Oncology Case Report Example
Doxorubicin Administration for Treatment of Oral Fibrosarcoma
A 9-year-old castrated male Labrador retriever presented to the hospital for an oncology consultation. He had a history of a rapidly growing mass on his right maxilla that the owner had noticed ten days previously. The owner had taken the dog to her regular veterinarian, where an incisional biopsy revealed a tumor consistent with an intermediate grade fibrosarcoma. The referring veterinarian (rDVM) had also performed skull and thoracic films at that time. The skull films showed evidence of bony lysis of the maxilla. The thoracic radiographs showed no evidence of metastatic disease.
Oral fibrosarcoma is generally locally invasive and aggressive. It is primarily seen in large breed dogs, often relatively young male retrievers, and predominantly occurs in the maxilla. Often these tumors can look benign or low-grade histologically, but behave as more aggressive and malignant tumors. Due to this biologically high-grade, but histologically low-grade behavior, they are often called “High-Low” fibrosarcomas. These tumors have a low metastatic rate (less than 20%), but are extremely locally invasive and have a high rate of recurrence after surgical excision.
The owner reported, on presentation to the oncology service, that the mass had continued to grow rapidly since it was first noted. The patient had no vomiting, diarrhea, or sneezing, although he did occasionally cough. The owner had switched the patient’s diet to soft food, and he was now eating well. They also reported that he was licking his lips excessively over the region of the tumor. The only other past medical history was an episode of chocolate toxicity two years previously. Although the dog had enrofloxacin (5.0 mg/kg PO q24 hours), and meloxicam (0.1 mg/kg PO q24 hours) prescribed by the rDVM, the owner had discontinued them, as she did not believe antibiotics were necessary for a tumor, or that the dog was in any pain. It was recommended that these treatments be restarted, as the mouth had a foul odor and was likely infected, and it was felt that the patient’s difficulty eating dry food was likely indicative of pain.
On physical exam the patient was quiet, alert and responsive. He weighed 35.6 kg with a body condition score of 5 out of 9. His temperature was 101.8°F (normal 100°F-102.5°F), his pulse rate was 96 bpm (normal 80-100 bpm), and his respiratory rate was 15 breaths/min (normal 12-20 breaths/min). His heart and lungs ausculted normally. His abdomen was not painful on palpation, and no masses or organomegaly were noted.
Oral exam showed a firm mass protruding from the right maxillary bone just rostral to his right eye. The mass extended to the edge of the bony orbit. Intra-orally, the exposed surface of the mass had areas of necrotic tissue. The upper third and fourth premolars were missing. The mass extended approximately 1-1.5 cm toward the midline. The mass was predominantly pink inside the oral cavity, while the majority of the normal mucous membranes were black in color. While the right eye retropulsed normally, the patient had excessive tearing from that eye, presumably due to blockage of the tear duct. All of the lymph nodes, including the right submandibular lymph node, were within normal limits. He had multiple soft, freely moveable subcutaneous masses over the thorax and abdomen. The rest of the physical exam was unremarkable.
The recommendation was made that the patient have a CT scan of the head performed that afternoon to evaluate the underlying disease and the true extent of the tumor. This information would be necessary to make further treatment recommendations such as surgery, radiation therapy, chemotherapy, or some combination of these modalities. The CT scan showed severe bony destruction, soft tissue involvement, and invasion into the nasal cavity. The options of surgery with adjunctive radiation therapy, or radiation therapy alone were discussed, with the goal of attempting local control of the disease. Due to the invasiveness of this tumor it was unlikely that surgical margins would be obtainable, and the likelihood of dehiscence necessitating a second surgery was discussed. The owners were also offered palliative treatment with doxorubicin and pain medications, with the goal of preserving quality of life for as long as possible. The patient was discharged, on no additional medications, pending the owners decision. After careful consideration, the owners elected not to pursue radiation or surgery, and elected to treat with doxorubicin therapy only.
