Soft tissue sarcomas comprise a heterogenous population of malignant tumors that arise from a variety of mesenchymal cell types.1 Although STSs can occur anywhere in the body, the skin and subcutaneous tissues are the most common locations.1 Grossly, STSs are pseudoencapsulated, and histologically, they are ill defined with infiltration into fascial planes. Grade 1 and 2 STSs are generally characterized as being locally invasive with low metastatic potential, making local tumor control crucial in successful treatment.1
Tumor excision with wide surgical margins is currently the standard of care for STSs in dogs. Unfortunately, adequate margins are often difficult to achieve without radical surgery owing to the tumors’ infiltrative characteristics. Furthermore, aggressive procedures are often considered unacceptable to pet owners. Local recurrence rates following marginal surgical excision alone have been reported to range from 4 of 35 (11%) to 5 of 16.2,3 In addition, primary re-excision of incompletely excised STSs has been shown to decrease the rate of local tumor recurrence.4
When wide surgical margins cannot be achieved during excision of STSs, postoperative RT has historically been recommended as an adjunctive treatment.1 Full-course postoperative RT has been shown to provide long-term local control of incompletely excised STSs in dogs.5,6 Adverse effects following definitive RT have been reported to occur infrequently and have typically been described as mild. In 1 study5 that included 48 dogs with incompletely excised STSs treated by means of definitive RT, acute adverse effects consisted of radiodermatitis, mild persistent alopecia, and hyperpigmentation of affected skin.
Postoperative hypofractionated RT for treatment of marginally excised STSs has been investigated as well, resulting in local tumor control and long-term survival rates similar to those achieved with definitive RT protocols.7 Clinically important complications related to surgery and hypofractionated RT for treatment of STSs were reported for 6 of 56 (11%) dogs in 1 study,7 and these consisted of wound dehiscence, self-induced traumatic injury, and osteonecrosis of underlying bone.
Currently, the role of systemic chemotherapy in the treatment of STS remains to be clearly defined.1,8 Traditional cytotoxic chemotherapy with doxorubicin was reported to be of little benefit when used alone or in combination with surgical excision in a retrospective study8 of 39 canine patients with high-grade STSs. However, other investigators found that metronomic therapy with piroxicam and low-dose cyclophosphamide significantly delayed local tumor recurrence for dogs with incompletely excised STS, compared with that of dogs that had similar surgical results and did not undergo chemotherapy.9
Although surgery followed by RT and metronomic chemotherapy has proven to be effective at delaying recurrence of STSs in dogs,5–7,9 these treatment modalities are often declined by owners because of financial limitations, inability to comply with time schedules, or both. For this reason, other localized treatment options continue to be investigated.
Intralesional chemotherapy has been used in veterinary and human medicine; intralesional cisplatin treatment, in particular, has been used to combat cutaneous neoplasia in canine and equine patients.10–12 Cisplatin delivered IV has been used to treat many types of neoplasia in dogs, but despite its antitumor efficacy, this treatment has been associated with severe adverse effects including nephrotoxicosis, bone marrow suppression, and gastrointestinal effects such as anorexia, vomiting, and diarrhea.10 To avoid systemic toxicosis while taking advantage of the antitumor effects of cisplatin, intralesional administration of the drug has been explored in dogs with STSs and other tumor types.13–16 An investigation was performed to assess the complication rate and local tumor recurrence rate in canine patients with STS treated with marginal excision and intraoperative implantation of cisplatin in a biodegradable implant delivery system.13 Wound complications were reported in 16 of 19 dogs, with 1 dog requiring limb amputation.13 Of the 18 dogs still alive at the end of the study, 3 had developed tumor recurrence, with recurrence detected 874, 264, and 214 days after surgery.13 Results of another study15 revealed high complication rates (with 19/32 [59%] implant sites developing swelling) when biodegradable implants of OPLA-Pt were placed in the surgical wound at the time of STS tumor removal with marginal resection. Complication rates related to the OPLA-Pt were determined to be unacceptably high, with 9 of 32 (28%) tumor sites in 30 dogs requiring implant removal and 10 of 32 (31%) tumors recurring locally.15
Implants of OPLA-Pt have also been used in combination with limb-sparing surgical procedures and IV cisplatin administration for treatment of osteosarcoma of the radius in dogs.16 Local complication and infection rates of dogs treated with OPLA-Pt did not differ from those of dogs that received OPLA implants without cisplatin in 1 study.16
Although local adverse effects were common in previous studies13–16 investigating intralesional administration of cisplatin in dogs, systemic adverse effects were not detected. Despite this, the treatment method is not widely used in small animal medicine.
