.
        PMID: 1375094 [PubMed - indexed for MEDLINE]

              84: Robinson RG, Preston DF, Spicer JA, Baxter KG.

        Radionuclide therapy of intractable bone pain: emphasis on strontium-89.
        Semin Nucl Med. 1992 Jan;22(1):28-32. Review.
        PMID: 1589803 [PubMed - indexed for MEDLINE]

              85: Holmes RA.

        [153Sm]EDTMP: a potential therapy for bone cancer pain.
        Semin Nucl Med. 1992 Jan;22(1):41-5. Review.
        PMID: 1589805 [PubMed - indexed for MEDLINE]


              88: Turner JH, Claringbold PG.

        A phase II study of treatment of painful multifocal skeletal metastases 
        with single and repeated dose samarium-153 ethylenediaminetetramethylene 
        phosphonate.
        Eur J Cancer. 1991;27(9):1084-6.
        PMID: 1720321 [PubMed - indexed for MEDLINE]

              95: Goodman JH, Gahbauer RA, Kanellitsas C, Clendenon NR, Laster 
              BH, Fairchild RG.

        Theoretical basis and clinical methodology for stereotactic interstitial 
        brain tumor irradiation using iododeoxyuridine as a radiation sensitizer 
        and 145Sm as a brachytherapy source.
        Stereotact Funct Neurosurg. 1990;54-55:531-4.
        PMID: 1964244 [PubMed - indexed for MEDLINE]

              96: Turner JH, Claringbold PG, Hetherington EL, Sorby P, 
              Martindale AA.

        A phase I study of samarium-153 ethylenediaminetetramethylene 
        phosphonate therapy for disseminated skeletal metastases.
        J Clin Oncol. 1989 Dec;7(12):1926-31.
        PMID: 2585026 [PubMed - indexed for MEDLINE]

              97: Singh A, Holmes RA, Farhangi M, Volkert WA, Williams A, 
              Stringham LM, Ketring AR.

        Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer.
        J Nucl Med. 1989 Nov;30(11):1814-8.
        PMID: 2478681 [PubMed - indexed for MEDLINE]

              99: Turner JH, Martindale AA, Sorby P, Hetherington EL, Fleay RF, 
              Hoffman RF, Claringbold PG.

        Samarium-153 EDTMP therapy of disseminated skeletal metastasis.
        Eur J Nucl Med. 1989;15(12):784-95.
        PMID: 2483138 [PubMed - indexed for MEDLINE]

              100: Fairchild RG, Kalef-Ezra J, Packer S, Wielopolski L, Laster 
              BH, Robertson JS, Mausner L, Kanellitsas C.

        Samarium-145: a new brachytherapy source.
        Phys Med Biol. 1987 Jul;32(7):847-58.
        PMID: 3615583 [PubMed - indexed for MEDLINE]

              101: Logan KW, Volkert WA, Holmes RA.

        Radiation dose calculations in persons receiving injection of 
        samarium-153 EDTMP.
        J Nucl Med. 1987 Apr;28(4):505-9.
        PMID: 3572536 [PubMed - indexed for MEDLINE]

              102: Ketring AR.

        153Sm-EDTMP and 186Re-HEDP as bone therapeutic radiopharmaceuticals.
        Int J Rad Appl Instrum B. 1987;14(3):223-32.
        PMID: 3117736 [PubMed - indexed for MEDLINE]

              103: Goeckeler WF, Troutner DE, Volkert WA, Edwards B, Simon J, 
              Wilson D.

        153Sm radiotherapeutic bone agents.
        Int J Rad Appl Instrum B. 1986;13(4):479-82.
        PMID: 3793505 [PubMed - indexed for MEDLINE]


              107: Muller WA, Schaffer EH, Linzner U.

        Studies on incorporated short-lived beta-emitters with regard to the 
        induction of late effects.
        Radiat Environ Biophys. 1980;18(1):1-11.
        PMID: 6934560 [PubMed - indexed for MEDLINE]


              108: Shah Syed GM, Maken RN, Muzzaffar N, Shah MA, Rana F.

        Effective and economical option for pain palliation in prostate cancer 
        with skeletal metastases: 32P therapy revisited.
        Nucl Med Commun 1999 Aug;20(8):697-702
        PMID: 10451877 [PubMed - indexed for MEDLINE]
        
109: 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):1654-60.
        PMID: 11920525 [PubMed - indexed for MEDLINE]

109: Windsor PM.

        Predictors of response to strontium-89 (Metastron) in skeletal 
        metastases from prostate cancer: report of a single centre's 10-year 
        experience.
        Clin Oncol (R Coll Radiol). 2001;13(3):219-27.
        PMID: 11527299 [PubMed - indexed for MEDLINE]

110: Dafermou A, Colamussi P, Giganti M, Cittanti C, Bestagno M, 
              Piffanelli A.