The dog presented for doxorubicin treatment two weeks later. His temperature was 101.6°F, pulse 100 bpm, and he was panting. His weight today was 33.8 kg, down 1.8 kg since initial presentation. The owners reported no change in his appetite or energy level from before; however, he was still having some difficulty eating anything other than soft food. The mass was measured by the technician, to be better able to assess any response to the chemotherapy in the future. External measurements were 6cm dorsal/ventral, 6.5 cm cranial/caudal, and 4.5 cm medial/lateral. The patient had severe halitosis, and the mass still had areas of necrosis. The technician drew blood for a complete cell count (CBC). The patient’s total white blood cell (WBC) count was 8,600/ml (reference range 6,000-17,000/ml); his neutrophil count 7,000/ml (3,500-12,000/ml), hematocrit (HCT) 40% (37-55%), and his platelet count was 511,000/ml(200,000-500,000/ml). This was deemed more than adequate for treatment. A CBC should always be run prior to administration of any cytotoxic agent. Myelosuppression occurs secondary to damage caused by the chemotherapeutic agent to the precursor cells in the bone marrow. The circulating neutrophil life span is 5.5-7.6 hours; thrombocytes approximately 10 days, and erythrocytes approximately 73 days. The blood cells with the shortest life span are the first to show the damage, therefore decreased neutrophil and platelet counts are most commonly seen clinically. Treatment should be delayed if the neutrophil count is less than 1,500 to 2,000, or the platelet count is less than 50,000. The exception to this would be if the low cell counts are believed to be secondary to the tumor itself, in which case treatment would be necessary to resolve the cytopenia.
A dose of doxorubicin was calculated by the technician at 30 mg/m2, and then checked by another staff member. All chemotherapy doses should be checked by two staff members, as well as checked against doses previously received, if any. It is also advisable to check the weight against any previously recorded weights for the patient. This is to minimize mis-dosing which can be life threatening. A substitution of pounds for kilograms, for example, would result in a double dose.
Per hospital protocol, the patient was given a dose of diphenhydramine 2.0 mg/kg SQ 30 minutes prior to doxorubicin infusion. While gowned, gloved, and masked, the technician placed a 20 gauge, one-inch sovereign catheter in the left cephalic vein, and secured it with 2 pieces of ½ inch tape, leaving the insertion site visible. This catheter must always be perfectly placed, with no leakage into the perivascular tissues. The catheter was flushed with 10 cc 0.9% sodium chloride to assure patency, and then attached to a 250 ml bag of 0.9% normal saline via a Y-connector with a luer lock line. A dose of dexamethasone sodium phosphate (0.2 mg/kg) was given IV and the line again flushed with saline. A 60 ml syringe with a luer lock tip, containing 31.5 mg (15.75 mls) doxorubicin was then attached to the second Y-port, and the syringe filled with saline to a volume of 40 mls. The doxorubicin was then given IV slowly over 20 minutes, into the freely flowing line of saline. After infusion, the line was disconnected. An alcohol soaked gauze pad was wrapped around the hub of the syringe while disconnecting the doxorubicin to catch any drops that might spill, and the catheter was flushed with 10 mls saline again, to clear any remaining drug from the line, and the catheter was pulled. The patient was discharged on clindamycin 11.0 mg/kg PO q12 hours for the oral infection, metoclopramide 0.3 mg/kg PO q12 hours to be used as needed for nausea, and metronidazole 8.0 mg PO q12 hours to be used as needed for diarrhea.
Doxorubicin is an anthracycline antineoplastic antibiotic. It intercalates with DNA, inhibiting protein synthesis, and promoting the formation of free radicals. It is cell cycle phase nonspecific. Although it does have antimicrobial activity, it is considered too toxic to be used for that purpose, and is instead used for its antitumor activity against a wide range of neoplasms.
Familiarity with the side effects of doxorubicin is extremely important for the administrator. The drug can have both acute and cumulative effects. Doxorubicin can cause immediate histamine-mediated hypersensitivity reactions. This can manifest in the dog as pruritis, dyspnea, or vomiting. Premedication with diphenhydramine and dexamethasone sodium phosphate as mentioned above can help prevent these effects. If a hypersensitivity reaction does occur, it is appropriate to stop the infusion until the side effects subside, then restart at a slower rate. Diphenhydramine and dexamethasone sodium phosphate can be administered again, if indicated. It is important to note that doxorubicin is physically incompatible with both heparin and dexamethasone sodium phosphate, and therefore catheters should only be flushed with non-heparinized saline, and lines should be flushed between administration of dexamethasone sodium phosphate and doxorubicin administration.
Another potentially serious side effect is severe tissue necrosis and sloughing if the drug is accidentally administered perivascularly. A perfectly placed indwelling catheter should always be used, with the insertion site readily visible to the administrator. At no time should the patient be left alone during the administration. Administration through a freely flowing IV line helps assure the administrator of continued catheter potency. If extravasation does occur, the catheter should be immediately aspirated to withdraw as much drug as possible, and then the catheter pulled. Cold compresses should be applied to the area to minimize dissemination of the drug throughout the tissues. An IV catheter should be placed in another vein, and dexrazoxane given as a slow IV bolus at a dose of ten times that of the doxorubicin. Dexrazoxane protects against the free radical formation caused by doxorubicin and has been used to minimize the cardiotoxic effects of doxorubicin, and well as the perivascular tissue sloughing. Care should be taken however, as this drug is also a vesicant.