Cisplatin-containing biodegradable beads have been used with success in equine patients for local control of various cutaneous neoplasms including sarcoids, fibromas, fibrosarcomas, PNSTs, squamous cell carcinomas, and melanomas (in gray horses).11,12 These beads have been used by direct implantation into tumors at 30-day intervals; however, the treatment is thought to be more effective when combined with reduction of the tumor burden to minimal residual disease.12 The cisplatin-containing beads are made from a commercially available matrix material (calcium sulfate and dextran sulfate), to which cisplatin is added to a final concentration of 7%.12 Each 3-mm-diameter bead contains approximately 1.6 mg of cisplatin.12,17 The product was granted minor use–minor species status for use in horses by the FDA in 2009; there is currently no equivalent product available that is approved for veterinary use. An in vivo investigation of subcutaneously placed cisplatin-containing beads showed that cisplatin traveled to a radial distance of approximately 1.5 cm, with the concentration of drug gradually decreasing as distance from the bead increased.a On the basis of this finding, current recommendations include placement of the beads at approximately 1.5-cm intervals to cover the tumor bed.12 Cisplatin-containing beads were found to be well tolerated in a retrospective study11 of 59 horses with neoplasia, with moderate swelling, erythema, and residual subtle scars being the most commonly reported adverse effects. Overall, complications noted by owners were considered fairly minimal, and most owners reported being pleased with the treatment results.11 To the authors’ knowledge, there are no peer-reviewed studies evaluating the use of cisplatin-impregnated beads in dogs available to date.
The purpose of the study reported here was to evaluate outcomes for dogs following marginal tumor excision and intralesional placement of cisplatin-impregnated beads for the treatment of cutaneous or subcutaneous STSs and to assess local toxic effects of the intralesional cisplatin treatment in these patients. We hypothesized that the local STS recurrence rate and time to local recurrence in dogs undergoing this treatment would be similar to those previously described for dogs treated for STSs by means of marginal or incomplete tumor resection and postoperative RT5–7 and that adverse effects associated with the treatment would be infrequent, local to the bead implantation site, and non–life-threatening.
Materials and Methods
Case selection
Medical records of dogs seen at the Pittsburgh Veterinary Specialty and Emergency Center between January 1, 2009, and September 30, 2012, were reviewed to identify patients with STSs that underwent incomplete or marginal tumor resection followed by intralesional placement of cisplatin-impregnated beads. For study inclusion purposes, marginal resection was defined as tumor excision performed just outside the tumor pseudocapsule.3,13 Dogs with a primary or locally recurrent STS were eligible for inclusion. All dogs were evaluated by a board-certified veterinary surgeon prior to bead placement. Only patients with a histopathologic diagnosis of STS and tumor grade information (according to the grading scheme previously described by Kuntz et al,18 in which tumors are evaluated on the basis of differentiation, tumor necrosis, and mitotic index on a scale of 1 [least aggressive] to 3 [most aggressive]) provided or verified by a board-certified veterinary pathologist were eligible for inclusion.
Medical records review
Patient signalment, weight, tumor location, tumor type and grade, date of tumor resection or scar revision, date of cisplatin-containing bead placement, number of beads placed, and concurrent treatments were recorded. Records were also reviewed to obtain follow-up data regarding local toxic effects associated with the beads within the 10 to 14 days prior to suture removal. In addition, all records were reviewed for signs of illness within the 14-day period following bead placement that could represent systemic adverse effects to the cisplatin beads. For patients that were not returned to the study hospital for bead site evaluation, information was obtained from referring veterinarians, who were contacted by telephone.
Information regarding local tumor recurrence was also recorded; included were the date that tumor recurrence was suspected by the examining veterinarian or owner, diagnostic methods performed to determine tumor recurrence, and the diagnostic evaluation results. Recurrence was confirmed with cytologic or histopathologic examinations where possible. Tumor recurrence was presumed to have occurred if masses were detected in the region of the scar for patients that had further diagnostic testing or surgery declined by the owner. For patients that had not been evaluated ≤ 6 months before retrospective data collection, referring veterinarians were contacted for follow-up information. Referring veterinarians were asked to indicate the date of the most recent recheck examination and whether there was evidence of tumor recurrence at that time. For patients that had not been evaluated by the primary care veterinarian ≤ 6 months before data collection, owners were contacted by telephone and asked if they had observed any new growths or tumors on or near the previous tumor site at any point during the dog's life after treatment; if the patient was deceased, owners were asked to indicate the cause of death (if known). All phone calls to referring veterinarians and owners were performed by 1 investigator (NSB). Patients that did not have a minimum of 4 months of follow-up after the date of tumor excision were excluded from the follow-up analysis.