        A multicentre observational study of radionuclide therapy in patients 
        with painful bone metastases of prostate cancer.
        Eur J Nucl Med. 2001 Jul;28(7):788-98.
        PMID: 11504074 [PubMed - indexed for MEDLINE]

117: Blake GM, Zivanovic MA, McEwan AJ, Condon BR, Ackery DM.
          
        Strontium-89 therapy: strontium kinetics and dosimetry in two patients 
        treated for metastasising osteosarcoma.
        Br J Radiol 1987 Mar;60(711):253-9
        
118: Giammarile F, Mognetti T, Resche I.

        Bone pain palliation with strontium-89 in cancer patients with bone 
        metastases.
        Q J Nucl Med. 2001 Mar;45(1):78-83. Review.
        PMID: 11456379 [PubMed - indexed for MEDLINE]

119: Fuster D, Herranz R, Alcover J, Mateos JJ, Martin F, 
              Vidal-Sicart S, Pons F.

        [Treatment of metastatic bone pain with repeated doses of strontium-89 
        in patients with prostate neoplasm]
        Rev Esp Med Nucl. 2000 Aug;19(4):270-4. Spanish.
        PMID: 11062097 [PubMed - indexed for MEDLINE]


120: Silberstein EB.

        Systemic radiopharmaceutical therapy of painful osteoblastic metastases.
        Semin Radiat Oncol 2000 Jul;10(3):240-9 
        PMID: 11034634 [PubMed - indexed for MEDLINE]
     

      121: Kossman SE, Weiss MA.        

        Acute myelogenous leukemia after exposure to strontium-89 for the 
        treatment of adenocarcinoma of the prostate.
        Cancer 2000 Feb 1;88(3):620-4 

        
122: Quilty PM, Kirk D, Bolger JJ, Dearnaley DP, Lewington VJ, Mason MD, Reed 
                    NS, Russell JM, Yardley J.

        A comparison of the palliative effects of strontium-89 and external beam 
        radiotherapy in metastatic prostate cancer.
        Radiother Oncol 1994 Apr;31(1):33-40   


              123: Dearnaley DP, Bayly RJ, A'Hern RP, Gadd J, Zivanovic MM, Lewington VJ.

        Palliation of bone metastases in prostate cancer. Hemibody irradiation 
        or strontium-89?
        Oncol (R Coll Radiol) 1992 Mar;4(2):101-7
        PMID: 1372817 [PubMed - indexed for MEDLINE]


124: Kothari K, Samuel G, Banerjee S, Unni PR, Sarma HD, Chaudhari PR, 
        Unnikrishnan TP, Pillai MR.
       
        186Re-1,4,8,11-tetraaza cyclotetradecyl-1,4,8,11-tetramethylene 
        phosphonic acid: a novel agent for possible use in metastatic bone-pain 
        palliation. Nucl Med Biol 2001 Aug;28(6):709-17 
    PMID: 11518653 [PubMed - indexed for MEDLINE] 
  

        125: Berk L. 

        Prospective trials for the radiotherapeutic treatment of bone 
        metastases. 
        Am J Hosp Palliat Care 1995 Jul-Aug;12(4):24-8  
        PMID: 7543272  indexed for MEDLINE


    126: Powsner RA, Zietman AL, Foss FM.

        Bone marrow suppression after strontium-89 therapy and local radiation 
        therapy in patients with diffuse marrow involvement.
        Clin Nucl Med 1997 Mar;22(3):147-50  
        PMID: 9067666 [PubMed - indexed for MEDLINE]





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Radiotherapy


        Targeting of radiotherapy can be based on improving physical dose distribution of radiation delivered or on utilization of specific biological processes for targeting. Tools for physical targeting include Brach therapy, hadron therapy, conformal radiotherapy, stereotactic radiotherapy, stereotactically guided conformal fractionated radiotherapy, and intensity-modulated radiotherapy. Biological targeting can be based on specific metabolic pathways such as uptake of iodine-131 by thyroid cancer cells, difference in substrate uptake between cancer cells and normal cells (e.g. boronophenylalanine in boron neutron capture therapy), targeting of radioactive isotopes by specific carrier molecules (radioimmunotherapy, labeled hormone derivatives or bone-seeking phosphonates), or on the distribution of elements in the         body (therapy of bone metastases with a calcium analog strontium-89 or phosphorus-32). [29]

Painful bone metastases are common in oncologic practice. The role of surgery should be limited to patients with neurologic compression or severe mechanical instability. [102]  Ninety percent of patients with symptomatic bone metastases obtain some pain relief with a low dose, brief course of palliative radiotherapy. One half of the responding patients may experience complete pain relief. A single dose of 800 cGy in the setting of painful bone metastasis may provide pain control comparable to more protracted treatment at a higher dose of radiation. [80] There seem to be no significant differences in pain relief between the different fractionation schedules. A palliation is ensured in 75% of all cases with a partial response of 42% and complete response of 33%. With regard to pain response these results do not justify a recommendation for a standard fractionation schedule. Current fractionation schedules such as 10 x 3 Gy for 2 weeks or 5 x 4 Gy for 1 week should probably be used.[53]   In one study, two short courses of radiation for bone pain were compared: 20 Gy in one week (daily dose 4 Gy), and 30 Gy in 3 weeks (daily dose 2 Gy).  There was a light trend favoring 30 Gy in frequency of pain relief and recalcification. [78] However, it is not known whether these short radiation schedules are adequate for patients with longer prognoses, or what the optimal fractionation schedule is for maintaining the structural integrity of the bone.

