Acta Oto-Laryngologica. 2015; Early Online, 1–7
ORIGINAL ARTICLE
Pharyngocutaneous fistula after salvage laryngectomy
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NILDA SÜSLÜ1, REZARTA TAGA SENIRLI1, R. ÖNDER GÜNAYDIN1, SERDAR ÖZER1, JALE KARAKAYA2 & A. S¸ EFIK HO¸S AL1 1
Department of Otorhinolaryngology-Head and Neck Surgery and 2Department of Biostatistics, Hacettepe University Faculty of Medicine, Ankara, Turkey
Abstract Conclusion: Preoperative chemoradiotherapy (CRT) was associated with a significantly higher rate of pharyngocutaneous fistula (PCF). Objective: PCF is the most frequent complication following total laryngectomy. Although organ-preserving radiotherapy (RT) or CRT offer good locoregional control, many patients still require salvage laryngectomy. The aim of this study was to evaluate the factors that predispose patients to PCF, with a focus on preoperative RT, induction chemotherapy (ICT), and CRT. Methods: This was a retrospective case series; 151 patients who underwent TL were reviewed. Preoperative RT, ICT, CRT, and some surgical parameters were analyzed as potential risk factors. Results: The overall PCF rate was 13%. CRT was the only preoperative treatment that had a significant effect on PCF (35.3%, p = 0.004, odds ratio (OR) = 10.75). Surgery extended to the pharynx (p = 0.005, OR = 8.34) and vacuum drain duration (p = 0.012, OR = 5.16) were observed to be associated with PCF.
Keywords: Total laryngectomy, radiotherapy, chemoradiotherapy
Introduction Pharyngocutaneous fistula (PCF) is communication between the digestive and cervical skin, which manifests as the appearance of saliva on the skin surface after swallowing. Communication with the skin typically occurs at the level of a surgical incision or – less frequently – around a tracheostoma [1]. The continuous flow of saliva is the primary cause of infection that hinders PCF closure. PCF is the most common local complication following total laryngectomy. The incidence of PCF varies from 3% to 65% [2]; however, rates between 13% and 25% have been reported recently [1,3,4]. The formation of PCF prolongs hospitalization more than any other complication, and delays oral intake of food. Nasogastric tube or gastrostomy feeding of long duration results in significant discomfort and negatively affects patient well-being. In addition, a salivary fistula causes wound breakdown and interferes with
subsequent adjuvant therapies that target tumor control. Furthermore, it sometimes results in catastrophic consequences such as carotid artery rupture, particularly in patients with concurrent radical neck dissection. Various risk factors associated with the formation of PCF have been studied, but the findings are inconsistent. Factors reported to predispose to PCF include preoperative radiation therapy, types of surgery, radical neck dissection, types of pharyngeal closure and suture material, positive tumor margins, preoperative tracheotomy, poor general health status, tumor localization, advanced tumor stage, low hemoglobin (Hb) level, intraoperative blood transfusion, prophylactic antibiotic use, hematoma formation, and wound infection [2,5,6]. In recent years, the number of patients undergoing total laryngectomy due to failure of organ-preserving concurrent chemoradiotherapy (CRT) has been increasing. Although preoperative treatment, including radiotherapy
Correspondence: Nilda Süslü, MD, Department of Otorhinolaryngology-Head and Neck Surgery, Hacettepe University Faculty of Medicine, 06100, Sıhhiye, Ankara, Turkey. Tel: +90 312 305 1785. Fax: +90 312 311 3500. E-mail: [email protected]
(Received 11 November 2014; accepted 6 January 2015) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2015.1009639
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(RT), concurrent CRT, and induction chemotherapy (ICT), is considered a risk factor for PCF, an insufficient number of studies have compared the risk of PCF associated with different preoperative treatment modalities. As such, the present study aimed to determine the effect of preoperative concurrent CRT on PCF formation, and to compare the rate of PCF formation associated with preoperative concurrent CRT, RT, and ICT. Furthermore, factors that predisposed patients to PCF were evaluated.