Cisplatin-impregnated beads
Cisplatin-containing beads (each 3 mm in diameter and containing approx 1.6 mg of cisplatin) were obtained from a compounding pharmacy.b Tumor resection was performed by a board-certified surgeon or was performed prior to referral to the study hospital by a general practitioner. Scar revision surgeries were performed at the study hospital in some cases to remove residual disease according to the discretion of the attending surgeon and the owner's wishes. All beads were implanted by a board-certified veterinary surgeon immediately following tumor resection and prior to wound closure, at the time of scar revision surgery, or after the primary incision was healed. Beads were placed while patients were under general anesthesia, which was induced with protocols selected according to the attending anesthetist's discretion. For dogs undergoing bead placement after the incision was healed, the site was aseptically prepared for surgery, and small stab incisions were made in the skin at 1- to 2-cm intervals along the scar and approximately 2 cm lateral to the scar on both sides. One cisplatin-impregnated bead was implanted into each stab incision, which was then closed with a single interrupted skin suture. Suture material was chosen at the discretion of the surgeon and included polypropylene, polydioxanone, nylon, and poliglecaprone 25.
After bead placement and wound closure, patients received analgesic medication (tramadol [3 to 5 mg/kg {1.4 to 2.3 mg/lb}, PO, q 8 h], an NSAID [carprofen, 2.2 mg/kg {1 mg/lb}, PO, q 12 h; meloxicam, 0.1 mg/kg {0.05 mg/lb}, PO, q 24 h; or firocoxib, 5 mg/kg, PO, q 24 h], or both). In addition, some patients received antimicrobials (cephalexin [22 to 30 mg/kg {10 to 13.6 mg/lb}, PO, q 12 h], amoxicillin-clavulanic acid [13.75 mg/kg {6.25 mg/lb}, PO, q 12 h], or clindamycin [11 mg/kg {5 mg/lb}, PO, q 12 h]) at the preference of the surgeon. Patients were monitored routinely after surgery. Upon hospital discharge, all clients were advised to keep an Elizabethan collar on the dog until incisions were healed and sutures were removed. Postoperative treatments in some patients included metronomic chemotherapy, which was typically initiated at the time of suture removal. Metronomic chemotherapy included cyclophosphamide (12 to 15 mg/m2, PO, q 24 h) with or without piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h) and doxycycline (3 to 5 mg/kg, PO, q 24 h).
Evaluation of local toxicosis
Complications of wound healing associated with the bead sites were graded retrospectively on the basis of physical examinations recorded during the postoperative period (up to 14 days after surgery). The grading of toxic changes was performed on the basis of a classification scheme according to Dunn et al14 and used by Havlicek et al.13 Changes were graded as mild (fluctuant swelling with no drainage or tissue necrosis), moderate (swelling with heat, erythema, drainage, and wound breakdown without tissue necrosis), or severe (drainage with tissue necrosis). For patients that had multiple surgical wounds for bead placement, the wound with the highest grading was used for analysis. Patients were excluded from the analysis of local toxicosis if the incisions were not described in the follow-up physical examination records.
Statistical analysis
The DFI was defined as the interval between surgical excision prior to bead placement and evidence of local tumor recurrence. Kaplan-Meier analysis was used to determine median DFI and percentages of patients that remained free of STS at 1, 2, and 3 years after surgery. Patients that were lost to follow-up or did not have tumor recurrence at the time of completion of the study were censored. A Fisher exact test was used to assess differences in the frequency of local toxicosis attributable to cisplatin beads for beads placed at the time of tumor resection versus beads placed after healing of the primary incision. A Fisher exact test was also used to assess the differences between recurrence rates of tumors in patients that underwent scar revision and patients that did not have scar revision prior to cisplatin bead placement. The Wilcoxon rank sum test was used to assess differences in the median time to bead placement for dogs that developed tumor recurrence and those that did not develop recurrence. All analyses were performed with a statistical software package.c Values of P < 0.05 were accepted as significant.
Results
Dogs
Sixty-four dogs underwent placement of cisplatin-impregnated beads during the study period. Two dogs were excluded from the study because beads were placed into gross tumors without previous tumor excision. Of the remaining 62 dogs, 31 (50%) were spayed females, 30 (48%) were neutered males, and 1 (2%) was a sexually intact male. Median age of dogs at the time of tumor excision was 10.0 years (range, 3.91 to 13.65 years). The most commonly represented breeds were mixed (n = 16), Golden Retriever (9), Labrador Retrievers (5), Boxer (4), Siberian Husky (3), Shetland Sheepdog (3), Beagle (2), Rottweiler (2), and Whippet (2). Other breeds included Maltese, Wheaton Terrier, Cairn Terrier, Pit Bull Terrier, Standard Poodle, Miniature Schnauzer, Cocker Spaniel, Springer Spaniel, Dachshund, Weimaraner, Collie, Greyhound, German Shorthaired Pointer, Doberman Pinscher, Border Collie, and Newfoundland (1 each).
Each dog underwent treatment for 1 tumor. Forty-four (71%) were primary tumors, and 18 (29%) were tumors that had recurred after previous surgical excision. Fifty (81%) tumors were resected by board-certified surgeons, and 12 (19%) were resected by general practitioners. For recurrent tumors, previous treatment had consisted of surgery alone in most (16/18) cases. One patient with a grade 3 tumor was previously treated with surgery followed by RT (18 fractions of 3 Gy each; 54 Gy total), and another patient with a grade 1 tumor had previously undergone surgery and metronomic chemotherapy with cyclophosphamide, deracoxib, and doxycycline.