For patients with symptomatic widespread bone metastases, options include bisphosphonates or radiotherapy.  There are two forms of systemic radiotherapy available: hemibody irradiation and intravenous injection of radionuclides. Studies have shown the combination of either focal irradiation and hemibody irradiation or focal irradiation and the injection of strontium-89 prolongs the pain-free duration of the patients. [80,100,125]   HBI is a powerful palliative treatment in patients with multiple symptomatic bone metastases.  Analysis of one study of 78 procedures on 71 patients, treated with 6 Gy (upper half-body) or 8 Gy (lower half-body) HBI in single fraction: Complete (37.5%) or partial responses were observed in 72/78 (92.3%) procedures, 80% appearing during the first 72 hours. A mean response duration of 101 days over a mean overall survival of 141 days implies coverage of 70% of patient's life span.  [72]
A slower development of motor deficits before beginning of radiotherapy means a better therapeutic effect and a more favorable functional outcome after treatment. The prognosis is extraordinarily poor if severe deterioration of motor function occurs within 48 hours before radiotherapy.  [54]
A meta-analysis of the literature on Radiotherapy for Skeletal Metastases was done in 1996. It was based on 171 scientific articles involving over 13,000 patients, and states:   "Radiotherapy has been well documented as a method for alleviating pain, but the mechanisms underlying this effect are largely unknown. When used for pain palliation, radiotherapy achieves freedom from pain, or substantial alleviation of pain in nearly all cases, with few side effects. Half-body irradiation is effective in treating multiple metastatic sites and should be considered for use more frequently. However, this increases the requirements on equipment, dosimetry, and hospital beds. Systemic radiotherapy with radionuclides may be indicated for generalized skeletal pain. The role of radiotherapy in preventing or healing fractures is not fully evaluated. Optimum dose levels and fractionation schedules have not been established. Early radiotherapy for spinal cord compression may prevent symptoms from worsening, but the effects on existing paralysis are modest." [55] 
"Local radiotherapy plays an important and responsible role in the management of bone metastases according to the different treatment objectives in the sense of pain relief, remineralization and cord decompression. Radiotherapy schedules, aimed at the relief of pain, need to take into consideration life expectancy. Patients with a reduced life expectancy could have a good high chance of achieving pain relief with a single dose of 8 Gy. Patients with a solitary metastasis, patients with a longer life expectancy and patients with a pathological fracture should be treated with 'curative' irradiation doses, aimed at killing the maximum number of tumor cells. In addition to pain relief, remineralization is also an important treatment goal. Conventional radiotherapy with doses of 40-50 Gy resulted in pain relief in 70-100% and in remineralization in 60-80% of the patients. Remineralization could not be accelerated by short-course fractionation courses, but resulted in faster pain relief. Short-course fractionation schedules are not indicated as a 'standard' treatment in the vertebral column. Surgery is the treatment of choice for immediate cord decompression and stabilization of a pathological vertebral fracture. Radiotherapy alone could decrease neurological impairment and is suitable for patients with gradual onset and progression of symptoms, no spinal instability and lesions of the cauda equina." [134]
Intensity and severity of radiation-induced nausea and emesis depend on a number of factors including irradiation site, irradiation dose, treatment field (width and length), and age of the patients. Although less intensive than that induced by chemotherapy, during protracted courses of fractionated radiotherapy discomfort can be substantial. As early as 1953, Court-Brown [2] described characteristic symptoms after single-fraction radiotherapy as "acute irradiation syndrome": irradiation was followed by asymptomatic period of 40-90 minutes, after that the patient experienced an acute episode of emesis, usually without preceding nausea. After a period of relative stabilization, additional episodes of emesis occurred for six hours after irradiation, decreasing its intensity with time. Danjoux et al. [5] noted a higher incidence of radiation-induced emesis after the upper half-body irradiation (UHBI) than after the lower half-body irradiation (LHBI), lack of efficacy of antiemetics administered, and similar response to emesis after the lower or the upper half-body irradiation. These results suggested that critical area was the upper abdomen. [117]


For Pubmed search on Treatment of Bone Metastases with Radiotherapy:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20metastases%20radiotherapy%20treatment



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References:

29: Joensuu H, Tenhunen M.
      
