CASE REPORTS
Hemorrhagic Cystitis in a Dog Receiving Carboplatin Valerie MacDonald, DVM, DACVIM (Oncology), Ryan Dickinson, DVM, DACVP
ABSTRACT An 8 yr old castrated male Labrador retriever mixed-breed dog with osteosarcoma (OSA) of the left proximal humerus receiving carboplatin presented 10 days after the third chemotherapy treatment with hematuria, stranguria, and pollakiuria. A presumptive diagnosis of hemorrhagic cystitis was made based on clinical signs, urinalysis, and cytologic analysis of a traumatic catheterization sample. Carboplatin was removed from the chemotherapy treatment plan and was substituted with doxorubicin. The dog was treated with meloxicam for pain, and the cystitis signs subsided over a period of 4 wk. Carboplatin is commonly used as adjuvant chemotherapy for dogs with OSA following amputation and is not known to cause hematuria in dogs, although there are reports of this occurring in humans. To the authors’ knowledge, there are no reports in the veterinary literature of this toxicity. (J Am Anim Hosp Assoc 2014; 50:67–70. DOI 10.5326/JAAHA-MS-5965)
Introduction
because recording those events will provide data such that a
Oncology patients are at risk for developing hemorrhagic cystitis
better idea of the true incidence of hemorrhagic cystitis can be
for various reasons, including toxic chemical agents, thrombo-
determined.
cytopenia, radiation, or infection secondary to myelosuppression.1 Sterile hemorrhagic cystitis has been reported in dogs receiving
Case Report
cyclophosphamide with either acute or delayed onset of clinical
An 8 yr old castrated male Labrador retriever mixed-breed dog was
2–4
signs.
Common presenting complaints include hematuria,
referred to the Veterinary Medical Centre, Western College of
stranguria, dysuria, and pollakiuria. The clinical signs that result
Veterinary Medicine, for treatment options for osteosarcoma
from cyclophosphamide are not a direct toxicity of the compound
(OSA) of the left proximal humerus. Following amputation, the
but rather of its toxic metabolites, in particular acrolein, although
dog received three doses of carboplatina. The protocol at the
the exact mechanism of action is still unknown.1 Hemorrhagic
Veterinary Medical Centre involved four to six 21 day cycles of
cystitis following treatment with carboplatin has been reported in
carboplatin at a dose of 300 mg/m2 IV beginning within 10–
the human literature; however, to the authors’ knowledge, has not
14 days following amputation. The premixed aqueous solution of
been reported in the veterinary literature.5–11 The authors of the
10 mg/mL carboplatin was administered undiluted over 15 min.
case reports in human patients with carboplatin-associated he-
Ten days after the third treatment, the dog presented on an
maturia and/or renal failure propose the potential need for hy-
emergency basis with a 1 day history of hematuria, stranguria, and
dration prior to carboplatin administration to avoid hemorrhagic
pollakiuria. A free-catch urinalysis was submitted. The urine
cystitis. By reporting this case, the study authors wish to make
specific gravity was 1.047; pH was 5.0; there was 21 protein, 11
other veterinarians aware of the potential for hemorrhagic cystitis
bilirubin, 41 blood; and no glucose and ketones. The sediment
to occur. The authors propose that clinicians using carboplatin
contained 0–3 white blood cells/high-power field, 25–40 red
judiciously monitor for development of hemorrhagic cystitis
blood cells/high-power field, 0–2 epithelial cells with few clumps,
From the Department of Small Animal Clinical Sciences (V.M.) and Prairie Diagnostic Services (R.D.), Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
OSA osteosarcoma
Correspondence: [email protected] (V.M.)