Local toxicosis
Follow-up data for bead site reactions were available for 51 of 62 (82%) patients. Tumor types for these 51 patients, as described by the reporting pathologist, included PNST or hemangiopericytoma (n = 39), STS of undetermined histogenesis (5), spindle cell sarcoma (1), myxosarcoma (2), fibrosarcoma (2), liposarcoma (1), and hemangiosarcoma (1). There were 38 grade 1, 9 grade 2, and 4 grade 3 tumors. Tumor localization was as follows: limbs and tail (n = 38), trunk (7), and head or neck (5). The tumor location for 1 patient was not recorded.
Twenty-seven of 51 (53%) patients had no evidence of local toxic changes associated with the site of cisplatin-impregnated bead placement. Local toxicosis was detected in the remaining 24 (47%) dogs and graded as mild in 12 (24%), moderate in 10 (20%), and severe in 2 (4%). All incisions healed with local wound management and antimicrobial treatment at the discretion of the attending clinician. No patients required subsequent surgeries at the treatment site or limb amputation.
Median time to bead placement after tumor excision in 51 dogs was 21 days (range, 0 to 94 days). Most (40/51 [78%]) dogs had cisplatin-containing beads placed after the primary incision from tumor resection had healed. Seventeen of these 40 (43%) dogs had evidence of local toxicosis (mild in 9, moderate in 7, and severe in 1). Eleven of the 51 (22%) dogs had beads placed into the surgical wound at the time of tumor removal or scar revision surgery; local toxicosis was identified in 7 of these 11 dogs (mild in 3, moderate in 3, and severe in 1). The proportion of dogs that that had beads placed at the time of tumor resection and developed local toxicosis (17/40) did not differ significantly (P = 0.310) from that of dogs that developed the condition following delayed bead placement (7/11).
Systemic toxicosis
The median total dose of cisplatin delivered through bead application was 15.5 mg/m2 (range, 4.0 to 51.69 mg/m2). One dog that received a total cisplatin dose of 51.69 mg/m2 was evaluated at the study hospital because of diarrhea and lethargy 14 days after bead placement. On examination, the dog had a high body temperature (40.6°C [105.1°F]); a CBC and serum biochemical analysis revealed cytopenias (WBC concentration, 0.5 × 103 cells/µL [reference range, 6.0 × 103 cells/µL to 17.0 × 103 cells/µL]; granulocyte concentration, 0.2 × 103 cells/µL [reference range, 3.5 × 103 cells/µL to 12.0 × 103 cells/µL]; platelet count, 47 × 103 platelets/µL [reference range, 200 × 103 platelets/µL to 500 × 103 platelets/µL]) with Hct within the reference range. Indicators of renal function (serum BUN and creatinine concentrations) were within the respective reference ranges at this time. The dog was hospitalized and treated for presumptive neutropenic sepsis with IV fluids and broad-spectrum antimicrobials. The patient recovered without further complications. No other patients in the study had clinical signs of systemic toxicosis.
Outcomes
Follow-up data were available for 51 of 62 (82%) study dogs, of which 43 (84%) were among those with sufficient information available for inclusion in the short-term analysis of local toxicosis. The median follow-up time was 513 days (range, 99 to 1,156 days).
Tumor types for the 51 dogs with outcome data available included PNST or hemangiopericytoma (n = 37), STS of undetermined histogenesis (7), spindle cell sarcoma (1), myxosarcoma (2), fibrosarcoma (3), and liposarcoma (1). There were 39 grade 1, 8 grade 2, and 4 grade 3 tumors. Twelve of these patients had been treated for recurrent tumors and 39 for primary tumors. Fifteen of 51 (29%) dogs had local tumor recurrence. Recurrence was reported for 11 of 39 grade 1 tumors, 0 of 8 grade 2 tumors, and 4 of 4 grade 3 tumors. Of the grade 1 tumors that recurred, 10 were PNSTs or hemangiopericytomas, and 1 was a myxosarcoma. All grade 3 tumors were PNSTs or hemangiopericytomas.
Forty-five of 51 tumors of dogs with follow-up data had histologically determined margins reported, most of which were either incomplete (n = 35) or had margins that were ≤ 3 mm in at least 1 area (n = 9) as reported by the pathologist. Six of the 51 tumors did not have reported histologic margins. Two of the 6 tumors without margin data were determined to be grade 3 and recurred. One tumor had histopathologic margins reported to be 1 to 2 cm, but this tumor was also high grade and recurred. Out of the 51 tumors with follow-up data, 15 (29%) tumors recurred.
A median DFI for all dogs was not reached. The disease-free survival rates of dogs at 1, 2, and 3 years after tumor resection and cisplatin-impregnated bead placement were 81%, 69%, and 59%, respectively (Figure 1).