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Material and methods Patients This retrospective study included patients diagnosed as having laryngeal/hypopharyngeal cancer who underwent total laryngectomy/partial laryngopharyngectomy at the Department of OtorhinolaryngologyHead and Neck Surgery, Hacettepe University Faculty of Medicine, between 2002 and 2012. In total, 151 patients underwent total laryngectomy (n = 136) or partial laryngopharyngectomy (n = 15) with primary closure. Patients that underwent more complex reconstruction techniques (e.g. pedicled or free flaps) for closure were excluded from the study to prevent confounding factors associated with technique differences. The mean age of the 146 (96%) male and 5 (4%) female patients was 60 years (range 33–84 years). Preoperative treatment Total laryngectomy/laryngopharyngectomy was performed according to tumor stage (T4 or selected T3 or T2) or failure to respond to organ-preserving protocols. In all, 94 of the 151 cases (62%) underwent primary total laryngectomy/laryngopharyngectomy (PL). Salvage laryngectomy (SL) was performed for persistent or locally recurrent disease. Preoperative treatment in the salvage patients included RT alone (SL-RT) (n = 28, 19%) and concurrent CRT (SL-CRT) (n = 17, 11%); 12 of the patients (8%) that did not respond to ICT underwent surgery, as RT failure was predicted. Surgery Total laryngectomy was performed in 136 (90%) of the patients, whereas partial pharyngectomy in addition to total laryngectomy was performed in 15 patients (10%) that had tumor extension to the pyriform sinus. In all cases surgery was performed or supervised by surgeons with extensive experience in oncological ENT surgery. The pharynx was closed via
horizontal closure of the pharyngeal mucosa with continuous Vicryl 3/0 sutures in 146 (97%) of the patients. A submucosal closure was performed with interrupted sutures as a second layer, followed by a third layer using sutures through the suprahyoid muscles and the inferior pharyngeal constrictor muscles. Horizontal linear repair was performed in all patients, except those that underwent partial pharyngectomy combined with total laryngectomy; in these patients the pharyngeal defect was closed via T-type closure. In five (3%) patients T-closure of the pharynx was performed with three continuous mucosal sutures that converged in the center of the neopharynx. The second and third layers of the T-closure were the same as in horizontal closure. Total laryngectomy was combined with neck dissection (including selective, modified radical, or radical neck dissection) in 115 (76%) patients. In all, 36 patients (24%) underwent total laryngectomy without a neck procedure because of preoperative RT to the neck region. Postoperative follow-up A vacuum drainage system was used and maintained for at least 48 h. Antibiotic therapy (amoxicillinclavulanate 1.2 g/8 h or ampicillin-sulbactam 1.5 g/6 h was administered post surgery until vacuum drainage was stopped. In 132 of the 151 patients a nasogastric tube was not inserted and oral feeding began immediately after surgery. A nasogastric tube was inserted intraoperatively in the remaining 19 patients (12.6%). In 87.4% of the patients early oral feeding without a nasogastric tube began within 3 days of surgery. Oral feeding was started 24 h post surgery in 68 (45%) of the patients and 48 h post surgery in 83 (55%) of the patients. Water was given for initial oral intake because it is particle-free and does not irritate the pharyngeal wall. Frequently, oral intake of water was followed by other clear fluids (e.g. fruit juice), and then milk. Oral feeding continued with semi-solid food in the following 10 days. Daily caloric intake during the postoperative period was closely monitored by dieticians and maintained at 2100 calories in males and 1850 calories in the female patients. In patients with PCF food was withheld until closure of the fistula. Risk factors associated with PCF In addition to RT and concurrent CRT, the following factors were analyzed for their association with PCF formation: patient age, surgery extended to the pharynx, associated neck dissection, history of tracheotomy, intraoperative blood transfusion, postoperative
Pharyngocutaneous fistula after salvage laryngectomy Hb level, insertion of a nasogastric tube, duration of vacuum drainage, and post-surgical time to oral feeding.
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Statistical analysis Descriptive statistics are expressed as mean ± SD for numerical variables. Descriptive statistics for categorical variables are presented as number and percentage. The independent samples t test was used to compare mean values of age. Associations between categorical variables were examined using Pearson’s chi-squared test for continuity correction or Fisher’s exact test. Logistic regression analysis was performed to identify the risk factors for PCF. A logistic regression model was constructed using independent variables and the binary dependent variable (PCF). Using the logistic model, odds ratios (ORs) and their respective 95% confidence intervals (CIs) were calculated. The level of statistical significance was set at p < 0.05. All statistical analyses were performed using SPSS v.15.0 for Windows. Results In total, 20 of the 151 patients (13%) developed PCF following PL. PCF occurred in a mean of 9 days post surgery (range 6–24 days). In all, three patients that received preoperative concurrent CRT had a persistent PCF that was surgically treated. Univariate analysis of prognostic factors Patient age was analyzed as a risk factor for the formation of PCF. The mean age of the patients with and without PCF was 58 and 61 years, respectively; the difference was not significant (p = 0.348). Based on the chi-squared test there was no significant difference in the frequency of PCF formation between the patients that underwent SL (11/57, 19.3%) and PL (9/94, 9.6%) (p = 0.144); however, the frequency of PCF formation was higher in the SL-RT and SLICT patients (10.7% and 16.7%, respectively) than in the patients that underwent PL, but the difference was not significant (p = 1.0 and p = 0.610, respectively). The occurrence of PCF formation in the SL-CRT patients (6/17, 35.3%) was significantly higher than in those that underwent PL (9/94, 9.6%) (p = 0.011). Table I summarizes the univariate analysis of the predisposing factors for the formation of PCF. PCF occurred in 13 (9.6%) of the patients that underwent total laryngectomy (n = 136), versus 7 (46.7%) of those that underwent laryngopharyngectomy (n = 15); the difference in the formation of PCF between the surgical procedures was significant
