Risk Factors for Postoperative Complications in Oral Cancer and Their Prognostic Implications FREE

APPROXIMATELY 30 000 new cases of oral cavity and pharyngeal cancer are diagnosed annually in the United States, with almost 58% being located in the tongue and other parts of mouth.¹ In Brazil 10 980 new cases of mouth cancer were estimated for the year 2000.² The main goal of the treatment is the eradication of the cancer through control of the primary lesion and regional metastasis, with restoration of form and function.³ The anatomical extension of the disease, evaluated by the TNM system, is the most important prognostic factor.⁴ However, the unpredictable clinical evolution of some patients has led to the searching of other prognostic markers such as surgical margins,⁵ histopathological features,^{6 - 7} molecular abnormalities,⁸ and comorbidities.^{9 - 12} Recent advances in the anesthetic and cancer ablative techniques, as well as microvascular reconstruction of the resultant defect allowed more radical oncological procedures for advanced head and neck cancer.¹³ Nevertheless, the curative intent can be limited by the hazard of life-threatening postoperative complications. The prompt recognition of risk factors for complications based on preoperative clinical characteristics of the patient with oral cancerplus the identification of the risks associated with the surgical procedure itself can help determine the appropriate therapeutic planning to prevent severe complications.¹⁰ The objectives of this article are to identify the risk factors associated with the development of postoperative complications and to establish their prognostic significance on the survival of patients with oral cancer.

We reviewed 247 medical records of patients with squamous cell carcinoma of the oral tongue or floor of the mouth, admitted to the Centro de Tratamento e Pesquisa Hospital do Câncer A. C. Camargo, São Paulo, Brazil, from January 1, 1990, to December 31, 1994. The following criteria were used for inclusion in the study: a histologically confirmed diagnosis; absence of previous oncological treatment for this primary tumor; complete clinical evaluation allowing APACHE II (Acute Physiology and Chronic Health Evaluation II), American Society of Anesthesiologists, National Cancer Institute, and Functional Severity Index (FSI) classifications; absence of distant metastasis at diagnosis; and surgical treatment with a curative purpose, exclusive or as part of a multidisciplinary approach. A total of 110 patients met the criteria for inclusion in the study.

Data collection from the medical records was performed using a specially designed form. These data included demographic information, smoking status, alcoholism status, TNM staging (Union Internationale Contre le Cancer or American Joint Committee on Cancer classification),⁴ tumor site, surgical risk (American Society of Anesthesiology Scale), type of surgery and neck dissection, type of reconstruction, comorbidities according to National Cancer Institute classification,¹⁴ FSI,¹² extended clinical severity stage (ECSS),¹² APACHE II score,¹⁵ length of stay in an intensive care unit (ICU), and nosocomial and postoperative complications. Outcome measures included development of complications in the immediate postoperative period (until 30 days) and 5-year overall survival. Patients were followed up from the date of diagnosis to the date of last objective evaluation or death. Only 4.5% of the patients were lost to follow-up.

The FSI was created through the identification of 9 variables that influenced prognosis based on the following Cox proportional hazards regression model: daily alcohol consumption, neck lump, dysphagia, weight loss, hematocrit of 0.35 or lower, age older than 50 years, National Cancer Institute comorbidity index level 2 (>3 comorbidities), earache, and oral cavity bleeding. The FSI was built through the multiplication of the values of the hazard ratio (HR) for each patient. When the condition was absent, we gave the value of 1 for that category. The score ranged from 1 to 258.23, and the results allowed for grouping patients into 3 categories, based on the percentiles 30 and 60: high (score ≥8.7), intermediate (score >3.8 and <8.7), and low (score ≤3.8) grade of functional commitment. Consolidation of the FSI categories with the TNM system created the extended clinical severity staging system (ECSS), consisting of 4 stages (1 [best] to 4 [worst]).¹²

The APACHE II classification is a revised version of the APACHE prototype system. It includes 12 physiologic measures (temperature; mean arterial pressure; heart rate; respiratory rate; oxygenation; levels of arterial sodium, serum potassium, and serum creatinine; hematocrit, white blood cell count, and Glasgow Coma Scale score), age, and severe chronic health problems. The physiologic score is determined from the worst value, eg, the lowest hematocrit or the highest respiratory rate, during the initial 24 hours after admission to the ICU.¹⁵ In our study we also applied APACHE II for patients not referred to the ICU, based on findings of the first 24 hours of the postoperative period.