Doxorubicin has been shown to have cumulative myocardial toxicity in dogs. Breeds such as Dobermans and Great Danes that have a predisposition to dilated cardiomyopathy should have a baseline echocardiogram prior the use of this drug. The current recommendation is that the cumulative dose of doxorubicin should not exceed 180-240 mg/m2. As mentioned above dexrazoxane can be given for its cardioprotective effects as a slow IV bolus starting 30 minutes prior to the administration of doxorubicin. This drug can be somewhat cost-prohibitive, however.
Other side effects that can be seen with doxorubicin are myelosuppression, gastrointestinal (GI) toxicity, and cumulative nephrotoxicity in felines. Transient arrhythmias have also been noted during administration in canines, but are rare. Myelosuppression, as mentioned above, is caused by damage to the precursor cells in the bone marrow. A CBC should be drawn prior to each treatment, and often 7-10 days post treatment, to assess the nadir. GI toxicity, if mild, can often be treated at home by the owners, with oral anti-emetic and antidiarrheal medications. More severe GI toxicity may require hospitalization.
Not to be overlooked is the potential toxicity to hospital personnel. All persons administering cytotoxic drugs should be familiar with the risks involved with exposure. It has been established that some drugs, such as cyclophosphamide, can be absorbed through the skin. All staff members involved in the handling of chemotherapeutics should be trained in safe handling. During administration, both administrator and restrainer should wear protective garments, ideally gowns and gloves rated for chemotherapy protection, and masks that protect both mouth and eyes.
This patient had a recheck exam three weeks later. At this exam the mass had reduced in size more that 50% to 3 cm x 5 cm. The patient was eating well and the halitosis had resolved. With this strong partial response, the plan was made to administer a total of six doses three weeks apart. By the fourth dose, the patient was clinically normal, with no measurable disease. The owners elected to stop chemotherapy after the fifth dose. The patient is currently alive with no recurrence.
Case report by Kristin Sears
References
Withrow, S., Vail, D. Small Animal Clinical Oncology ed. 4. Saunders Elsevier 2007
Plumb, D Veterinary Drug Handbook ed. 5. Blackwell 2005
ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs, American Society of Hospital Pharmacists, Inc. 1990
A 9-year-old castrated male Labrador retriever presented to the hospital for an oncology consultation. He had a history of a rapidly growing mass on his right maxilla that the owner had noticed ten days previously. The owner had taken the dog to her regular veterinarian, where an incisional biopsy revealed a tumor consistent with an intermediate grade fibrosarcoma. The referring veterinarian (rDVM) had also performed skull and thoracic films at that time. The skull films showed evidence of bony lysis of the maxilla. The thoracic radiographs showed no evidence of metastatic disease.
Oral fibrosarcoma is generally locally invasive and aggressive. It is primarily seen in large breed dogs, often relatively young male retrievers, and predominantly occurs in the maxilla. Often these tumors can look benign or low-grade histologically, but behave as more aggressive and malignant tumors. Due to this biologically high-grade, but histologically low-grade behavior, they are often called “High-Low” fibrosarcomas. These tumors have a low metastatic rate (less than 20%), but are extremely locally invasive and have a high rate of recurrence after surgical excision.
The owner reported, on presentation to the oncology service, that the mass had continued to grow rapidly since it was first noted. The patient had no vomiting, diarrhea, or sneezing, although he did occasionally cough. The owner had switched the patient’s diet to soft food, and he was now eating well. They also reported that he was licking his lips excessively over the region of the tumor. The only other past medical history was an episode of chocolate toxicity two years previously. Although the dog had enrofloxacin (5.0 mg/kg PO q24 hours), and meloxicam (0.1 mg/kg PO q24 hours) prescribed by the rDVM, the owner had discontinued them, as she did not believe antibiotics were necessary for a tumor, or that the dog was in any pain. It was recommended that these treatments be restarted, as the mouth had a foul odor and was likely infected, and it was felt that the patient’s difficulty eating dry food was likely indicative of pain.
On physical exam the patient was quiet, alert and responsive. He weighed 35.6 kg with a body condition score of 5 out of 9. His temperature was 101.8°F (normal 100°F-102.5°F), his pulse rate was 96 bpm (normal 80-100 bpm), and his respiratory rate was 15 breaths/min (normal 12-20 breaths/min). His heart and lungs ausculted normally. His abdomen was not painful on palpation, and no masses or organomegaly were noted.