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Table I. Univariate analysis of predisposing factors for pharyngocutaneous fistula (PCF). Characteristics
PCF (%)
Treatment (1)
0.144
PL
9/94 (9.6)
SL
11/57 (19.3)
Treatment (2)
1.000
PL
9/94 (9.6)
SL-RT
3/28 (10.7)
Treatment (3)
0.011
PL
9/94 (9.6)
SL-CRT
6/17 (35.3)
Treatment (4)
0.610
PL
9/94 (9.6)
SL-ICT
2/12 (16.7)
Treatment (5)
0.063
SL-RT
3/28 (10.7)
SL-CRT
6/17 (35.3)
Treatment (6)
0.408
SL-ICT
2/12 (16.7)
SL-CRT
6/17 (35.3)
Neck dissection No Yes
1.000 5/36 (13.9) 15/115 (13)
Postoperative Hb
1.000
£ 10 g/dl
3/24 (12.5)
> 10 g/dl
17/126 (13.5)
Prior tracheotomy No Yes
1.000 3/24 (12.5) 17/127 (13.4)
Surgery extended to pharynx No Yes
0.001 13/136 (9.6) 7/15 (46.7)
Pharynx closure Horizontal T-closure
p Value
0.017 17/146 (11.6) 3/5 (60)
NG insertion (intraoperative)
0.022
No
14/132 (11)
Yes
6/19 (32)
Duration of vacuum drainage
0.042
£ 4 days
6/81 (7.4)
> 4 days
14/70 (20)
Blood transfusion
0.487
No
10/90 (11)
Yes
10/61 (16)
Significant values are shown in bold type. CRT, chemoradiotherapy; Hb, hemoglobin; ICT, induction chemotherapy; NG, nasogastric tube; PL, primary total laryngectomy/laryngopharyngectomy; RT, radiotherapy; SL, salvage laryngectomy.
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(p = 0.001). Primary closure of pharynx was analyzed as a risk factor for PCF. In total, 146 patients had horizontal closure and 5 patients had T-closure; PCF occurred in 11.6% and 60% of these patients, respectively, and the difference was significant (p = 0.017). PCF occurred in 15 (13%) of the 115 patients that underwent concurrent neck dissection, and in 5 (13.9%) of the 36 patients that did not; the difference was not significant (p = 1.0). In all, 24 patients underwent tracheotomy due to involvement of the airway, of which 3 (12.5%) developed PCF. However, in the 127 patients that did not undergo tracheotomy, PCF occurred in 17 patients (13.4%); based on Fisher’s exact test, the difference was not significant (p = 1.0). Among the 126 patients with a postoperative Hb level > 10 g/dl and the 24 patients with a level £ 10 g/dl, the frequency of PCF formation was similar – 13.5% and 12.5%, respectively; as such, the postoperative Hb level was not considered a risk factor for PCF in the study’s patient population (p = 1.000). PCF developed in 10 (16%) of 61 patients that received intraoperative blood transfusion and in 10 (11%) of the 90 patients that did not, but the difference was not significant (p = 0.487). The mean duration of postoperative vacuum drainage was 4 days (range 2–12 days), which was used as a cut-off point for the comparison of the risk of PCF. PCF was observed in 6 (7.4%) of the 81 patients with vacuum drainage duration £ 4 days, versus 14 (20%) of the 70 patients with vacuum drainage duration > 4 days; the difference was significant (p = 0.042). In total, 6 (32%) of 19 patients in whom a nasogastric tube was inserted intraoperatively developed PCF, versus 11% of 132 patients that did not use a nasogastric tube; the difference was significant
(p = 0.022). Among the patients without a nasogastric tube inserted intraoperatively, early oral feeding was started within 3 days post surgery. In all, 16% of the 68 patients that were fed 24 h post surgery and 11% of those that were fed 48 h post surgery developed PCF; the difference was not significant (p = 0.471). Among the 25 patients that received preoperative RT and did not use a nasogastric tube, initial feeding was 24–72 h post surgery; there was not a significant difference in the formation of PCF between the patients that were fed 24 h post surgery (1/14) and those fed later (1/11) (p = 1.00). Finally, there were no significant differences in the frequency of PCF formation according to patient age, preoperative RT alone, preoperative ICT, concurrent neck dissection, preoperative tracheotomy, postsurgical Hb level, intraoperative blood transfusion, or postoperative time of oral feeding. Table II summarizes the relationship between PCF formation and the investigated parameters.
Multivariate analysis Multivariate analysis was used to examine the prognostic factors associated with PCF formation. The incidence of PCF following SL was significantly higher than that following PL (p = 0.041). Among the patients that received preoperative treatment, only concurrent CRT was strongly associated with the formation of PCF, with a hazard ratio of 10.75 (p = 0.004). Patients in which surgery was extended to the pharynx had a significantly higher incidence of PCF (p = 0.005) than the other patients. Duration of vacuum drainage > 4 days was an independent risk factor for PCF (p = 0.012). Table II
Table II. Multivariate analysis of risk factors for pharyngocutaneous fistula (PCF). 95% CI for OR Variable
p Value
OR
Constant
0.002
0.001
Age
0.713
0.991
Lower
Upper
0.943
1.041
Surgery extended to the pharynx
0.005
8.337
1.929
36.020
Nasogastric feeding
0.119
3.047
0.750
12.381
Pharynx closure
0.567
0.447
0.028
7.075
Duration of vacuum drainage
0.012
5.156
1.425
18.648
1.647
0.355
7.633
Preoperative treatment
0.041
Preoperative RT only
0.524
Preoperative ICT
0.645
1.553
0.239
10.081
Preoperative concurrent CRT
0.004
10.751
2.127
54.335
Significant values are shown in bold type. CI, confidence interval; CRT, chemoradiotherapy; ICT, induction chemotherapy; OR, odds ratio; RT, radiotherapy.