Time-to-event curve depicting DFI for 51 client-owned dogs of various breeds with primary (n = 39) or locally recurrent (12) STSs treated by marginal resection and placement of cisplatin-impregnated beads. Dogs were required to have a minimum follow-up time of 4 months after tumor excision to be included in the analysis. Patients without evidence of tumor recurrence at the time of last follow-up and those that died without tumor recurrence were censored on the applicable date. Owing to the high disease-free survival rate of dogs during the study period, a median DFI was not reached for the overall study population.
Citation: Journal of the American Veterinary Medical Association 248, 10; 10.2460/javma.248.10.1148
The DFIs for dogs with grade 3 tumors were compared with those of dogs with grade 1 and 2 tumors combined. The median DFI for the 4 dogs with grade 3 STS was 148 days, while a median DFI was not reached for the 47 dogs with grade 1 and 2 tumors (P < 0.001; Figure 2). The disease-free survival rates for dogs with grade 1 and 2 tumors were 88%, 75%, and 64% at 1, 2, and 3 years after tumor resection, respectively.
Time-to-event curves depicting DFI for the same dogs as in Figure 1 categorized according to tumor grade (1 or 2 [black line; n = 47] vs 3 [gray line; 4]). A median DFI for dogs with grade 1 and 2 tumors was not reached, whereas that for dogs with grade 3 tumors was 148 days (P < 0.001).
Citation: Journal of the American Veterinary Medical Association 248, 10; 10.2460/javma.248.10.1148
Outcome for dogs that underwent marginal excision and cisplatin-impregnated bead placement as part of the treatment for primary tumors was compared with that for dogs that underwent this treatment for tumors that had recurred. A significantly (P = 0.004) higher proportion of dogs treated for recurrent tumors (6/12) had subsequent local tumor recurrence than did dogs treated for primary tumors (9/39). The median DFI for dogs treated for recurrent tumors was 417 days, whereas a median DFI was not reached for dogs treated for primary tumors (Figure 3).
Time-to-event curves depicting DFI for the same dogs as in Figure 1 categorized as having been treated for primary (gray line; n = 39) versus recurrent tumors (black line; 12). A median DFI for dogs that were treated for primary, de novo tumors was not reached, whereas that for dogs treated for recurrent tumors was 417 days (P = 0.004).
Citation: Journal of the American Veterinary Medical Association 248, 10; 10.2460/javma.248.10.1148
Nine of the 51 dogs with follow-up data available had cisplatin-impregnated beads placed following scar revision. Three of these 9 patients had tumor recurrence subsequent to the treatment, which was similar (P = 1.000) to the recurrence rate observed in the patients that did not have scar revision surgery (12/42 [29%]). The median time from tumor resection or scar revision to bead placement for the 51 dogs was 22 days (range, 0 to 94 days). Median time to bead placement for the 15 patients that subsequently had local recurrence of tumors was 21 days (range, 0 to 41 days), and that for the 36 patients that did not develop local tumor recurrence was 23.5 days (range, 0 to 94 days). This difference was not significant (P = 0.841).
Two of 9 dogs that had beads placed at the time of tumor resection and had follow-up available had local tumor recurrence, whereas 13 of the remaining 42 dogs (which had beads placed through a subsequent surgery after tumor resection) had recurrence. These recurrence rates did not differ significantly (P = 0.370).
Seven patients received metronomic cyclophosphamide-based chemotherapy with or without piroxicam and doxycycline following tumor resection and placement of cisplatin-containing beads. Four of these dogs had tumor recurrence detected 121, 175, 192, and 436 days after tumor resection. Tumors of these patients had been characterized as grades 3, 3, 3, and 1, respectively. The other 3 dogs that had systemic chemotherapy in addition to the intralesional treatment were disease free at last follow-up 284, 575, and 637 days after tumor excision; the tumors of all 3 dogs were grade 1.
Discussion
Overall, cisplatin-impregnated beads were considered to be well tolerated by most dogs in this retrospective study. Local toxicosis was fairly common (observed in 24/51 [47%] patients with data available), but these effects were non–life-threatening and generally considered mild (12/27) or moderate (10/27). Only 1 dog had signs consistent with systemic toxicosis (suspected neutropenic sepsis), which resolved with medical treatment. Healing of the surgical bead placement sites was not affected in dogs that had local toxic changes classified as mild. Even for patients with severe local toxicosis, the effects were focal and located at individual bead placement sites. These lesions were small, measuring < 1 to 2 cm in diameter, and resolved with local wound management and antimicrobial treatment.
