Soft tissue sarcomas are rare neoplasms that are often treated with a multidisciplinary approach using radiation and wide local excision with or without chemotherapy. Preoperative radiation followed by resection has become routinely used in the setting of localized disease, yielding excellent rates of local control and survival while offering advantages of decreased radiation dose and field size and facilitation of surgical resection [4-6, 15, 17, 18, 21, 23, 27, 34, 35]. However, preoperative radiation leads to a higher risk of postoperative wound complications compared with postoperative radiation [3, 8, 11, 15, 17, 37]. In addition to preoperative radiation, factors that have been demonstrated to contribute to postsurgical wound complications in patients with soft tissue sarcomas include, but are not limited to, lower extremity tumors, diabetes, tumor proximity to the skin surface, tumor size and volume, and patient age [2, 3, 15, 17, 37].
There is an association between glycemic control and wound outcomes in various nononcologic procedures, in which elevated blood glucose and/or hemoglobin A1c levels lead to a higher risk of postoperative wound complications [1, 7, 10, 14, 16, 19, 20, 25, 26, 28, 30, 32]. Although a link between diabetes and wound complications has been established in patients with coronary artery disease, joint disease, and spine and hepatobiliary disease [10, 12, 14, 16, 32, 36], the association between postoperative glucose levels and this outcome has not been studied in patients with soft tissue sarcomas.
Glycemic control is complicated in a subset of patients who undergo major orthopaedic operations and those who have multiple comorbidities, in particular diabetes. It is known that elevated blood glucose levels in patients lead to higher numbers of wound complications in the nononcologic setting [1, 10, 13, 14, 16, 25, 26, 31-33, 36]. However, it remains to be determined if oncology patients with elevated blood glucose levels are at an increased risk for postoperative wound complications as well. Because blood glucose levels may be modified, understanding if glucose levels relate to wound complications has potential importance in modifying the occurrence of wound complications.
The purposes of this study were (1) to evaluate if postoperative early morning blood glucose is associated with the development of wound complications in soft tissue sarcomas; (2) to determine a blood glucose cutoff that may be associated with an increased risk of wound complications; and (3) to evaluate if patients with diabetes have higher postoperative blood glucose and an associated increased risk of wound complications.
Patients and Methods
All investigators completed training in both human research and patient privacy and obtained approval from the institutional review board for this retrospective chart review. Patient records from the musculoskeletal oncology database and tumor registry at the Medical College of Wisconsin were then retrospectively reviewed for all patients with soft tissue sarcomas of the extremity or chest wall treated with preoperative radiation between 2000 and 2015. Pathology review was done at the time of initial diagnosis. Patients were staged according to the 2009 American Joint Committee on Cancer (AJCC) system, seventh edition.
Exclusion criteria included metastatic disease on initial presentation, age < 18 years old, soft tissue sarcomas in locations other than the extremity or chest wall, patients who did not receive preoperative radiation, recurrent sarcomas at first presentation to our sarcoma center, and small subcutaneous tumors. Patients who did not have complete medical records including treatment information and pathology report, at least one postoperative early morning blood glucose level, or followup of < 6 months were also excluded. Histopathologic types demonstrating rhabdomyosarcoma, bone sarcomas, extraosseous primitive neuroectodermal tumor, Kaposi’s sarcoma, angiosarcoma, aggressive fibromatosis, and dermatofibrosarcoma protuberans were also excluded, because treatment does not typically include preoperative radiation.
All patients were discussed at a multidisciplinary tumor board consisting of surgical and orthopaedic oncologists, medical and radiation oncologists, radiologists, and pathologists. Treatment recommendations from this tumor board were presented to the patient.
Radiotherapy and Chemotherapy
Radiation was recommended in patients who had deep, intermediate- to high-grade tumors or patients who had tumors near neurovascular bundles. Patients received a median preoperative radiation dose of 50 Gy using three-dimensional conformal radiation or intensity-modulated radiotherapy. Tumor volumes were designated based on CT simulations and, if possible, an MRI acquired in the treatment position.
Chemotherapy was recommended and administered in patients who were typically < 70 years of age with large (> 5 cm), deep, high-grade lesions. Sixty-nine (36%) patients received chemotherapy. Chemotherapy was delivered before radiation using Adriamycin and ifosfamide for two to three cycles.