Pharyngocutaneous fistula after salvage laryngectomy shows the predisposing factors associated with PCF (with hazard ratios) based on multivariate analysis.
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Discussion The rate of PCF formation among 151 patients following total laryngectomy in the present study was 13%, which is in agreement with earlier reports [1–6]. Organ-preserving RT or CRT for laryngeal carcinoma results in good locoregional control and survival comparable to that achieved with total laryngectomy and postoperative RT, with the added benefit of preserving the voice and swallowing function in a significant number of patients [7,8]. Despite such results, many patients still experience recurrent or persistent disease requiring salvage surgery, most frequently total laryngectomy. It has been suggested that radiation diminishes the healing capacity of tissues due to a dysfunctional fibroblast population, which results in hypovascularity and aggravation of atherosclerosis via induction of myointimal fibrosis [2]. Many researchers have suggested that patients who receive preoperative RT have a high incidence of PCF – up to 58% [2,9,10]. A meta-analysis of postlaryngectomy PCF showed that preoperative RT increased the risk of PCF formation, and that the severity and duration of fistulae were greater than those in patients that had not undergone preoperative RT [11]. In contrast, other studies report that there is no association between PCF formation and preoperative RT [1,5]. In the present study the incidence of PCF in the SL-RT patients was 10.7%, which was not significantly different from that in the patients that underwent PL (9.6%). ICT was also reported to increase the occurrence of postoperative wound complications in patients with advanced-stage head and neck carcinoma [18]. Whether or not the addition of ICT to RT is associated with a higher risk of postoperative complications than RT only in patients undergoing SL remains uncertain. Newman et al. reported a PCF rate of 11.5% in a group of 28 patients that received preoperative ICT and RT [12]. To reduce the additional risk of RT in the present study’s analysis only the patients that underwent SL due to failure of preoperative ICT were included. There was no significant difference in the frequency of PCF formation between the patients that received ICT and PL. In recent years the use of concurrent CRT for organ preservation in patients with advanced laryngeal carcinoma has been increasing. It has been suggested that the concurrent addition of chemotherapy multiplies the damaging effects of RT on normal tissue, which results in PCF formation that persists post SL [13]. Weber et al. reported that the incidence of post-
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laryngectomy PCF was higher in patients that underwent concurrent CRT (30%) than in those the received RT only (15%) [13]. It was reported that when PCF develops in patients that undergo salvage surgery the severity and duration of the fistulae are significantly greater, and they are more likely to require surgical intervention than when they occur in patients treated with PL. However, the reported rate of PCF formation in patients treated with salvage surgery varies in the literature; in all of the recent studies a statistically significantly higher PCF formation rate in SL patients than PL patients has been reported (Table III) [14–16]. To the best of our knowledge the literature has not included any studies from a single institute that compare complications associated with salvage surgery in patients that received preoperative ICT and concurrent CRT; therefore, the present study was designed and performed. The present findings show that the incidence of PCF in the SL-CRT patients (35.3%) was higher than that in the SL-RT patients (10.7%, OR = 1.6) and SL-ICT patients (16.7%, OR = 1.5); however, the difference was not significant. We think that the synergistic or additive effect of RT and chemotherapy increased the normal tissue damage and increased the risk of PCF 10.75-fold. In the present study surgery extended to the pharynx (laryngopharyngectomy) increased the risk of PCF 8.7-fold, as compared with PL, which is consistent with other reports [14,15]. We believe that the high risk of PCF observed in the present study was related to the tension on the suture lines at the conjunction of the neopharynx, as only patients that underwent primary closure of this large defective mucosal region were included. Delaying oral feeding to prevent fistula development is common practice among head and neck surgeons. At present, the efficacy of early oral feeding remains controversial. Early initiation of oral feeding is thought to play a role in the development of PCF; as such, nasogastric feeding for 7–14 days is considered safe practice [2,17]. In contrast, some retrospective studies did not observe an association between fistulae Table III. Comparison of PCF rates in patients that underwent PL and SL. Study
SL (%)
PL (%)
Tsou et al. (2010) [14]
58.3
21.4
Patel and Keni (2009) [15]
57
27
Sewnaik et al. (2012) [16]
50
This study
19.3
– 9.6
PCF, pharyngocutaneous fistula; PL, primary total laryngectomy/ laryngopharyngectomy; SL, salvage laryngectomy.
