Does Postoperative Infection After Soft Tissue Sarcoma Resection Affect

Oncologic Outcomes?

NICOLE K. BEHNKE, MD,1* VIGNESH K. ALAMANDA, BS,2 YANNA SONG, MS,3 KRISTIN R. ARCHER, PhD,2

JENNIFER L. HALPERN, MD,2 HERBERT S. SCHWARTZ, MD,2 AND GINGER E. HOLT, MD2

1Division of Orthopaedic Surgery, University of Alabama at Birmingham Medical Center, Birmingham, Alabama2Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee

3Department of Biostatisics, Vanderbilt University Medical Center, Nashville, Tennessee

Background and Objectives: Prior studies have demonstrated postoperative infection may confer a survival benefit after osteosarcomaresection. Our aim was to determine whether infection after soft tissue sarcoma resection has similar effects on metastasis, recurrence andsurvival.Methods: A retrospective review was conducted; 396 patients treated surgically for a soft tissue sarcoma between 2000 and 2008 were identified.Relevant oncologic data were collected. Fifty‐six patients with a postoperative infection were compared with 340 patients without infection. Hazardratios and overall cumulative risk were evaluated.Results: There was no difference in survival, local recurrence or metastasis between patients with or without a postoperative infection. Patients wereevenly matched for age at diagnosis, gender, smoking status, and diabetes status. Tumor characteristics did not differ between groups in tumor size,location, depth, grade, margin status, stage, and histologic subtype. There was no difference in utilization of chemotherapy or radiation therapybetween groups. From our competing risk model, only positive margin status significantly impacted the risk of local recurrence. An increase in tumorsize corresponded to an increased risk of metastasis and death.Conclusions: Postoperative infection neither conferred a protective effect, nor increased the risk of adverse oncologic outcomes after soft tissuesarcoma resection.J. Surg. Oncol. 2014;109:415–420. � 2013 Wiley Periodicals, Inc.

KEY WORDS: sarcoma; infection; metastasis; recurrence

INTRODUCTION

Little is known about the oncologic implications of a postoperativewound infection in patients undergoing resection of a primarymalignancy. Historically, William B. Coley’s work using heat‐killedStreptococci to treat sarcoma patients (so‐called “Coley’s toxin”) hasbeen cited in attempts to correlate the body’s response to infection withimproved oncologic outcomes, though results have been inconclusivethus far. There are reports in the literature that postoperative infectionmay confer a protective survival benefit after resection of some types ofprimary malignancies [1,2], but similar studies in other types havedemonstrated decreased survival and higher rates of recurrence inpatients with infection [3–5]. This relationship has also been explored inosteosarcoma, both in humans [6,7], and in canines [8], but withconflicting results, and no studies have investigated this in patients withprimary soft tissue sarcomas.

Postoperative infection after resection of a primary soft tissuesarcoma (STS) is a major complication with both local and systemicimplications for patients. The estimated incidence of infection is 5–13%and can range in severity from cellulitis and wound breakdown tocomplete loss of limb and even sepsis [9,10]. Postoperative infectionalso may also delay critical adjuvant treatment such as chemotherapy orlocal radiation therapy; this delay in multi‐modality treatment has thepotential to negatively affect rates of recurrence, metastasis or evendisease‐specific death [11–13].

Prior studies have demonstrated postoperative infection may confer aprotective effect on survival after osteosarcoma resection. Our aim wasto determine whether infection after soft tissue sarcoma resection has asimilar effect on metastasis, recurrence or survival.

