Pharyngocutaneous fistula after total laryngectomy: Systematic review of risk factors

Transcription

1 CLINICAL REVIEW David W. Eisele, MD, Section Editor Pharyngocutaneous fistula after total laryngectomy: Systematic review of risk factors Rogerio Aparecido Dedivitis, MD, PhD, 1* Felipe Toyama Aires, MD, 2 Claudio Roberto Cernea, MD, PhD, 1 Lenine Garcia Brand~ao, MD, PhD, 1 1 Department of Head and Neck Surgery, Hospital das Clınicas, University of S~ao Paulo School of Medicine, S~ao Paulo, Brazil, 2 Department of General Surgery, Hospital Ana Costa, Santos, Brazil. Accepted 18 June 2014 Published online 26 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Pharyngocutaneous fistula (PCF) is the most common surgical complication after total laryngectomy. Controversy still remains regarding the multiple risk factors implicated. The purpose of this study was to evaluate the potential risk factors for PCF. Methods. The strategy for our literature survey included research in MEDLINE up to December The risk factors analyzed were age, sex, smoking habit, alcohol use, comorbidity, preoperative hemoglobin level, blood transfusion, preoperative tracheotomy, previous radiotherapy and chemoradiotherapy, primary tumor site, T classification, cartilage invasion, tumor grade, surgical margins, suture material, second layer of suture, reconstruction, tracheoesophageal prosthesis, and neck dissection. Results. The electronic search resulted in 311 studies from which 63 met the inclusion criteria. Conclusion. Chronic obstructive pulmonary disease (COPD), previous hemoglobin <12.5g/dL, blood transfusion, previous radiotherapy or chemoradiotherapy, advanced primary tumors, supraglottic subsite, hypopharyngeal tumor site, positive surgical margins, and the performance of neck dissection were risk factors for PCF. VC 2014 Wiley Periodicals, Inc. Head Neck 37: , 2015 KEY WORDS: meta-analysis, cutaneous fistula, postoperative complications, laryngectomy, laryngeal neoplasms, carcinoma, squamous cell carcinoma INTRODUCTION Pharyngocutaneous fistula (PCF) is the most common surgical complication after total laryngectomy. It is a troublesome complication in the early postoperative period after laryngectomy. PCF occurs when there is a failure in the pharyngeal repair resulting in salivary leak. It is associated to a higher incidence of morbidity, hospital permanence, and cost. 1 Its incidence after head and neck surgery varies on average around 20% to 25% The large variety of incidence of salivary fistula described in the available literature can be explained by the different patients selections and the surgical technique used. 65 Furthermore, some studies may be limited by small sample sizes, the tumor site and stage, and the type of surgery and reconstruction performed. 61 A major limitation was the retrospective nature of all the articles. Multiple risk factors have been implicated. However, because the same factors have not seemed to be significant in all studies, controversy still remains in identifying highrisk patients. 66 In addition, some authors did not find any factor predictive for PCF. 65 Thus, currently, there is no consensus on which factors are most significant. *Corresponding author: R. A. Dedivitis, Department of Head and Neck Surgery, Hospital das Clınicas, University of S~ao Paulo School of Medicine, Rua Olinto Rodrigues Dantas, 343 conj. 92, , Santos, S~ao Paulo, Brazil. dedivitis.hns@uol.com.br The purpose of this study was to evaluate the potential risk factors for PCF after total laryngectomy through a meta-analysis of observational studies. MATERIALS AND METHODS Identification and selection of the studies We conducted a literature survey and performed the systematic review of the available evidence. It included the research in the MEDLINE database up to December The search strategy (laryngeal neoplasms OR laryngectomy) AND (pharyngocutaneous fistula OR cutaneous fistula) was used. Inclusion and exclusion criteria The casuistry was composed of patients diagnosed with laryngeal cancer who underwent total laryngectomy. Risk factors evaluated The analyzed risk factors were age, sex, smoking habit, alcohol use, comorbidity (diabetes mellitus, chronic obstructive pulmonary disease [COPD] and hypothyroidism), preoperative hemoglobin level, blood transfusion, preoperative tracheotomy, previous radiotherapy, previous chemoradiotherapy, tumor primary site (glottic vs supraglottic; and larynx vs hypopharynx), T classification (T1/ T2 vs T3/T4; and T3 vs T4), presence of cartilage invasion, histological differentiation grade, surgical margins, technical details (type of suture material and second layer HEAD & NECK DOI /HED NOVEMBER