        Physical and biological targeting of radiotherapy.
        Acta Oncol 1999;38 Suppl 13:75-83 
        PMID: 10612500 [PubMed - indexed for MEDLINE]


 	53: Koswig S, Buchali A, Bohmer D, Schlenger L, Budach V.  

      [Palliative radiotherapy of bone metastases. A retrospective analysis of 176 patients] [Article in German] 
      Strahlenther Onkol 1999 Oct;175(10):509-14
      PMID: 10554646 [PubMed - indexed for MEDLINE] 


54: Rades D, Blach M, Nerreter V, Bremer M, Karstens JH

      Metastatic spinal cord compression. Influence of time between onset of motoric deficits and start of irradiation on therapeutic effect. 
      Strahlenther Onkol 1999 Aug;175(8):378-81
      PMID: 10481768 [PubMed - indexed for MEDLINE]


55: Moller T.

Acta Oncol 1996;35 Suppl 7:125-36 
Skeletal metastases. 
PMID: 9154105 [PubMed - indexed for MEDLINE] 


72: Algara M, Valls A, Ruiz V, Jaume M, Lacruz M, Foro P.

[Half-body irradiation. Palliative efficacy and predictive factors of response in 78 procedures] [Article in Spanish] 
Med Clin (Barc) 1994 Jun 18;103(3):85-8
PMID: 8065222 [PubMed - indexed for MEDLINE]


78: Niewald M, Tkocz HJ, Abel U, Scheib T, Walter K, Nieder C, Schnabel K, Berberich W, Kubale R, Fuchs M.

Rapid course radiation therapy vs. more standard treatment: a randomized trial for bone metastases. 
Int J Radiat Oncol Biol Phys 1996 Dec 1;36(5):1085-9 
PMID: 8985030 [PubMed - indexed for MEDLINE] 

              80:  Hoegler D.

        Radiotherapy for palliation of symptoms in incurable cancer.
        Curr Probl Cancer 1997 May-Jun;21(3):129-83
        PMID: 9202888 [PubMed - indexed for MEDLINE] 


                	100: Quilty PM, Kirk D, Bolger JJ, Dearnaley DP, Lewington VJ, Mason MD, Reed 
        NS, Russell JM, Yardley J. 

        A comparison of the palliative effects of strontium-89 and external beam 
        radiotherapy in metastatic prostate cancer.
        Radiother Oncol 1994 Apr;31(1):33-40
        PMID: 7518932 [PubMed - indexed for MEDLINE] 

102: Micheletti E, Ippolito V, Tonoli S, Barbera F, Saccalani M. 

[Is radiotherapy still the first choice treatment in spinal metastases from breast cancer?] [Article in Italian] 
Radiol Med (Torino) 1996 Oct;92(4):470-4 
PMID: 9045251 [PubMed - indexed for MEDLINE] 

117: Jeremic B.   

[Ondansetron in the prevention of radiation-induced nausea and emesis in patients treated with single-fraction irradiation] [Article in Serbo-Croatian (Cyrillic)]   
Srp Arh Celok Lek 1996 May-Jun;124(5-6):131-4 
PMID: 9102832 [PubMed - indexed for MEDLINE]

      		125: Berk L. 

        Prospective trials for the radiotherapeutic treatment of bone 
        metastases. 
        Am J Hosp Palliat Care 1995 Jul-Aug;12(4):24-8  
        PMID: 7543272  indexed for MEDLINE

134: Eble MJ, Eckert W, Wannenmacher M 

[Value of local radiotherapy in treatment of osseous metastases, pathological fractures and spinal cord compression] [Article in German] 
Radiologe 1995 Jan;35(1):47-54 
PMID: 7534426 [PubMed - indexed for MEDLINE




