Click on the link below for our quick reference guide on managing Osteosarcoma.

Managing Osteosarcoma

Pain is the unpleasant sensation that develops with the stimulation of specialized sensory nerve endings, called pain receptors. Pain most often develops from damage, irritation or inflammation of tissues or structures of the body. Pain is a protective mechanism. It causes the animal to react and to move away from the source of the stimulus.

Manifestations of pain are highly variable in animals. Some signs are obviously related to pain, while others are more subtle. The individual personality of the animal and its tolerance for pain also affect the clinical manifestations of pain. Animals in pain often present with a wide variety of signs. Some signs that are associated with pain include the following:

• altered behavior-quieter than normal, avoidance of other animals or people, hiding, aggressive behavior, fear biting, mental dullness and depression, agitation, restlessness, pacing.
• Altered movement or gait-lameness, reluctance to move, reluctance to get up, wobbliness, abnormal carriage or use of one or more legs, stiffness.
• Vocalization-growling, howling, yipping, moaning.
• Decreased or lack of appetite (anorexia).
• Increased respiratory rate or increased heart rate

The purpose of pain management is not only to decrease the discomfort your dog feels, but to provide maintenance of quality of life. Pain management is directed at the source of the pain to control it, or used to change how the dog perceives the pain. There are both medicinal and non-medicinal methods of achieving pain control, and often times both modalities are combined in some way to attain the best result possible.

Non-Medicinal Modalities

Amputation

Amputation provides definitive pain relief. Amputation will restore quality of life, and in many cases, actually extend if, since dogs with severe pain from bone cancer are often euthanized at an early stage to end their suffering. Management of post operative pain can be successfully achieved with several of the modalities described herein.

Palliative Radiation

Palliative radiation is prescribed for those dogs who cannot undergo amputation. It can heal micro-fractures and decrease inflammation.

Debulking Surgery

In some cases, debulking surgery might be indicated to relieve pressure on vital structures and decrease tumor size. It is not a common procedure for bone cancer, but can be an option for soft tissue or joint tumors. This is done only for palliative pain relief. Neurostimulation

The use of transcutaneous electrical nerve stimulation has been tried as a palliative approach to pain management. Similar to techniques used in humans, this technique involves the use of non-painful impulses that block the transmission of painful impulses along the nerves.

Acupuncture & Chiropractic Medicine

Also considered a palliative technique, and often combined with other modalities. There are many veterinarians that are certified in acupuncture and chiropractic care. www.animalchiropractic.org

Medicinal Modalities

Studies have shown that the continuous use of pain medications is more effective than using them "as needed". Chronic pain is best managed with stable blood levels of the medication, avoiding a "see-saw" effect when the medicines are only given "as needed". It is particularly difficult to assess when a dog actually needs the medication, since many of them are stoic and may not exhibit classic signs of pain on a regular basis (limping, decreased appetite, panting, decrease in mobility, etc). Administering the medications on a regular schedule may also allow for decrease in dosage, since the pain level is also decreased.

Non-Narcotic Pain Medications

Non Steroidal Anti-inflammatory Drugs

These include aspirin and other anti-inflammatory drugs, known as NSAIDs (non steroidal anti-inflammatory drugs). The most commonly used drugs in the NSAID category are carboprofen (Rimadyl), etodolac, phenylbutazone, aspirin, deracoxib (Deramaxx), piroxicam, and meloxicam (Metacam), but others are available as well. Both the meloxicam and the carboprofen are available in injectable form as well.

NSAIDs work by inhibiting an enzyme called "cyclooxygenase", which controls the amount of inflammatory substances known as prostaglandins. They can be used alone or in conjunction with narcotic medication to increase their effectiveness.

Gastrointestinal (GI) irritation in varying degrees is a common side effect with these medications. To minimize this side effect, stomach-protecting medications are often prescribed in conjunction with the NSAIDs. The most commonly used medications for this purpose are misoprostol and sucralfate. Other medications such as ranitidine (Pepcid) or cimetidine (Tagamet) have been used but are not as effective in preventing the GI side effects. These medicines are more effective if used once the damage to the GI tract has occurred. Symptoms can range from nausea and decreased appetite to bleeding in the GI tract. Dark, tarry or bloody stools, or vomiting blood or "coffee ground" material (indicating digested blood in the GI tract) are signs of bleeding in the GI tract and must be reported to the veterinarian immediately.