Patients were electively referred to the ICU based on 1 of the following criteria: expected operative time longer than 6 hours and/or the presence of a comorbidity diagnosed preoperatively, such as coronary insufficiency or advanced chronic obstructive pulmonary disease, requiring strict cardiopulmonary monitoring.

Wound infection was recorded only for patients who present suppurative drainage and/or who developed a mucocutaneous fistula.¹⁶ Wounds noted to have erythema or erythema and edema may be considered infected in the presence of fever, based on an evaluation performed by the surgeon.

The information on the forms was entered in a database (DBase for Windows; Borland International, Scotts Valley, Calif). Periodically, revisions were made to verify the internal consistency of the data. For statistical analysis, commercially available software (Statistical Product and Service Solutions for Windows, release 7.5; SPSS Inc, Chicago, Ill) was used. Descriptive statistics were used as a preliminary analysis of the relationship between the baseline variables and outcome events. The t test was used to compare means. The Pearson coefficient was used to confirm correlation between the continuous variables; the χ² test was used to verify the association between categorical variables. Survival analysis was performed using the Kaplan-Meier method (with the log rank test value being used to compare groups). Logistic regression was used to find risk factors for postoperative complications and the Cox proportional hazards regression model was chosen to identify independent prognostic factors. For all statistical tests α = .05.

The cohort of 110 patients included 93 men (84.5%) and 17 women (15.5%); 93 patients were white and 17 belonged to other ethnic groups. The patients' ages ranged from 31 to 80 years (mean age, 57.5 years). Fifty-nine patients had tumors in the tongue; 51 had tumors in the floor of the mouth. Eighty-two patients (75.6%) were daily drinkers of alcohol, while there was an equal division between patients who never drank alcohol and social drinkers (12.7% in each group). One hundred patients (90.9%) were tobacco users and 10 (9.1%) had never smoked. Pain was the most frequently reported symptom (affecting 69 patients [62.7%]) followed by weight loss (affecting 46 patients [41.8%]). Earache, odynophagia, and oral cavity bleeding affected only 19 patients (17.3%) who had symptoms. According to the comorbidity National Cancer Institute index,¹² 64 patients (58.1%) were classified as being at level 1 (0-3 comorbidities) and the remaining 46 patients (41.9%) were classifed as being at level 2 (>3 comorbidities). Patients' distribution according to FSI, ECSS, and TNM is given in Table 1.

Sixty-four patients (58.2%) did not have lymph node involvement (N0). Clinical neck metastasis was detected in 46 patients (41.8%) with the following distribution: N1, 11 patients (36.7%); N2a, 1 patient (0.9%); N2b, 12 patients (10.9%); N2c, 10 patients (9.1%); and N3, 3 patients (2.7%). Among patients classified as having TNM stage IV, 13 (11.8%) had bilateral neck involvement. All patients underwent surgery as the primary treatment; 69 received irradiation as adjuvant therapy. They underwent the following types of surgery: partial glossectomy or pelvectomy (17 patients), pelviglossectomy or pelviglossomandibulectomy (80 patients), and hemiglossectomy or total glossectomy (13 patients). Forty-four patients (40%) underwent marginal or sectional mandibulectomy. Neck dissection was performed in 97 patients (88.2%), with 57 (51.8%) unilateral surgical procedures and 40 (36.4%) bilateral surgical procedures. Supraomohyoid, classic radical, or a modified radical neck dissection was performed unilaterally in 22 patients (20%), 20 (18.2%), and 15 (13.6%), respectively. Among those who had bilateral neck dissections, the combination of radical neck dissection and contralateral supraomohyoid was performed in 19 patients (17.3%) and bilateral supraomohyoid neck dissection was the therapy used in 12 patients (10.9%). Simultaneous bilateral comprehensive neck dissection or bilateral modified radical neck dissection was performed in 5 (4.5%) and 4 (3.6%) patients, respectively. The surgical defect was closed primarily in 50 patients (45.5%). A tongue flap was used in 29 patients (26.3%), pectoralis major myocutaneous flap in 24 (21.8%), a microvascular flap in 4 (3.6%), and other myocutaneous flaps in 3 (2.7%).