Dogs in the present study had signs of toxicosis less commonly, and the signs were generally less severe, compared with results of previous studies13,15 in which biodegradable implants were used for intralesional delivery of cisplatin in dogs. Authors of those studies13,15 reported severe wound reactions with necrosis that required surgical removal of the implant in 9 of 32 tumors treated in 30 dogs15 and limb amputation in 1 case out of 19.13 However, the incidence of local toxicosis associated with the cisplatin-containing beads in our study was greater than that reported for dogs that received coarse-fractionated RT following marginal excision of STSs.7 The complication rate following coarse-fractionated RT in that study7 was reported as 6 of 56 (11%) dogs with complications including wound dehiscence, self-induced traumatic injury, and osteonecrosis. Adverse effects of postoperative full-course (definitive) RT used for treatment of incompletely excised STS in dogs have also been reported to be fairly infrequent and mild, consisting primarily of local skin irritation with alopecia and hyperpigmentation in the radiation field.5 It is difficult to directly compare toxicosis associated with implantation of cisplatin-impregnated beads to radiation site toxicosis, considering that the expected adverse effects of these treatments are considerably different.
Owner compliance likely impacted the local toxicosis data in the present study. There were multiple records reporting that patients were allowed to lick the bead site at home, which likely contributed to local irritation at the bead sites. Strict use of Elizabethan collars, and possibly soft bandages, until time of suture removal is recommended for dogs that have cisplatin-containing beads placed.
Systemic adverse effects were not a primary focus of the present study because authors of other studies13–16 investigating the use of intralesional cisplatin have not observed such adverse effects. However, 1 dog in the present study had cytopenias and suspected sepsis 14 days after cisplatin-containing bead implantation, suggesting bone marrow suppression secondary to systemic cisplatin absorption. That dog had received the highest dose of cisplatin (51.69 mg/m2) of all patients in the study but did not have any evidence of azotemia. It is possible that subclinical bone marrow suppression would have been detected in more patients if CBCs had been routinely obtained for patients undergoing the bead implantation. In addition, although nephrotoxicosis was not identified in any dogs during the study, serum biochemical analysis and measurement of urine specific gravity were not routinely performed for all patients after surgery. Given this instance of suspected adverse systemic effects attributable to cisplatin-impregnated beads and the standard IV dose of cisplatin used in dogs (60 to 70 mg/m2),10,16 we recommend using caution when approaching this dose range until pharmacodynamic studies are performed. Additionally, patients with large tumor beds requiring doses > 50 mg/m2 for adequate coverage may be best served by placing the beads in a staged procedure (dividing the bead dose in half and implanting the 2 portions into wound bed 14 to 21 days apart) to avoid delivering a large dose of cisplatin all at once and thus possibly avoid systemic adverse effects. Even in staged procedures, larger cumulative doses of cisplatin should be used with caution because of the potential for systemic toxicosis (including nephrotoxicosis). Given the observation of possible systemic toxicosis in 1 patient of the present study, research evaluating the pharmacodynamics of cisplatin-containing beads and their systemic adverse effects in dogs is warranted.
The timing of bead placement relative to tumor resection was not significantly associated with development of local toxicosis in the present study. Anecdotally, the surgeons performing the bead implantation had observed that wound complications were worse in patients that received beads at the time of tumor resection or scar revision, suggesting that intralesional cisplatin or the biodegradable bead material might inhibit or impede wound healing. Beads implanted at the time of tumor resection or scar revision may have the potential to migrate, especially in large wound beds, and this could potentially lead to uneven cisplatin distribution and increase the risk of tumor recurrence. We found no associations between timing of bead placement and development of local toxicosis or tumor recurrence; however, this should be interpreted cautiously because of the small sample size involved.
Cisplatin distribution throughout the tumor bed may be affected by the timing of bead placement. Theoretically, beads that are placed immediately into the primary tumor resection site may provide better coverage of the deep surgical margin, whereas beads placed in a staggered pattern to cover the scar and 2 cm surrounding the scar after the primary incision has healed could provide better coverage of the lateral margins. When data for dogs of the present study that did and did not have tumor recurrence were compared, there was no significant difference in median time to cisplatin-impregnated bead placement after surgery between groups. It is possible that implantation of beads at the time of primary tumor resection with repeated bead implantation at the time of primary incision healing would result in the most uniform cisplatin distribution. However, the staged combination treatment strategy could result in higher rates of local toxicosis. Although the risk of clinically relevant systemic absorption from these cisplatin-containing beads is unknown, the potential for systemic toxicosis should be taken into account when considering repeated bead placement.