2 DEDIVITIS ET AL. of suture), reconstruction with a flap, tracheoesophageal prosthesis (TEP) impact, and neck dissection. Statistical analysis The measures of each risk factor was expressed through absolute values and analyzed by means of the difference of the absolute risk, under the confidence interval of 95%- IC 95%. Inconsistences among clinical trials were evaluated through the chi-square heterogeneity test (Lavelle et al 2 )and quantified using the I 2 test. The chi-square test shows the percentage of total variation across studies caused by heterogeneity and was used to judge the degree of consistency evidence obtained. Values lower than 20% were considered presenting low heterogeneity, from 20% to 50% presenting moderate heterogeneity, and higher than 50% presenting high heterogeneity. To identify studies that generated heterogeneity, we used visual analysis of the funnel plot. RESULTS The electronic search resulted in 311 studies. After evaluating their titles and abstracts, 248 studies were excluded because they clearly did not fill the inclusion criteria. The findings of this review were based on the data of 63 primary studies The results are summarized in Table 1. Age, sex, smoking habit, alcohol use, T3 versus T4 staging, cartilage tumoral invasion, histological grade, second suture layer, reconstruction with musculocutaneous flap, primary placement of tracheoesophageal prosthesis, and radical versus selective neck dissection were not considered risk factors. After excluding the studies responsible for heterogeneity, diabetes mellitus and previous tracheotomy did not configure as risk factors any further. Comorbidity COPD was evaluated in 6 studies. 31,41,44,46,49,54 Patients with COPD presented an absolute risk of 14% (p <.01 and I %). Excluding the studies responsible for heterogeneity, 31,54 the observed effect was kept, with a risk of 16% (p 5.01 and I 2 5 0%). Previous hemoglobin and blood transfusion Five studies evaluated hemoglobin levels as a risk factor considering 12.5g/dL as the cutoff. 2,10,31,34,50 Patients with hemoglobin levels lower than 12.5g/dL presented an increase of PCF risk of 15% (IC 95% ; p <.001 and I %). Three articles 20,25,61 analyzed the blood transfusion as a risk factor. There was an increase in PCF development of 17% among patients who received blood transfusions (IC 95% ; p <.001 and I %). A similar effect was verified after excluding the article that generated heterogeneity 25 (23%; p <.001 and I 2 5 0%). Previous radiotherapy and chemoradiotherapy Thirty-nine articles 2 5,7 10,12,15,17,18,20 23,29,31,32,35 43,45,46,49,52,55 58,60,61,63 evaluated previous radiotherapy as a risk factor for PCF. Among the patients who underwent previous radiotherapy, 24.6% presented PCF, with PCF occurring in 15.5% of the patients who did not undergo radiotherapy. Thus, the absolute risk increase was 10% (IC 95% ; p <.001 and I %). After excluding the studies that generated heterogeneity, 3,5,12,15,18,32,36,43,61 the absolute risk was kept as high as 8% (IC 95% ; p <.001 and I 2 5 5%). Five articles 48,56,58,59,62 evaluated patients who underwent previous organ-preservation protocol based on combined chemoradiotherapy as a risk factor for PCF. The patients under this previous treatment presented an increase in the risk of PFC formation of 11% (IC 95% ; p 5.04 and I 2 5 0%). Tumor staging Twenty-one articles 2,4,9,14,17 20,22,29,35,39 41,45,46,49,50,54,58,61,64 compared the incidence of PCF among patients with earlystage primary tumors (T1 and T2) and those with advanced-stage tumors (T3 and T4). There was a trend of risk factors for PCF formation (p 5.06% and I %). Excluding the study that caused high heterogeneity, 54 an increase of risk factors of 4% was observed (IC 95% ; p 5.02 and I %) in patients with advanced tumors. Tumor subsite, supraglottis versus glottis Twenty-three articles 2,7,9,13 47,49,50,54,58,61 studied the incidence of PCF according to the location of the laryngeal primary subsite. Because infraglottic tumors are uncommon, the other 2 subsites were compared. Patients with supraglottic tumors presented an increase of 3% in the absolute risk of PCF formation (IC 95% ; p 5.03 and I %) when compared to those with glottic tumors. After excluding the articles that generated heterogeneity, 41,42 similar results were obtained (p 5.04 and I 2 5 0%). Tumor site, only larynx versus larynx with hypopharynx Fifteen studies 7,9,15,18,21,31,33,41 44,48,49,54,58 focused on tumoral hypopharyngeal involvement as risk factor, with an increase of 9% (IC 95% ; p <.001 and I %). Even