SURGICAL SITE INFECTION AFTER PREOPERATIVE NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED ORAL SQUAMOUS CELL CARCINOMA

ORIGINAL ARTICLE SURGICAL SITE INFECTION AFTER PREOPERATIVE NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED ORAL SQUAMOUS CELL CARCINOMA Shih-An Liu, MD, PhD, 1,2,3 Yong-Kie Wong, BDS, MSc, 4 Ching-Ping Wang, MD, 1,2 Chen-Chi Wang, MD, 1,2 Rong-San Jiang, MD, PhD, 1 Hui-Ching Ho, MSc, 5 Jin-Ching Lin, MD, PhD 2,6 1 Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan 2 Faculty of Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan 3 Chung Hwa University of Medical Technology, Tainan, Taiwan 4 Department of Oral and Maxillofacial Surgery, Taichung Veterans General Hospital, Taichung, Taiwan 5 Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan 6 Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan. E-mail: jclin@vghtc.gov.tw Accepted Published online 12 November 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21560 Abstract: Background. We investigated whether preoperative neoadjuvant chemotherapy is associated with increased surgical site infection (SSI) rate in patients with locally advanced oral cancer. Methods. In this hospital-based study, we retrospectively reviewed over 2000 chart records of patients with oral cavity cancer from March 1994 to December 2007. Those who received neoadjuvant chemotherapy were identified and matched for age, sex, tumor classification, primary site, and reconstruction methods to hospitalized patients who did not receive chemotherapy. Data were analyzed for the relationship between chemotherapy and SSI. Results. A total of 306 patients were enrolled for final analyses. The overall postoperative SSI rate was 31.0%. The SSI rate in patients after neoadjuvant chemotherapy was similar to that in patients who did not receive the chemotherapy (33.3% vs 29.9%, p ¼.631). Conclusions. Preoperative neoadjuvant chemotherapy was not associated with increased SSI rate in patients with locally advanced oral cancer. VC 2010 Wiley Periodicals, Inc. Head Neck 33: 954 958, 2011 Keywords: surgical site infection; chemotherapy; oral cavity; squamous cell carcinoma; surgery Correspondence to: J.-C. Lin Contract grant sponsor: Taichung Veterans General Hospital, Taichung, Taiwan; contract grant number: TCVGH-987004C. VC 2010 Wiley Periodicals, Inc. Oral cancer is 1 of the leading cancers in the world and has become a public health issue in many parts of the globe. 1 In spite of the development of new strategies in the treatment of many cancers, the overall 5-year survival rate in patients with oral cancer has not changed significantly during the past 2 decades. 2 Traditional standard treatments with surgical resection plus postoperative adjuvant radiotherapy or chemotherapy have resulted in only limited improvements in survival. 3 In some institutes, an approach with preoperative chemotherapy or chemoradiotherapy has been established. However, concrete evidence providing sufficient data from prospective randomized studies is still scant for preoperative chemoradiotherapy. 4 The rationale for neoadjuvant chemotherapy is based on 2 hypotheses. The first is the better delivery of chemotherapeutic agents in untreated, well-vascularized tumors, whereas the second is the eradication of the micrometastatic disease. Furthermore, patients without previous cancer treatments might be more tolerant of the adverse effects of the chemotherapy than those who have been irradiated. 5 After introduction of prophylactic antibiotic, the instances of surgical site infection (SSI) after extirpation of head and neck cancer dropped dramatically. 6 However, the risk of SSI remains high after major head and neck surgery, and this is probably because of the complex anatomic structure of the head and neck and the contamination of the environment near the region of mouth and throat. 7 Risk factors for SSI after major head and neck operations include tumor classification, previous chemotherapy, tracheostomy, diabetes mellitus, perioperative blood transfusion, flap reconstruction, and concurrent neck dissection. 7 11 Few studies have focused on the influence of neoadjuvant chemotherapy on SSI after major head and neck surgery. Therefore, the purpose of this study was to determine the SSI rate after neoadjuvant chemotherapy in patients with locally advanced oral cancer and compare it with that of patients without neoadjuvant chemotherapy. 954 Wound Infection after Preoperative Chemotherapy in Oral Cavity Cancer HEAD & NECK DOI 10.1002/hed July 2011

