The long-term survival of patients with moderate-advanced head and neck squamous cell carcinoma (HNSCC) has not improved significantly in the past 40 years (1). During this period, surgery has remained the most common and effective treatment for primary HNSCC (2). Radical resection for moderate-advanced HNSCC involves large-scale tumor resection and neck dissection (ND), and some procedures involve free flap reconstructions and tracheostomy (3, 4). Even if the defect is repaired and reconstructed intraoperatively, a decline or loss of important functions and aesthetics is common after a major operation (2, 5).

Postoperative complications (POCs) as the most important reason for surgical failure, not only increase the patient’s health and economic burden, delay adjuvant treatment, and reduce short-term or long-term quality of life but also increase the risk of sequelae and a poor prognosis. Therefore, the prevention and management of surgical complications is becoming an issue that deserves more attention (6–8). It is important for HNSCC patients who undergo free flap reconstruction to obtain primary recovery without any POC, which may have a significant correlation with short-term outcomes and long-term survival (9, 10).

Many valuable works had been done about POCs of free-flap reconstruction for head and neck cancers, and reported rates of POCs ranged from 15% to 62% in published studies (10–15). Most of the literatures are retrospective study based on medical records or public database, while the occurrence and severity of complications were usually not defined or described so clearly (10–13). Despite many indexes, including the Frailty index (16), Kaplan-Feinstein score comorbidity index (17), Washington University Head and Neck Comorbidity Index (WUHNCI) (12), and Adult Comorbidity Evaluation-27 (ACE-27) (18), have been used to evaluate the preoperative status of populations with head and neck cancers and demonstrated to be related to increased risks of complications and decreased survival rates with increasing index scores, standardized methods for risk prediction developed specifically for POCs of HNSCC surgery with free flap reconstruction were still in need.

This prospective study was designed to investigate predictors of POCs occurring after HNSCC surgery with free flap reconstruction and their influence on survival in a real-world setting. Specifically, we sought to better characterize short-term and long-term outcomes after HNSCC surgery with free flap reconstruction and evaluate whether specific patient characteristics would be predictive of treatment effects, with the goal of providing useful guidance for clinical decision making.

Demographic factors (age, sex, Body Mass Index (BMI) and weight loss), tumor anatomy and pathological features (tumor site, T stage, pathological nodal [pN] stage, clinical features, and growth patterns) and operation‐related variables (operation time, blood loss, intraoperative fluid, tracheostomy[yes/no], type of flaps used, ND (unilateral/bilateral), type of antibiotic prophylaxis and red blood cell (RBC) transfusion during the operation[yes/no]) were recorded. Based on World Health Organization (WHO) cutoff points of BMI status, BMI were categorized into obese (≥30.0 kg/m²), overweight (25.0–29.9 kg/m²), normal weight (18.5–24.9 kg/m²), and underweight (<18.5 kg/m²) (14). Weight loss was defined as “weight loss >10% of the body weight within the past 6 months (21). Preoperative comorbidities (ACE-27 comorbidity index, hypertension, and diabetes) and habitual factors (smoking and alcohol histories) were collected and recorded through a person-to-person survey before surgery.

The early postoperative period is a vulnerable time for HNSCC patients who have undergone a major operation with free flaps, as the risk of complications is increased. Reducing complications has become a major target for improving the quality of patient care and healthcare cost savings. A comprehensive analysis of the rates and types of complications is essential to develop appropriate interventions to reduce them.

Immediate flap reconstruction is generally associated with fewer POCs, a shorter hospital stay, reduced treatment costs and more favorable aesthetic and functional outcomes than cancer resection without flap reconstruction (22). However, reconstructive surgery using a microvascular free flap is also considered to be a great challenge, as it may lead to a longer operation time and more blood loss, both of which have been demonstrated to be associated with a high incidence of POCs (23, 24). Therefore, the significance of free flap reconstruction in the prognosis and occurrence of complications in HNSCC patients is complicated (25).