after excluding the articles responsible for heterogeneity, 7,43 the results remained similar (p <.001 and I %). Surgical margins Twelve articles 15,17,18,31,32,35,39,49,53,57,62,63 also evaluated the surgical margins as a risk factor. Patients with positive margins presented an increase in the risk for PCF of 8% (IC 95% ; p 5.01 and I %). A similar result was obtained after excluding the studies responsible for higher heterogeneity 18,31,35,49,53 (16%; IC 95% ; p <.001 and I 2 5 6%). Suture material Five articles 17,18,29,41,46 compared absorbable sutures for pharyngeal closure with catgut and vicryl. Patients who were submitted to vicryl sutures presented a 10% lower risk of PCF (IC 95% ; p <.001 and I %). After excluding the studies that caused high heterogeneity, 41,46 the lower risk was 19% (IC 95% ; p <.001 and I 2 5 0%). Neck dissection Twenty-one articles 15,18,21,23,28,29,35,36,39 43,45,46,48,54,57,62 64 evaluated neck dissection as a risk factor for PCF 1692 HEAD & NECK DOI /HED NOVEMBER 2015

3 PHARYNGOCUTANEOUS FISTULA AFTER TOTAL LARYNGECTOMY TABLE 1. Meta-analysis of risk factors for pharyngocutaneous fistula formation after total laryngectomy. Risk factor No. of studies No. of patients No. of events Absolute risk difference (M-H, fixed, IC 95% ) p value I 2 Age <60 y (IC 95% to 0.06).18 0% >60 y Sex Female (IC 95% to 0.06).73 0% Male Smoking habit Yes (IC 95% to 0.11).23 74% No Alcohol use Yes (IC 95% to 0.07).51 0% No Diabetes mellitus Yes (IC 95% 0.11 to 0.23) < % No COPD Yes (IC 95% 0.07 to 0.20) < % No Previous hemoglobin < (IC 95% 0.09 to 0.21) <.01 86% > Blood transfusion Yes (IC 95% 0.07 to 0.27) < % No Previous radiotherapy Yes (IC 95% 0.08 to 0.12) < % No Previous chemoradiotherapy Yes (IC 95% 0.01 to 0.21).04 0% No Previous tracheotomy Yes (IC 95% 0.01 to 0.08) % No T classification T1 T (IC 95% to 0.00).06 33% T3 T Advanced T classification T (IC 95% to 0.01).13 75% T Tumor subsite Supraglottis (IC 95% 0.00 to 0.06).03 34% Glottis Tumor site Hypopharynx (IC 95% 0.05 to 0.13) < % Only larynx Cartilage invasion Yes (IC 95% to 0.06).44 0% No Tumor grade I (IC 95% to 0.04).73 25% II III Surgical margins Positive (IC95% 0.02 to 0.14).01 66% Free Suture material Catgut (IC 95% 0.05 to 0.15) < % Vicryl Second suture layer Yes (IC 95% to 0.06).49 32% No Musculocutaneous flap Yes (IC 95% to 0.12).14 15% No HEAD & NECK DOI /HED NOVEMBER

4 DEDIVITIS ET AL. TABLE 1. Continued Risk factor No. of studies No. of patients No. of events Absolute risk difference (M-H, fixed, IC 95% ) p value I 2 Primary TEP Yes (IC 95% to 0.07).69 86% No Neck dissection Yes (IC 95% 0.00 to 0.06).05 63% No Type of neck dissection Radical (IC 95% to 0.08).69 63% Selective Abbreviations: M H, Mantel-Haenszel Test; IC 95%, confidence interval of 95%; COPD, chronic obstructive pulmonary disease; TEP, tracheoesophageal prosthesis. formation. Patients who underwent neck dissection presented an increase in this risk of 3% (IC 95% ; p ). This result is associated with high heterogeneity level (I %). After excluding the studies responsible for this condition, 28,29,57,63,64 the increase in risk for PCF because of neck dissection was 6% (IC 95% ; p <.01 and I 2 5 8%). DISCUSSION PCF is the most common complication of total laryngectomy. The number of possible disease risk factors is very high, although it should be noted that some factors often overlap or are included in several categories. 54 A review of the literature reveals conflicting results, including contradictory conclusions as to which parameters influence PCF formation. From a methodological point of view, most studies have not performed multivariate statistical analysis and have a relatively small number of cases. A multicentric study of 2063 patients showed that 10% of patients had some complication of the surgical wound. Although that study did not specifically mention which complications appeared, it must be supposed that many of them were PCF. By using a multiple logistic regression model, the variables independently associated with those complications were surgery extending beyond 10 hours, preoperative radiotherapy, low albumin levels, and diabetes mellitus. 67 It was widely stated that the postoperative incidence of PCF was not influenced by age and sex. 30,39,41 43,46,47,49,59,61 However, 1 preliminary series 1 indicated that the development of salivary fistula did not correlate with sex, but with age, increasing after 60 years of age. Other authors did not demonstrate any significant association between smoking habit and development of PCF. 41,46,47,61 No statistical difference was demonstrated in terms of alcohol use. 59,61 The use of the Cumulative Illness Rating Scale revealed the absence of any correlation of comorbidities with the development of PCF. 1 Other authors did not find significant higher fistula rates in patients with liver disease, diabetes mellitus, hypothyroidism, COPD, or peripheral vascular disease. 