MATERIALS AND METHODS In this hospital-based study, we retrospectively reviewed over 2000 chart records of patients with oral cavity cancer undergoing surgical intervention in the studied hospital from March 1994 to December 2007. The study protocol was approved by the Institutional Review Board of Taichung Veterans General Hospital. In our institute, surgical intervention was preferred for the treatment of patients with oral cancer. Patients with resectable primary tumor and who were willing to undergo surgical excision went straight to surgery, whereas those with unresectable primary tumor, who either hesitated in accepting surgical intervention or did not have surgery available because of a busy schedule, were selected for neoadjuvant chemotherapy. During the period of neoadjuvant chemotherapy, patients were educated and encouraged to undergo surgery after completion of chemotherapy. If patients still insisted in nonsurgical treatment, radiotherapy was arranged. All patients who received neoadjuvant chemotherapy as a result of locally advanced oral squamous cell carcinoma (OSCC) were identified. The regimen of neoadjuvant chemotherapy consisted of a combination of cisplatinbased multidrugs. 12,13 Those who had no pathologic report, had been treated at other institutes, or had inadequate chart records were excluded. All patients were reclassified in accord with the guidelines of the American Joint Committee on Cancer. Basic demographic data including age and sex were collected as well as tumor-related features. In addition, pathologic report, type of surgical intervention, and relevant past history were all recorded. The definition of SSI was purulent discharge either spontaneously or by incision and drainage from the head and neck region or the presence of an orocutaneous fistula regardless of etiology within 30 days after operation. 14 The null hypothesis is that there is no clinically meaningful difference in SSI rate between those who did and those did not receive neoadjuvant chemotherapy, that is, the odds ratio (OR) ¼ 1. We sought to have an 80% chance of detecting an OR significantly different from 1 at the 5% level. If an OR of 2 would be considered an important difference between the 2 groups, the estimated sample size should be at least 150 subjects in each group. Therefore, patients receiving neoadjuvant chemotherapy were compared with a matched control group without neoadjuvant chemotherapy from the same source population in a ratio of 1:2. In all, 204 patients who did not receive neoadjuvant chemotherapy were chosen from those who were hospitalized during the same period, and were matched for age, sex, tumor classification, primary tumor site, and reconstruction method to the 102 patients who received neoadjuvant chemotherapy. We used descriptive statistics for general data presentation. Comparisons of nominal or ordinal variables between patients who received and those who did not receive neoadjuvant chemotherapy were analyzed by chi-square test, whereas continuous variables were examined by Student s t test. In addition, a backward stepwise multiple logistic regression model was used to identify relevant factors associated with SSI. All statistical analyses were performed using the SPSS software system for Windows (version 10.1; SPSS, Chicago, IL). Statistical significance was considered as p <.05. RESULTS In all, there were 102 patients with OSCC undergoing surgical intervention after neoadjuvant chemotherapy. All patients had stage IV disease, and