MATERIALS AND METHODS

Following IRB approval, we conducted a retrospective review of aprospectively collected database and 396 patients treated surgically for aSTS between 2000 and 2008 were identified. Patients were excluded ifthey were younger than 18 years of age, lacked adequate documentationor did not have postoperative follow‐up. Data were collected from thepatients’ electronic medical records and were managed usingREDCapTM electronic data [14] capture tools hosted at VanderbiltUniversity. Patient characteristics included sex and age at time ofsurgery. Given that postoperative wound infection was our primaryvariable of interest, we collected data on smoking status and whether ornot patients had diabetes listed as a medical problem in their medicalrecord, as these are two factors known to affect post‐surgical woundhealing [15,16]. Tumor characteristics were described, includinghistologic subtype, margin status after resection (positive or negative)depth (superficial or deep to the fascia of involved muscle), size,histologic grade (low, intermediate, or high), and site (upper or lowerextremity). Staging of the patient followed the American Joint

*Correspondence to: Nicole K. Behnke, MD, Division of OrthopaedicSurgery, University of Alabama at Birmingham Medical Center, 131313th Street South, Suite 225, Birmingham, AL 35205. Fax: 205.930.8570.E‐mail: nkbehnke@uabmc.edu

Received 28 August 2013; Accepted 9 November 2013

DOI 10.1002/jso.23518

Published online 28 November 2013 in Wiley Online Library(wileyonlinelibrary.com).

Journal of Surgical Oncology 2014;109:415–420

� 2013 Wiley Periodicals, Inc.

Committee on Cancer (AJCC) guidelines [17]. Use of chemotherapyand/or radiation therapy was noted, with receipt of radiation therapybeing subdivided into neoadjuvant, adjuvant, or combined treat-ment. Prognostic outcomes identified from the medical records includedlocal recurrence at the primary site, presence of distance metastasis, anddeath.

Within this group of 396 total patients, 56 patients with evidence of apostoperative infection were identified, and their clinicopathologiccharacteristics were compared with 340 patients without infection.Postoperative infection was defined as documentation in the patient’smedical record of (1) requiring oral or intravenous antibiotics; (2) anin‐clinic irrigation and debridement plus antibiotics; or (3) a surgicalirrigation and debridement plus antibiotics, specifically to treat asurgical wound complication within 6 months of definitive sarcomaresection.

Patient demographics, tumor characteristics, chemotherapy andradiation therapy were compared across postoperative infection groupsusing Wilcoxon rank sum tests for continuous variables and Chi‐squareor Fisher’s exact tests for categorical variables. Survival Curves forrecurrence free survival, metastasis free survival and disease specificsurvival were calculated and presented using Kaplan–Meier [18] orcompeting risk methods [19,20]. For the disease free survival curve, theprimary end point of the study was designated as death due to sarcoma.Death was treated as a competing risk for patients who died from a causenot directly related to their STS (n¼ 52). Log‐rank was calculated andused to compare the disease‐specific hazards of recurrence andmetastasis between the postoperative infection groups, while Gray’stest was used to compare the competing risk of disease‐specificdeath [19,21]. Separate multivariable Cox proportional hazardsregression analyses were used to assess the relation between groupsand prognostic outcomes [18], after controlling for age, sex, radiationtherapy, diabetes, smoking status, and tumor site, depth, margin, andsize. Statistical software R (version 3.0.1, www.r‐project.org) was usedfor all data analysis. Reported P values were two‐tailed and a P‐value ofless than 0.05 was considered to indicate statistical significance.

RESULTS

A total of 396 patients were included in the study. Fifty‐six patientsdemonstrated evidence of postoperative infection, as defined by criteriaoutlined above; the remaining 340 patients did not meet criteria forinfection. Demographics, clinical information and tumor characteristicsare described in Table I. Median follow‐up time was calculated frommost recent clinic visit; time to death was calculated from a known datein the electronic medical record, or from the Social Security DeathIndex.