42 Diabetes mellitus was considered a strong independent risk factor for PCF by some authors 34,46 ; however, other authors failed to find this association. 39,41 Patients with diabetes are at an increased risk for adverse outcomes of surgery. Insulin deficiency and insulin resistance are aggravated by surgery and anesthesia. The consequences of hyperglycemia are glycosuria, volume depletion secondary to osmotic dieresis, impairment of wound healing, and leukocyte function with increased susceptibility to infections. 46 Serum albumin level is a marker of protein-energy malnutrition. Thus, it is considered an adequate indicator of nutritional status. 46 It has been reported that malnutrition was observed in 35% to 50% of the patients undergoing head and neck oncologic surgery. Nutritional deficiency increases impaired wound healing. PCF was demonstrated as statistically more common in patients with lower albumin levels. 31,49,50 The interpretation of such studies has been considered to have shortcomings because the definition of malnutrition was unclear, the patient population was relatively small, and the patient groups were heterogeneous. Three articles found higher rates of PCF among patients with lower serum albumin levels 31,45,61 ; however, as the cutoff values were different, it was not possible to perform a statistical evaluation in this meta-analysis. Some studies revealed significant correlations between the presence of anemia and PCF, 34,49,50 between postoperative levels of hemoglobin and incidence of fistula 31 and low preoperative and postoperative detected hemoglobin levels and PCF formation. 12,43,61 A postoperative low hemoglobin level plays a role in PCF development by leading to impaired wound healing. 31 The cutoff value of 12.5g/dL was chosen on the basis of previous data 2 ; however, in developing countries, the cutoff is generally lower. 59 A significant correlation between intraoperative 20 and postoperative 43 blood transfusion and incidence of PCF was noted. On the other hand, other articles did not find evidence of significant association. 25,34,59 Patients who received a blood transfusion were more likely to develop PCF than those who did not. However, this seems to be related to the extent of resection. When the extent of surgery is controlled, there is no significant effect of a blood transfusion. 43 Some studies reported that preoperative administration of radiotherapy increased the incidence of PCF because of a decrease in nutrient supply to the tissue, 2,12,20 22,32,34,36,41,43,45,47,48,52,57 whereas others did not find similar correlation. 23,29,30,34,39,42,46,59 Since the introduction of organ-preservation protocols for laryngeal carcinoma, laryngectomy has become increasingly reserved for 1694 HEAD & NECK DOI /HED NOVEMBER 2015

5 PHARYNGOCUTANEOUS FISTULA AFTER TOTAL LARYNGECTOMY surgical salvage in case of persistent or recurrent disease. Despite some decrease in the survival rates in countries where this strategy was widely adopted, the nonsurgical treatment of laryngeal and hypopharyngeal cancer has gradually become the mainstay of therapy in patients without cartilaginous invasion. 56 Previous primary concurrent chemoradiation is an independent predictor of PCF developing. This may be due to direct toxic effects of this treatment on tissue healing as well as to impaired nutritional status, common among these patients. High dose and wide field irradiation and concurrent chemotherapy probably have an impact on the rate of PCF developing. 40 Radiation-induced obliterative endarteritis and fibrosis impair wound healing. 65 This results in tissue hypoxia, which is maximal at the center of the treatment field. The hypovascularity and hypoxia of irradiated tissue can impair wound healing, thereby increasing PCF incidence in salvage surgery. 56,64 Preoperative tracheotomy is a local risk factor contributing to PCF formation. This surgical approach is frequently performed for advanced tumors. As a result, it may contribute to PCF development. Some articles demonstrated significant association between preoperative tracheotomy 42,46 48 and development of fistulas and others did not. 19,29,31,34,35,39,49,57 59,61 63 Laryngeal and hypopharyngeal T classification has been incriminated in some studies with fistula formation, with a higher frequency occurring with more-advanced tumors, 6,23,29 whereas others have found no relationship. 