ª 2014 by American Animal Hospital Association
JAAHA.ORG
67
scant struvite and bilirubin crystals, 0–2 granular casts/low-power field, and negative bacteria. Urine was submitted for culture and sensitivity, and a complete blood count was normal. Serum biochemical analysis was performed with no abnormalities except mild hypercholesterolemia (cholesterol was 7.57 mmol/L; reference range, 2.70–5.94 mmol/L). As the dog was receiving myelosuppressive therapy, antibiotics were started (amoxicillinb 22 mg/kg per os q 12 hr) pending urine culture results and were discontinued when the culture was found to be negative. No improvement in clinical signs was seen after 24 hr of therapy. The dog returned for further diagnostics. Abdominal radiographs were unremarkable. An abdominal ultrasound showed an irregularly thickened urinary bladder wall cranioventrally. No bladder masses were visualized, and no uroliths were present. The urine contained a moderate amount of floating debris. Those findings were considered more consistent with cystitis than with neoplasia. The following day, cystoscopy was performed. Again, no
FIGURE 1
Urine cytology from an 8 yr old canine patient experi-
encing hematuria, stranguria, and pollakiuria following treatment with carboplatin chemotherapy. Depicted are moderately pleomorphic transitional cells. Modified Wright’s stain, original magnification 3600.
masses were visualized but the bladder wall appeared thickened and edematous. While anesthetized for cystoscopy, attempts to
follow-up examination (48 mo postdiagnosis of OSA), the dog was
biopsy bladder mucosa were unsuccessful. Instead, a traumatic
alive with no evidence of metastatic disease and no signs of cystitis.
catheterization of the trigone area was performed. Cytologic evaluation of the catheterized urine sample revealed many clusters
Discussion
of pleomorphic transitional epithelial cells, characterized by large
Platinum analogs are commonly used in the treatment of canine
size and variable nucleus/cytoplasm ratio with abundant, deep
OSA either alone or in combination with doxorubicin.12–19 Because
basophilic, finely granular cytoplasm and blebbed cytoplasmic
of the toxicities of renal damage and severe nausea and vomiting
margins. Nuclei were round and oval with coarsely stippled
seen with cisplatin, other platinum compounds were developed.20
chromatin and occasional prominent nucleoli. Moderate to
Carboplatin has similar activity in canine OSA and appears to
marked anisocytosis and anisokaryosis were noted in the pop-
provide equivalent clinical effectiveness with survival times
ulation (Figure 1). Those findings were interpreted as possibly
ranging from 262 days to 540 days.12–19 Carboplatin is not
representative of transitional cell carcinoma; however, nonma-
emetogenic and is significantly less nephrotoxic than cisplatin,
lignant inflammation of the bladder urothelium could also cause
thus negating the need for diuresis and antiemetic therapy.20
those morphologic changes. The dog was treated with meloxicamc
Nevertheless, carboplatin is associated with other toxicities, for
(0.1 mg/kg per os q 24 hr) for pain, and clinical signs associated
which diligent monitoring is still indicated.
with cystitis subsided over a period of 4 wk. Meloxicam was ad-
Acute renal failure due to carboplatin is rare in humans and,
ministered daily for 7 days, tapered over the next 3 wk, and then
to the authors’ knowledge, has not been reported in the veterinary
stopped. Clinical signs of cystitis did not recur when meloxicam
literature.5,6 Hemorrhagic cystitis is considered to be even rarer in
was discontinued. Meloxicam was subsequently used for joint
humans. Indeed, a literature review reveals only a single case of
pain on an as needed basis. Carboplatin was removed from the
presumed recurrent hemorrhagic cystitis in a patient receiving
chemotherapy treatment plan and was substituted with doxo-
high-dose carboplatin.7 The patient described in this report was
rubicin (30 mg/m 21 days after the last carboplatin treatment).
thrombocytopenic during the first episode, but on the second
The dog received one treatment of doxorubicin with no adverse
occasion the platelet count was normal. The patient did not have
effects. Further doxorubicin treatments were recommended but
cystoscopy performed so the diagnosis could not be confirmed.
declined by the owner.