Recurrence of STS treated by marginal excision alone has been examined through multiple studies2,3,9 with a wide range of results. Marginal excision as the sole treatment modality of low-grade STSs was shown to result in a local recurrence rate of 4 of 37 (11%) and mean DFI after tumor excision of 697.8 days, suggesting that marginal excision alone might be adequate for controlling local disease in low-grade tumors3; however, other sources1,9 have reported much lower DFIs for dogs with STS. For example, a study9 comparing results for dogs that underwent marginal tumor excision alone versus marginal excision combined with metronomic chemotherapy for treatment of cutaneous STS found a median DFI of 211 days for patients treated with marginal excision alone. The proportions of dogs with grade 1, 2, and 3 tumors within this historical control group were 14 of 55 (25%), 37 of 55 (67%), and 4 of 55 (7%), respectively.9 The higher percentages of dogs with grade 2 and 3 (vs grade 1) tumors could explain the shorter median DFI, compared with that of studies evaluating primarily grade 1 and 2 tumors.2,3
In the present study, the disease-free survival rates of dogs with STS treated by marginal excision and adjuvant local chemotherapy with cisplatin-containing beads were 81%, 69%, and 59% at 1, 2, and 3 years after tumor excision, respectively, and those of dogs with grade 1 and 2 tumors that underwent the same treatment were 88%, 75%, and 64%, respectively. Although a concurrent control group for this population of dogs would serve as the most appropriate basis for comparison, dogs in the present study had a longer DFI than dogs of the untreated control group (211 days) in a previous study.9
The results from the present study were also similar to findings of previous studies5–7 examining local recurrence of tumors treated with marginal excision and hypofractionated or definitive RT. Hypofractionated RT (4 once-weekly 8- to 9-Gy fractions) with marginal excision resulted in a local STS tumor recurrence rate of 10 of 56 (18%), and the percentages of dogs that were disease free 1 and 3 years after conclusion of RT protocol were 82% and 70%, respectively.7 Definitive RT following incomplete excision of STS in dogs has been investigated in 2 independent studies.5,6 In a study5 of 48 dogs with low- and intermediate-grade STSs that underwent surgery and definitive RT (three 3-Gy fractions/wk for a total of 21 fractions), 8 (17%) developed local tumor recurrence, and the median DFI was 1,082 days.5 The 1- and 2-year survival rates were each 87%, and the 3- and 4-year survival rates were each 81%. In a study6 of 35 dogs with various grades of STS treated with surgery and definitive RT (3- to 4.5-Gy fractions given once daily, Monday through Friday, for a total radiation dose of 42 to 57 Gy), 11 of 35 (31%) developed local recurrence, and a median time to local recurrence was not reached (in > 798 days).6 The percentages of dogs that were disease free 1, 2, and 3 years after surgery and RT were 71%, 60%, and 57%, respectively. These results were similar to the local recurrence rate (15/51 [29%]) and percentages of patients disease free 1, 2, and 3 years after tumor excision in our study (81%, 69%, and 59%, respectively).
Re-excision (scar revision surgery) of STSs alone has been shown to potentially decrease the rate of tumor recurrence, compared with marginal excision alone, in dogs.4 Although 9 patients in the present study underwent scar revision prior to placement of cisplatin-impregnated beads, this did not significantly impact tumor recurrence rate. In addition, Kaplan-Meier analysis comparing DFI between these 2 groups found no significant difference.
Seven dogs in the present study had received metronomic chemotherapy after placement of cisplatin-containing beads. Considering that metronomic chemotherapy has been shown to delay local recurrence of incompletely resected STS,9 it is possible that outcomes for these patients were influenced by this treatment. However, 3 of these dogs had grade 3 tumors and had tumor recurrence diagnosed 121, 175, and 192 days after surgery. These results suggested that cisplatin-containing beads used with the protocol described in this study are ineffective in preventing tumor recurrence, even with the addition of metronomic chemotherapy, in dogs with grade 3 STS. Although we found encouraging results for dogs with grade 1 or 2 STSs, 4 of 4 grade 3 tumors recurred within a short interval after tumor excision (median DFI, 148 days). Although the number of dogs with such high-grade tumors in this study was small, these results indicated that marginal excision followed by placement of cisplatin-containing beads as described here should not be considered an appropriate treatment option for local control of high-grade STS.
Limitations of the present study were largely attributable to, and inherent in, its retrospective design. Uniform bead placement relative to the surgical bed, wound evaluations, and follow-up examinations were lacking, which could have affected the data for local toxicosis and tumor recurrence. Not only were wound evaluations performed by multiple surgeons, but the wound descriptions from historical examinations were used to give each wound a toxicosis rating. In an attempt to collect follow-up information regarding tumor sites, referring veterinarians and owners were contacted by telephone, and records quality or recollection ability of these contacts has impacted some of the data. In addition, the low sample size available for analysis precluded accurate isolation of risk factors related to outcome. Importantly, the lack of a concurrent control group in our study makes it impossible to determine whether the placement of cisplatin-impregnated beads alone delays STS recurrence, compared with marginal excision alone. Recommendations for future prospective studies include comparison of marginal excision combined with cisplatin-containing bead placement versus marginal excision alone for treatment of dogs with low- and intermediate-grade STSs; these studies should incorporate a standardized scale for evaluation of signs of local toxicosis at bead placement sites and a uniform reexamination schedule to evaluate dogs for tumor recurrence.