2,22,30,31,34,35,39,41,49 The incidence of PCF was higher in supraglottic than in glottic tumors. Because of extralaryngeal spread, supraglottic tumors may necessitate partial pharyngectomy in addition to total laryngectomy. The resection of large areas of pharyngeal mucosa can lead to closure under tension. Extended pharyngeal resection has also been reported as associated with a higher rate of PCF. 31,39,43,48,66 However, other studies demonstrate no association with extended hypopharyngeal mucosa excision and PCF. 29,35 A closure under tension, caused by a resection of large areas of pharyngeal mucosa, could increase the incidence of PCF. 41 Pyriform sinus tumors requiring a partial pharyngectomy have been stated to increase the risk of PCF after total laryngectomy. 7,34,42 A careful, atraumatic surgical technique and delicate management of the mucosa during surgery are probably the most important factors in reducing PCF formation; however, this is a difficult factor to evaluate. 33 Many studies do not even refer to the type of suture used. The weakest point is the 3-point junction, if a T- or Y-shaped closure is performed, stressing the importance of the vertical line repair. 69 In a series of 157 total laryngectomies, in the first 90 procedures, a pharyngeal closure technique with T-shaped interrupted stitches reinforced with constrictors was performed, whereas in the other 67 cases, a doubled continuous suture technique with reinforcement with the cutaneous flap was developed. In all, 25.5% of the cases sutured with the interrupted stitches and 2.9% of the patients who underwent continuous suture developed a fistula. 54 Positive surgical margins may explain the higher frequency of PCF development as a result of the deficient healing occurring locally at the surgical wound, especially pharyngoplasty. The continued presence of tumoral cells may modify or negatively influence the healing process and wound closure. Some authors found no correlation with PCF and positive margin, 31,35,39,49,57,62 with which some authors disagree. 32 Some recent comparative studies have compared manual and mechanical closures of the pharynx in patients undergoing total laryngectomy. This procedure is reserved for endolaryngeal tumors, whose staging should be based on meticulous preoperative assessment by means of endoscopy and imaging. A favorable outcome includes a tension-free suture line, watertight closure of the pharynx and hemostasis with preserved viability of the mucosa, and double-staggered rows of staples remaining in the pharynx and in the laryngeal specimen, minimizing the risk of contamination of the surgical field by oral and pharyngeal secretions. In order to evaluate the advantages of the mechanical suture in the pharyngeal closure, a meta-analysis selected 4 articles with a total of 417 patients. In the group of patients in whom the stapler was used, the incidence of PCF was 8.7%, whereas in the group of manual sutures, it was 22.9%, with reduction of the absolute risk of 15% (IC 95% ; p 5.02 and I %). The surgical time presented a difference of 80 minutes in favor of the stapler group (IC 95% minutes; p <.006). The difference for starting oral feeding was 8 days in favor of the mechanical suture (IC 95% days; p <.001). Furthermore, patients who underwent mechanical sutures had a shorter hospitalization period, with an average of 6 days. 70 As already mentioned, fistula incidence after salvage total laryngectomy has a higher risk of PCF. Prophylactic vascularized tissue flaps to reinforce the pharyngeal suture line may reduce fistula incidence and fistula severity in such scenario. 64 Despite the postulation that healthy vascular nonradiated tissue improves wound healing and protects against fistula formation, the results have been controversial. 58,62 There are limited possibilities for fistula prevention. Routine use of a pectoralis major musculocutaneous flap of pharyngeal reinforcement in salvage laryngectomies does not seem to reduce the fistula rate. 71 Conversely, the incidence of fistulas diminished when microvascular free tissue transfers were used for reconstruction of the hypopharynx in a small series of cases. 72 With respect to tracheoesophageal speech, the purpose is to restore the voice and achieve fluent speech, which re-establishes a patient s ability to communicate verbally. To this end, TEP is the current standard of care and the preferred method to restore verbal communication. Much of the debate about primary or secondary TEP has focused on voice-related issues, not on the complication rates. There is still controversy regarding the appropriate timing of the procedure in order to prevent complications. A significant difference in complications was noted, with 50% of PCF for the primary TEP group compared to 0% for the secondary group. 