Oral exam showed a firm mass protruding from the right maxillary bone just rostral to his right eye. The mass extended to the edge of the bony orbit. Intra-orally, the exposed surface of the mass had areas of necrotic tissue. The upper third and fourth premolars were missing. The mass extended approximately 1-1.5 cm toward the midline. The mass was predominantly pink inside the oral cavity, while the majority of the normal mucous membranes were black in color. While the right eye retropulsed normally, the patient had excessive tearing from that eye, presumably due to blockage of the tear duct. All of the lymph nodes, including the right submandibular lymph node, were within normal limits. He had multiple soft, freely moveable subcutaneous masses over the thorax and abdomen. The rest of the physical exam was unremarkable.
The recommendation was made that the patient have a CT scan of the head performed that afternoon to evaluate the underlying disease and the true extent of the tumor. This information would be necessary to make further treatment recommendations such as surgery, radiation therapy, chemotherapy, or some combination of these modalities. The CT scan showed severe bony destruction, soft tissue involvement, and invasion into the nasal cavity. The options of surgery with adjunctive radiation therapy, or radiation therapy alone were discussed, with the goal of attempting local control of the disease. Due to the invasiveness of this tumor it was unlikely that surgical margins would be obtainable, and the likelihood of dehiscence necessitating a second surgery was discussed. The owners were also offered palliative treatment with doxorubicin and pain medications, with the goal of preserving quality of life for as long as possible. The patient was discharged, on no additional medications, pending the owners decision. After careful consideration, the owners elected not to pursue radiation or surgery, and elected to treat with doxorubicin therapy only.
The dog presented for doxorubicin treatment two weeks later. His temperature was 101.6°F, pulse 100 bpm, and he was panting. His weight today was 33.8 kg, down 1.8 kg since initial presentation. The owners reported no change in his appetite or energy level from before; however, he was still having some difficulty eating anything other than soft food. The mass was measured by the technician, to be better able to assess any response to the chemotherapy in the future. External measurements were 6cm dorsal/ventral, 6.5 cm cranial/caudal, and 4.5 cm medial/lateral. The patient had severe halitosis, and the mass still had areas of necrosis. The technician drew blood for a complete cell count (CBC). The patient’s total white blood cell (WBC) count was 8,600/ml (reference range 6,000-17,000/ml); his neutrophil count 7,000/ml (3,500-12,000/ml), hematocrit (HCT) 40% (37-55%), and his platelet count was 511,000/ml(200,000-500,000/ml). This was deemed more than adequate for treatment. A CBC should always be run prior to administration of any cytotoxic agent. Myelosuppression occurs secondary to damage caused by the chemotherapeutic agent to the precursor cells in the bone marrow. The circulating neutrophil life span is 5.5-7.6 hours; thrombocytes approximately 10 days, and erythrocytes approximately 73 days. The blood cells with the shortest life span are the first to show the damage, therefore decreased neutrophil and platelet counts are most commonly seen clinically. Treatment should be delayed if the neutrophil count is less than 1,500 to 2,000, or the platelet count is less than 50,000. The exception to this would be if the low cell counts are believed to be secondary to the tumor itself, in which case treatment would be necessary to resolve the cytopenia.
A dose of doxorubicin was calculated by the technician at 30 mg/m2, and then checked by another staff member. All chemotherapy doses should be checked by two staff members, as well as checked against doses previously received, if any. It is also advisable to check the weight against any previously recorded weights for the patient. This is to minimize mis-dosing which can be life threatening. A substitution of pounds for kilograms, for example, would result in a double dose.
Per hospital protocol, the patient was given a dose of diphenhydramine 2.0 mg/kg SQ 30 minutes prior to doxorubicin infusion. While gowned, gloved, and masked, the technician placed a 20 gauge, one-inch sovereign catheter in the left cephalic vein, and secured it with 2 pieces of ½ inch tape, leaving the insertion site visible. This catheter must always be perfectly placed, with no leakage into the perivascular tissues. The catheter was flushed with 10 cc 0.9% sodium chloride to assure patency, and then attached to a 250 ml bag of 0.9% normal saline via a Y-connector with a luer lock line. A dose of dexamethasone sodium phosphate (0.2 mg/kg) was given IV and the line again flushed with saline. A 60 ml syringe with a luer lock tip, containing 31.5 mg (15.75 mls) doxorubicin was then attached to the second Y-port, and the syringe filled with saline to a volume of 40 mls. The doxorubicin was then given IV slowly over 20 minutes, into the freely flowing line of saline. After infusion, the line was disconnected. An alcohol soaked gauze pad was wrapped around the hub of the syringe while disconnecting the doxorubicin to catch any drops that might spill, and the catheter was flushed with 10 mls saline again, to clear any remaining drug from the line, and the catheter was pulled. The patient was discharged on clindamycin 11.0 mg/kg PO q12 hours for the oral infection, metoclopramide 0.3 mg/kg PO q12 hours to be used as needed for nausea, and metronidazole 8.0 mg PO q12 hours to be used as needed for diarrhea.