The two groups of patients were equally matched, in terms of age atdiagnosis (P¼ 0.96) and gender (P¼ 0.075.) Neither patient smokingstatus nor a diagnosis of diabetes were significantly different between thetwo groups of patients (P¼ 0.46 and P¼ 0.39, respectively.) Tumorcharacteristics did not differ between groups, when comparing tumorsize (P¼ 0.13), location (P¼ 0.088), depth (P¼ 0.6), grade (P¼ 0.27),margin status (P¼ 0.14), stage (P¼ 0.49), and histologic subtype(P¼ 0.32). Patients with and without evidence of postoperativeinfection did not differ with respect to utilization of chemotherapy(P¼ 0.72) or radiation therapy (P¼ 0.55), in general, however patientsreceiving neoadjuvant radiation therapy or combined neoadjuvant andadjuvant radiation therapy had a higher incidence of infection thanpatients who received adjuvant‐only radiation (P¼ 0.008 andP¼ 0.013, respectively).

Overall, the presence of a postoperative infection did not have astatistically significant effect on the oncologic outcome for patients, interms of local recurrence, distant metastasis, or sarcoma‐specificsurvival (Table II). Our competing risk model demonstrated othervariables did have an affect on oncologic outcomes (Table III).

Local Recurrence

At 14 years of total follow‐up, 8 of the 56 patients with evidence ofinfection (14%) and 46 of the 340 patients without evidence of infection(14%) had developed local recurrence (Fig. 1). This difference was notstatistically significant. Hazard ratio for infection and local recurrencewas 0.93 (95% CI: 0.41–2.09; P¼ 0.866). From our competing riskmodel, the only variable affecting local recurrence was a positivesurgical margin, with a hazard ratio of 2.93 (95% CI: 1.50–5.72;P¼ 0.0016) for a positive margin.

Distant Metastasis

At 14 years of follow‐up, 12 of the 56 patients (21%) in the infectiongroup had evidence of distant metastasis, while 104 of the 340 patientswithout infection (31%) had metastatic disease (Fig. 2). Hazard ratio forinfection and distant metastasis was 0.6 (95% CI: 0.33–1.11; P¼ 0.103)and not statistically significant. Our competing risk model demonstratedthat the variables affecting sarcoma‐specific distant metastasis weretumor stage at presentation greater than stage 1 (hazard ratio of 26.54;95% CI: 6.96–101.2; P< 0.001), positive margins (hazard ratio 2.04;95% CI: 1.14–3.68; P¼ 0.017), and tumor size, with a 1‐cm increase intumor size corresponding to a 4% increase in risk of metastasis, or ahazard ratio of 1.04 (95% CI: 1.02–1.07; P¼ 0.0004).

Sarcoma‐Specific Death

At 14 years of follow‐up, 13 of the 56 patients with a postoperativeinfection (23%) were dead of disease, and 75 of the 340 patients withoutpostoperative infection (22%) were dead of disease (Fig. 3). Hazard ratiofor infection and sarcoma‐specific death was 0.91 (95% CI: 0.47–1.75;P¼ 0.78) and not statistically significant. Similar to the risk of metastaticdisease, stage of sarcoma at presentation greater than stage 1 (Hazardratio 23.59, 95% CI: 4.47–124.44; P< 0.001) negatively affectedsurvival in our competing risk analysis. Tumor size also stronglydemonstrated a negative affect on disease‐specific survival, with risk ofdeath increasing 5% for every 1‐cm increase in primary tumor size.(Hazard ratio 1.05, 95% CI: 1.03–1.08; P¼ 0.0001).

DISCUSSION

Prior studies have demonstrated postoperative infection may confer aprotective effect on survival after osteosarcoma resection. The aim of thecurrent study was to examine this relationship specifically in patientswith a primary STS. Our data suggests that there is no significantdifference in local recurrence, metastasis or disease‐specific death forpatients with and without postoperative infection. Previous reportsspecifically investigating the role of infection in osteosarcoma followthis trend of uncertainty. Jeys et al. [7] demonstrated improved survivalfor patients with postoperative infection in their analysis of 547 patients.This relationship has also been reported in canine osteosarcoma, withLascalles et al. [8] and Thrall et al. [22] both finding infection to be astatistically significant predictor of improved survival in their smallseries of dogs. On the contrary, Lee et al. [6] found no difference insarcoma‐specific survival between patients with and withoutpostoperative infection.