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and early oral feeding [3,6]. Medina and Khafif compared early oral intake with delayed feeding following total laryngectomy without pharyngectomy [18]. They noted that early oral feeding (48 h post total laryngectomy) did not increase the rate of fistula formation. Seven et al. evaluated the safety and efficacy of early oral feeding in a prospective study that compared oral intake with feeding via primary tracheoesophageal puncture. They concluded that initiation of oral feeding on postoperative day 1 was safe clinical practice [19]. In addition, use of a nasogastric tube causes local trauma and significantly increases stress to the pharyngeal suture line, which may contribute to fistula formation. It has also been reported that use of a nasogastric tube is associated with such disadvantages as gastroesophageal reflux, poor cosmetic appearance, and low quality of life. It was suggested that a nasogastric tube might induce damage to the pharyngeal mucosa primarily via acidic gastroesophageal reflux [6]. It is clear that use of a nasogastric tube for 1–2 weeks is uncomfortable for patients. Since patients are in psychological discomfort because of their cancer and losing their larynx, placement of a nasogastric tube creates an additional stress on their well-being. Instead of using a nasogastric tube, we have been initiating oral intake with water in the first 24 h following total laryngectomy since 1979. With or without a nasogastric tube, patients swallow their saliva and the pharynx is never totally at rest during the postoperative period. In the light of the present findings we believe that early water intake is not associated with the formation of PCF, and in fact may facilitate early restoration of normal swallowing function. In the present study, the incidence of PCF in patients that used a nasogastric tube intraoperatively was significantly higher than in those in which feeding was started orally, including patients that received preoperative RT alone and concurrent CRT. Since a higher incidence was reported for those who received prior radiotherapy alone or concurrent CRT, another question in our mind was the time of starting oral feeding. However, when the incidence of PCF formation was observed in the patients that received prior treatment, the incidence was not higher in patients in whom oral feeding was started after 24 h, when compared with later days. The present findings indicate that early oral feeding had no effect on the incidence of PCF in patients that received preoperative RT only or concurrent CRT. Simultaneous neck dissection was another possible predisposing factor for PCF taken into account, as suggested by previous reports [2]. Neck dissection might increase the risk of fistula formation because of burdening the postoperative recovery due to extensive surgical
intervention; however, in the present study no such correlation was observed, which is in agreement with other similar studies [1,4,20]. Preoperative tracheotomy has been considered by some to be a predisposing factor for PCF. Tracheotomy is frequently performed for more advanced tumors, sometimes in emergency situations due to dyspnea in heavily burdened patients. These reasons may possibly contribute to an increase in the rate of fistula formation. It had been thought that an increased risk of PCF was due to preoperative tracheotomy, whereas in the present study a similar relationship was not noted [1]. Although the postoperative Hb level was reported to be associated with an increase in the risk of fistula development in earlier studies [5,11], in the present study there was no significant difference in the incidence of PCF between the patients with an Hb level < 10 g/dl and > 10 g/dl. Additionally, despite a tendency for PCF in the patients that received blood transfusion in the present study, this was not strongly correlated. Duration of vacuum drainage was another associated risk factor for PCF in the present study. To the best of our knowledge the present study is the first to examine the effect of vacuum drainage on the formation of PCF. It can be assumed that the long-term vacuum drainage is a result of undiagnosed low-level saliva flow through the neopharynx; therefore, we think that when the contents of vacuum drainage continue to have a dirty appearance instead of hemorrhagic characteristics, surgeons should consider PCF. Conclusion Although the incidence of PCF following SL was higher than that following PL in the present study, preoperative concurrent CRT was most strongly associated with PCF formation. The other two primary factors associated with the occurrence of PCF were surgery extended to the pharynx and vacuum drainage duration > 4 days. When considering which organpreserving protocols to use, clinicians should be aware that unsuccessful preoperative concurrent CRT might cause severe complications following SL. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Markou KD, Vlachtsis KC, Nikolaou AC, Petridis DG, Kouloulas AI, Daniilidis IC. Incidence and predisposing factors of pharyngocutaneous fistula formation after total
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pharyngocutaneous fistula. Arch Otolaryngol Head Neck Surg 2006;132:67–72. Newman JP, Turris DJ, Pinto HA, Fee WE Jr, Goode RL, Goffinet DR. Surgical morbidity of neck dissection after chemoradiotherapy in advanced head and neck cancer. Ann Otol Rhinol Laryngol 1997;106:117–21. Weber RS, Berkey BA, Forastiere A, Cooper J, Maor M, Goepfert H, et al. Outcome of salvage total laryngectomy following organ preservation therapy. The radiation therapy oncology group trial 91–11. Arch Otolaryngol Head Neck Surg 2003;129:44–9. Tsou Y-A, Hua C-H, Lin M-H, Tseng H-C, Tsai M-H, Shaha A. Comparison of pharyngocutaneous fistula between patients followed by primary laryngopharyngectomy and salvage laryngopharyngectomy for advanced hypopharyngeal cancer. Head Neck 2010;32:1494–500. Patel UA, Keni SP. Pectoralis myofascial flap during salvage laryngectomy prevents pharyngocutaneous fistula. Otolaryngol Head Neck Surg 2009;141:190–5. Sewnaik A, Keereweer S, Al-Mamgani A, Baatenburg de Jong RJ, Wieringa MH, Meeuwis CA, et al. High complication risk of salvage surgery after chemoradiation failures. Acta Otolaryngol 2012;132:96–100. Volling P, Singelmann H, Ebeling O. Incidence of salivary fistulae in relation to timing of oral nutrition after laryngectomy. HNO 2001;49:276–82. Medina JE, Khafif A. Early oral feeding following total laryngectomy. Laryngoscope 2001;111:368–72. Seven H, Calis AB, Turgut S. A randomized controlled trial of early oral feeding in laryngectomized patients. Laryngoscope 2003;113:1076–9. Cavalot AL, Gervasio CF, Nazionale G, Albera R, Bussi M, Staffieri A, et al. Pharyngocutaneous fistula as a complication of total laryngectomy: review of the literature and analysis of case records. Otolaryngol Head Neck Surg 2000;123:587– 92.