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PERCUTANEOUS VERTEBROPLASTY

Vertebroplasty is an minimally invasive technique in which polymethyl methacrylate, a surgical cement, is injected into a vertebral body in order to provide increased strength and immediate and longterm pain relief in vertebrae weakened by bony lesions [metastases, multiple myeloma, aggressive hemangiomas, and osteoporotic fractures].   It is a newly developed technique, reported upon in several case series, including one with 187 subjects.  Percutaneous vertebroplasty can effect significant pain relief and increased mobility in over 70% of patients with osteolytic lesions.  Pain relief was apparent within two days, and persisted for at least months to years.  While it is probable that percutaneous vertebroplasty can also strengthen the vertebral bodies, it is unproven whether it can prevent further fractures in the treated vertebrae.  How long the effects last is not known, as longterm follow-up on cancer patients can be difficult to obtain. [all references below] Pain relief can occur despite insufficient lesion filling. [46]
"Percutaneous vertebroplasty has only recently been introduced as a treatment for osteolytic lesions and osteoporotic compression fractures of the vertebrae, but early results are promising. Up to 80 percent of patients with pain unresponsive to correct medical treatment experience a significant degree of pain relief, and few serious complications have been reported. However, relatively few patients have undergone this procedure, and there are no data from controlled clinical trials or from studies with long-term follow-up. At the present time this procedure is still in the investigational stages, but may be appropriate for patients with no other reasonable options for medical treatment." [45] Vertebroplasty is simple and effective but should be performed only in centers with neurosurgical and/or orthopedic surgery units because of the possibility of severe complications. [101] Complications of the procedure were rare. Clinically insignificant leakage of bone cement into the surrounding tissues does occur, and in a few cases the leakage of methacrylate caused neuralgia or pressure on spinal nerve roots. Also reported were several instances of pulmonary embolism. [45]
"Although criteria for use of percutaneous vertebroplasty are still under development, it will probably be considered appropriate treatment for patients with vertebral lesions resulting from osteolytic metastasis and myeloma, hemangioma, and painful osteoporotic compression fractures if the following criteria have been met:
o Severe debilitating pain or loss of mobility that cannot be relieved by correct medical therapy.
o Other causes of pain, such as herniated intervertebral disk have been ruled out by computed tomography or magnetic resonance imaging. 
o The affected vertebra has not been extensively destroyed and is at least one third of its original height. 
o Radiation therapy or concurrent surgical interventions, such as laminectomy, may also be required in patients with compression of the spinal cord due to ingrowth of a tumor. " [45]

"We report the pathological findings in cases of acrylic implants obtained by direct intratumoral injection of polymethyl-methacrylate (PMMA) and
N-butyl-cyano-acrylate (NBCA). Direct intratumoral injection of acrylic implants was performed for a variety of primary and secondary bone lesions. These types
of treatments have been used at our institution in the last 4 years for 40 vertebroplasty (PMMA) procedures and for nine bone lesions of other locations
(PMMA, NBCA). Postmortem histology became available for 1 case of PMMA and for 5 cases with NBCA intratumoral acrylic implants. The pathological findings
associated with PMMA and NBCA were evaluated and compared. PMMA exhibited a macroscopic and microscopic rim of tumor necrosis, 6 months after implantation.
NBCA exhibited compressive effects on the nearby tumor tissue, however, without signs of significant necrosis outside the acrylic tumor cast. Tumor captured
inside the acrylic cast showed extensive to near complete necrosis. Acrylic implants may lead to necrosis when injected directly in tumors. The necrotizing
effect may extend beyond the limits of an implant in the case of PMMA. Such an extended effect of PMMA, when compared with NBCA, may be due to the variable
toxicity of acrylic implants, including the different degrees of the exothermic reaction during polymerization." [1]

Johns Hopkins radiologists have reported on a series of 205 percutaneous vertebroplasty procedures carried out without pre-treatment venography, avoiding contrast-related complications. There were no major complications or cement leakage in this series.  Reported in: Murphy, Kieran J., American Journal of Neuroradiology, June 2002. Johns Hopkins.




For more information and access to PubMed/Medline abstracts:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=percutaneous%20vertebroplasty    

References for this section:

1: San Millan Ruiz D, Burkhardt K, Jean B, Muster M, Martin JB, Bouvier J, Fasel JH, Rufenacht DA, Kurt AM. Pathology findings with acrylic implants. Bone  1999 Aug;25(2 Suppl):85S-90S 
13: Ratliff J, Nguyen T, Heiss J.  Root and spinal cord compression from methylmethacrylate vertebroplasty, Spine 2001 Jul 1;26(13):E300-2
18: Peh WC, Gilula LA, Zeller D. Percutaneous vertebroplasty: a new technique for treatment of painful compression fractures.  Mo Med 2001 Mar;98(3):97-102 
41: Barr JD, Barr MS, Lemley TJ, McCann RM. Percutaneous vertebroplasty for pain relief and spinal stabilization.  Spine 2000 Apr 15;25(8):923-8
45: Levine SA, Perin LA, Hayes D, Hayes WS. An evidence-based evaluation of percutaneous vertebroplasty. Manag Care 2000 Mar;9(3):56-60, 63
46: Cotten A, Dewatre F, Cortet B, Assaker R, Leblond D, Duquesnoy B, Chastanet P, Clarisse J. Percutaneous vertebroplasty for osteolytic metastases and myeloma: effects of the percentage of lesion filling and the leakage of methyl methacrylate at clinical follow-up. Radiology 1996 Aug;200(2):525-30
94: Chiras J, Depriester C, Weill A, Sola-Martinez MT, et. al., Percutaneous vertebral surgery. Technics and indications. J Neuroradiol 1997 Jun;24(1):45-59
101: Cortet B, Cotten A, Boutry N, Dewatre F, et.al., Percutaneous vertebroplasty in patients with osteolytic metastases or multiple myeloma. Rev Rhum Engl Ed 1997 Mar;64(3):177-83   Comment in: Rev Rhum Engl Ed. 1997 Mar;64(3):145-6. 
113: Cotten A, Dewatre F, Cortet B, Assaker R, et.al.,  Percutaneous vertebroplasty for osteolytic metastases and myeloma: effects of the percentage of lesion filling and the leakage of methyl methacrylate at clinical follow-up. Radiology 1996 Aug;200(2):525-30 
118: Weill A, Chiras J, Simon JM, Rose M, Sola-Martinez T, Enkaoua E., Spinal metastases: indications for and results of percutaneous injection of acrylic surgical cement. Radiology 1996 Apr;199(1):241-7 