In our study, a positive margin was the greatest predictor of localrecurrence; margin positivity also predicted metastasis. Tumor size andstage at presentation were the strongest variables predicting disease‐specific metastases and death. This is consistent with previous literature,with negative surgical margins being critical for local and distant controlin STS [23–28]. Standard of care for STS typically involves externalbeam radiation, as it has been shown to be beneficial with respect tooncologic outcomes [23,29–36]. Unfortunately, one of the majordrawbacks of radiation therapy is the increase in wound complications at

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the site of treatment [37–39], with infection often arising in the woundbed. Though this complication is significantly more problematic inpatients receiving neoadjuvant external beam radiation as compared toadjuvant radiation, the literature has shown no demonstrable differencein oncologic outcomes between neoadjuvant and adjuvant radiationtherapy [29,32,39–41]. As most patients with a STS receive radiationtherapy at some point during their treatment, and are thus at an elevatedrisk for postoperative infection, exploring the relationship betweenpostoperative infections and the overall oncologic outcomes for patientswith STS is of interest.

Often, discussion about infection’s pro‐tumor effect focuses onmalignancy as an immune‐stimulator, with tumor necrosis factor alpha

and a host of pro‐inflammatory chemokines and cytokines acting in aself‐perpetuating cycle promoting tumor growth [42]. Inflammationwithin the tumor microenvironment promotes angiogenesis, vascularinvasion, cellular migration, and tumor proliferation, and is frequentlycited when discussing the role of infection and malignancy [43,44]. Thetrials of immune‐modulating drugs focus on interrupting these cycles forprevention and treatment in many carcinoma subtypes [45], with recentadvances in immunotherapy potentially being useful in sarcoma‐specifictreatment, as well [46]. Conversely, there are studies that suggest anti‐tumor effects from upregulation of the inflammatory system. Thesereports discuss the role of cytotoxic T‐cells and Natural Killer (NK) cellsin tumor cell‐specific destruction [47,48]. It appears that the role of

TABLE I. Patient and Tumor Characteristics, by Postoperative Infection

N (%) N¼ 396 Infection N¼ 56 No infection N¼ 340 P‐value

Sex 0.075Male 211 (53%) 36 (64%) 175 (51%)Female 185 (47%) 20 (36%) 165 (49%)

Age at diagnosis (yrs) 57 (�17) 56 (�17) 56 (�17) 0.96Smoker 0.46Yes 166 (42%) 26 (46%) 140 (41%)No 230 (58%) 30 (54%) 200 (59%)

Diabetes 0.39Yes 56 (14%) 10 (18%) 46 (14%)No 340 (86%) 46 (82%) 294 (86%)

Tumor siteUpper extremity 108 (27%) 10 (18%) 98 (29%) 0.088Lower extremity 288 (73%) 46 (82%) 242 (71%)

Tumor size (cm) 10.9 (�7.7) 12.1 (�7.8) 10.6 (�7.6) 0.13Tumor deptha

Superficial 66 (17%) 8 (14%) 58 (17%) 0.6Deep 330 (83%) 48 (86%) 282 (83%)

Histologic gradeG1 96 (24%) 9 (16%) 87 (26%) 0.27G2 51 (13%) 9 (16%) 42 (12%)G3 249 (63%) 38 (68%) 211 (62%)

Microscopic marginNegative 351 (89%) 53 (95%) 298 (88%) 0.14Positive 45 (11%) 3 (5%) 42 (12%)

AJCC stageb

I 119 (30%) 14 (25%) 105 (31%) 0.49II 74 (19%) 11 (20%) 63 (19%)III 86 (22%) 17 (30%) 69 (20%)IV 117 (29%) 14 (25%) 103 (30%)