Surgical procedure included a tracheostomy in 96 patients (87.3%). No significant statistical association was noted between tracheostomy and chest infection (P = .49).

Operative time varied from 25 to 810 minutes (mean ± SD = 334.8 ± 164.2 minutes). Twenty-nine (67.4%) of 43 patients with operative times longer than 6 hours developed postoperative complications in contrast to 26 (39.4%) of 66 patients with operative times shorter than 6 hours (P = .004). A higher rate of systemic complications (14%) between patients with operative times longer than 6 hours (P = .03) as well as more frequent occurrence of wound infection (39.5%) (P = .001) were observed.

All but 1 patient received prophylactic antibiotic agents starting in the operating room, immediately before surgery, for a period that varied from 24 to 288 hours (median time, 72 hours). Fifty-four patients (49.1%) received a combination of 4 g/d of cephalothin sodium plus 4 g/d of chloramphenicol succinate, 45 patients received 1.8 g/d of clindamycin phosphate (40.9%), and 10 patients (9.1%) received other types of antibiotic agents. There was no association between the type of antibiotic used and postoperative complications (P = .63). We also could not observe a statistically significant difference between the mean period of antibiotic therapy in the group that had postoperative complications (97.3 hours) and the group without postoperative complications (95.1 hours) (P = .86). There was no difference in the frequency of postoperative complications comparing patients receiving antibiotic therapy up to 24 hours and patients receiving antibiotic therapy for longer than 24 hours (P = .82).

Forty-seven patients (42.7%) were electively referred to the ICU. The length of stay in the ICU varied from 1 to 13 days (mean length of ICU stay, 2 days). The APACHE II score was 10 or fewer in 76 patients (69.1%) and higher than 10 in 34 patients. The length of hospital stay ranged from 2 to 54 days (mean length of hospital stay, 9 days).

The overall complication rate was 50%. Postoperative complications are listed in Table 2.

The occurrence of postoperative complications was associated with neck dissection (P = .002), APACHE II score (P = .008), type of reconstruction (P = .02), ECSS (P = .02), type of surgery (P = .03), FSI (P = .03), tracheostomy (P = .004), operative time (P = .004), and staying in the ICU (P = .03). The number of complications was significantly correlated with the length of hospital stay (r = 0.24, P = .01) and FSI (r = 0.19, P = .04). In a multivariate analysis bilateral neck dissection (relative risk [RR] = 3.57, P = .01) and an APACHE II score higher than 10 (RR = 3.86, P = .02) were independent risk factors for complications.

Five-year overall survival was affected by the type of complications (none, 41.7%; local, 34.1%; and local plus systemic, 0%; P<.001) (Figure 1), staying in the ICU (no, 46.3%; yes, 20.7%; P = .001) (Figure 2), and ECSS (stage 1, 75.6%; stage 2, 50%; stage 3, 28.6%; and stage 4, 10.2%; P<.001). The predictive prognostic model was composed by staying in the ICU (HR = 1.83), local plus systemic complications (HR = 6.27), and ECSS (stage 3, HR = 3.57; and stage 4, HR = 6.34).