Nevertheless, the complication was reported as hemorrhagic
d
2
A follow-up abdominal ultrasound was performed 5 mo after
cystitis.
the initial diagnosis. The urinary bladder, as well as all other
Two other case reports are very similar in that patients with
abdominal organs, appeared grossly normal. At the time of the last
ovarian carcinoma and no history of renal disease developed gross
68
JAAHA |
50:1 Jan/Feb 2014
Hemorrhagic Cystitis Following Carboplatin Treatment
hematuria after receiving carboplatin.8,9 Both patients had normal
to the hematuria in this patient, leaving carboplatin administration
platelet counts, and diagnostic tests revealed bilateral ureteral
as the sole cause of hemorrhagic cystitis in this case, especially
obstruction secondary to blood clots that caused renal failure.
because the signs resolved following discontinuation of carboplatin
A woman with locally advanced breast cancer received one cycle
therapy and treatment with nonsteroidal anti-inflammatory drugs.
10
Authors of case reports involving carboplatin-associated hematuria
She presented 2 days after completion of chemotherapy with
and renal failure in humans propose the potential necessity for
a history of gross hematuria. Blood work and urine cultures were
aggressive hydration, as is typically recommended for cisplatin and
normal. Results of computed tomography and ultrasound of the
cyclophosphamide, as a means of avoiding hemorrhagic cystitis.
abdomen and pelvis were normal. Cystoscopy was also normal
Further monitoring for that type of toxicity in canine patients is
with no evidence of hemorrhagic cystitis. A retrograde pyelo-
warranted to help determine whether diuresis is also indicated in
gram did not show either any tumor or filling defects. Neither
canine patients receiving carboplatin.
of chemotherapy with carboplatin, docetaxel, and trastuzumab.
trastuzumab nor docetaxel are known to cause hematuria. Thus, carboplatin was removed from the protocol and the patient’s hematuria resolved. In contrast to those reports, a phase 2 study of single-agent carboplatin for testicular seminoma reported one patient suffered from hematuria, but the authors of that study did not believe there was a likely relationship to either the tumor or carboplatin.11 However, as the aim of that study was efficacy rather than toxicity, no further investigation was performed to identify a causal relationship between carboplatin and hematuria; therefore, a possible toxicity could not be ruled out. Authors believe that platinum analogs in general and carboplatin in particular can be toxic to transitional epithelium, causing sloughing and bleeding.8 Although the pathogenesis of such an effect is unclear, it may be similar to that for the metabolites of cyclophosphamide, ifosfamide, and other related compounds that are also well known to be toxic to the urothelium.
Conclusion In the patient discussed in this report, a presumptive diagnosis of hemorrhagic cystitis was made based on clinical signs, urinalysis, and cytologic analysis of a traumatic catheterization sample. As there was no immediate indication for biopsy, it was not performed on the patient to further confirm cystitis histologically. Even though hematuria is not a recognized complication of carboplatin therapy, there are several case reports in the human literature. In some of those cases, other chemotherapy drugs were used concomitantly that may have had an idiosyncratic interaction leading to that particular toxicity. However, carboplatin was used as a single agent in some of those cases, so it is more likely that it was the underlying cause. The clinical history, imaging results, and urinalysis findings in the canine patient described in this report are similar to those seen in dogs with either cyclophosphamideinduced cystitis or an occult urinary tract infection. However, the history and work-up ruled out both processes as contributors