NSAIDs can also affect kidney and liver function, and should not be used in dogs with decreased liver or kidney function, or prior history of liver or kidney disease. Caution is recommended if NSAIDs are being prescribed along with other medications that may affect the liver or kidneys. This should be discussed with your veterinarian. Baseline kidney and liver function tests should be done before the medication is started, and should be repeated periodically while the dog is taking the medicine.

NSAIDs may affect clotting function by decreasing the way platelets stick to each other (this is known as platelet aggregation). Platelets are little blood cells that stick together to start formation of a blood clot, whenever there is tissue damage. This effect is reversible with NSAIDs and only lasts while the drug is in the system, however it is irreversible when aspirin is used, and will last for the life of the platelet cell. This effect of the NSAIDs may be exacerbated by the use of herbal anti-inflammatory medications or aspirin, and are not recommended to be used together. If your dog is taking any herbal medications, please consult with your primary or holistic veterinarian before combining these medicines.

In addition, several of the NSAIDs listed here are also used for their anti-angiogenic properties, which serves as an adjuvant in the management of cancer. "Anti-angiogenic" means that these medications may decrease the formation of new blood vessels in the cancer tissue, which in turn decreases the nutrients and rate of growth in the tumor.

Tramadol

Tramadol is a centrally acting analgesic that stimulates an opioid receptor in the brain, which provides pain relief. It is not a narcotic medication, and does not cause addiction. It has become a good addition to the pain management protocols that use NSAIDs. It has 1/10 the analgesic potency of morphine, and should not be prescribed in conjunction with morphine or fentanyl, because it will likely decrease the efficacy of those drugs. The brand name of tramadol is Ultram. It does not usually cause sedation but this is a possibility with higher doses or very sensitive dogs. T will rarely cause constipation and nausea. It should not be given to dogs who take Depreny for Cushings disease, dogs with cognitive disorders or dogs taking certain anti-depressant medications, including serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOs). It is often used with NSAIDs and can be given to dogs who take steroids.

In human medicine there is a medication called Ultracet which is a combination of tramadol with acetaminophen-this should not be given to dogs.

Narcotic Pain Medications

Butorphanol

Butorphanol is an opioid analgesic. In addition to its use for pain management, it is also used to induce sedation and to suppress coughing. It can be administered either by injection (Torbugesic) or by pills (Torbutrol). It should be used with caution in animals with an under active thyroid, kidney impairment, elderly or severe illness, and should be avoided in animals with head trauma or nervous system dysfunction. It is a short acting drug and is often administered several times a day.

Butorphanol may interact with other medications. Consult with your veterinarian to determine if other drugs your pet is receiving tranquilizers, barbiturates and antihistamines. The most significant side effects associated with butorphanol are sedation, lack of appetite and diarrhea.

Buprenorphine

Buprenorphine is a synthetic opiate that binds to opiate receptors and stimulates them. It is similar to one of the original opiates, morphine. It is 30 times as potent as morphine and does not result in the negative gastrointestinal effects typically associated with morphine. Although it is not approved for veterinary used, it can legally be prescribed for use as an "extra-label" drug. It is given via injection and its effect usually lasts 8 hours.

While generally safe and effective when prescribed by a veterinarian, buprenorphine can cause side effects, the most common one being sedation. It should be avoided in animals with kidney disease, underactive thyroid gland and Addison's disease. It should be used with caution in animals with head trauma, compromised cardiovascular function and geriatric or severely debilitated animals. Since it is metabolized by the liver, buprenorphine should be used with caution in animals with liver disease. It may interact with other medications, such as certain antihistamines, tranquilizers, barbiturates and monoamine oxidase inhibitors. As with other opiates, in rare cases it can slow down breathing.