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PERCUTANEOUS INTRATUMORAL THERAPY 

Direct Injection of Cytotoxic Agents Into Tumors.

Below is a small selection of possible intratumoral injections, mostly dealing with direct chemical or biological cytotoxic agents, but not including the vaccines, dendritic cell vaccines, oncolytic viruses, gene therapy, and other fiendishly clever and sometimes even effective combinations.  

Intratumoral Alcohol Injections
"Reduction of pain without systematic side effects can be achieved in advanced stages of cancer with precise percutaneous techniques guided with computed tomography (CT). CT guidance allows exact needle positioning, reducing complications and improving the results. Regional analgesia ...is achieved by injection of alcohol or phenol and involves intentional destruction of a nerve or nerves to interrupt pathways for weeks or months. Percutaneous alcoholization of bone metastasis is indicated ... if conventional anticancer therapy is ineffective .... Bone packing with acrylic glue (methyl methacrylate) is used to prevent pathologic fractures and pain in patients with vertebral body tumors and acetabular metastasis." [42]
"Percutaneous injection of methylmethacrylate or ethanol may provide marked pain relief or bone strengthening in patients with malignant acetabular osteolyses who are unable to tolerate surgery. Injection of methylmethacrylate is usually indicated when osteolysis involves the weight-bearing part of the acetabulum ... in all other cases, ethanol injection is preferred. Ethanol and methylmethacrylate injections may be performed together if both weight-bearing and nonweight-bearing parts of the acetabulum are involved or extensive soft-tissue involvement is present. Moreover, these injections may be performed prior to radiation therapy, which complements their action due to similar but delayed effects on pain, or after radiation therapy that failed to relieve pain or in cases of local recurrence. Radiography and computed tomography must be performed prior to therapeutic percutaneous injection to assess the location and extent of the lytic process, the presence of cortical destruction or fracture, and the presence of soft-tissue involvement. Fever and transitory worsening in pain may occur secondary to inflammatory reaction in the hours following injection; however, these side effects usually resolve spontaneously within 1-3 days. The decision to perform therapeutic percutaneous injections should be made by a multidisciplinary team because the choice between this option and alternative methods of treatment depends on several factors including the location of the lesion, the local and general extent of the disease, the pain and functional disability experienced by the patient, and the patient's state of health and life expectancy." [17] Potential complications include vertebral collapse and infection. [16] Percutaneous intralesional alcohol injections are generally successful and safe. [16, 65, 69]
"Micro-invasive CT-guided intratumoral therapy (MIC-ITT) when used in combination with sympathectomy [destruction of the nerves near the tumor] can be an excellent palliative treatment with little impairment. ... Rapid as well as complete reduction of pain without systemic side effects can be achieved under local anesthesia in patients in advanced tumor stages by the direct instillation of 50 to 96% alcohol and/or a locally efficacious low toxic cytostatic (Mitoxantron) under CT guidance. CT enables not only exact puncture without injuring endangered structures but also a controlled application of medication. ..."[1]
"Repeated micro invasive intratumoral treatment was performed ... In all patients conventional therapeutic strategies had been exhausted or were no longer applicable ... Treatment was performed in combination with sympathetic neurolysis at the upper tumor pole in all cases."   Pain reduction of 75% or more was achieved in 80+% of patients.  For patients with bone and soft tissue mets, a reduction in tumor size was shown in 25%, no change in 62% and progression in 13%.  For those with vertebral metastases, a reduction in tumor size (<50%) in 18%, no change in tumor size in 66%, and progression in 16% of the patients. Furthermore, necrotic zones could be shown in 27%, and recalcification of tumor area in 35%.  "All treatments were free of complications." [1]
"On the whole the results of therapeutic approach are encouraging. In particular one aspect should be mentioned: with respect to palliative treatment the reduction of tumor size is not crucial. The decisive factor is the improvement in quality of life of the patient using an intervention which impairs the patient only minimally. Furthermore this micro invasive approach should always involve the combination of local tumor treatment with treatment or lysis of the autonomic sympathetic nervous system in tumor vicinity." [1]