FOOTNOTES a Carboplatin; Novopharm, Toronto, ON, Canada b Nu-Amoxi; Nu-Pharm, Richmond Hill, ON, Canada c Metacam; Boehringer Ingelheim, Burlington, ON, Canada d Doxorubicin; Novopharm, Toronto, ON, Canada REFERENCES 1. Strope SA, Hafez KS. Urologic emergencies. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology. 8th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2008: 2455–60. 2. Peterson JL, Couto CG, Hammer AS, et al. Acute sterile hemorrhagic cystitis after a single intravenous administration of cyclophosphamide in three dogs. J Am Vet Med Assoc 1992;201(10): 1572–4. 3. Crow SE, Theilen GH, Madewell BR, et al. Cyclophosphamideinduced cystitis in the dog and cat. J Am Vet Med Assoc 1977;171(3): 259–62. 4. Charney SC, Bergman PJ, Hohenhaus AE, et al. Risk factors for sterile hemorrhagic cystitis in dogs with lymphoma receiving cyclophosphamide with or without concurrent administration of furosemide: 216 cases (1990–1996). J Am Vet Med Assoc 2003;222 (10):1388–93. 5. Alberts DS, Hess LM, vonHoff DD, et al. Pharmacology and therapeutics in gynecologic cancer. In: Barakat RR, Markman M, Randall ME, eds. Principles and practice of gynecologic oncology. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2009: 409–62. 6. Frenkel J, Kool G, de Kraker J. Acute renal failure in high dose carboplatin chemotherapy. Med Pediatr Oncol 1995;25(6):473–4. 7. Ettinger LJ, Krailo MD, Gaynon PS, et al. A phase 1 study of carboplatin in children with acute leukemia in bone marrow relapses. Cancer 1993;72:917–22. 8. Agraharkar M, Nerenstone S, Palmisano J, et al. Carboplatin-related hematuria and acute renal failure. Am J Kidney Dis 1998;32(5):E5–8. 9. Krishnan SG, VanderBrink B, Weiss G, et al. Renal pelvic hemorrhage and acute renal failure associated with carboplatin therapy. Urology 2007;70(6):1222.e5–7. 10. Taj A, Vijendra D, Shafiq Q, et al. Carboplatin-induced hematuria in a patient of breast carcinoma. A case report. Am J Ther 2011;8(6): e269–70. 11. Krege S, Boergermann C, Baschek R, et al. Single agent carboplatin for CS IIA/B testicular seminoma. A phase II study of the German
JAAHA.ORG
69
12.
13.
14.
15.
16.
70
Testicular Cancer Study Group (GTCSG). Ann Oncol 2006;17(2): 276–80. Bergman PJ, MacEwen EG, Kurzman ID, et al. Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991 to 1993). J Vet Intern Med 1996;10(2):76–81. Bacon NJ, Ehrhart NP, Dernell WS, et al. Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999–2006). J Am Vet Med Assoc 2008;232(10):1504–10. Bailey D, Erb H, Williams L, et al. Carboplatin and doxorubicin combination chemotherapy for the treatment of appendicular osteosarcoma in the dog. J Vet Intern Med 2003;17(2):199–205. Berg J, Weinstein MJ, Schelling SH, et al. Treatment of dogs with osteosarcoma by administration of cisplatin after amputation or limb-sparing surgery: 22 cases (1987–1990). J Am Vet Med Assoc 1992;200(12):2005–8. Kent MS, Strom A, London CA, et al. Alternating carboplatin and doxorubicin as adjunctive chemotherapy to amputation or
JAAHA |
50:1 Jan/Feb 2014
17.
18.
19.
20.
limb-sparing surgery in the treatment of appendicular osteosarcoma in dogs. J Vet Intern Med 2004;18(4):540–4. Mauldin GN, Matus RE, Withrow SJ, et al. Canine osteosarcoma. Treatment by amputation versus amputation and adjuvant chemotherapy using doxorubicin and cisplatin. J Vet Intern Med 1988;2(4): 177–80. Phillips B, Powers BE, Dernell WS, et al. Use of single-agent carboplatin as adjuvant or neoadjuvant therapy in conjunction with amputation for appendicular osteosarcoma in dogs. J Am Anim Hosp Assoc 2009;45(1):33–8. Shapiro W, Fossum TW, Kitchell BE, et al. Use of cisplatin for treatment of appendicular osteosarcoma in dogs. J Am Vet Med Assoc 1988;192(4):507–11. Reed E, Chabner BA. Platinum analogues. In: Chabner BA, Longo DL, eds. Cancer chemotherapy and biotherapy: principles and practice. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2011: 310–22.
