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10.1245/ASO.2005.01.011
Annals of Surgical Oncology 12:1073-1083 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Improved Survival Associated With Postoperative Wound Infection in Dogs Treated With Limb-Salvage Surgery for Osteosarcoma

B. Duncan X. Lascelles, BVSc, PhD1, William S. Dernell, DVM, MS2, Maria T. Correa, MSc, PhD3, Mary Lafferty2, Chad M. Devitt, DVM, MS2, Charles A. Kuntz, DVM, MS2, Rodney C. Straw, DVM, MS2 and Stephen J. Withrow, DVM2

1 Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606
2 Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado 80523
3 Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606

Correspondence: Address correspondence and reprint requests to: B. Duncan X. Lascelles, BVSc, PhD; E-mail: duncan_lascelles{at}ncsu.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Limb-salvage surgery and adjuvant chemotherapy are performed as a treatment of appendicular osteosarcoma in dogs. Approximately 50% of dogs that undergo limb-salvage surgery develop postoperative surgical wound infections. Postoperative surgical infections may affect survival in cancer patients. The purposes of this study were to examine the effect of surgical wound infection on survival, local recurrence, and metastasis in relation to other prognostic factors for dogs with spontaneous osteosarcoma treated with limb-salvage surgery.

Methods: Forty-seven client-owned dogs with osteosarcoma of the distal radius were treated with limb-salvage surgery and adjuvant chemotherapy—either carboplatin or carboplatin and doxorubicin. Hazard ratios were estimated by using the Cox proportional hazard model, and survival functions were estimated by using the Kaplan-Meier product-limit life-table method.

Results: Of the 47 dogs in this study, 32 (68%) developed a postoperative wound infection. Infection, dog weight, and extent of the primary tumor (percentage of length) significantly affected survival, and infection and percentage of length significantly affected time to metastasis. None of the variables considered in this study affected local recurrence. Dogs that were diagnosed with an infection were less likely to die (hazard ratio, .446), and dogs with greater body weight and greater percentage length involvement were more likely to die (hazard ratios of 3.37 and 3.66, respectively).

Conclusions: In dogs with osteosarcoma treated with limb-salvage surgery, infection has a positive influence on survival, as does a smaller initial length of radius involved and lower body weight.

Key Words: Osteosarcoma • Canine • Limb salvage • Postoperative infection


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Spontaneously occurring canine osteosarcoma is biologically similar to human osteosarcoma, characterized as a locally destructive malignancy with a high incidence of occult micrometastasis present at the time of diagnosis.1,2 In dogs, surgical excision of the primary cancer and adjuvant chemotherapy protocols have improved the outcome of appendicular osteosarcoma from approximately 10% survival at 1 year to 40% to 50% survival at 1 year.1,3–9 With this improvement in survival, interest turned to saving the legs of dogs with osteosarcoma, and limb-salvage techniques have been reported.3,6,10 Functional use of the limb is good or excellent in 70% of dogs with radioulnar limb-salvage surgery.6 It has been considered that limb salvage itself does not affect overall survival when compared with dogs that have undergone amputation and similar adjuvant chemotherapy regimens.6,10 Despite strict aseptic technique, the most common complication of canine limb salvage is postoperative surgical wound infection, which occurs in approximately 50% of cases.6,10 It is interesting to note that dogs with a postoperative surgical wound infection after preoperative limb radiotherapy followed by limb-salvage surgery had increased survival times compared with their noninfected correlates.11

At the end of the 19th century, William B. Coley performed experiments looking at the effect of infection, or components of bacteria, on neoplastic processes, and this eventually led to the discovery of tumor necrosis factor (TNF) and early work in cancer immunotherapy.12 Clinically, improved survival after resection of pulmonary carcinoma and laryngeal cancer has been associated with postoperative bacterial infections in humans.13–15 However, postoperative wound infections have been associated with both increased16,17 and decreased18 incidences of local tumor recurrence for stage II melanoma and head and neck cancers. Improvements in survival may be associated with nonspecific modulators of the immune system.13,15,19 The purpose of this study was to describe the effect of postoperative surgical wound infection on survival, local recurrence, and metastasis in relation to other variables in spontaneous canine osteosarcoma of the distal radius treated with limb-salvage surgery and chemotherapy.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
Forty-seven client-owned dogs with histopathologically confirmed osteosarcoma of the distal radius fulfilled the criteria for treatment by limb salvage with an allograft at the Colorado State University Veterinary Teaching Hospital between January 1996 and January 2001. All dogs received local chemotherapy to attempt to decrease the incidence of local recurrence,20 and all dogs received postoperative systemic chemotherapy as treatment of micrometa-static disease. Baseline data included clinical examination, hematology, a serum biochemistry profile (including serum alkaline phosphatase), urinalysis, regional radiographs, three-view thoracic radiographs, and needle-core biopsy of the bone lesion and a whole-body 99mTc scintigraphic scan.