Limb-sparing resection was performed in all patients 4 to 6 weeks after radiation. Wide surgical resection was performed by fellowship-trained musculoskeletal oncologists through normal tissue planes. Preservation of neurovascular structures was performed when possible and only sacrificed when directly involved by tumor. The goal of surgery was to achieve negative margins. Vascular or reconstructive plastic surgeons were involved in patients who underwent vascular reconstruction (55 of 191), had difficult wound closures (10 of 191), and free flap reconstructions (71 of 191).
Assessment of Early Morning Blood Glucose
Data were obtained through medical records and included information on patient, tumor, and treatment characteristics, medical history as well as postoperative early morning blood glucose levels. Postoperative early morning blood glucose was acquired between the hours of 4:00 AM and 6:00 AM on postoperative day (POD) 1. Patients who had postoperative blood glucose levels between 180 and 200 mg/dL were assessed by an internal medicine or endocrinology consultant. Postoperative patients were then treated with sliding scale insulin at the discretion of the comanaging teams.
Patients at the institution were monitored with the following protocol. Followup care was coordinated by the oncologists in a multidisciplinary clinic in conjunction with medical oncology, surgical oncology, radiation oncology, and interventional radiology. An MRI of the primary site and a PET/CT scan, if insurance approved, or a CT of the chest, abdomen, and pelvis were obtained for initial staging. Once therapies were initiated, typical followup, depending on stage, included an interval history, physical examination, and imaging with CT of the chest, abdomen, and pelvis every 3 to 6 months for the first 2 years, 6 to 12 months until Year 5, then yearly after Year 5 to monitor for disease progression. MRI of the primary tumor was also acquired every 4 to 6 months for the first 2 years, 6 to 12 months until Year 5, then yearly after Year 5 until physician discretion or if any localized symptoms ensued. Followup occurred until the patient died or decided to pursue hospice measures. The median followup was 3.6 years (range, 0.5-15 years). The mean followup was 4.6 years. No patients were lost to followup at 6 months.
Postoperative wound complications were defined as those resulting in a surgical procedure or prolonged wound care for 6 months postresection. Patients who underwent a reoperation or had prolonged wound care after resection were considered to have wound complications.
Patient variables evaluated included age, Karnosfky Performance Status, presence or absence of cardiovascular disease, diabetes, body mass index (BMI), smoking history, and POD 1 early morning blood glucose. BMI was assessed as a continuous variable. Tumor variables included size, location, grade, and histology. Treatment variables included the use of chemotherapy, intraoperative steroids, and flap reconstruction at the time of tumor resection (Table 1).
Staging of patients was performed using the AJCC guidelines. There were 73 women and 118 men. The mean age at diagnosis for patients presenting with Stage I to III disease was 56 years (range, 19-92 years). The majority of patients had high-grade tumors (82%). The median BMI was 29 kg/m2.
A multidisciplinary review of our institutional soft tissue sarcoma registry identified 298 patients. Fifty-two patients were treated with postoperative radiation, 24 were nononcologic excisions, and 31 did not have complete records for the variables assessed for this study. As such, 191 patients presented with extremity or chest wall tumors that were treated with preoperative radiation and were eligible for analysis. All 191 patients underwent definitive resection and were followed at the treating institution by the surgeon and radiation oncologist, per the previously stated protocol. All 191 patients had known data points for the variables analyzed.
Clinical, pathologic, and treatment characteristics for wound complications were assessed and are summarized (Table 1). Wound outcomes were a dichotomous variable. POD 1 early morning blood glucose was measured as a continuous variable. Statistical software MedCalc (Version 15.6; MedCalc Software bvba, Ostend, Belgium) was used for all data analysis. Fisher’s exact test was used for univariate analysis. Median POD 1 early morning blood glucose in patients with and without wound complications was 158 mg/dL and 111 mg/dL, respectively. If a variable had a p value of < 0.25, then it was used in the multivariate model. A logistic regression analysis was used for multivariate analysis. For all analyses, a type I error was maintained at 0.05 and all tests were two-sided. A probability of < 0.05 was accepted as statistically significant. Receiver operative curve (ROC) analysis was performed to determine the early morning blood glucose level that was best associated with postoperative wound complications.