Hemorrhagic Cystitis in a Dog Receiving Carboplatin Valerie MacDonald, DVM, DACVIM (Oncology), Ryan Dickinson, DVM, DACVP
ABSTRACT An 8 yr old castrated male Labrador retriever mixed-breed dog with osteosarcoma (OSA) of the left proximal humerus receiving carboplatin presented 10 days after the third chemotherapy treatment with hematuria, stranguria, and pollakiuria. A presumptive diagnosis of hemorrhagic cystitis was made based on clinical signs, urinalysis, and cytologic analysis of a traumatic catheterization sample. Carboplatin was removed from the chemotherapy treatment plan and was substituted with doxorubicin. The dog was treated with meloxicam for pain, and the cystitis signs subsided over a period of 4 wk. Carboplatin is commonly used as adjuvant chemotherapy for dogs with OSA following amputation and is not known to cause hematuria in dogs, although there are reports of this occurring in humans. To the authors’ knowledge, there are no reports in the veterinary literature of this toxicity. (J Am Anim Hosp Assoc 2014; 50:67–70. DOI 10.5326/JAAHA-MS-5965)
Introduction
because recording those events will provide data such that a
Oncology patients are at risk for developing hemorrhagic cystitis
better idea of the true incidence of hemorrhagic cystitis can be
for various reasons, including toxic chemical agents, thrombo-
determined.
cytopenia, radiation, or infection secondary to myelosuppression.1 Sterile hemorrhagic cystitis has been reported in dogs receiving
Case Report
cyclophosphamide with either acute or delayed onset of clinical
An 8 yr old castrated male Labrador retriever mixed-breed dog was
2–4
signs.
Common presenting complaints include hematuria,
referred to the Veterinary Medical Centre, Western College of
stranguria, dysuria, and pollakiuria. The clinical signs that result
Veterinary Medicine, for treatment options for osteosarcoma
from cyclophosphamide are not a direct toxicity of the compound
(OSA) of the left proximal humerus. Following amputation, the
but rather of its toxic metabolites, in particular acrolein, although
dog received three doses of carboplatina. The protocol at the
the exact mechanism of action is still unknown.1 Hemorrhagic
Veterinary Medical Centre involved four to six 21 day cycles of
cystitis following treatment with carboplatin has been reported in
carboplatin at a dose of 300 mg/m2 IV beginning within 10–
the human literature; however, to the authors’ knowledge, has not
14 days following amputation. The premixed aqueous solution of
been reported in the veterinary literature.5–11 The authors of the
10 mg/mL carboplatin was administered undiluted over 15 min.
case reports in human patients with carboplatin-associated he-
Ten days after the third treatment, the dog presented on an
maturia and/or renal failure propose the potential need for hy-
emergency basis with a 1 day history of hematuria, stranguria, and
dration prior to carboplatin administration to avoid hemorrhagic
pollakiuria. A free-catch urinalysis was submitted. The urine
cystitis. By reporting this case, the study authors wish to make
specific gravity was 1.047; pH was 5.0; there was 21 protein, 11
other veterinarians aware of the potential for hemorrhagic cystitis
bilirubin, 41 blood; and no glucose and ketones. The sediment
to occur. The authors propose that clinicians using carboplatin
contained 0–3 white blood cells/high-power field, 25–40 red
judiciously monitor for development of hemorrhagic cystitis
blood cells/high-power field, 0–2 epithelial cells with few clumps,
From the Department of Small Animal Clinical Sciences (V.M.) and Prairie Diagnostic Services (R.D.), Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
OSA osteosarcoma
Correspondence: [email protected] (V.M.)