the average age of patients was 50.3 9.9 years. Most of them were male patients (n ¼ 99, 97.1%). Thirty-four patients (33.3%) eventually developed SSI. More than half of the patients had buccal cancers (n ¼ 55, 53.9%), followed by tongue cancers (n ¼ 25, 24.5%). The average preoperative body mass index was 22.5 3.9 weight in kilograms/height in meters squared (kg/m 2 ); preoperative serum albumin and hemoglobulin levels were 3.70 0.47 and 10.6 1.6 g/dl, respectively. The most common reconstruction type was pectoris major myocutaneous flap (n ¼ 37, 36.3%) followed by free flap (n ¼ 19, 18.6%) and locoregional flap (n ¼ 19, 18.6%). Most of the patients needed perioperative blood transfusion (n ¼ 89, 87.3%). The average operation duration was 492 152 minutes. All patients received appropriate prophylactic antibiotics (clindamycin or cefazolin from 1 hour before incision to at least 24 hours postoperation) in accord with the guidelines. There was no significant difference in SSI rate between patients who received neoadjuvant chemotherapy and those who did not (33.3% vs 29.9%, p ¼.631). There was also no statistical significance between the 2 groups in age, sex, reconstruction type, body mass index, operation duration, and diabetes mellitus. However, a higher perioperative blood transfusion rate was noted in patients who received neoadjuvant chemotherapy compared with those who did not (87.3% vs 71.6%, p ¼.048). In addition, the average preoperative hemoglobulin concentration and serum albumin level were lower in patients who received neoadjuvant chemotherapy compared with those who did not (10.6 1.6 vs 13.1 þ 2.1 g/dl, p <.001 and 3.70 0.47 vs 3.99 þ 0.50 g/dl, p <.001, respectively). Perioperative blood loss was greater in patients who received neoadjuvant chemotherapy compared with those who did not (1086 646 vs 528 149 ml, p <.001). The detailed comparisons of variables between 2 groups are presented in Table 1. For ease of statistical analysis, all continuous variables were divided into 2 groups by a proper cutoff point determined by a receiver operating characteristic curve. A backward stepwise logistic regression model was used to determine relevant risk factors for SSI Wound Infection after Preoperative Chemotherapy in Oral Cavity Cancer HEAD & NECK DOI 10.1002/hed July 2011 955

Table 1. Descriptive and bivariate analyses of the studied population. No. of patients (%) Variable Total no. of patients (%) Preoperative chemotherapy group Control group p value Age, y.998 <40 41 (13.4) 14 (13.7) 27 (13.2) 40 49 110 (35.9) 36 (35.3) 74 (36.3) 50 59 99 (32.4) 33 (32.4) 66 (32.4) 60 56 (18.3) 19 (18.6) 37 (18.1) Sex.999 Female 10 (3.3) 3 (2.9) 7 (3.4) Male 296 (96.7) 99 (97.1) 197 (96.6) Primary tumor site.999 Lip 6 (2.0) 2 (2.0) 4 (2.0) Gingiva 19 (6.2) 6 (5.9) 13 (6.4) Mouth floor 13 (4.2) 5 (4.9) 8 (3.9) Anterior tongue 79 (25.8) 25 (24.5) 54 (26.5) Buccal 162 (52.9) 55 (53.9) 107 (52.5) Palate 18 (5.9) 6 (5.9) 12 (5.9) Retromolar trigone 9 (2.9) 3 (2.9) 6 (2.9) Body mass index.207 <23 kg/m 2 172 (56.2) 63 (61.8) 109 (53.4) 23 kg/m 2 134 (43.8) 39 (38.2) 95 (46.6) Reconstruction type.089 Primary closure 44 (14.4) 9 (8.8) 35 (17.2) Free flap 53 (17.3) 19 (18.6) 34 (16.7) Pectoris major myocutaneous flap 112 (36.6) 37 (36.3) 75 (36.8) Locoregional flap 36 (11.8) 18 (17.6) 18 (8.8) Split thickness skin graft 61 (19.9) 19 (18.6) 42 (20.6) Mandibulectomy.999 No 108 (35.3) 36 (35.3) 72 (35.3) Yes 198 (64.7) 66 (64.7) 132 (64.7) Diabetes mellitus.409 No 271 (88.6) 93 (91.2) 178 (87.3) Yes 35 (11.4) 9 (8.8) 26 (12.7) Perioperative blood transfusion.003 No 71 (23.2) 13 (12.7) 58 (28.4) Yes 225 (76.8) 89 (87.3) 146 (71.6) Preoperative hemoglobulin <.001 <11.5 g/dl 121 (39.5) 75 (73.5) 46 (22.5) 11.5 g/dl 185 (60.5) 27 (26.5) 158 (77.5) Preoperative albumin.006 <3.5 g/dl 56 (18.3) 28 (27.5) 28 (13.7) 3.5 g/dl 250 (79.9) 74 (72.5) 176 (86.3) Surgical site infection.631 No 211 (69.0) 68 (66.7) 143 (70.1) Yes 95 (31.0) 34 (33.3) 61 (29.9) after operation. The most significant risk factor