In the current study, we first developed a novel tool to predict the risk of POCs after HNSCC surgery with free flap reconstruction based on a prospective cohort with real-world data. Six parameters that may objectively reflect the risk of POCs were evaluated: preoperative factors (ACE-27 index and weight loss), tumor characteristics (T stage and tumor site) and perioperative factors (operation time and antibiotic prophylaxis). According to the validation, the predictive ability of our nomogram is reliable, and it can be widely used to predict POCs. However, considering that the limited number of patients may have influenced the veracity of our model, the nomogram was not externally validated.

Infective complications, including SSI and pneumonia, were the main types of POCs in HNSCC patients who underwent free flap reconstruction in this study. The probability of severe respiratory and circulatory complications is not high, which may have been due to strict preoperative preparation. While hair removal, antibiotic prophylaxis, the avoidance of hypothermia and perioperative glycemic control have been widely adopted to reduce infection-related complications (26), apart from a long surgery time and increased blood loss, ND and primary tumor site, which increase the risk of wound exposure to a microbacterial environment, can be high-level risk factors for SSI (27).

An increased risk of wound infections with flap reconstruction has been demonstrated (28, 29). Most clinicians agree that antibiotic prophylaxis is the most effective means to prevent infective complications (28, 30). According to American Society of Health-System Pharmacists (ASHP) guidelines (29, 31), cefazolin or cefuroxime with metronidazole, or ampicillin-sulbactam are recommended for oncological clean-contaminated head and neck surgery. The guidelines also suggest the use of clindamycin in patients with a beta-lactam allergy (29, 31). However, clindamycin may cause a 2-3 times higher risk of infective complications than beta-lactam in clean-contaminated head and neck cases (30, 32) and it was reported that no significant difference was observed between clindamycin and no antibiotic (33). Our study also demonstrated that prophylactic clindamycin led to a substantially higher risk of POCs than cephalosporin, suggesting that clindamycin is not sufficient and a broader antibiotic is needed.

An ever-expanding complex oncological surgery with free flap reconstruction often means a higher risk of massive intraoperative or postoperative hemorrhage, which may require a blood transfusion and lead to subsequent complications. Hemoglobin (Hb) was a critical indicator and the value below 7 g/dl was considered as a threshold for blood transfusion in head and neck surgical oncology according to guidelines (34), which was also accepted and used in our department. Moreover, the literature has demonstrated that blood transfusion may be considered as an important indicator for adverse short-term outcomes in patients undergoing oncological surgery (34, 35) and it was reported an almost 30% higher five-year overall survival rate of non-transfused OSCC patients than patients with transfusion (36). In this study, we found that 34.3% of patients required an RBC transfusion during the hospital stay, with a higher rate in the POC (+) group than in the POC (-) group. The univariate analysis also showed that patients who received a transfusion during surgery had a higher risk of POCs. Transfusion was also demonstrated to be a risk factor for long-term OS in the univariate and multivariate Cox regression analyses. Transfusion should be considered an important short-term outcome and a remarkable risk factor for long-term survival.

As maximum cytoreduction has been considered the ideal treatment for advanced HNSCC for decades, aggressive removal of the tumor to the greatest extent possible to improve survival is chosen by most oral and maxillofacial surgeons (37). Tumor characteristics are the main limitation of surgery for cancer patients (38). In our study, we found that not only long-term survival but also POC occurrence was highly associated with advanced T stage and N stage. A stage T4b tumor invades many important surrounding anatomical structures, such as the pterygoid plates, skull base or internal carotid artery, making complete excision of the tumor and hemostasis difficult and leading to a higher risk of POCs such as hematoma. A wide range of tumor resection may also result in surgical dead space and postoperative infections (26). Tumors in an advanced pN stage have extensive lymphatic metastasis or extranodal extension. Both of these are strongly associated with a poor prognosis.