A total of 29% (55 of 191) of patients in this study developed a postoperative wound complication. After controlling for potentially relevant confounding variables such as patient comorbidities and tumor and treatment characteristics, it was shown that lower extremity soft tissue sarcomas (p = 0.002; odds ratio [OR], 6.4; 95% confidence interval [CI], 1.98-20.85) and elevated POD 1 early morning blood sugars (p < 0.0001; OR, 1.1; 95% CI, 1.05-1.11) were associated with increased wound complications postoperatively. Thus, the odds of a wound complication increase by 10% compared with an early morning blood sugar of a patient that is < 127 mg/dL. In addition, when early morning blood glucose was measured as a categorical variable with a cutoff of 127, the OR was 45.42 (95% CI, 12.23-199.67; p < 0.0001). Intraoperative dexamethasone was administered in 17% of patients (33 of 191; Table 1). Patients given steroids intraoperatively did not have an increased risk of developing postoperative wound complications (OR, 0.534; 95% CI, 0.125-2.287; p = 0.398).
ROC analysis revealed that POD 1 early morning blood glucose of > 127 mg/dL was associated with postoperative wound complications with a sensitivity of 89% (area under the curve 0.898, p < 0.0001) (Fig. 1).
Median POD 1 early morning blood glucose in patients without diabetes was 118 mg/dL and 153 mg/dL in patients with diabetes (p = 0.02). However, with the numbers available, the diagnosis of diabetes was not associated with postoperative wound complications on multivariate analysis (OR, 0.426; 95% CI, 0.10-1.85; p = 0.25).
A correlation between glycemic control and postoperative wound complications has been shown in patients undergoing surgery for hepatobiliary, cardiac, spine, and joint disorders [10, 12, 14, 16, 32, 36]; however, we found only one study that assessed the impact of blood glucose on wound complications in the setting of soft tissue sarcoma . All patients with soft tissue sarcomas who undergo preoperative radiation are known to be at higher risk of postoperative wound complications [11, 15, 17, 18]. Patients with diabetes who undergo undergoing various procedures also have a higher number of postoperative complications [25, 26, 31], yet it is not known whether it is poor perioperative glucose control rather than diabetes per se that leads to the increased risk of postoperative morbidity, including wound complications. In this study, an elevated early morning POD 1 glucose was found to be associated with a higher number of wound complications and a fasting glucose level of > 127 mg/dL was associated with an increased propensity of this adverse effect. As such, the odds of a wound complication increase by 10% compared with an early morning blood sugar of a patient that is < 127 mg/dL. With the numbers and patient population we had, we could not demonstrate that patients with diabetes did not have a higher incidence of postoperative wound complications, although these patients had higher POD 1 early morning blood glucose. To date, this is the only study, to our knowledge, that has attempted to associate the development of wound complications with postoperative early morning blood glucose in patients with soft tissue sarcoma treated with preoperative radiation.
The main limitation of this study includes the method as to which early morning glucose was acquired. The assessment of early morning blood glucose was through electronic medical record alone. Early morning glucose was determined to be the glucose level obtained between the hours of 4:00 AM and 6:00 AM. However, hospital records did not record whether glucose values were fasting, and there was no verification if the patient had any oral intake within 8 hours of the fasting glucose level that was acquired. In addition, the patient population was heterogeneous by diagnosis, adjunctive treatments, and surgical factors such as the use of rotational or free soft tissue transfers. We could not demonstrate that these factors were associated with wound complications, but with the small numbers we had, we cannot fully exclude these as confounding factors. A study incorporating other factors that may impede wound healing such as nonsteroidal antiinflammatories, steroids, and immunosuppressants would potentially shed further light on variables that influence postoperative wound complications. Furthermore, implementation of a standard insulin titration protocol may be worth investigating, because it may reduce wound complications by improving glycemic control. Other limitations of the study include the time range in which blood glucose was measured. As measurement devices for blood glucose evolve, so does the potential accuracy of these readings. Between 2000 and 2015, there may have been changes in the methodology or machines for measurement of blood glucose, which might have resulted in errors that could impact the quality of test results. Lastly, additional variables that may affect wound healing such as hematoma, drain output, operation time, skin comorbidities, and anemia were not included in this analysis.