Morphine

Morphine is a well-known drug used to alleviate pain. It can affect various body functions: dogs may vomit after administration and will usually defecate immediately following injection. Panting may also occur. If necessary, the effects of the drug can be reversed with administration of naloxone. Although it is not approved for veterinary used, it can legally be prescribed for use as an "extra-label" drug. While its most common use is to treat pain, it can also be used to reduce coughing and diarrhea in dogs. Morphine should be used with extreme caution in cats. The enzyme that helps metabolize morphine is deficient in cats, which results in potential brain and spinal cord stimulation.

Morphine should be avoided in animals with liver disease, kidney disease, underactive thyroid gland, hyperactivity, toxin-induced diarrhea, victims of scorpion bites or Addison's disease. It should be used with extreme caution in animals with head trauma, acute abdominal conditions and lung disease. It may interact with other medications, such as antihistamines, anesthetics, tranquilizers and monamine oxidase inhibitors.

Adverse effects associated with morphine include nausea, vomiting, slowed intestinal movement, constipation, restlessness, low blood pressure, slowed heart rate, slowed breathing, behavior changes and seizures. The most profound adverse effects associated with morphine are suppression of breathing and sedation.

Morphine can be administered by injection, oral tablets, oral solution and rectal suppositories.

Fentanyl

Fentanyl is a very potent opiate narcotic analgesic. It is 100 times as potent as morphine. The injectable form is used to sedate and tranquilize. The fentanyl patches (Duragesic) are used for pain control. Doses of the patch range from 25 to 100 micrograms (not milligrams). The dose of fentanyl is based on the weight of the animal:

• animals under 20 pounds (10 kg) receive 25 micrograms
• animals 20 to 40 pounds (10 to 20 kg) receive 50 micrograms
• animals 40 to 60 pounds (20 to 30 kg) receive 75 micrograms
• animals over 60 pounds (30 kg) receive 100 micrograms

For very small animals, 1/2 of the patch can be used. The patch should NEVER be cut. Placing tape to cover 1/2 of the patch is sufficient to reduce the dose. Although it is not approved for veterinary used, it can legally be prescribed for use as an "extra-label" drug.

Other nervous system depressant drugs and sedatives must be used with caution when combined with fentanyl. As with most opiates, this drug can cause breathing activity to diminish. This can be a problem, especially if there is lung disease already present. Care must be taken when treating an animal with a fever or if using direct heat to the area. Increased body temperature can increase the amount of fentanyl absorbed and lead to overdosing. Fentanyl may interact with other medications, such as antihistamines, tranquilizers, barbiturates, other narcotics and monoamine oxidase inhibitors.

The patch should be applied to an area of the dog's body that cannot be reached by licking or chewing. The pet must be prevented from eating a fentanyl patch. An overdose may result, leading to excessive sedation and depression. The area should be shaved or the hair clipped very close to the skin. Avoid areas that are irritated or otherwise damaged. The skin should be cleansed with alcohol and thoroughly dried before applying the patch. Once applied, the patch should then be held in place for 5 minutes, to allow body heat to activate the adhesive substance. It can be held in place with a bandage if necessary. A skin rash may develop at the site of the patch. The patch is only effective for three days and, if pain persists, the patch should be replaced following strict instructions by a veterinarian. Skin sites should be rotated to minimize accumulation in subcutaneous depots, which could result in erratic blood levels.

The more common side effects include sleepiness, constipation, dizziness and nausea. Less common side effects include difficulty breathing, confusion, tremors, vomiting, decreased breathing rate, and lack of coordination. Rare side effects include hiccups and hallucinations.

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Palliative therapy is "comfort care"-it is intended to maintain a good quality of life for patients in whom long-term cancer control is not possible. Palliative radiation therapy (PRT) can be used to control symptoms that cannot be relieved surgically or by other means...in the case of osteosarcoma, it may be indicated for patients who are not candidates for amputation. It might also be indicated for treatment of painful bone metastases (spread to other bones) even after amputation, under specific circumstances. The goal of PRT is to provide relief of symptoms, not to cure the cancer.