ORIGINAL ARTICLE
Pharyngocutaneous fistula after salvage laryngectomy
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NILDA SÜSLÜ1, REZARTA TAGA SENIRLI1, R. ÖNDER GÜNAYDIN1, SERDAR ÖZER1, JALE KARAKAYA2 & A. S¸ EFIK HO¸S AL1 1
Department of Otorhinolaryngology-Head and Neck Surgery and 2Department of Biostatistics, Hacettepe University Faculty of Medicine, Ankara, Turkey
Abstract Conclusion: Preoperative chemoradiotherapy (CRT) was associated with a significantly higher rate of pharyngocutaneous fistula (PCF). Objective: PCF is the most frequent complication following total laryngectomy. Although organ-preserving radiotherapy (RT) or CRT offer good locoregional control, many patients still require salvage laryngectomy. The aim of this study was to evaluate the factors that predispose patients to PCF, with a focus on preoperative RT, induction chemotherapy (ICT), and CRT. Methods: This was a retrospective case series; 151 patients who underwent TL were reviewed. Preoperative RT, ICT, CRT, and some surgical parameters were analyzed as potential risk factors. Results: The overall PCF rate was 13%. CRT was the only preoperative treatment that had a significant effect on PCF (35.3%, p = 0.004, odds ratio (OR) = 10.75). Surgery extended to the pharynx (p = 0.005, OR = 8.34) and vacuum drain duration (p = 0.012, OR = 5.16) were observed to be associated with PCF.
Keywords: Total laryngectomy, radiotherapy, chemoradiotherapy
Introduction Pharyngocutaneous fistula (PCF) is communication between the digestive and cervical skin, which manifests as the appearance of saliva on the skin surface after swallowing. Communication with the skin typically occurs at the level of a surgical incision or – less frequently – around a tracheostoma [1]. The continuous flow of saliva is the primary cause of infection that hinders PCF closure. PCF is the most common local complication following total laryngectomy. The incidence of PCF varies from 3% to 65% [2]; however, rates between 13% and 25% have been reported recently [1,3,4]. The formation of PCF prolongs hospitalization more than any other complication, and delays oral intake of food. Nasogastric tube or gastrostomy feeding of long duration results in significant discomfort and negatively affects patient well-being. In addition, a salivary fistula causes wound breakdown and interferes with
subsequent adjuvant therapies that target tumor control. Furthermore, it sometimes results in catastrophic consequences such as carotid artery rupture, particularly in patients with concurrent radical neck dissection. Various risk factors associated with the formation of PCF have been studied, but the findings are inconsistent. Factors reported to predispose to PCF include preoperative radiation therapy, types of surgery, radical neck dissection, types of pharyngeal closure and suture material, positive tumor margins, preoperative tracheotomy, poor general health status, tumor localization, advanced tumor stage, low hemoglobin (Hb) level, intraoperative blood transfusion, prophylactic antibiotic use, hematoma formation, and wound infection [2,5,6]. In recent years, the number of patients undergoing total laryngectomy due to failure of organ-preserving concurrent chemoradiotherapy (CRT) has been increasing. Although preoperative treatment, including radiotherapy
Correspondence: Nilda Süslü, MD, Department of Otorhinolaryngology-Head and Neck Surgery, Hacettepe University Faculty of Medicine, 06100, Sıhhiye, Ankara, Turkey. Tel: +90 312 305 1785. Fax: +90 312 311 3500. E-mail: [email protected]
(Received 11 November 2014; accepted 6 January 2015) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2015.1009639
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(RT), concurrent CRT, and induction chemotherapy (ICT), is considered a risk factor for PCF, an insufficient number of studies have compared the risk of PCF associated with different preoperative treatment modalities. As such, the present study aimed to determine the effect of preoperative concurrent CRT on PCF formation, and to compare the rate of PCF formation associated with preoperative concurrent CRT, RT, and ICT. Furthermore, factors that predisposed patients to PCF were evaluated.