In this study, patients with elevated preoperative blood glucose and POD 1 early morning blood glucose levels had a higher risk of postoperative complications. The influence of glycemic control on postoperative complications has been recognized, especially in nononcologic procedures [10, 12, 14, 16, 32, 36]. Zerr et al.  evaluated deep sternal wound infections in 1585 patients with diabetes who underwent cardiac procedures from 1987 to 1993. Mean blood glucose levels were obtained from fingerstick glucometers. In Zerr et al.’s study , patients with infections had a higher mean blood glucose level through POD 2 after controlling for relevant confounding factors. Mraovic et al.  retrospectively analyzed 1948 patients (101 with infections and 1847 without infections) who underwent primary THA and TKA. All preoperative blood glucose values were random and nonfasting, which were acquired at the preoperative visit. Postoperative blood glucose levels were fasting and obtained before 8:00 AM. Other findings in this study include the commonly known variables of lower extremity tumors leading to a higher number of postoperative wound complications in soft tissue sarcomas [3, 8, 11, 17]. The wound healing cascade involves several mechanisms that occur at various time points [9, 22-24, 29, 30]. Hyperglycemia affects wound healing by various mechanisms that occur within the first 24 hours of wound healing and may be related to the importance of POD 1 glycemic control [9, 23, 24, 29, 30]. As such, clinicians should carefully assess POD 1 early morning glucose levels and consult with comanaging specialities to ensure proper glycemic control is obtained. Moreover, future studies, not only within the orthopaedic setting, may consider assessment of POD 1 glucose and its effect on postoperative morbidity.
The current study also showed that POD 1 early morning blood glucose levels of > 127 mg/dL were weakly associated with an increased risk postoperative wound complications and those patients with POD 1 early morning blood glucose >200 mg/dL had a greater association with wound complications. A blood glucose of > 200 mg/dL has been well established as a threshold for the development of wound complications in many disease settings. Olsen et al.  performed a case-control study of patients who underwent spine surgery at a tertiary hospital. Of the 273 patients, 46 developed superficial, deep, or organ space surgical site infections. On multivariate analysis, a preoperative serum glucose of > 125 mg/dL and postoperative serum glucose level > 200 mg/dL were found to be associated with an increased risk of surgical site infections . Similarly, Trick et al.  found that a preoperative serum blood glucose of > 200 mg/dL within 24 hours of surgery affected rates of postoperative sternal infections in patients receiving a coronary artery bypass graft . The relationship between elevated blood glucose and adverse postoperative events has also been evaluated in oncologic patients. Vilar-Compte et al.  performed a case-control series to establish the correlation between serum glucose levels and rates of postoperative infection in 265 patients undergoing mastectomy for breast cancer. Five blood glucose levels were acquired for each patient, including early morning blood glucose before surgery, at anesthesia induction, intraoperatively, at recovery room arrival, and 24 hours after mastectomy. They found that patients with at least one elevated blood glucose level of ≥ 150 mg/dL had higher rates of postsurgical infections (70% versus 43.3%) .
In our study, although patients with diabetes had higher POD 1 early morning blood glucose levels, the diagnosis of diabetes (as opposed to acute hyperglycemia on POD 1) was not associated with the development of wound complications; after controlling for confounding variables such as tumor size, location, diabetes, cardiovascular disease, flap reconstruction, and intraoperative steroid use, postoperative hyperglycemia was the only variable that was associated with postoperative infection, indicating that hyperglycemic states, rather than diabetes, might have an effect on the development of wound complications. Stryker et al.  reviewed postoperative blood glucose and preoperative hemoglobin A1c levels in 1702 patients undergoing primary total joint arthroplasty. In this study, the wound complication rate was significantly higher in those with a postoperative serum glucose of > 200 mg/dL and an A1c value of > 6.7% .
Elevated POD 1 early morning blood glucose was associated with an increased risk of developing postsurgical wound complications, especially above a threshold of 127 mg/dL. Although patients with diabetes had higher postoperative early morning glucose levels, with the numbers we had, we could not show that these patients had an associated higher incidence of postoperative wound complications. Because preoperative radiation in soft tissue sarcomas is commonly used, the importance of tight glycemic control after surgery may be important to prevent the development of postoperative wound complications. To confirm our preliminary findings, larger studies with more careful confirmation of fasting glucose determinations are necessary. It remains to be demonstrated whether better glycemic control will reduce the frequency of wound complications in patients undergoing surgery for soft tissue sarcomas.
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