Ask your radiation oncologist if a bone scan is necessary before starting the PRT, to look for other bone areas that might be involved, even without symptoms. You should also ask about the possibility of combining the PRT with chemotherapy if your dog is not a candidate for amputation.

PRT is particularly useful to alleviate pain from osteosarcoma (bone cancer). It is usually combined with pain medications. Approximately 65% of patients will show a moderate to significant improvement in symptoms, and the effects can last for several weeks to several months. It may begin to have effect several days after the first treatment, or it may take a few weeks before improvement is noted.

PRT delivers radiation over a period of time. The treatment plan should be discussed with the radiation oncologist, regarding frequency and interval between treatments. The procedure requires anesthesia because the dog must remain perfectly still, and the dog should not eat on the day of the procedure.

Aside from the potential side effects of anesthesia, side effects from PRT are usually limited to the area involved by radiation. The side effects usually begin several weeks after PRT has started, and can last several weeks. The skin area that receives PRT will be pink or even red, with loss of hair and possibly some flaking or dryness of the skin. This is known as "radiation dermatitis". In some cases it will look like a severe sunburn or even a blistering rash. Topical medications prescribed by the veterinarian may help, and preventing the dog from licking, rubbing or scratching the treated area will also be of benefit. Eventually the skin will become very dark, even black and there may be some hair re-growth. Long term side effects such as risk of non-healing wounds usually occur after a year, but are much less common due to the life expectancy of most dogs with osteosarcoma treated with PRT.

It is unusual for dogs to develop nausea or vomiting from PRT, unless part of the abdomen is involved in the radiation field. If PRT is being recommended for bones involving the head/skull, there can be side effects involving the eyes or mucous membranes and salivary glands of the mouth. These side effects should be discussed in detail with your radiation oncologist.

Please note: PRT cannot be used in conjunction with artemisinin, an herb that is frequently used in the management of osteosarcoma. If your dog is currently taking artemisinin and you are considering PRT, the artemisinin must be stopped for at least several weeks.

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The aim of the limb sparing procedure is to save the leg instead of performing an amputation. The goal is to provide a functional, pain-free leg while not jeopardizing the chances of survival. Medical indications for limb sparing include previous amputation of another limb, severe concurrent osteoarthritis, or neurologic disease. For example, in over 300 limb sparing surgeries performed at Colorado State University, 85% of the patients have experienced good to excellent function. The average survival after limb sparing and chemotherapy is 50% or better at 1 year, which is equal to the survival of dogs receiving amputation and chemotherapy.

It is extremely important to determine if the dog is a candidate for limb sparing procedure. The pretreatment evaluation should include a CBC, urinalysis, biochemical profile (paying particular emphasis to the serum alkaline phosphatase, which can have negative prognostic implications), chest x-ray, and a bone survey or nuclear bone scan. 10-15% of patients will have multiple lesions at the time of diagnosis which carries a worse prognosis. Pathologic fractures are a relative contraindication due to soft tissue contamination via hemorrhage and hematoma. If there is evidence of spread of the cancer, limb sparing surgery is not an option.

Limb sparing surgery is most successful for dogs with primary bone tumors in the distal radius and ulna. Dogs with osteosarcoma of the front leg at the "wrist" (distal radius or ulna) with no evidence of cancer spread to other sites in the body may be candidates for limb sparing. Candidates for limb sparing surgery include dogs with tumors confined to the bone, minimal extension into adjacent soft tissue, and involvement of less than 50% of the bone length. The extent of bone involvement is most accurately determined using CT scans. Other locations are often associated with higher rate of complications and poor postoperative limb function.

To see if your dog is eligible for a limb sparing, several tests will be done, such as blood tests, x-rays, bone scan, ultrasound or computed tomography scans to look for evidence of cancer in other parts of the body. If the tumor is found only in the leg, then limb sparing may be an option. If limb sparing is contemplated, the biopsy technique and position should be carefully planned. Preoperative treatment with cisplatin (chemotherapy) and radiation makes the surgery easier and decreases the chance of recurrence. The optimal dose, route of delivery, and timing of cisplatin relative to the radiation is still unclear. However, this adds significantly to the cost of treatment and is not commonly used.