ª 2014 by American Animal Hospital Association
JAAHA.ORG
67
scant struvite and bilirubin crystals, 0–2 granular casts/low-power field, and negative bacteria. Urine was submitted for culture and sensitivity, and a complete blood count was normal. Serum biochemical analysis was performed with no abnormalities except mild hypercholesterolemia (cholesterol was 7.57 mmol/L; reference range, 2.70–5.94 mmol/L). As the dog was receiving myelosuppressive therapy, antibiotics were started (amoxicillinb 22 mg/kg per os q 12 hr) pending urine culture results and were discontinued when the culture was found to be negative. No improvement in clinical signs was seen after 24 hr of therapy. The dog returned for further diagnostics. Abdominal radiographs were unremarkable. An abdominal ultrasound showed an irregularly thickened urinary bladder wall cranioventrally. No bladder masses were visualized, and no uroliths were present. The urine contained a moderate amount of floating debris. Those findings were considered more consistent with cystitis than with neoplasia. The following day, cystoscopy was performed. Again, no
FIGURE 1
Urine cytology from an 8 yr old canine patient experi-
encing hematuria, stranguria, and pollakiuria following treatment with carboplatin chemotherapy. Depicted are moderately pleomorphic transitional cells. Modified Wright’s stain, original magnification 3600.
masses were visualized but the bladder wall appeared thickened and edematous. While anesthetized for cystoscopy, attempts to
follow-up examination (48 mo postdiagnosis of OSA), the dog was
biopsy bladder mucosa were unsuccessful. Instead, a traumatic
alive with no evidence of metastatic disease and no signs of cystitis.
catheterization of the trigone area was performed. Cytologic evaluation of the catheterized urine sample revealed many clusters
Discussion
of pleomorphic transitional epithelial cells, characterized by large
Platinum analogs are commonly used in the treatment of canine
size and variable nucleus/cytoplasm ratio with abundant, deep
OSA either alone or in combination with doxorubicin.12–19 Because
basophilic, finely granular cytoplasm and blebbed cytoplasmic
of the toxicities of renal damage and severe nausea and vomiting
margins. Nuclei were round and oval with coarsely stippled
seen with cisplatin, other platinum compounds were developed.20
chromatin and occasional prominent nucleoli. Moderate to
Carboplatin has similar activity in canine OSA and appears to
marked anisocytosis and anisokaryosis were noted in the pop-
provide equivalent clinical effectiveness with survival times
ulation (Figure 1). Those findings were interpreted as possibly
ranging from 262 days to 540 days.12–19 Carboplatin is not
representative of transitional cell carcinoma; however, nonma-
emetogenic and is significantly less nephrotoxic than cisplatin,
lignant inflammation of the bladder urothelium could also cause
thus negating the need for diuresis and antiemetic therapy.20
those morphologic changes. The dog was treated with meloxicamc
Nevertheless, carboplatin is associated with other toxicities, for
(0.1 mg/kg per os q 24 hr) for pain, and clinical signs associated
which diligent monitoring is still indicated.
with cystitis subsided over a period of 4 wk. Meloxicam was ad-
Acute renal failure due to carboplatin is rare in humans and,
ministered daily for 7 days, tapered over the next 3 wk, and then
to the authors’ knowledge, has not been reported in the veterinary
stopped. Clinical signs of cystitis did not recur when meloxicam
literature.5,6 Hemorrhagic cystitis is considered to be even rarer in
was discontinued. Meloxicam was subsequently used for joint
humans. Indeed, a literature review reveals only a single case of
pain on an as needed basis. Carboplatin was removed from the
presumed recurrent hemorrhagic cystitis in a patient receiving
chemotherapy treatment plan and was substituted with doxo-
high-dose carboplatin.7 The patient described in this report was
rubicin (30 mg/m 21 days after the last carboplatin treatment).
thrombocytopenic during the first episode, but on the second
The dog received one treatment of doxorubicin with no adverse
occasion the platelet count was normal. The patient did not have
effects. Further doxorubicin treatments were recommended but
cystoscopy performed so the diagnosis could not be confirmed.
declined by the owner.