For dogs to be considered for limb-salvage surgery, the following criteria had to be fulfilled:

  1. The dog was free of pulmonary metastatic disease as determined by three-view thoracic radiographs.
  2. The dog was free of occult bony metastatic disease as determined by 99mTc-methylenediphosphonate (MDP) scintigraphy.
  3. The primary neoplasm involved <50% of the bone length, and no pathologic fracture was present.
  4. The extent of soft tissue involvement, as determined by physical evaluation, did not preclude preservation of blood supply to the distal extremity.
  5. The dog was free of comorbidities that could preclude survival beyond 1 year after surgery.

Surgical Procedure
After aseptic preparation of the affected limb, a craniolateral approach to the radius and ulna was made. Excision was accomplished as described previously.2,6,20 Reconstruction with a massive cortical fresh-frozen allograft was performed as described previously.2,6,20 In all patients, the medulla of the allograft was packed with tobramycin- and vanco-mycin-impregnated polymethylmethacrylate to augment the structural stability of the allograft-implant construct.21 Reconstruction of the distal radius necessitated pancarpal arthrodesis. A biodegradable cisplatin-containing implant (open-cell polylactic acid [OPLA-Pt]; Kensey Nash Corporation, Exton, PA) was placed in the surgical wound before closure of the surgical wound.20

Perioperative Antibiotic Protocol
Before initiation of the surgical procedure, first-generation cephalosporins were administered intravenously and repeated if necessary during the surgical procedure (cefazolin 20 mg/kg every 90 minutes). Patients were continued on the same intravenous antibiotic (cefazolin 20 mg/kg intravenously every 8 hours) until surgical drain removal and were then switched to oral antibiotics (cephalothin 20 mg/kg by mouth every 8 hours) until 4 weeks after the end of the chemotherapy regimen. Antibiotics were reinstituted if clinically indicated. When postoperative infection was not controlled by oral antibiotics, tobramycin- and vancomycin-impregnated polymethyl-methacrylate beads were placed in the surgical site.22

Perioperative Analgesic Protocol
Perioperative analgesia was provided by using a combination of preoperative opioids (morphine .5 mg/kg intramuscularly), a preoperative brachial plexus block in some cases (3–7 mL of 2% bupivacaine), postoperative fentanyl infusions (2–6 µg/kg/hour), postoperative oral morphine (.5 mg/kg up to three times daily), and nonsteroidal anti-inflammatory drugs (NSAIDs; carprofen 2 mg/kg twice daily, piroxicam .3 mg/kg once daily, etodolac 10–15 mg/kg once daily, or acetaminophen/codeine combination, dosed at 10–15 mg/kg of acetaminophen twice daily).

Chemotherapy
All patients received intraoperative OPLA impregnated with cisplatin (OPLA-Pt).20 This biodegradable polymer was placed in the wound bed before closure of the surgical wound. The total dose of cisplatin administered was 25 to 60 mg/m2. This provided for a sustained release of cisplatin with the aim of reducing the incidence of local recurrence.

All patients received postoperative systemic chemotherapy with either single-agent carboplatin (doses of 300 mg/m2 with the intent of giving four doses at 2-week intervals) or dual-agent carboplatin and doxorubicin (carboplatin 300 mg/m2 and doxorubicin 30 mg/m2, each drug given alternately at 3-week intervals, with the intent of giving six cycles of chemotherapy [three of each drug]).

Classification of Surgical Wound
Postoperative surgical wounds were evaluated at each follow-up interval. The gross appearance of the surgical wound was classified as follows:

  1. Normal: clean, dry, and intact cutaneous covering.
  2. Questionable infection: limb swelling, significant wound drainage, and negative culture.
  3. Definite infection: significant wound drainage and positive culture.
  4. Occult infection: identified at postmortem evaluation.

The affected surgical wounds were further classified regarding the onset of infection (early, time of onset <111 days after surgery; late, time of onset >111 days after surgery), duration of infection (<2 or >2 months), and severity of infection (mild: incisional drainage; moderate: incisional drainage and partial wound dehiscence; and severe: drainage, wound dehiscence, and tissue loss resulting in exposed bone). Aerobic and anaerobic cultures were submitted of aseptically collected deep tissue aspirates. Data regarding the genus and species of each bacterial isolate and the antibiotics used were recorded.