In limb sparing surgery, the tumor and the affected piece of bone are removed. The space created after the tumor removal is usually filled with an allograft, autograft, or metal implant. An allograft is sterile, frozen bone that has been stored in a bone bank and harvested from dogs that died of other causes. An autograft involves surgically separating the tumor site from the leg and then treating it with a high dose of radiation to "kill" the tumor. Once the allograft, autograft or metal implant is inserted into the defect, a stainless steel plate is applied, and the wrist is fused. The plate is not removed unless it causes problems. Although the wrist can no longer bend, this is not painful and dogs can use the leg almost normally as they compensate by increasing elbow and shoulder motion. In some cases, dogs with tumors of the ulna may not require an allograft or fusion of the wrist.

The surgery itself takes about 2 to 3 hours, but generally anesthesia may last 4 to 5 hours. Dogs stay in the hospital for 2-4 days after surgery. After surgery, a soft padded bandage (usually not a cast or splint) will be applied to the leg, to prevent licking of the wound. The bandages may be changed every few days. Elizabethan collars should be used for dogs who are adamant about licking the bandages. Weight-bearing and range-of-motion exercises can be started immediately after surgery but should be restricted to leashed walks for the first 4 weeks. Exercise is important to prevent contractures of the toes and to decrease swelling in the limb. Most dogs resume normal activities within one to two months after surgery. Medications that are routinely used after surgery include antibiotics and pain medications.

Chemotherapy is usually be started 2 weeks after surgery, with drugs such as cisplatin, carboplatin, or doxorubicin. Four to six treatments, 3 weeks apart, may be recommended depending on the drugs used. This is necessary to try and prevent metastatic cancer. If no chemotherapy is given, there is only a 10% chance that your dog will be alive one year after surgery. However, if chemotherapy is given, the one-year survival probability is 50% and the 2-year survival is 30%.

The most commonly reported complications with limb-sparing surgery are implant failure, local tumor recurrence, and infection. Implant failure occurs in approximately 10% of cases. The use of an orthopedic cement known as methylmethacrylate reduces the incidence of screw loosening, implant failure, and fracture. Local tumor recurrence is caused by incomplete resection or, more commonly, residual neoplastic cells in the soft tissue adjacent to the tumor capsule after marginal resection of the primary bone tumor.

Infection is the most significant postoperative complication encountered with limb-sparing surgery. The cause of infection is unknown, although the extensive resection of soft tissues, poor soft tissue coverage, use of orthopedic implants, and administration of local and systemic chemotherapy are thought to contribute. The use of antibiotic impregnated cement has decreased the risk of infection, which was about 40%. Initially, infections are treated with antibiotics, saline lavages, and wet-to-dry bandages. If the infection is unresponsive or recurs despite treatment, antibiotic-impregnated methylmethacrylate beads can be surgically implanted adjacent to the infected bone. Amputation of the limb may be necessary as a salvage procedure in dogs with uncontrollable infection.

There is generally less than a 20% chance that the tumor will regrow in the leg (local recurrence). Insertion of an absorbable chemotherapy (cisplatin) sponge into the wound at the time of surgery decreases the chances of local recurrence. The chemotherapy sponge is a biodegradable polymer, which slowly breaks down in the body, releasing cisplatin in very high concentrations to the tissues in the surgery site. Only a low dose of cisplatin gets into the blood stream. This high local dose of cisplatin will kill cancer cells remaining in the leg after limb sparing surgery. This material does not usually affect healing, is well tolerated and does not cause noticeable side effects.

Periodic physical examinations as well as chest and leg x-rays will be necessary to follow the dog's progress. Unless covered by a funded study, the cost of a limb spare surgery ranges from $3,500-$5,000, depending on the amount of the work-up already done by your veterinarian. Follow-up chemotherapy can range from $1,000-$4,000, depending on the drugs chosen. The total cost for one year of treatment and follow-up can be as high as $10,000. It is possible that your dog may be eligible for certain trials investigating various aspects of limb sparing and the treatment of OSA.