associated with SSI was perioperative blood transfusion. The OR was 13.03 (95% confidence interval [CI]: 2.950 57.53, p ¼.001) for patients who received perioperative blood transfusion compared with those who did not. In addition, those with diabetes mellitus had a higher rate of SSI than that of those without (OR: 2.471, 95% CI: 1.142 5.348, p ¼.022). The detailed results are shown in Table 2. DISCUSSION To the best of our knowledge, this is the first study to address the issue of SSI after preoperative chemotherapy in patients with oral cavity cancer. Complications after major head and neck cancer surgeries are not uncommon in clinical practice, and SSI is the most common postoperative complication. 7 It not only increases medical expense but also delays adjuvant therapy. Furthermore, it will influence patients quality of life and even cause mortality in some cases if not appropriately handled. Although previous studies found that SSI was significantly related to prior chemotherapy, 8,10 our study failed to demonstrate a significant difference in SSI rate after operations for advanced oral cancers between patients who received and those who did not receive neoadjuvant chemotherapy. The reason might be that the different populations in previous studies included a variety of patients with head and neck cancer, whereas our study included only patients with oral cancer. Another explanation might be that different chemotherapy regimens or protocols were used in the aforementioned studies. 956 Wound Infection after Preoperative Chemotherapy in Oral Cavity Cancer HEAD & NECK DOI 10.1002/hed July 2011

Table 2. Logistic regression model of factors associated with surgical site infection. Factor No. of patients (n ¼ 304) OR p value Lower limit 95% CI Upper limit Diabetes mellitus No 271 1.000 Yes 35 2.471.022 1.142 50.348 Mandibulectomy No 108 1.000 Yes 198 2.471.018 1.154 4.744 Perioperative blood transfusion No 71 1.000 Yes 235 13.030.001 2.950 57.530 Abbreviations: OR, odds ratio; CI, confidence interval. Reference group. In the current study, over half of patients had buccal cancers. This is probably attributable to the high prevalence of betel quid chewing in Taiwan. 15 The overall SSI rate after operations was 31.0% (ie, 95 of 306 patients). It was higher when compared with that of patients with oral cancer who underwent surgical interventions from our previous study (SSI ¼ 19.8%). 7 However, because the current study included only patients with stage IV diseases, it is easy to understand that the complexity of operations is different from that of previous series. More than half of the studied population underwent pectoris major myocutaneous flap/free flap reconstruction in the current study (165/306), whereas only 31% of patients received pectoris major myocutaneous flap/free flap reconstruction in our previous study (309/994). Nevertheless, the SSI rate in the current study was comparable with that of previous studies, which investigated factors related to wound infection in patients receiving operation for late stage head and neck cancers. 8 11 Because matched patients were selected as a control group, there were no significant differences between patients who received and those who did not receive neoadjuvant chemotherapy in age, sex, and primary tumor site. It is conceivable that healthier patients with a better performance status might be selected for neoadjuvant chemotherapy. In such a situation, the incidence of surgical infections in this group may seem artificially low compared with that of patients who went straight to surgery. Our study did not collect the performance status of patients before initiation of neoadjuvant chemotherapy. Thus, we did not know whether patients receiving neoadjuvant chemotherapy were healthier than those without. However, the average preoperative hemoglobulin level was lower in patients receiving neoadjuvant chemotherapy. It is well known that some chemotherapy agents can induce myelosuppression, thereby influencing the production of hemoglobulin. In addition, the coagulation function can also be influenced by thrombocytopenia, and this eventually leads to more perioperative blood loss in patients who receive neoadjuvant chemotherapy. Other side effects caused by chemotherapy include nausea, emesis, mucositis, and diarrhea. 