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Material and methods Patients This retrospective study included patients diagnosed as having laryngeal/hypopharyngeal cancer who underwent total laryngectomy/partial laryngopharyngectomy at the Department of OtorhinolaryngologyHead and Neck Surgery, Hacettepe University Faculty of Medicine, between 2002 and 2012. In total, 151 patients underwent total laryngectomy (n = 136) or partial laryngopharyngectomy (n = 15) with primary closure. Patients that underwent more complex reconstruction techniques (e.g. pedicled or free flaps) for closure were excluded from the study to prevent confounding factors associated with technique differences. The mean age of the 146 (96%) male and 5 (4%) female patients was 60 years (range 33–84 years). Preoperative treatment Total laryngectomy/laryngopharyngectomy was performed according to tumor stage (T4 or selected T3 or T2) or failure to respond to organ-preserving protocols. In all, 94 of the 151 cases (62%) underwent primary total laryngectomy/laryngopharyngectomy (PL). Salvage laryngectomy (SL) was performed for persistent or locally recurrent disease. Preoperative treatment in the salvage patients included RT alone (SL-RT) (n = 28, 19%) and concurrent CRT (SL-CRT) (n = 17, 11%); 12 of the patients (8%) that did not respond to ICT underwent surgery, as RT failure was predicted. Surgery Total laryngectomy was performed in 136 (90%) of the patients, whereas partial pharyngectomy in addition to total laryngectomy was performed in 15 patients (10%) that had tumor extension to the pyriform sinus. In all cases surgery was performed or supervised by surgeons with extensive experience in oncological ENT surgery. The pharynx was closed via
horizontal closure of the pharyngeal mucosa with continuous Vicryl 3/0 sutures in 146 (97%) of the patients. A submucosal closure was performed with interrupted sutures as a second layer, followed by a third layer using sutures through the suprahyoid muscles and the inferior pharyngeal constrictor muscles. Horizontal linear repair was performed in all patients, except those that underwent partial pharyngectomy combined with total laryngectomy; in these patients the pharyngeal defect was closed via T-type closure. In five (3%) patients T-closure of the pharynx was performed with three continuous mucosal sutures that converged in the center of the neopharynx. The second and third layers of the T-closure were the same as in horizontal closure. Total laryngectomy was combined with neck dissection (including selective, modified radical, or radical neck dissection) in 115 (76%) patients. In all, 36 patients (24%) underwent total laryngectomy without a neck procedure because of preoperative RT to the neck region. Postoperative follow-up A vacuum drainage system was used and maintained for at least 48 h. Antibiotic therapy (amoxicillinclavulanate 1.2 g/8 h or ampicillin-sulbactam 1.5 g/6 h was administered post surgery until vacuum drainage was stopped. In 132 of the 151 patients a nasogastric tube was not inserted and oral feeding began immediately after surgery. A nasogastric tube was inserted intraoperatively in the remaining 19 patients (12.6%). In 87.4% of the patients early oral feeding without a nasogastric tube began within 3 days of surgery. Oral feeding was started 24 h post surgery in 68 (45%) of the patients and 48 h post surgery in 83 (55%) of the patients. Water was given for initial oral intake because it is particle-free and does not irritate the pharyngeal wall. Frequently, oral intake of water was followed by other clear fluids (e.g. fruit juice), and then milk. Oral feeding continued with semi-solid food in the following 10 days. Daily caloric intake during the postoperative period was closely monitored by dieticians and maintained at 2100 calories in males and 1850 calories in the female patients. In patients with PCF food was withheld until closure of the fistula. Risk factors associated with PCF In addition to RT and concurrent CRT, the following factors were analyzed for their association with PCF formation: patient age, surgery extended to the pharynx, associated neck dissection, history of tracheotomy, intraoperative blood transfusion, postoperative
Pharyngocutaneous fistula after salvage laryngectomy Hb level, insertion of a nasogastric tube, duration of vacuum drainage, and post-surgical time to oral feeding.