Nevertheless, the complication was reported as hemorrhagic
d
2
A follow-up abdominal ultrasound was performed 5 mo after
cystitis.
the initial diagnosis. The urinary bladder, as well as all other
Two other case reports are very similar in that patients with
abdominal organs, appeared grossly normal. At the time of the last
ovarian carcinoma and no history of renal disease developed gross
68
JAAHA |
50:1 Jan/Feb 2014
Hemorrhagic Cystitis Following Carboplatin Treatment
hematuria after receiving carboplatin.8,9 Both patients had normal
to the hematuria in this patient, leaving carboplatin administration
platelet counts, and diagnostic tests revealed bilateral ureteral
as the sole cause of hemorrhagic cystitis in this case, especially
obstruction secondary to blood clots that caused renal failure.
because the signs resolved following discontinuation of carboplatin
A woman with locally advanced breast cancer received one cycle
therapy and treatment with nonsteroidal anti-inflammatory drugs.
10
Authors of case reports involving carboplatin-associated hematuria
She presented 2 days after completion of chemotherapy with
and renal failure in humans propose the potential necessity for
a history of gross hematuria. Blood work and urine cultures were
aggressive hydration, as is typically recommended for cisplatin and
normal. Results of computed tomography and ultrasound of the
cyclophosphamide, as a means of avoiding hemorrhagic cystitis.
abdomen and pelvis were normal. Cystoscopy was also normal
Further monitoring for that type of toxicity in canine patients is
with no evidence of hemorrhagic cystitis. A retrograde pyelo-
warranted to help determine whether diuresis is also indicated in
gram did not show either any tumor or filling defects. Neither
canine patients receiving carboplatin.
of chemotherapy with carboplatin, docetaxel, and trastuzumab.
trastuzumab nor docetaxel are known to cause hematuria. Thus, carboplatin was removed from the protocol and the patient’s hematuria resolved. In contrast to those reports, a phase 2 study of single-agent carboplatin for testicular seminoma reported one patient suffered from hematuria, but the authors of that study did not believe there was a likely relationship to either the tumor or carboplatin.11 However, as the aim of that study was efficacy rather than toxicity, no further investigation was performed to identify a causal relationship between carboplatin and hematuria; therefore, a possible toxicity could not be ruled out. Authors believe that platinum analogs in general and carboplatin in particular can be toxic to transitional epithelium, causing sloughing and bleeding.8 Although the pathogenesis of such an effect is unclear, it may be similar to that for the metabolites of cyclophosphamide, ifosfamide, and other related compounds that are also well known to be toxic to the urothelium.
Conclusion In the patient discussed in this report, a presumptive diagnosis of hemorrhagic cystitis was made based on clinical signs, urinalysis, and cytologic analysis of a traumatic catheterization sample. As there was no immediate indication for biopsy, it was not performed on the patient to further confirm cystitis histologically. Even though hematuria is not a recognized complication of carboplatin therapy, there are several case reports in the human literature. In some of those cases, other chemotherapy drugs were used concomitantly that may have had an idiosyncratic interaction leading to that particular toxicity. However, carboplatin was used as a single agent in some of those cases, so it is more likely that it was the underlying cause. The clinical history, imaging results, and urinalysis findings in the canine patient described in this report are similar to those seen in dogs with either cyclophosphamideinduced cystitis or an occult urinary tract infection. However, the history and work-up ruled out both processes as contributors