Histologic subtype 0.32Fibrosarcoma 24 (6%) 2 (4%) 22 (6%)Leiomyosarcoma 38 (10%) 8 (14%) 30 (9%)Liposarcoma 92 (23%) 17 (30%) 75 (22%)MPNSTc 9 (2%) 2 (4%) 7 (2%)MFH/UPSd 148 (37%) 15 (27%) 133 (39%)Synovial sarcoma 31 (8%) 3 (5%) 28 (8%)Angiosarcoma 15 (4%) 2 (4%) 13 (4%)Rhabdomyosarcoma 5 (1%) 2 (4%) 3 (1%)Other 34 (9%) 5 (9%) 29 (9%)

RadiotherapyNo 105 (27%) 13 (23%) 92 (27%) 0.55Yes 291 (73%) 43 (77%) 248 (73%)Neoadjuvant only 51 (18%) 14 (37%) 37 (11%) 0.008Adjuvant only 195 (67%) 22 (52%) 173 (51%) 0.14Both 45 (15%) 7 (13%) 38 (11%) 0.013

ChemotherapyYes 77 (19%) 10 (18%) 67 (20%) 0.72No 319 (81%) 46 (82%) 273 (80%)

Total 396 (100%) 56 (14%) 340 (86%)

aSuperficial, above the investing fascia of the extremity; deep, below the investing fascia.bAmerican Joint Committee on Cancer staging system; stage of tumor on presentation.cMalignant peripheral nerve sheath tumor.dMalignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma.

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TABLE II. Outcome Data by Presence of Postoperative Infection

N (%) (N¼ 396) Infection N¼ 56 No. of infections (N¼ 340) P‐value

Local recurrence P¼ 0.886Yes 54 (14%) 8 (14%) 46 (14%)No 342 (86%) 48 (86%) 294 (86%)Hazard ratioa 0.93 (0.41–2.09)

Distant metastasis P¼ 0.103Yes 116 (29%) 12 (21%) 104 (31%)No 280 (71%) 44 (79%) 236 (69%)Hazard ratio 0.6 (0.47–1.75)

Survival P¼ 0.780Alive 256 (65%) 34 (61%) 222 (65%)Dead of disease 88 (22%) 13 (23%) 75 (22%)Dead, unknown cause 52 (13%) 9 (16%) 43 (13%)Hazard ratio 0.9 (0.47–1.11)

aHazard ratio (95% confidence interval), calculated from a Cox model.

TABLE III. Competing Risk Analysis for Factors Affecting Oncologic Outcome

Disease‐specific death Distant metastasis Local recurrence

Hazard ratio (90% CI) P‐value Hazard ratio (90% CI) P‐value Hazard ratio (90% CI) P‐value

Infection 0.91 (0.45, 1.75) 0.78 0.60 (0.33, 1.11) 0.1 0.93 (0.41, 2.09) 0.886Age 1.01 (1.00, 1.02) 0.14 1.00 (0.99, 1.01) 0.68 1.02 (1.00, 1.04) 0.06Sitea 0.87 (0.52, 1.44) 0.58 1.22 (0.77, 1.93) 0.4 0.60 (0.32,1.10) 0.1Depthb 0.89 (0.67, 1.17) 0.4 1.19 (0.65, 2.19) 0.57 1.38 (0.60, 3.19) 0.45Radiotherapy 1.34 (0.72, 2.48) 0.36 0.82 (0.51, 1.31) 0.4 0.76 (0.39, 1.45) 0.4Marginc 0.79 (0.39, 1.58) 0.5 2.04 (1.14–3.68) 0.017 2.93 (1.50, 5.72) 0.002Size 1.05 (1.03, 1.08) <0.01 1.04 (1.02, 1.07) <0.001 1.00 (0.96, 1.04) 0.98Tumor graded 1.03 (0.66, 1.63) 0.89 1.08 (0.72, 1.64) 0.7 1.23 (0.68, 2.20) 0.5Tumor stagee 23.59 (4.47, 124.44) <0.001 26.54 (6.96, 101.20) <0.001 1.51 (0.48, 4.76) 0.48Diabetes 1.09 (0.61 1.92) 0.79 0.96 (0.57, 1.61) 0.88 1.21 (0.59, 2.49) 0.61Smoking 1.08 (0.68, 1.69) 0.76 0.97 (0.66, 1.44) 0.89 0.77 (0.41, 1.42) 0.4

