|Bone: Intratumoral Injections and Some Systemic Options
written and compiled by doctordee
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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. [see references.] Pain relief can occur despite insufficient lesion filling. 
"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." 
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.  Complications of the procedure were rare. Clinically insignificant leakage of bone cement into the surrounding tissues does occur, but in a few cases the leakage of methacrylate caused neuralgia or pressure on spinal nerve roots. Also reported were several instances of pulmonary embolism. 
"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." 
"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." 
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.]
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|Direct Injections Into Tumors|
Percutaneous Intratumoral Injection -- 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 Injection|
"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." 
"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."  Potential complications include vertebral collapse and infection.  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. ..."
"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." 
"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." 
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|Intratumoral Chemotherapy Injection|
# An aggressive, bone-destructive metastasis of squamous cell carcinoma was injected intratumorally with cisplatin, followed by radiotherapy, for relief of symptoms. 
# An endoscopic intratumoral injection of 5-fluorouracil was given into a gastric cancer primary, along with systemic chemotherapy, which brought about a partial response. 
# 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. 
# A Merkel cell carcinoma of the mandibular area was treated successfully by direct intratumoral administration of recombinant human tumor necrosis factor. 
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|Intratumoral Radioisotope Injection|
One of the difficulties of direct injection of radioisotope into a tumor, is the absorption of the radioisotope from the site and its distribution to other body tissues.
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 are not safe enough for intratumoral injection, since it is mobilized from the injection site and delivers a high dose to the entire organism. 
"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."
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RadioImmunotherapy is a process by which the radioisotope is attached to an antibody to specific tissue so it doesn't irradiate non-target tissue. The radioisotope-antibody attaches itself to either the cancer tumor 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. 
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Other Systemic Treatment
With leiomyosarcoma, chemotherapy is best saved for neoadjuvant treatment, or for inoperable metastases that are potentially life threatening, such as lung, liver, or brain. In these situations, judicious use of selected chemotherapy with bone marrow support has increased survival time.
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 other options may not abound.
For further information General Approach to Treatment of Leiomyosarcoma
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 some of the aromatase inhibitors would increase the tendency toward osteoporosis. Bone metastases grow sooner and better in osteoporotic bone.
Androgen blockage [LHRH + antiandrogen] has been useful in prostate cancer, but it is unknown whether androgen hormone receptor positive LMS would respond to this. As well as the possible osteoporotic effect on bone mass.
For further information Hormones and LMS
compiled/written by doctordee
with thanks to Lynette and Laura
updated December 2003
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