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BISPHOSPHONATES-Please discuss all information with your vet

In humans, bisphosphonates are used to treat osteoporosis and to help lower high calcium levels due to certain types of cancer. They are also used to stabilize bones that are at risk for fracture from metastatic cancer or from multiple myeloma. The most common bisphosphonates are oral alendronate (Fosamax), oral risedronate (Actonel) and intravenous pamidronate (Aredia).

In dogs, bisphosphonates are used as adjuvant therapy for the management of osteosarcoma. They inhibit osteoclast cells which are responsible for bone breakdown. This inhibition gives the osteoblast cells (bone builders) a chance to work without interference, strengthening the existing bone and creating new bone. Increasing the strength of the existing bone helps to decrease the risk of fractures, and stronger bone is less painful.

When studied in the laboratory, bisphosphonates also have a direct toxic effect on bone cancer cells, contributing to their death. There is also evidence that by inhibiting the growth of new blood vessels within the cancer, they also inhibit cancer growth.

The most commonly used bisphosphonate in the treatment of bone cancer in dogs is the intravenous pamidronate. It is used often in conjunction with radiation therapy, given in several cycles every few weeks. Recent studies have also shown that the oral alendronate may have a similar role in the stabilization of cancerous bone, by increasing the formation of healthy bone and decreasing the risk of fracture. There can be significant improvement in pain when bisphosphonates are used. Ongoing research suggests that bisphosphonates may also have a role in the inhibition of metastatic bone cancer cells, by their direct toxic effect. The indication for their use after amputation and chemotherapy remains to be defined, but there is promising laboratory evidence to support this theory.

The major side effects of bisphosphonates include gastrointestinal toxicity (nausea, vomiting, diarrhea or change in appetite) and kidney toxicity. Urine tests and electrolyte and kidney blood tests should be checked prior to institution of therapy and periodically during treatment, particularly if other medications such as anti-inflammatories are being prescribed. Intravenous pamidronate is usually administered over several hours. When the oral alendronate is prescribed, it is usually administered in the morning as a single dose, followed by a small meal 30 minutes later.

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Metronomic:low dose, continuous timed intervals

The metronomic protocol can be used at all stages. No amputation, maintenance protocol (with or without chemo), and the onset of lung mets. Individual components can be given as stand-alone.

Major components:

• Anti-inflammation
• Oral chemotherapy agent
• Anti-angiogenesis
• Bisphosphonates

Angiogenesis Foundation

The Metronomic Protocol (more common)

• Piroxicam, Deramaxx, Metacam, Rimadyl (NSAIDs)
• Cyclophosphamide
• Doxycycline
• Fosamax

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DOXYCYCLINE-Please discuss all information with your vet

Doxycycline is used as part of the metronomic protocol in conjunction with cyclophosphamide and anti-inflammatory medicines such as piroxicam or carprofen (Rimadyl)for the management of canine osteosarcoma.

The principles behind its use include:

• its ability to suppress matrix metalloproteinases (MMPs) which are enzyme systems that stimulate cancer cells and formation of metastatic deposits. Increased MMP activity has been correlated with the metastatic potential of many canine cancers, including osteosarcoma, melanoma, hemangiosarcoma and lymphoma.
• doxycycline can inhibit tumor cell proliferation by inducing programmed tumor cell death (known as apoptosis)
• may help to suppress the formation of new blood vessels within the tumor (known as anti-angiogenic effect).
• doxycycline is also highly osteotropic (greater affinity for bone) and thus may have greater value in managing primary bone cancer patient or in the prevention of bone metastasis.

SIDE EFFECTS

Nausea and vomiting are the most commonly reported side effects of Doxycycline in dogs, the incidence of which can be decreased by giving the medication with food.

INTERACTIONS WITH OTHER DRUGS

Doxycycline should not be given at the same time as calcium-containing antacids or vitamins that contain iron. These two substances will affect absorption of the Doxycycline, decreasing its benefits. Doxycycline should be given at least two hours away from either of these substances. Doxycycline may cause nausea if used in combination with theophylline (an airway dilator). It can also increase the effect of a heart medication known as Digoxin.

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