Follow-Up Evaluation
Dogs were released to their owners’ care 3 to 5 days after surgery. Patients were maintained in a soft padded bandage until suture removal or as otherwise clinically indicated. Follow-up evaluations were performed at each time chemotherapy was administered and then every 30 days for the first 3 months and every 3 months thereafter. Follow-up evaluations were performed at Colorado State University Veterinary Teaching Hospital or referring veterinarians’ practices. At each follow-up, a full physical examination was performed, and three-view (left and right lateral and ventrodorsal) thoracic radiographs were made. All radiographs were evaluated by a board-certified veterinary radiologist. If local recurrence was suspected, it was confirmed by either radiography or biopsy. Other sites of possible metastasis were evaluated as needed.

Statistical Evaluation
Descriptive statistics were obtained for all putative variables: sex of dog, dog weight, chemotherapy type, preoperative serum alkaline phosphatase level, infection, time of onset of infection, severity of infection, chronic use of NSAIDs, percentage of length of the bone originally involved, tumor site, and the application of antibiotic-impregnated beads at the wound site. Variables were redefined if the data were sparse or if the data distribution presented gaps, to produce a smaller number of categories for model stability (Table 1Go). Survival functions (survival and time to metastasis) were estimated by using the Kaplan-Meier product-limit life-table method, whereas the effects of variables on survival and time to metastasis were assessed with the Cox proportional hazards model. Three models were considered: (1) with time to death for survival, (2) with time to metastasis as the end point, and (3) with time to recurrence as the end point. A no-interaction forward-modeling algorithm was used to determine each variable’s contribution to the outcome of interest, as determined by the likelihood ratio {chi}2 test at a P value of ≤ .05. Variables that statistically contributed to the outcome of interest were included in further multivariate models. The sex of the dog was evaluated as a possible confounder; confounding was defined as the change of one unit on the hazard ratio (HR) in each direction.


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  		TABLE 1. Variable definition for statistical modeling
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The dogs in this study were larger-breed dogs, with an average weight of 49 kg. Twenty-five were castrated males, 5 were intact males, 15 were spayed females, and 2 were intact females. All dogs underwent limb-salvage surgery; 23 of the dogs received single-agent carboplatin chemotherapy, and 24 received a combination of carboplatin and doxorubicin chemotherapy. The median dose of cisplatin used in the wound was 40 mg/m2 (range, 25–60 mg/m2). Of the 47 dogs in this study, 32 (68%) developed a postoperative wound infection. Twelve (37.5%) of those infections were classified as severe, and the rest were classified as mild to moderate. Of the 32 dogs that developed infection some time after surgery, 15 (47%) developed the infection during the course of chemotherapy, and 17 (53%) did so after the course of chemotherapy. Sixteen dogs developed infection at some point <111 days after surgery (early onset), and 16 did so at some point >111 days after surgery (late onset). In all but 4 dogs, the infection was continuous from the time it was established to the end of the study. Overall, the duration of infection (mean ± SD) was 350 ± 293 days. In 27 of the 32 dogs that developed infection, culture results were positive. Eight of these had single isolates grown (Staphylococcus species in 5 and Pseudomonas species in 3), and 19 had multiple isolates. The most common bacteria isolated were Staphylococcus species (14 isolates), followed by Pseudomonas species (9 isolates) and then Streptococcus species (6 isolates).

In the dogs that developed an infection, the antibiotics most commonly used were cephalothin (24 dogs), enrofloxacin (20 dogs), clavulanatepotentiated amoxicillin (9 dogs), amoxicillin (6 dogs), and ciprofloxacin (4 dogs). The species of bacteria cultures and the antibiotic used were not used in the models because of the sparse nature of data on any individual species or antibiotic.

At the conclusion of the study, 38 of the dogs were dead, 8 were alive and free of metastatic or local disease, and 1 was alive with metastatic disease. NSAID use after the immediate postoperative period was known for only 19 of the 47 dogs, and of these, NSAIDs were used chronically (for the remainder of the dog’s life) in 14 cases.

For all dogs, the overall median time to metastasis was 315 days, and the overall median survival time was 429 days.