Intratumoral Chemotherapy Injections
# An aggressive, bone-destructive metastasis of squamous cell carcinoma was injected intratumorally with cisplatin, followed by radiotherapy, for relief of symptoms. [19] 
# An endoscopic intratumoral injection of 5-fluorouracil was given into a gastric cancer primary, along with systemic chemotherapy, which brought about a partial response. [18]
# A case of a gigantic cystic craniopharyngioma was treated with intratumoral injections of bleomycin. The mass had eroded the skull base and extended to the sphenoid bone. A total of eight intratumoral injections through an Ommaya reservoir were given. Six months after treatment, there was complete regression of the lesion and improvement in both visual and endocrinological symptomatology. [24]
# A Merkel cell carcinoma of the mandibular area was treated successfully by direct intratumoral administration of recombinant human tumor necrosis factor. [29]


Intratumoral Radioisotope Injections

Studies of biodistribution and therapeutic action were carried out on the effect of a single intratumoral dose of chromic phosphate, carrying the radioisotope 32P, in large particle size, for the treatment of solid tumors. Therapeutic action showed a 50% reduction in tumor size.
Biodistribution studies showed that approximately 50% remains in the tumor, 10% [+/- 5%] in the liver, 30% eliminated in feces and 7% in urine.  Large colloidal particles of chromic 32-P is not safe enough for intratumoral injection, since it is mobilized from the injection site and delivers a high dose to the entire organism.  [23]

"Human macroaggregated albumin (MAA), ... labeled with technetium-99m (99mTc) ... was directly labeled with yttrium-90 (90Y)-acetate. This study evaluated whether 90Y-MAA could be potential radiotherapeutic agent for regional radiotherapy against malignant tumors. ... Following the intratumoral administration of 90Y-MAA, ... in nude mice bearing human neuroblastoma ... More than 93% of the radioactivity of the injected dose was found on the subcutaneous tumor over 168 h. ... A slight increase in radioactivity was noted in the liver, kidneys, and spleen over the 168-h periods. In conclusion, 90Y-MAA may be a potential agent for regional radiotherapy ... because of the sufficient persistence in the tumor following an intratumoral administration."[20]


RadioImmunotherapy

This occurs when the radioisotope is attached to an antibody that will attach itself to either the cancer tumor itself, or nearby tissue, and not to normal tissue in the rest of the body.  This will result in a high local dose to cancer tumors, and less radiation exposure to normal tissue.  In a pilot study, Yttrium-90 was attached [conjugated] to a monoclonal antibody [this is an antibody to one specific target] to part of a cancer cell [in this case glioma].   This 'radio-immuno conjugate' was injected into recurrent tumors.  There was prolonged retention of the isotope by the tumor cavity, with low activity in the bloodstream.  Doses and dose rates to the tumor were very high compared to normal tissue doses. [25]


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References:
            
1: Wien Med Wochenschr 1993;143(12):312-21    
[Microinvasive CT-controlled tumor therapy of soft tissue and skeletal metastases][Article in German]
Gronemeyer DH, Seibel RM.
Institut fur Diagnostische und Interventionelle Radiologie, Universitat Witten/Herdecke, Mulheim a.d. Ruhr, Deutschland.
PMID: 7692678 [PubMed - indexed for MEDLINE]
        
        
16: AJNR Am J Neuroradiol 1999 Jun-Jul;20(6):1091-6
Comment in: AJNR Am J Neuroradiol. 1999 Jun-Jul;20(6):959-60. 
Alcohol ablation of symptomatic vertebral hemangiomas. 
Goyal M, Mishra NK, Sharma A, Gaikwad SB, Mohanty BK, Sharma S. 
Department of Neuroradiology, All India Institute of Medical Sciences, New Delhi. 
PMID: 10445448 [PubMed - indexed for MEDLINE] 

17: Radiographics 1999 May-Jun;19(3):647-53 
Therapeutic percutaneous injections in the treatment of malignant acetabular osteolyses. 
Cotten A, Demondion X, Boutry N, Cortet B, Chastanet P, Duquesnoy B, Leblond D. 
Department of Skeletal Radiology, Hopital Roger Salengro-CHRU de Lille, France. 
PMID: 10336194 [PubMed - indexed for MEDLINE]

18: Gan To Kagaku Ryoho  1998 Jan;25(1):121-4 
[A case of advanced gastric cancer with multiple bone metastasis successfully treated by both methotrexate and 5-fluorouracil sequential therapy, and endoscopic intratumoral injection of 5-fluorouracil] [Article in Japanese]
Sasahara K, Uchida Y, Kamei M, Matsuda K, Kawabata H, Nishioka M.
Third Dept. of Internal Medicine, Kagawa Medical University.
PMID: 9464338 [PubMed - indexed for MEDLINE]

19: Isr J Med Sci  1997 Oct;33(10):674-6 
Squamous cell carcinoma of the cervix with psoas abscess-like metastasis in an HIV-negative patient.
Bar-Dayan Y, Fishman A, Levi Z, Rachmani R.
Department of Medicine, Meir Hospital, Kfar-Saba, Sackler Faculty of Medicine,Tel Aviv University, Israel.
PMID: 9397142 [PubMed - indexed for MEDLINE]