51 Concern with patients undergoing primary TEP is that surgical dissection along the wall may predispose them to compromised healing at the level of the inferior pharyngeal closure and the TEP site. Additionally, factors affecting surgical healing, such as previous radiotherapy, may increase the incidence of PCF associated with primary TEP. 58 Other authors did not find HEAD & NECK DOI /HED NOVEMBER

6 DEDIVITIS ET AL. significant evidence of an increase in incidence of PCF fistulas in patients undergoing primary TEP. 30,37,39,73 Some studies indicated higher rates of PCF formation after neck dissection combined with total laryngectomy 36,43 ; however, the majority demonstrate a lack of any significant association. 28,33,39,42,46 48,57,59,61,62 A significant association was found between lymph node metastasis and PCF incidence. One possible reason is that therapeutic neck dissection prolongs operation time compared to elective neck dissection. Furthermore, dissection of metastatic lymph nodes is more difficult than reactive lymph nodes and wound complications (hematoma, suppuration, and chylous fistula) are more common in radical neck dissection. 49 CONCLUSIONS The evidence synthesis allows us to conclude that COPD, previous hemoglobin <12.5g/dL, blood transfusion requirement, previous radiotherapy or chemoradiotherapy, supraglottic tumor subsite, hypopharyngeal tumor site, advanced primary tumors, positive surgical margins, and the performance of neck dissection (regardless of the type) were risk factors associated with higher incidences of PCF after total laryngectomy. REFERENCES 1. Dedivitis RA, Ribeiro KC, Castro MA, Nascimento PC. Pharyngocutaneous fistula following total laryngectomy. Acta Otorhinolaryngol Ital 2007; 27: Lavelle RJ, Maw AR. The aetiology of post-laryngectomy pharyngo-cutaneous fistulae. J Laryngol Otol 1972;86: Joseph DL, Shumrick DL. Risks of head and neck surgery in previously irradiated patients. Arch Otolaryngol 1973;97: Bresson K, Rasmussen H, Rasmussen PA. Pharyngo-cutaneous fistulae in totally laryngectomized patients. J Laryngol Otol 1974;88: Stell PM, Cooney TC. Management of fistulae of the head and neck after radical surgery. J Laryngol Otol 1974;88: Dedo DD, Alonso WA, Ogura JH. Incidence, predisposing factors and outcome of pharyngocutaneous fistulas complicating head and neck cancer surgery. Ann Otol Rhinol Laryngol 1975;84: Gall AM, Sessions DG, Ogura JH. Complications following surgery for cancer of the larynx and hypopharynx. Cancer 1977;39: Cummings CW, Johnson J, Chung CK, Sagerman R. Complications of laryngectomy and neck dissection following planned preoperative radiotherapy. Ann Otol Rhinol Laryngol 1977;86(6 Pt 1): Lundgren J, Olofsson J. Pharyngocutaneous fistulae following total laryngectomy. Clin Otolaryngol Allied Sci 1979;4: Horgan EC, Dedo HH. Prevention of major and minor fistulae after laryngectomy. Laryngoscope 1979;89(2 Pt 1): Aluffi E, Astesiano A, Aversa F, Ferrari F, Gandolfi G, Miscioscia D. Pharyngocutaneous salivary fistula after laryngectomy (author s transl) [in Italian]. Ann Osp Maria Vittoria Torino 1980;23: Wei WI, Lam KH, Wong J, Ong GB. Pharyngocutaneous fistula complicating total laryngectomy. Aust N Z J Surg 1980;50: Thawley SE. Complications of combined radiation therapy and surgery for carcinoma of the larynx and inferior hypopharynx. Laryngoscope 1981;91: Kent SE, Liu KC, Das Gupta AR. Post-laryngectomy pharyngo-cutaneous fistulae. J Laryngol Otol 1985;99: Shemen LJ, Spiro RH. Complications following laryngectomy. Head Neck Surg 1986;8: Johansen LV, Overgaard J, Elbrïnd O. Pharyngo-cutaneous fistulae after laryngectomy. Influence of previous radiotherapy and prophylactic metronidazole. Cancer 1988;61: Verma A, Panda NK, Mehta S, Mann SB, Mehra YN. Post laryngectomy complications and their mode of management an analysis of 203 cases. Indian J Cancer 1989;26: Sarkar S, Mehta SA, Tiwari J, Mehta AR, Mehta MS. Complications following surgery for cancer of the larynx and pyriform fossa. J Surg Oncol 1990;43: McCombe AW, Jones AS. Radiotherapy and complications of laryngectomy. J Laryngol Otol 1993;107: Hier M, Black MJ, Lafond G. Pharyngo-cutaneous fistulas after total laryngectomy: incidence, etiology and outcome analysis. J Otolaryngol 1993; 22: Natvig K, Boysen M, Tausjï J. Fistulae following laryngectomy