A poor preoperative nutritional status in surgically treated patients may be an important factor affecting surgical tolerance and increasing the risk of complications (39, 40). Preoperative weight loss and BMI often reflect the nutritional status of patients. Preoperative weight loss may be more common in oral cancer (located at the beginning of the digestive tract) than in cancers at other locations because eating function is affected. In this study, preoperative weight loss occurred in 22.3% of patients, and it was identified as an important risk factor for POC occurrence and long-term survival. Preventing a decline in the nutritional status prior to surgery could be a means to reduce these negative consequences. In another study, our team found that the incidence of complications after OSCC surgery was highest (33.3%) in the low BMI group, but no significant relationship between BMI and POCs was demonstrated in this study (14). This may be due to the stricter screening procedure before free flap reconstruction for patients enrolled in this study.

A comorbidity assessment may be a crucial predictive factor for complications (41). The ACE-27 comorbidity index is a widely accepted comorbidity evaluation system for oncology patients. The ACE-27 index consists of 12 categories and 27 subcategories, each of which quantifies a specific disease within the circulatory, respiratory, digestive or nervous system and its severity (42). The index has been proven to be a validated, relevant scoring system for patients undergoing surgery for HNSCC (43, 44). Our study showed that an ACE-27 score>1 was significantly related to complications, which means that 2 or more comorbidities or a severe comorbidity can be a high-risk factor for poor short-term outcomes but not for long-term outcomes. Thus, the ACE-27 index can be useful when deciding which treatment option is more suitable for advanced-stage HNSCC patients.

It is well known that a prolonged operative time is often accompanied by a prolonged anesthesia time and more blood loss and may lead to many adverse events (45), such as SSI, wound disruption, reoperation or transfusion. A prolonged operative time was demonstrated to be associated with an increased risk of POCs in our studies. A long operation time increases wound exposure and decreases the effects of sterilization and antibacterial measures. It is generally believed that the operation time is closely related to the surgeon’s experience, the type of reconstruction, and a good preoperative design. Tracheostomy is a useful method to prevent asphyxia caused by airway obstruction after surgery. Direct exposure of the respiratory tract caused by tracheostomy may result in contamination, leading to adverse events such as pulmonary infection, which was demonstrated in our study. Tracheostomy tends to be used during tongue, floor of mouth or mandible resection, indicating a high risk of POCs.

Several limitations to this study need to be considered. Complications after complex surgery can never be completely eliminated and may have consequences that extend well beyond the postoperative period (38). Although based on a prospective real-world study, our study is still a single-center observational study with a limited sample size. However, the lost to follow-up rate of the research is very low, and the quality of prospective data can be well guaranteed. The avoidance of POCs remains a worthwhile goal, and further work is still needed to understand their occurrence. A multicenter prospective study with a large sample size may provide useful guidance for clinical decision making.

The occurrence of POCs significantly increases the burden on patients and leads to poor long-term OS. More attention should be paid on operation time and blood loss. Measures should be taken to prevent weight loss before operation to reduce the risk of POCs. An antibiotic with a broader spectrum is better than clindamycin to prevent POCs.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Institutional Review Board of Beijing Stomatological Hospital. The patients/participants provided their written informed consent to participate in this study.

DL: Project administration, validation, writing-original draft, interpretation of data. CW: Data analysis, writing-original draft, interpretation of data. BL: Validation, writing-original draft, interpretation of data. WW: Design of the work, interpretation of data, revising it critically for the intellectual content. HL, AC, QN: Resources, writing-original draft, interpretation of data. ZH: Supervision, writing-review & editing, resources. ZF: Funding acquisition, project administration, supervision, writing-original draft, interpretation of data. All authors contributed to the article and approved the final version.

This article is supported by the Capital’s Funds for Health Improvement and Research (CFH2020-2-2143 and 2018-4-2082); the National Natural Science Foundation of China (82072984); the Project of Beijing Municipal Education Commission (KM202110025008); the Beijing Science and Technology Commission (Z161100000516201); the Discipline Construction Fund of Beijing Stomatological Hospital (18-09-21); and innovation Research Team Project of Beijing Stomatological Hospital, Capital Medical University, NO. CXTD202204.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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