20: Nucl Med Biol  1997 Jul;24(5):465-9 
Preparation of yttrium-90-labeled human macroaggregated albumin for regional radiotherapy.
Watanabe N, Oriuchi N, Igarashi H, Higuchi T, Yukihiro M, Fukushima Y, Tomiyoshi K, Hirano T, Inoue T, Endo K.
Department of Nuclear Medicine, Gunma University, School of Medicine, Japan.
PMID: 9290084 [PubMed - indexed for MEDLINE]

23: Acta Physiol Pharmacol Ther Latinoam  1996;46(2):103-10 
Great particles [32P]chromic phosphate for treatment of solid tumors.
Zubillaga MB, Boccio JR, Nicolini JO, Ughetti R, Lanari E, Caro RA.
Radioisotope Laboratory, Facultad de Farmacia y Bioquimica, Buenos Aires, Argentina. postmast@radioqui.ff)b.uba.ar
PMID: 8998364 [PubMed - indexed for MEDLINE]

24: J Neurosurg  1996 Jan;84(1):124-6 
Use of bleomycin in intratumoral chemotherapy for cystic craniopharyngioma. Case report.
Cavalheiro S, Sparapani FV, Franco JO, da Silva MC, Braga FM.
Neurosurgery Department, Sao Paulo Federal University, Brazil.
PMID: 8613819 [PubMed - indexed for MEDLINE]

25: Hopkins K, Chandler C, Bullimore J, Sandeman D, Coakham H, Kemshead JT.A pilot study of the treatment of patients with recurrent malignant gliomas with intratumoral yttrium-90 radioimmunoconjugates. Radiother Oncol  1995 Feb;34(2):121-31 

29: Arch Dermatol  1989 Aug;125(8):1093-5 
Merkel cell carcinoma. A successful treatment with tumor necrosis factor.
Ito Y, Kawamura K, Miura T, Ueda K, Onodera H, Takahashi H, Horikoshi T,
Sugiyama S, Takahashi M.
Department of Dermatology, Sapporo Medical College, Japan.
PMID: 2757406 [PubMed - indexed for MEDLINE]

42: Radiographics 1996 Nov;16(6):1289-304; discussion 1304-6
Interventional radiologic procedures with CT guidance in cancer pain management. 
Gangi A, Dietemann JL, Schultz A, Mortazavi R, Jeung MY, Roy C. 
Department of Radiology B, University Hospital of Strasbourg, France. 
PMID: 8946536 [PubMed - indexed for MEDLINE]

65: Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1995 Mar;162(3):232-5
[The percutaneous CT-guided treatment of osteoid osteomas: a combined procedure with a biopsy drill and subsequent ethanol injection] [Article in German] 
Adam G, Keulers P, Vorwerk D, Heller KD, Fuzesi L, Gunther RW. 
Klinik fur Radiologische Diagnostik, RWTH Aachen. 
PMID: 7718779 [PubMed - indexed for MEDLINE] 

69: J Comput Assist Tomogr 1994 Nov-Dec;18(6):932-5
Injection of alcohol into bone metastases under CT guidance. 
Gangi A, Kastler B, Klinkert A, Dietemann JL. 
Department of Radiology B, University Hospital of Strasbourg, France. 
PMID: 7962803 [PubMed - indexed for MEDLINE]



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Hyperthermia


The discussion of hyperthermia to treat bone metastases is on the Hyperthermia page.



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Other SYSTEMIC ANTICANCER TREATMENT


CHEMOTHERAPY

With leiomyosarcoma, Chemotherapy is best saved for inoperable metastases that are potentially life threatening, such as lung, liver, or brain.  In these situations, selected use of high-dose chemotherapy with bone marrow support has increased survival time. 

Therefore, one would not recommend using chemotherapy for LMS bone metastases.  The major problems from bone metastases, skeletal/vertebral instability, pain, hypercalcemia...can all be managed effectively with surgical, radiological, and/or other drug interventions.  Chemotherapy is not a necessity.  And you will want to preserve the Chemotherapy options you do have for life-threatening situations, where many options do not abound.

For further information see the Chemotherapy webpage.

HORMONES
The aromatase inhibitors seem to be more effective and better tolerated than the older agents, megestrol acetate and aminoglutethimide.  Whether estrogen receptor positive LMS will respond to their use is not known.  Certainly use of the aromatase inhibitors would increase the tendency toward osteoporosis.
Androgen blockage [LHRH + antiandrogen] has been useful in prostate cancer, but it is unknown whether androgen hormone receptor positive LMS would respond to this. 
For further information, see the Hormone webpage.


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Compiled/written by doctordee
With thanks to Lynette NZ and Laura NV
June 2002




 

 