in patients treated with irradiation. J Laryngol Otol 1993;107: Papazoglou G, Doundoulakis G, Terzakis G, Dokianakis G. Pharyngocutaneous fistula after total laryngectomy: incidence, cause, and treatment. Ann Otol Rhinol Laryngol 1994;103: Fradis M, Podoshin L, Ben David J. Post-laryngectomy pharyngocutaneous fistula a still unresolved problem. J Laryngol Otol 1995;109: Udaipurwala IH, Iqbal K, Jalisi M. Pharyngocutaneous fistula following laryngectomy. J Pak Med Assoc 1995;45: Celikkanat S, Koç C, Akyol MU, Ozdem C. Effect of blood transfusion on tumor recurrence and postoperative pharyngocutaneous fistula formation in patients subjected to total laryngectomy. Acta Otolaryngol 1995;115: Seikaly H, Park P. Gastroesophageal reflux prophylaxis decreases the incidence of pharyngocutaneous fistula after total laryngectomy. Laryngoscope 1995;105: Tomkinson A, Shone GR, Dingle A, Roblin DG, Quine S. Pharyngocutaneous fistula following total laryngectomy and post-operative vomiting. Clin Otolaryngol Allied Sci 1996;21: Nakamizo M, Kamata S, Kawabata K, Nigauri T, Hoki K. Pharyngo-cutaneous fistula after total laryngectomy [in Japanese]. Nihon Jibiinkoka Gakkai Kaiho 1997;100: Soylu L, Kiroglu M, Aydogan B, et al. Pharyngocutaneous fistula following laryngectomy. Head Neck 1998;20: Parikh SR, Irish JC, Curran AJ, Gullane PJ, Brown DH, Rotstein LE. Pharyngocutaneous fistulae in laryngectomy patients: the Toronto Hospital experience. J Otolaryngol 1998;27: Redaelli de Zinis LO, Ferrari L, Tomenzoli D, Premoli G, Parrinello G, Nicolai P. Postlaryngectomy pharyngocutaneous fistula: incidence, predisposing factors, and therapy. Head Neck 1999;21: Chee N, Siow JK. Pharyngocutaneous fistula after laryngectomy incidence, predisposing factors and outcome. Singapore Med J 1999;40: Herranz J, Sarandeses A, Fernandez MF, Barro CV, Vidal JM, Gavilan J. Complications after total laryngectomy in nonradiated laryngeal and hypopharyngeal carcinomas. Otolaryngol Head Neck Surg 2000;122: Cavalot AL, Gervasio CF, Nazionale G, et al. Pharyngocutaneous fistula as a complication of total laryngectomy: review of the literature and analysis of case records. Otolaryngol Head Neck Surg 2000;123: Ikiz AO, Uça M, G uneri EA, Erdag TK, S utay S. Pharyngocutaneous fistula and total laryngectomy: possible predisposing factors, with emphasis on pharyngeal myotomy. J Laryngol Otol 2000;114: Virtaniemi JA, Kumpulainen EJ, Hirvikoski PP, Johansson RT, Kosma VM. The incidence and etiology of postlaryngectomy pharyngocutaneous fistulae. Head Neck 2001;23: Karlen RG, Maisel RH. Does primary tracheoesophageal puncture reduce complications after laryngectomy and improve patient communication? Am J Otolaryngol 2001;22: Saydam L, Kalcioglu T, Kizilay A. Early oral feeding following total laryngectomy. Am J Otolaryngol 2002;23: Markou KD, Vlachtsis KC, Nikolaou AC, Petridis DG, Kouloulas AI, Daniilidis IC. Incidence and predisposing factors of pharyngocutaneous fistula formation after total laryngectomy. Is there a relationship with tumor recurrence? Eur Arch Otorhinolaryngol 2004;261: Ganly I, Patel S, Matsuo J, et al. Postoperative complications of salvage total laryngectomy. Cancer 2005;103: Galli J, De Corso E, Volante M, Almadori G, Paludetti G. Postlaryngectomy pharyngocutaneous fistula: incidence, predisposing factors, and therapy. Otolaryngol Head Neck Surg 2005;133: M akitie AA, Niemensivu R, Hero M, et al. Pharyngocutaneous fistula following total laryngectomy: a single institution s 10-year experience. Eur Arch Otorhinolaryngol 2006;263: Morton RP, Mehanna H, Hall FT, McIvor NP. Prediction of pharyngocutaneous fistulas after laryngectomy. Otolaryngol Head Neck Surg 2007; 136(4 Suppl):S46 S G uçl u E, Pinar E, Oncel S, Calli C. Pharyngocutaneous fistula after total laryngectomy: incidence and analysis of risk factors [in Turkish]. Kulak Burun Bogaz Ihtis Derg 2007;17: Wakisaka N, Murono S, Kondo S, Furukawa M, Yoshizaki T. Post-operative pharyngocutaneous fistula after laryngectomy. Auris Nasus Larynx 2008;35: Boscolo Rizzo P, De Cillis G, Marchiori C, Carpenè S, Da Mosto MC. Multivariate analysis of risk factors for pharyngocutaneous fistula after total laryngectomy. Eur Arch Otorhinolaryngol 2008;265: Saki N, Nikakhlagh S, Kazemi M. Pharyngocutaneous fistula after laryngectomy: incidence, predisposing factors, and outcome. Arch Iran Med 2008;11: Palomar Asenjo V, Sarroca Capell E, Tobıas Gomez S, Perez Hernandez I, Palomar Garcıa V. Pharyngocutaneous fistula following total laryngectomy. A case-control study of risk factors implicated in its onset [in Spanish]. Acta Otorrinolaringol Esp 2008;59: Pinar E, Oncel S, Calli C, Guclu E, Tatar B. Pharyngocutaneous fistula after total laryngectomy: emphasis on lymph node metastases as a new predisposing factor. J Otolaryngol Head Neck Surg 2008;37: HEAD & NECK DOI /HED NOVEMBER 2015