12 It was anticipated that all of these side effects could lead to anorexia and poor nutritional status in patients after neoadjuvant chemotherapy. Therefore, it is not surprising that the average preoperative albumin level was lower in patients receiving neoadjuvant chemotherapy. From the abovecited data, the general condition of patients receiving neoadjuvant chemotherapy seemed to be not as good as that of patients without neoadjuvant chemotherapy. As a result, the surgical infection rate in those who received neoadjuvant chemotherapy was expected to be higher than that of those who went straight to surgery. In the logistic regression model, diabetes mellitus, mandibulectomy, and perioperative blood transfusion were found to be independent risk factors for SSI. Diabetes mellitus is a systemic disease that leads to microvasculopathy and immunosuppression that ultimately influence wound healing. 16 Mandibulectomy implies extensive tumor involvement, and the need to open the upper aerodigestive tract along with a large surgical defect would be expected, thereby predisposing patients to develop postoperative wound infection. In addition, extensive tissue ablation increased the possibility of perioperative blood loss, which leads to the need for perioperative blood transfusion. Allogeneic blood transfusion is thought to induce an immunosuppressive consequence that increased the risk of SSI. 17 Previous studies pointed out that tumor stage is related to SSI. 7,8,11 Our study failed to demonstrate such correlation because all our patients had stage IV diseases. Although some articles found that the reconstruction with pectoris major myocutaneous flap/free flap was related to SSI, 7,9 the current study did not find such a relationship. This might be ascribed to different studied populations because other studies included patients from all stages and different primary sites, whereas our study comprised patients with oral cavity cancer with stage IV diseases. There are many potential risk factors and prior multivariate studies illustrated diverse significant risk factors for SSI. 7 11 Nevertheless, these studies might not be comparable with ours as a consequence of dissimilar SSI definitions or heterogeneous patient characteristics. Even though the usage of neoadjuvant chemotherapy is still controversial in the treatment of patients with locally advanced head and neck cancer, some studies did show promising results. 3,18 Our prior study found a high overall response rate after neoadjuvant chemotherapy in previously untreated patients with squamous cell carcinoma of the oral cavity. 12 However, the surgical excision after neoadjuvant chemotherapy was still made in accord with the tumor s initial size in spite of marked shrinkage of the tumor itself. The advantage of neoadjuvant Wound Infection after Preoperative Chemotherapy in Oral Cavity Cancer HEAD & NECK DOI 10.1002/hed July 2011 957

chemotherapy is that the surgeon can access and extirpate the tumor more easily. Whether neoadjuvant chemotherapy can reduce the recurrence or distant metastasis rate needs further prospective randomized trials. Although the current study was not a prospective design, we believe it has some major advantages. We selected only patients with oral cavity cancer with stage IV diseases. In addition, we matched patients who received neoadjuvant chemotherapy for age, sex, primary tumor site, and reconstruction type to patients hospitalized in the same period (control group). On the other hand, there are certainly several limitations in the present study. First, external validity of the findings is limited because it was conducted at a single hospital. Second, this was a retrospective study and it was difficult to