For model 1, with survival as the end point, infection, percentage length, and dog weight had a significant effect: HRs were .446 for infection, 3.37 for dog weight, and 3.66 for percentage length (Table 2Go). In other words, dogs that were diagnosed with an infection were half as likely to die. Dogs in which the original tumor length was >29% of the total radial length were 3.7 times more likely to die than dogs in which the percentage length was <29%. Dogs weighing >49 kg were 3.4 times more likely to die than dogs weighing <49 kg. These effects are further illustrated by Kaplan-Meier estimations (Table 3Go; Figs. 1Go–3GoGo). Dogs that were diagnosed with an infection survived 252 days longer than dogs without an infection.


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  		TABLE 2. Cox proportional hazard final model with survival as the end point
 

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  		TABLE 3. Kaplan-Meier estimation of median survival times
 

Figure 1
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  		FIG. 1. Survival function for Kaplan-Meier estimation for survival in days by weight. Solid line, >49 kg; dotted line, <49 kg.

 

Figure 2
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  		FIG. 2. Survival function for Kaplan-Meier estimation for survival in days by infection. Solid line, dogs that developed wound infection; dotted line, dogs that did not develop wound infection.

 

Figure 3
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  		FIG. 3. Survival function for Kaplan-Meier estimation for survival in days by percentage length. Solid line, >29% of the radius involved; dotted line, <29% of the radius involved.

 
For model 2, with time to metastasis as the end point, infection and percentage length had a significant effect: HRs were .426 for infection and 3.21 for percentage length (Table 4Go). In other words, dogs that were diagnosed with an infection were half as likely to have metastasis diagnosed. However, dogs in which the original tumor length was >29% of the total radial length were >3.2 times more likely to have metastasis diagnosed than were dogs in which the percentage length was <29%. These effects are further illustrated by Kaplan-Meier estimations (Table 5Go; Figs. 4Go and 5Go). It is interesting to note that no factors were found to significantly affect local recurrence.


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  		TABLE 4. Cox proportional hazard final model with time to metastasis as the end point
 

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  		TABLE 5. Kaplan-Meier estimation of median times to metastasis
 

Figure 4
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  		FIG. 4. Survival function for Kaplan-Meier estimation for time to metastasis in days by infection. Solid line, dogs that developed wound infection; dotted line, dogs that did not develop wound infection.

 

Figure 5
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  		FIG. 5. Survival function for Kaplan-Meier estimation for time to metastasis in days by percentage length. Solid line, >29% of the radius involved; dotted line, <29% of the radius involved.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
From this study, it seems that, controlling for the effect of percentage length, there is a survival advantage for canine limb-salvage patients in whom the surgical site becomes infected over those that do not have infected surgical sites. Dogs that become infected are likely to live 250 days longer than dogs that do not become infected.

The literature contains a few accounts of improved outcome, as well as worsened outcome, associated with infection after cancer surgery. In 1966, Sensenig et al.14 reported the results of surgical treatment of bronchogenic carcinoma in which three of eight patients who developed empyema in the postoperative period survived >5 years. Ruckdeschel et al.15 also described improved survival in patients with surgical resection of carcinoma of the lung who developed empyema, reporting a 50% 5-year survival in infected patients and an 18% 5-year survival in noninfected patients. Schantz et al.13 reported improved survival with postoperative infection in laryngeal cancer, with a 73% 5-year survival rate in infected patients and a 32% 5-year survival rate in noninfected patients. Most recently, Sturgis et al.23 found that although this was not significant, in some groups of patients undergoing surgery for head and neck cancer, there was a trend toward improved survival in those who had a postoperative infection. However, Jackson and Rice17 reported increased local recurrence in laryngeal cancer patients with postoperative infection; this suggests that infection may have an adverse effect. Grandis et al.16 supported Jackson and Rice’s findings, reporting an increased recurrence rate with postoperative infection after resection of laryngeal carcinoma. A recent study also reported an increased risk of local tumor recurrence after surgery for rectal cancer in patients who developed local perineal infection; however, intra-abdominal sepsis had no effect on the rate of recurrence.24 No study has evaluated the effect of postoperative infection on survival in musculoskeletal tumor resection patients.

In canine appendicular osteosarcoma, Thrall et al.11 found a statistically significant positive relationship between allograft infection and survival and a nearly significant relationship between allograft infection and local tumor control. They suggested that these findings pointed to infection acting as an immunostimulant. The present study examined the effect of infection in relation to other factors. In our Cox proportional hazards model, infection had a positive effect on survival and time to metastasis. Previous studies have explored prognostic factors in osteosarcoma in dogs and humans.5,25–30 These studies have included the percentage necrosis after neoadjuvant chemotherapy, tumor size at presentation, surgical margin of resection, serum alkaline phosphatase activity, and location of the primary tumor as significant prognostic factors.