A surgical complication has been defined as a development, which is generally to the patient's detriment, arising at the time of operation or during the postoperative period.¹⁷ Complications after major surgery for patients with oral cancer increase treatment costs, delay adjuvant treatment, augment late sequelae, affect quality of life, and also can cause a patient's death if not diagnosed and promptly treated.¹⁸ During the last few years, advances in surgical techniques, the introduction of new antibiotic agents, a better understanding of fluid balance physiology, improved methods for blood transfusions, developments in anesthetic techniques, and the establishment of ICUs improved the safety of major head and neck oncological surgery decreasing the risk and severity of complications.¹⁹ Although the indications of surgical treatment are standardized in most institutions, the rates of complications are still high and the identification of risk factors associated with them can reduce morbidity and possibly improve survival in patients with oral cancer, thus achieving cost-effectiveness.^{20 - 22}

In our study the overall complication rate was 50%, similar to other reports in the literature.^{19 ,22} Infection was also the most frequent (22.7%) among local and systemic complications, again in agreement with the literature.^{16 ,22 - 23} Many recent studies^{24 - 26} have addressed the issue of identifying patients at high risk for developing a wound infection following head and neck oncological surgery. Advanced stage of tumor,¹⁶ type of reconstruction,¹⁶ preoperative radiotherapy,²¹ nutritional status,¹⁶ comorbidities,¹⁶ duration of surgery,¹⁶ classification of procedure,¹⁶ antibiotic prophylaxis,¹⁶ and alcohol consumption¹⁶ have been significantly related to the probability of postoperative wound infection. Robbins et al¹⁶ also noted that the use of blood replacement, surgical drains, and nasogastric tubes were significant predictors of wound infection even when it was hypothesized that this finding was essentially related to the extent and duration of surgery. The prognostic significance of postoperative wound infection on head and neck cancer is still controversial.

The variations in type and duration of antibiotic agents that were noted in our study can be explained by the lack of a standardized regimen in the study period. The benefit of prophylactic antibiotic therapy has been clearly proven, whereas the best regimen and length of time the antibiotic agents are administered remain controversial.^{24 ,26 - 28} Some authors reported that there was no statistically significant difference in the rate of wound infection noted in patients receiving distinct types of antibiotic agents²⁹ that was also noted in our study. However, another study showed that the rate of wound infection was significantly lower in patients receiving prophylaxis with a combined regimen of metronidazole and cefazolin vs cefazolin alone.¹⁶

Our incidence of chylous fistula is similar to other series.^{21 ,30 - 32} Our rate of hematoma (3.7%) is higher than the 1% and 1.9% incidence reported by Gall et al³³ and Yoder et al,²¹ respectively, but is lower than the 4.2% rate described by Johnson and Cummings.³⁴

In our series, a low rate of pneumonia was detected, whereas in other studies it ranged from 7% to 15%.^{20 ,35 - 37} Several aspects of head and neck surgery make pneumonia a frequent complication irrespective of the underlying functional class or medical condition. Probably, the intensive pulmonary care and the few patients who underwent hemiglossectomy or total glossectomy with risk for aspiration have contributed to the low rate of pneumonia in our patients.

Reported postoperative complication rates associated with tracheostomy vary considerably,³⁸ and the chest infection is the most common problem detected, achieving rates up to 20%.³⁹ Although tracheostomy was associated with postoperative complications in our study, this correlation with chest infection was unconfirmed.

The mortality rate (3.6%) in our study is comparable to other studies.^{19 - 20 ,33 ,40} The causes of postoperative death in our study were arterial rupture, hypovolemic shock, respiratory distress, and sudden death.

To our knowledge, no report analyzed the influence of the number of complications on the length of hospital stay for head and neck cancer until this article. However, some authors reported a strong correlation between wound infection and prolonged hospital stay.²⁰

Clinical conditions can adversely affect the rate of complications in head and neck cancer surgery.^{16 ,20 - 21 ,36 ,41} Such factors have been studied recently,^{10 ,13 ,37} with predictive value in determining the risk of complications in surgically treated patients with oral cancer.