clarify the causal relationships. Also, selection bias inevitably existed, given that the choice of preoperative neoadjuvant chemotherapy in our patients was not randomized. Last, although the treatment guidelines are standardized at the studied institute, individual variations among surgeons certainly exist. CONCLUSION Preoperative neoadjuvant chemotherapy in patients with locally advanced OSCC followed by radical surgery did not significantly increase the likelihood of postoperative wound infection rate. Acknowledgments. The authors thank the Biostatistics Task Force of Taichung Veterans General Hospital for statistical analysis consulting. REFERENCES 1. Warnakulasuriya S. Global epidermiology of oral and oropharyngeal cancer. Oral Oncol 2009;45:309 316. 2. Chen YJ, Chang JTC, Liao CT, et al. Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci 2008;99:1507 1514. 3. Sturgis EM, Moore BA, Glisson BS, Kies MS, Shin DM, Byers RM. Neoadjuvant chemotherapy for squamous cell carcinoma of the oral tongue in young adults: a case series. Head Neck 2005;27:748 756. 4. Klug C, Berzaczy D, Voracek M, Millesi W. Preoperative chemoradiotherapy in the management of oral cancer: a review. J Cranio-Maxillofac Surg 2008;36:75 88. 5. Cruz JJ, Ocana A, Navarro M, Barco ED, Fonseca E. New options in the treatment of locally advanced head and neck cancer: role for induction chemotherapy. Cancer Treat Rev 2008;34:268 274. 6. Liu SA, Tung KC, Shiao JY, Chiu YT. Preliminary report of associated factors in wound infection after major head and neck neoplasm operations: does the duration of prophylactic antibiotic matter? J Laryngol Otol 2008;122: 403 408. 7. Liu SA, Wong YK, Poon CK, Wang CC, Wang CP, Tung KC. Risk factors for wound infection after surgery in primary oral cavity cancer patients. Laryngoscope 2007;117:166 171. 8. Penel N, Lefebvre D, Fournier C, Sarini J, Kara A, Lefebvre JL. Risk factors for wound infection in head and neck cancer surgery: a prospective study. Head Neck 2001;23:447 455. 9. Lotfi CJ, Cavalcanti R de C, Costa e Silva AM, et al. Risk factors for surgical-site infections in head and neck cancer surgery. Otolaryngol Head Neck Surg 2008;138: 74 80. 10. Penel N, Fournier C, Lefebvre D, Lefebvre JL. Multivariate analysis of risk factors for wound infection in head and neck squamous cell carcinoma surgery with opening of mucosa. Study of 260 surgical procedures. Oral Oncol 2005;41:294 303. 11. Coskun H, Erisen L, Basut O. Factors affecting wound infection rates in head and neck surgery. Otolaryngol Head Neck Surg 2000;123:328 333. 12. Lin JC, Jan JS, Hsu CY, Wong DYK. High rate of clinical complete response to weekly outpatient neoadjuvant chemotherapy in oral carcinoma patients using a new regimen of cisplatin, 5- fluorouracil, and bleomycin alternating with methotrexate and epirubicin. Cancer 1999;85:1430 1438. 13. Lin JC, Wong YK, Liu SA, et al. Long-term outcome of an outpatient weekly neoadjuvant chemotherapy regimen: MEMOCLUB for advanced oral cancer. In: 2009 The 14th Taiwan Joint Cancer Conference, Taiwan; 2009. 14. Johnson JT, Myers EN, Thearle PB, et al. Antimicrobial prophylaxis for contaminated head and neck surgery. Laryngoscope 1984;94:46 51. 15. Chen IH, Chang JT, Liao CT, et al. Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area. Br J Cancer 2003;89:681 686. 16. Jeffcoate WJ, Price P, Harding KG. Wound healing and treatments for people with diabetic foot ulcers. Diabetes Metab Res Rev 2004;20(Suppl. 1):S78 S89. 17. Fergusson D, Khanna MP, Tinmouth A, Hebert PC. Transfusion of leukoreduced red blood cells may decrease post-operative infections: two meta-analyses of randomized controlled trials. Can J Anaesth 2004;51:417 424. 18. Freier K, Engel M, Lindel K, et al. Neoadjuvant concurrent radiochemotherapy followed by surgery in advanced oral squamous cell carcinoma (OSCC): a retrospective analysis of 207 patients. Oral Oncol 2008;44:116 123. 958 Wound Infection after Preoperative Chemotherapy in Oral Cavity Cancer HEAD & NECK DOI 10.1002/hed July 2011