aSite comparison is lower extremity:upper extremity.bDepth comparison is deep to investing fascia:superficial to investing fascia.cMargin comparison is positive:negative surgical margins.dTumor grade comparison is intermediate or high grade:low grade.eTumor stage comparison is greater than stage 1:stage 1.

Fig. 1. Kaplan–Meier analysis for disease‐specific recurrencedemonstrates no difference in recurrence between patients with andwithout postoperative infection. Log‐rank test: P¼ 0.886.

Fig. 2. Kaplan–Meier analysis for disease‐specific metastasisdemonstrates no significant difference in metastasis for patients withand without postoperative infection. Log‐rank test: P¼ 0.142.

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infection in cancer is multifactorial. Recently the concept ofimmunoediting has been introduced, describing the unifying conceptof infection having both promoting and inhibiting effects in malignancy[49,50].

In addition to the interplay between infection and malignancy on acellular level, the more broad implications of a postoperative infectionafter tumor resection should be noted. Specifically, the impact of delayedwound healing on the timely receipt of adjuvant chemotherapy andradiation therapy. Often, due to the immune‐suppressing effects ofstandard chemotherapeutic agents, patients cannot receive treatmentwith open wounds or ongoing infection. Similarly, there is hesitation toadminister adjuvant external beam radiation to an infected or unhealedwound bed. These variables are relevant confounding factors that maketeasing out a straightforward infection‐outcome relationship difficult,especially as STS treatment typically involves adjuvant therapies[33,36,51–53].

While our data does not show a significant difference in oncologicoutcomes for patients with and without postoperative infection, there arelimitations to our study. This was a retrospective study based onprospectively collected data, inevitably harboring differences in patientsurveillance, treatment algorithms despite generalized standards forSTS, and overall follow‐up after treatment. Because adjuvant treatmentfor STS can vary based on histologic subtype, use of radiation andchemotherapy is inherently not standardized. In our institution, patientswith STS are treated with external beam radiation therapy either pre‐ orpostoperatively, the timing of which is often patient‐dependent.Moreover, as a quaternary sarcoma referral center, patients in ourcare often present after receiving treatment elsewhere, having undergoneregimens that may differ from our protocols. A retrospective analysis isinherently unable to account for these variations.

There is a complex interplay between other biologic and clinicalvariables that makes analysis of cause and effect relationships in STSless straightforward. Clinical factors such as medical comorbidities,obesity, operating room time, smoking, and patient immuno‐competency were not controlled for and likely influence not only thecourse of the malignancy, but also the overall susceptibility todeveloping an infection. Tumor grade and stage clearly play a role inthe overall oncologic outcomes, as the literature demonstrates high‐grade tumors and patients with systemic metastatic disease atpresentation carrying a poorer prognosis, in general [36,54]. Thoughtumor grade was not a significant contributor to recurrence, metastasis or

death in our dataset, tumor stage at presentation did have a negativeinfluence.

CONCLUSIONS

We found no significant difference in the oncologic outcomes of localrecurrence, distant metastasis or disease‐specific survival in patientswith or without evidence of postoperative infection following surgicalresection. The presence of a postoperative infection likely has amultifactorial role in patient outcomes after sarcoma resection that isdifficult to tease out in one study. Further studies are warranted to bettercharacterize this complex relationship.

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