7 PHARYNGOCUTANEOUS FISTULA AFTER TOTAL LARYNGECTOMY 50. Akduman D, Naiboglu B, Uslu C, et al. Pharyngocutaneous fistula after total laryngectomy: incidence, predisposing factors, and treatment [in Turkish]. Kulak Burun Bogaz Ihtis Derg 2008;18: Emerick KS, Tomycz L, Bradford CR, et al. Primary versus secondary tracheoesophageal puncture in salvage total laryngectomy following chemoradiation. Otolaryngol Head Neck Surg 2009;140: Dirven R, Swinson BD, Gao K, Clark JR. The assessment of pharyngocutaneous fistula rate in patients treated primarily with definitive radiotherapy followed by salvage surgery of the larynx and hypopharynx. Laryngoscope 2009;119: Sarra LD, Rodrıguez JC, Garcıa Valea M, Bitar J, Da Silva A. Fistula following total laryngectomy. Retrospective study and bibliographical review [in Spanish]. Acta Otorrinolaringol Esp 2009;60: Iglesias Moreno MC, Gimeno Hernandez J, Gomez Serrano M, Carricondo F, Gil Loyzaga P, Poch Broto J. Pharyngo-cutaneous fistula: an old problem revisited. Acta Otolaryngol 2011;131: Stathas T, Mallis A, Mastronikolis NS, et al. Pharyngocutaneous fistula complicating laryngectomy: can metronidazole help? ORL J Otorhinolaryngol Relat Spec 2011;73: Klozar J, Cada Z, Koslabova E. Complications of total laryngectomy in the era of chemoradiation. Eur Arch Otorhinolaryngol 2012;269: White HN, Golden B, Sweeny L, Carroll WR, Magnuson JS, Rosenthal EL. Assessment and incidence of salivary leak following laryngectomy. Laryngoscope 2012;122: Dowthwaite SA, Penhearow J, Szeto C, et al. Postlaryngectomy pharyngocutaneous fistula: determining the risk of preoperative tracheostomy and primary tracheoesophageal puncture. J Otolaryngol Head Neck Surg 2012; 41: Aires FT, Dedivitis RA, Castro MA, Ribeiro DA, Cernea CR, Brand~ao LG. Pharyngocutaneous fistula following total laryngectomy [in Portuguese]. Braz J Otorhinolaryngol 2012;78: McLean JN, Nicholas C, Duggal P, et al. Surgical management of pharyngocutaneous fistula after total laryngectomy. Ann Plast Surg 2012;68: Erdag MA, Arslanoglu S, Onal K, Songu M, Tuylu AO. Pharyngocutaneous fistula following total laryngectomy: multivariate analysis of risk factors. Eur Arch Otorhinolaryngol 2013;270: Sousa Ade A, Porcaro Salles JM, Soares JM, et al. Predictors of salivary fistula after total laryngectomy. Rev Col Bras Cir 2013;40: Fernandez Prada M, Palomeque Vera JM, Gomez Hervas J, Gullen Solvas J, Sainz Quevedo M, Revelles Suarez H. Incidence, hospital stay and risk factors associated with the occurrence of pharyngo-cutaneous fistula after total laryngectomy [in Spanish]. Acta Otorrinolaringol Esp. 2014;65: Sayles M, Koonce SL, Harrison L, Beasley N, McRae AR, Grant DG. Pharyngo-cutaneous fistula complicating laryngectomy in the chemoradiotherapy organ-preservation epoch. Eur Arch Otorhinolaryngol 2014; 271: Paydarfar JA, Birkmeyer NJ. Complications in head and neck surgery: a meta-analysis of postlaryngectomy pharyngocutaneous fistula. Arch Otolaryngol Head Neck Surg 2006;132: Aarts MC, Rovers MM, Grau C, Grolman W, van der Heijden GJ. Salvage laryngectomy after primary radiotherapy: what are prognostic factors for the development of pharyngocutaneous fistulae? Otolaryngol Head Neck Surg 2011;144: Schwartz SR, Yueh B, Maynard C, Daley J, Henderson W, Khuri SF. Predictors of wound complications after laryngectomy: a study of over 2000 patients. Otolaryngol Head Neck Surg 2004;131: Weber RS, Berkey BA, Forastiere A, et al. Outcome of salvage total laryngectomy following organ preservation therapy: the Radiation Therapy Oncology Group trial Arch Otolaryngol Head Neck Surg 2003;129: Shah AK, Ingle MV, Shah KL. Some thoughts on prevention of postoperative salivary fistula. J Postgrad Med 1985;31: Aires FT, Dedivitis RA, Castro MA, Bernardo WM, Cernea CR, Brand~ao LG. Efficacy of stapler pharyngeal closure after total laryngectomy: a systematic review. Head Neck 2014;36: Gil Z, Gupta A, Kummer B, et al. The role of pectoralis major muscle flap in salvage total laryngectomy. Arch Otolaryngol Head Neck Surg 2009; 135: Teknos TN, Myers LL, Bradford CR, Chepeha DB. Free tissue reconstruction of the hypopharynx after organ preservation therapy: analysis of wound complications. Laryngoscope 2001;111: Cheng E, Ho M, Ganz C, et al. Outcomes of primary and secondary tracheoesophageal puncture: a 16-year retrospective analysis. Ear Nose Throat J 2006;85:262, HEAD & NECK DOI /HED NOVEMBER