The prevalence of infection for limb-salvage surgery in humans is approximately 6% to 13%.31–33 The infection rate in this study was 68%; the higher infection rate was possibly due to the tendency of dogs to lick wounds. Inadequate soft tissue coverage and wound complications are the most common identified risk factors for infection in the immediate and later postoperative period.31 Paucity of tissue over the allograft and implant is the most notable risk factor associated with infection.

Another factor playing a role in the establishment of wound infection in dogs is the surgical attenuation of blood supply in an already poorly perfused site (the distal end of the radius). Even given these factors, the infection rate in the dogs in this study was 68%—much higher than the previously reported rates of infection after allograft limb salvage surgery in dogs of 31%6 and 44%.10 The expected infection rate in clean surgery in veterinary medicine is <5%.34 One possible reason contributing to this difference may be the more diligent follow-up in the present series. However, the main difference between those cohorts of dogs and the present group was the use of local chemotherapy to attempt to decrease the local recurrence rate. This chemotherapy is a biodegradable implant, OPLA, containing 8% cisplatin (OPLA-Pt) by weight. Over time, the polymer degrades and releases cisplatin locally into the wound.35,36 Cis-platin has been associated with impaired wound healing with systemic use in limb-sparing surgery,37 and the use of OPLA-Pt subcutaneously as an adjuvant for treatment of metastatic canine osteosarcoma was associated with local tissue reactions in 39% of cases.38 When OPLA-Pt is used as a local form of chemotherapy, high local doses of chemotherapy result and likely lead to further impairment of wound healing and, thus, higher infection rates.20 One human study described the risk period for infection with bone allografts as being within the first year after surgery,32 and all of the infections except one occurred within 1 year after surgery in our study. However, in one human study,31 70% of the infections occurred within 1 month of the initial operation. In our study, the median time to the onset of infection was 111 days. The types of organisms cultured from infected wounds in our study were similar to those found in human infected limb-salvage surgery sites.31

The involvement of bone with tumor ranged from 15% to 60% of the length of the radius. It seems from these data that there is a significant relationship between percentage length involvement and survival. This needs to be evaluated more closely, because missing values in these data may have interfered with the modeling. This variable has not been examined in previous studies, although there is some indication that large tumor size is related to poor outcome in canine osteosarcoma39 and in human osteosarcoma.26,40 There does not seem to be a relationship between percentage length involvement and infection, but the modeling suggested that there may well be some interaction, and this also needs evaluation with larger numbers. As has been found once previously,5 dog weight significantly affected survival. Bergman et al.5 suggested that this may be due to suboptimal dosing strategies. Another possibility is that larger dogs may be euthanized earlier as the end of life is neared because of problems with nursing heavier dogs.

The mechanism responsible for the prolonged survival and disease-free interval in infected postoperative limb-salvage patients has yet to be elucidated, but it might be due to upregulation of antitumor immunity. This could be mediated by cellular or humeral factors resulting from the infection; another possibility is that rejection of the allograft might result in rejection of the osteosarcoma.

After William B. Coley’s work looking at the effect of infection or components of bacteria on neoplastic processes,12 investigators have treated canine osteosarcoma patients with intravenous bacille Calmette-Guérin with mixed, but relatively poor, success.41–43 Research subsequent to Coley’s work demonstrated that components of his toxin induced TNF-{alpha} , which caused the death of tumor cells.44,45 However, recent studies have shown that the tumor-inhibiting effect of infections might be independent of the stimulation of TNF-{alpha} .46 Another mechanism by which infections may alter the course of neoplasia is via the upregulation of macrophages, natural killer (NK) cells, and T cells. A lyophilized extract of Streptococcus pyogenes, OK-432, has been shown to have a beneficial effect in human patients with terminal malignancies.47–49 The positive effect is attributed to the enhanced NK cell activity and cascade of cytokines; these result in the activation of other immune effector cells.50,51 Lysosome-encapsulated muramyl tripeptide (L-MTP-PE) is a bacterial cell wall–derived macrophage activator incorporated into lysosomes and results in the activation of macrophage antitumor effects after intravenous administration.52,53 In dogs with osteosarcoma treated with amputation and adjuvant cisplatin chemotherapy and then randomized to receive L-MTP-PE or placebo, dogs that received L-MTP-PE had a significantly prolonged survival and disease-free interval compared with placebo-treated controls.54 It certainly seems that infection-induced tumor-targeted cytotoxic cells exist55,56; however, recent work demonstrates macrophage-independent and cytotoxic cell–independent suppression of tumor growth by infection.57 These studies suggest that experimental infection with Toxoplasma gondii resulted in tumor suppression via an antiangiogenic effect and that this effect was due to systemic factors.57 It is not yet known what factors are responsible for this: TNF-{alpha} , interferons, interleukins, transforming growth factor ß , and acute phase proteins are all possibilities.58