The choice of a neck dissection is based on the primary site as well as the number, size, and location of positive lymph nodes. In addition, the results and morbidity associated with each type of neck dissection must be considered. A selective neck dissection is often recommended for patients with cancer of the oral tongue who have a clinically N0 neck. Comprehensive neck dissection is required in the presence of palpable cervical metastases. Bilateral radical neck dissection has been used for many years for the treatment of proved or suspected bilateral metastatic disease, carrying significant morbidity and mortality rates.⁴² Our mortality rate for patients who underwent this procedure (7.5%) is similar to other rates described in the literature,^{42 - 43} but it is higher than 2.1% reported in a series of 193 bilateral radical neck dissections from our institution.⁴⁴

The APACHE II scoring system is primarily intended for patients in ICUs, but attempts have been made to use this score in patients with severe trauma,⁴⁵ abdominal sepsis,⁴⁶ postoperative enterocutaneous fistulas,⁴⁷ and acute pancreatitis.⁴⁸ The prognostic value of APACHE II has been shown in patients having major general surgery with indications that included lymphoma, colorectal cancer, breast cancer, gastric cancer, ovarian cancer, and pancreatic cancer,⁴⁹ but we could not find in the literature any study emphasizing the relation between the APACHE II score and postoperative complications in patients with head and neck cancer.

There is little information available about the level of utilization of the ICU by patients with head and neck cancer.^{50 - 51} Some centers prefer not admitting patients with cancer to an ICU⁵² while other centers admit all patients to an ICU after head and neck procedures.⁵³ Ryan and Hochman⁵⁴ could not find complications associated with early hospital discharge. Inversely to the expected, staying in an ICU for at least 3 days is encouraged for better monitoring of the patient's condition. In a retrospective study, 37 (1.5%) of 2346 patients undergoing head and neck surgery required admission to the ICU, since this access is extraordinary and reserved for patients requiring cardiopulmonary assistance or monitoring.⁵⁰ Another study comparing patients who had had major head and neck oncological resections and who were nursed postoperatively on a general ward with those who were referred to an ICU contrasts with the findings in our study that did not find differences in general morbidity (20% vs 27%).⁵¹ This observation is in partial agreement with our findings, since it was noted that a statistically significantly higher rate of postoperative complications were found in patients referred to the ICU. In this series, the advanced ECSS (stages 3 and 4), the type of surgery, and the surgical reconstruction (microvascular or myocutaneous flap) determined the necessity of the ICU. Characteristically, the patients who required ICU monitoring were those at high risk for complications (local and local plus systemic). Therefore, the use of this variable as a prognostic marker could not be reliable because it would be just a reflex of the severity of the disease. Moreover, excluding ICU from the predictive model of death, type of reconstruction emerges as a prognostic factor. This finding is in accord with the extension of surgery criteria used for ICU referral. The indication for admittance to the ICU for patients with oral cancer in our study was adequate and was supported by the lower inpatient postoperative death rates.

Some authors^{9 - 11} reported the negative influence of advanced comorbidities on survival of patients with head and neck cancer corroborating our findings, probably by alterations on biological interaction between tumor and host. Prediction of outcome is important in disease stratification and subsequent decision-making process.⁴⁹ The identification of risk factors for postoperative complications may assist the surgeon in classifying patients into groups with distinct probabilities of postoperative morbidity and mortality, and the prevention of complications can turn to a better prognosis.

Accepted for publication March 27, 2001.

Presented as a poster at the annual meeting of the American Head and Neck Society, Fifth International Conference on Head and Neck Cancer, San Francisco, Calif, July 29-August 2, 2000.

Corresponding author: Luiz P. Kowalski, MD, PhD, Department of Head and Neck Surgery, Centro de Tratamento e Pesquisa Hospital do Câncer A. C. Camargo, R. Professor Antônio Pudente, 211CEP 01509-010 São Paulo-SP, Brazil (e-mail: lp_kowalski@uol.com.br).