Results of the present study suggested that marginal excision with adjuvant local chemotherapy delivered by intralesional placement of cisplatin-impregnated beads may be a reasonable alternative to postoperative RT for treatment of low- and intermediate-grade STSs (grades 1 and 2, respectively) in dogs, although controlled prospective studies are needed to confirm this. Cisplatin-containing beads are emerging as an important treatment option for patients residing in locations where RT is not readily available. Furthermore, the cost of these beads is substantially less than that of RT, and the procedure requires fewer anesthetic events, indicating it may be advantageous in patients for which multiple anesthetic events may pose unacceptable risks.
Acknowledgments
The authors declare that there were no conflicts of interest.
Presented in abstract form at the 2013 Annual Veterinary Cancer Society Conference, Minneapolis, October 2013.
The authors did not receive any funding or financial support in connection with performing this study or in the writing and publication of the manuscript.
ABBREVIATIONS
| DFI | Disease-free interval |
| OPLA-Pt | Open-cell polyacetic acid impregnated with cisplatin |
| PNST | Peripheral nerve sheath tumor |
| RT | Radiation therapy |
| STS | Soft tissue sarcoma |
Footnotes
Marble GM, Sullins KE. A biodegradable matrix for cisplatin to treat equine skin neoplasia (abstr), in Proceedings. 10th Annu Am Coll Vet Surg Symp 2000;469.
Wedgewood Pharmacy, Swedesboro, NJ.
GraphPad Prism, version 6.07, Graphpad Software Inc, San Diego, Calif.
References
1. Liptak JM, Forrest LJ. Soft-tissue sarcomas. In: Withrow SJ, Vail DM, eds. Withrow and MacEwen's small animal clinical oncology. 4th ed. St Louis: Saunders Elsevier, 2007;425–453.
2. Graves GM, Bjorling DE, Mahaffey E. Canine hemangiopericytoma: 23 cases (1967–1984). J Am Vet Med Assoc 1988; 192: 99–102.
3. Stefanello D, Morello E, Roccabianca P, et al. Marginal excision of low-grade spindle cell sarcoma of canine extremities: 35 dogs (1996–2006). Vet Surg 2008; 37: 461–465.
4. Bacon NJ, Dernell WS, Ehrhart N, et al. Evaluation of primary re-excision after recent inadequate resection of soft tissue sarcomas in dogs: 41 cases (1999–2004). J Am Vet Med Assoc 2007; 230: 548–554.
5. McKnight JA, Mauldin GN, McEntee MC, et al. Radiation treatment for incompletely resected soft-tissue sarcomas in dogs. J Am Vet Med Assoc 2000; 217: 205–210.
6. Forrest LJ, Chun R, Adams WM, et al. Postoperative radiotherapy for canine soft tissue sarcoma. J Vet Intern Med 2000; 14: 578–582.
7. Demetriou JL, Brearley MJ, Constantino-Casas F, et al. Intentional marginal excision of canine limb soft tissue sarcomas followed by radiotherapy. J Small Anim Pract 2012; 53: 174–181.
8. Selting KA, Powers BE, Thompson LJ, et al. Outcome of dogs with high-grade soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy: 39 cases (1996–2004). J Am Vet Med Assoc 2005; 227: 1442–1448.
9. Elmslie RE, Glawe P, Dow SW. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. J Vet Intern Med 2008; 22: 1373–1379.
10. Barabas K, Milner R, Lurie D, et al. Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol 2008; 6: 1–18.
11. Hewes CA, Sullins KE. Use of cisplatin-containing biodegradable beads for treatment of cutaneous neoplasia in equidae: 59 cases (2000–2004). J Am Vet Med Assoc 2006; 229: 1617–1622.
12. Hewes CA. How to use bioabsorbable cisplatin beads to treat cutaneous neoplasia, in Proceedings. 53rd Annu Conv Am Assoc Equine Pract 2007; 53: 399–400.
13. Havlicek M, Straw RS, Langova V, et al. Intraoperative cisplatin for the treatment of canine extremity soft tissue sarcomas. Vet Comp Oncol 2009; 7: 122–129.
14. Dunn RL, Yewey GL, Fujita SM, et al. Sustained release of cisplatin in dogs from an injectable implant delivery system. J Bioact Compat Polym 1996; 11: 286–300.
15. Dernell WS, Withrow SJ, Straw RC, et al. Intracavitary treatment of soft tissue sarcomas in dogs using cisplatin in a biodegradable polymer. Anticancer Res 1997; 17: 4499–4505.
16. Withrow SJ, Liptak JM, Straw RC, et al. Biodegradable cisplatin polymer in limb-sparing surgery for canine osteosarcoma. Ann Surg Oncol 2004; 11: 705–713.
17. Cisplatin: implantable bead. Available at: www.wedgewoodpetrx.com/items/cisplatin-implantable-bead.html. Accessed Jan 16, 2016.
18. Kuntz CA, Dernell WS, Power BE, et al. Prognostic factors for surgical treatment of soft-tissue sarcomas in dogs: 75 cases (1986–1996). J Am Vet Med Assoc 1997; 211: 1147–1151.