Failure of chemotherapy likely results from selection pressure of chemoresistant clones within an occult micrometastasis.59 Cisplatin in combination with lipopolysaccharide or lipopolysaccharide-derived cytokines can overcome cisplatin resistance in experimental models and in vitro,60,61 and many other studies have found that cytokines enhanced the cytotoxicity of chemotherapeutic agents.62,63 It may well be that the effect of infection alone (whatever factors or mechanisms are involved) on tumor recurrence is limited but that the combined effect of chemotherapy and infection is more pronounced. However, a combination of adjuvant immunotherapy (transfer factor) and Nocardia rubra--cell wall skeleton significantly increased the 5- and 10-year disease-free intervals and survival rates in patients undergoing surgery for stage I non--small-cell lung carcinoma who did not receive any chemotherapy.64

Surgical wound infection after limb-salvage surgery for canine osteosarcoma may result in a cytokine cascade or production of other humoral factors that act synergistically to overcome chemoresistant clones in a manner similar to that which has been demonstrated in vitro. Alternatively, the infection may result in the upregulation of macrophages or other cytotoxic cells or may result in the production of antiangiogenic factors. It is, of course, very possible that multiple effects are responsible for the improved survival. Current efforts are under way to elucidate the mechanism of immunomodulation in postoperative infections in canine limb-salvage patients with osteosarcoma.

Other factors that may play a role in prolonged survival are (1) the use of NSAIDs and other analgesics and (2) antibiotics that may have anticancer effects themselves. Of interest is the recent finding that the provision of analgesics significantly reduces the tumor-promoting effects of undergoing and recovering from surgery.65 Undergoing surgery is well known to result in the suppression of several immune functions, including NK cell activity, in both animals66 and humans,67 probably as a result of released hormones such as catecholamines and prostaglandins. This suppression of NK cell activity can enhance metastasis.68 The reduction in tumor-promoting effects of surgery by analgesics seems to be due to the alleviation of pain-induced reduced NK cell function, but it is also likely that hitherto unrecognized factors other than immune cells probably also play a role.65 Recently, several investigators have looked at the anticancer properties of NSAIDs (to date, mainly only piroxicam has been examined) in canine tumors. Piroxicam has been found to have anticancer effects in rectal tubulopapillary polyps,69 transitional cell carcinoma,70–74 and oral squamous cell carcinoma.75 Clearly, the use of analgesic compounds might influence survival in canine limb-salvage patients. However, this is unlikely to have been a factor in this study, because all dogs were treated in the same fashion with regard to perioperative analgesia. The data on the chronic use of NSAIDs were sparse and incomplete, and it is possible that the use of NSAIDs affected survival, although this was not indicated in our model. This should be examined more closely in further studies.

The only antibiotics used in the dogs in this study that have been associated with anticancer effects are the fluoroquinolones. A variety of quinolones have been found to have anticancer effects against murine and human carcinoma cell lines in vitro,76,77 and studies have found an anticancer effect of ciprofloxacin and other fluoroquinolones on human osteosarcoma cell lines in vitro.78,79 This effect has been ascribed to the ability of quinolones to target type II topoisomerase enzymes, and there has been significant research into modifying quinolones to produce more effective anticancer agents.80 It was not possible to evaluate the effect of antibiotic use in this study because 24 of 32 of the dogs received quinolones (enrofloxacin, n = 20; ciprofloxacin, n = 4), and doses and duration of doses were not known. This factor needs to be evaluated more closely in further studies.

Overall, we conclude that there seems to be a survival advantage for canine limb-salvage patients in which infection becomes established. The mechanism of this effect is not understood but is worthy of investigation. We also found a survival advantage for smaller dogs and dogs with a lower initial percentage involvement of the radius with tumor.


   ACKNOWLEDGMENTS
 
Supported by grant 2 PO1 CA 29582 from the National Cancer Institute.

Received for publication January 24, 2005. Accepted for publication July 20, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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