Doxorubicin is an anthracycline antineoplastic antibiotic. It intercalates with DNA, inhibiting protein synthesis, and promoting the formation of free radicals. It is cell cycle phase nonspecific. Although it does have antimicrobial activity, it is considered too toxic to be used for that purpose, and is instead used for its antitumor activity against a wide range of neoplasms.
Familiarity with the side effects of doxorubicin is extremely important for the administrator. The drug can have both acute and cumulative effects. Doxorubicin can cause immediate histamine-mediated hypersensitivity reactions. This can manifest in the dog as pruritis, dyspnea, or vomiting. Premedication with diphenhydramine and dexamethasone sodium phosphate as mentioned above can help prevent these effects. If a hypersensitivity reaction does occur, it is appropriate to stop the infusion until the side effects subside, then restart at a slower rate. Diphenhydramine and dexamethasone sodium phosphate can be administered again, if indicated. It is important to note that doxorubicin is physically incompatible with both heparin and dexamethasone sodium phosphate, and therefore catheters should only be flushed with non-heparinized saline, and lines should be flushed between administration of dexamethasone sodium phosphate and doxorubicin administration.
Another potentially serious side effect is severe tissue necrosis and sloughing if the drug is accidentally administered perivascularly. A perfectly placed indwelling catheter should always be used, with the insertion site readily visible to the administrator. At no time should the patient be left alone during the administration. Administration through a freely flowing IV line helps assure the administrator of continued catheter potency. If extravasation does occur, the catheter should be immediately aspirated to withdraw as much drug as possible, and then the catheter pulled. Cold compresses should be applied to the area to minimize dissemination of the drug throughout the tissues. An IV catheter should be placed in another vein, and dexrazoxane given as a slow IV bolus at a dose of ten times that of the doxorubicin. Dexrazoxane protects against the free radical formation caused by doxorubicin and has been used to minimize the cardiotoxic effects of doxorubicin, and well as the perivascular tissue sloughing. Care should be taken however, as this drug is also a vesicant.
Doxorubicin has been shown to have cumulative myocardial toxicity in dogs. Breeds such as Dobermans and Great Danes that have a predisposition to dilated cardiomyopathy should have a baseline echocardiogram prior the use of this drug. The current recommendation is that the cumulative dose of doxorubicin should not exceed 180-240 mg/m2. As mentioned above dexrazoxane can be given for its cardioprotective effects as a slow IV bolus starting 30 minutes prior to the administration of doxorubicin. This drug can be somewhat cost-prohibitive, however.
Other side effects that can be seen with doxorubicin are myelosuppression, gastrointestinal (GI) toxicity, and cumulative nephrotoxicity in felines. Transient arrhythmias have also been noted during administration in canines, but are rare. Myelosuppression, as mentioned above, is caused by damage to the precursor cells in the bone marrow. A CBC should be drawn prior to each treatment, and often 7-10 days post treatment, to assess the nadir. GI toxicity, if mild, can often be treated at home by the owners, with oral anti-emetic and antidiarrheal medications. More severe GI toxicity may require hospitalization.
Not to be overlooked is the potential toxicity to hospital personnel. All persons administering cytotoxic drugs should be familiar with the risks involved with exposure. It has been established that some drugs, such as cyclophosphamide, can be absorbed through the skin. All staff members involved in the handling of chemotherapeutics should be trained in safe handling. During administration, both administrator and restrainer should wear protective garments, ideally gowns and gloves rated for chemotherapy protection, and masks that protect both mouth and eyes.
This patient had a recheck exam three weeks later. At this exam the mass had reduced in size more that 50% to 3 cm x 5 cm. The patient was eating well and the halitosis had resolved. With this strong partial response, the plan was made to administer a total of six doses three weeks apart. By the fourth dose, the patient was clinically normal, with no measurable disease. The owners elected to stop chemotherapy after the fifth dose. The patient is currently alive with no recurrence.
Case report by Kristin Sears
References
Withrow, S., Vail, D. Small Animal Clinical Oncology ed. 4. Saunders Elsevier 2007
Plumb, D Veterinary Drug Handbook ed. 5. Blackwell 2005
ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs, American Society of Hospital Pharmacists, Inc. 1990