FOOTNOTES a Carboplatin; Novopharm, Toronto, ON, Canada b Nu-Amoxi; Nu-Pharm, Richmond Hill, ON, Canada c Metacam; Boehringer Ingelheim, Burlington, ON, Canada d Doxorubicin; Novopharm, Toronto, ON, Canada REFERENCES 1. Strope SA, Hafez KS. Urologic emergencies. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology. 8th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2008: 2455–60. 2. Peterson JL, Couto CG, Hammer AS, et al. Acute sterile hemorrhagic cystitis after a single intravenous administration of cyclophosphamide in three dogs. J Am Vet Med Assoc 1992;201(10): 1572–4. 3. Crow SE, Theilen GH, Madewell BR, et al. Cyclophosphamideinduced cystitis in the dog and cat. J Am Vet Med Assoc 1977;171(3): 259–62. 4. Charney SC, Bergman PJ, Hohenhaus AE, et al. Risk factors for sterile hemorrhagic cystitis in dogs with lymphoma receiving cyclophosphamide with or without concurrent administration of furosemide: 216 cases (1990–1996). J Am Vet Med Assoc 2003;222 (10):1388–93. 5. Alberts DS, Hess LM, vonHoff DD, et al. Pharmacology and therapeutics in gynecologic cancer. In: Barakat RR, Markman M, Randall ME, eds. Principles and practice of gynecologic oncology. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2009: 409–62. 6. Frenkel J, Kool G, de Kraker J. Acute renal failure in high dose carboplatin chemotherapy. Med Pediatr Oncol 1995;25(6):473–4. 7. Ettinger LJ, Krailo MD, Gaynon PS, et al. A phase 1 study of carboplatin in children with acute leukemia in bone marrow relapses. Cancer 1993;72:917–22. 8. Agraharkar M, Nerenstone S, Palmisano J, et al. Carboplatin-related hematuria and acute renal failure. Am J Kidney Dis 1998;32(5):E5–8. 9. Krishnan SG, VanderBrink B, Weiss G, et al. Renal pelvic hemorrhage and acute renal failure associated with carboplatin therapy. Urology 2007;70(6):1222.e5–7. 10. Taj A, Vijendra D, Shafiq Q, et al. Carboplatin-induced hematuria in a patient of breast carcinoma. A case report. Am J Ther 2011;8(6): e269–70. 11. Krege S, Boergermann C, Baschek R, et al. Single agent carboplatin for CS IIA/B testicular seminoma. A phase II study of the German
JAAHA.ORG
69
12.
13.
14.
15.
16.
70
Testicular Cancer Study Group (GTCSG). Ann Oncol 2006;17(2): 276–80. Bergman PJ, MacEwen EG, Kurzman ID, et al. Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991 to 1993). J Vet Intern Med 1996;10(2):76–81. Bacon NJ, Ehrhart NP, Dernell WS, et al. Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999–2006). J Am Vet Med Assoc 2008;232(10):1504–10. Bailey D, Erb H, Williams L, et al. Carboplatin and doxorubicin combination chemotherapy for the treatment of appendicular osteosarcoma in the dog. J Vet Intern Med 2003;17(2):199–205. Berg J, Weinstein MJ, Schelling SH, et al. Treatment of dogs with osteosarcoma by administration of cisplatin after amputation or limb-sparing surgery: 22 cases (1987–1990). J Am Vet Med Assoc 1992;200(12):2005–8. Kent MS, Strom A, London CA, et al. Alternating carboplatin and doxorubicin as adjunctive chemotherapy to amputation or
JAAHA |
50:1 Jan/Feb 2014
17.
18.
19.
20.
limb-sparing surgery in the treatment of appendicular osteosarcoma in dogs. J Vet Intern Med 2004;18(4):540–4. Mauldin GN, Matus RE, Withrow SJ, et al. Canine osteosarcoma. Treatment by amputation versus amputation and adjuvant chemotherapy using doxorubicin and cisplatin. J Vet Intern Med 1988;2(4): 177–80. Phillips B, Powers BE, Dernell WS, et al. Use of single-agent carboplatin as adjuvant or neoadjuvant therapy in conjunction with amputation for appendicular osteosarcoma in dogs. J Am Anim Hosp Assoc 2009;45(1):33–8. Shapiro W, Fossum TW, Kitchell BE, et al. Use of cisplatin for treatment of appendicular osteosarcoma in dogs. J Am Vet Med Assoc 1988;192(4):507–11. Reed E, Chabner BA. Platinum analogues. In: Chabner BA, Longo DL, eds. Cancer chemotherapy and biotherapy: principles and practice. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2011: 310–22.