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Statistical analysis Descriptive statistics are expressed as mean ± SD for numerical variables. Descriptive statistics for categorical variables are presented as number and percentage. The independent samples t test was used to compare mean values of age. Associations between categorical variables were examined using Pearson’s chi-squared test for continuity correction or Fisher’s exact test. Logistic regression analysis was performed to identify the risk factors for PCF. A logistic regression model was constructed using independent variables and the binary dependent variable (PCF). Using the logistic model, odds ratios (ORs) and their respective 95% confidence intervals (CIs) were calculated. The level of statistical significance was set at p < 0.05. All statistical analyses were performed using SPSS v.15.0 for Windows. Results In total, 20 of the 151 patients (13%) developed PCF following PL. PCF occurred in a mean of 9 days post surgery (range 6–24 days). In all, three patients that received preoperative concurrent CRT had a persistent PCF that was surgically treated. Univariate analysis of prognostic factors Patient age was analyzed as a risk factor for the formation of PCF. The mean age of the patients with and without PCF was 58 and 61 years, respectively; the difference was not significant (p = 0.348). Based on the chi-squared test there was no significant difference in the frequency of PCF formation between the patients that underwent SL (11/57, 19.3%) and PL (9/94, 9.6%) (p = 0.144); however, the frequency of PCF formation was higher in the SL-RT and SLICT patients (10.7% and 16.7%, respectively) than in the patients that underwent PL, but the difference was not significant (p = 1.0 and p = 0.610, respectively). The occurrence of PCF formation in the SL-CRT patients (6/17, 35.3%) was significantly higher than in those that underwent PL (9/94, 9.6%) (p = 0.011). Table I summarizes the univariate analysis of the predisposing factors for the formation of PCF. PCF occurred in 13 (9.6%) of the patients that underwent total laryngectomy (n = 136), versus 7 (46.7%) of those that underwent laryngopharyngectomy (n = 15); the difference in the formation of PCF between the surgical procedures was significant
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Table I. Univariate analysis of predisposing factors for pharyngocutaneous fistula (PCF). Characteristics
PCF (%)
Treatment (1)
0.144
PL
9/94 (9.6)
SL
11/57 (19.3)
Treatment (2)
1.000
PL
9/94 (9.6)
SL-RT
3/28 (10.7)
Treatment (3)
0.011
PL
9/94 (9.6)
SL-CRT
6/17 (35.3)
Treatment (4)
0.610
PL
9/94 (9.6)
SL-ICT
2/12 (16.7)
Treatment (5)
0.063
SL-RT
3/28 (10.7)
SL-CRT
6/17 (35.3)
Treatment (6)
0.408
SL-ICT
2/12 (16.7)
SL-CRT
6/17 (35.3)
Neck dissection No Yes
1.000 5/36 (13.9) 15/115 (13)
Postoperative Hb
1.000
£ 10 g/dl
3/24 (12.5)
> 10 g/dl
17/126 (13.5)
Prior tracheotomy No Yes
1.000 3/24 (12.5) 17/127 (13.4)
Surgery extended to pharynx No Yes
0.001 13/136 (9.6) 7/15 (46.7)
Pharynx closure Horizontal T-closure
p Value
0.017 17/146 (11.6) 3/5 (60)
NG insertion (intraoperative)
0.022
No
14/132 (11)
Yes
6/19 (32)
Duration of vacuum drainage
0.042
£ 4 days
6/81 (7.4)
> 4 days
14/70 (20)
Blood transfusion
0.487
No
10/90 (11)
Yes
10/61 (16)
Significant values are shown in bold type. CRT, chemoradiotherapy; Hb, hemoglobin; ICT, induction chemotherapy; NG, nasogastric tube; PL, primary total laryngectomy/laryngopharyngectomy; RT, radiotherapy; SL, salvage laryngectomy.
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(p = 0.001). Primary closure of pharynx was analyzed as a risk factor for PCF. In total, 146 patients had horizontal closure and 5 patients had T-closure; PCF occurred in 11.6% and 60% of these patients, respectively, and the difference was significant (p = 0.017). PCF occurred in 15 (13%) of the 115 patients that underwent concurrent neck dissection, and in 5 (13.9%) of the 36 patients that did not; the difference was not significant (p = 1.0). In all, 24 patients underwent tracheotomy due to involvement of the airway, of which 3 (12.5%) developed PCF. However, in the 127 patients that did not undergo tracheotomy, PCF occurred in 17 patients (13.4%); based on Fisher’s exact test, the difference was not significant (p = 1.0). Among the 126 patients with a postoperative Hb level > 10 g/dl and the 24 patients with a level £ 10 g/dl, the frequency of PCF formation was similar – 13.5% and 12.5%, respectively; as such, the postoperative Hb level was not considered a risk factor for PCF in the study’s patient population (p = 1.000). PCF developed in 10 (16%) of 61 patients that received intraoperative blood transfusion and in 10 (11%) of the 90 patients that did not, but the difference was not significant (p = 0.487). The mean duration of postoperative vacuum drainage was 4 days (range 2–12 days), which was used as a cut-off point for the comparison of the risk of PCF. PCF was observed in 6 (7.4%) of the 81 patients with vacuum drainage duration £ 4 days, versus 14 (20%) of the 70 patients with vacuum drainage duration > 4 days; the difference was significant (p = 0.042). In total, 6 (32%) of 19 patients in whom a nasogastric tube was inserted intraoperatively developed PCF, versus 11% of 132 patients that did not use a nasogastric tube; the difference was significant
(p = 0.022). Among the patients without a nasogastric tube inserted intraoperatively, early oral feeding was started within 3 days post surgery. In all, 16% of the 68 patients that were fed 24 h post surgery and 11% of those that were fed 48 h post surgery developed PCF; the difference was not significant (p = 0.471). Among the 25 patients that received preoperative RT and did not use a nasogastric tube, initial feeding was 24–72 h post surgery; there was not a significant difference in the formation of PCF between the patients that were fed 24 h post surgery (1/14) and those fed later (1/11) (p = 1.00). Finally, there were no significant differences in the frequency of PCF formation according to patient age, preoperative RT alone, preoperative ICT, concurrent neck dissection, preoperative tracheotomy, postsurgical Hb level, intraoperative blood transfusion, or postoperative time of oral feeding. Table II summarizes the relationship between PCF formation and the investigated parameters.
Multivariate analysis Multivariate analysis was used to examine the prognostic factors associated with PCF formation. The incidence of PCF following SL was significantly higher than that following PL (p = 0.041). Among the patients that received preoperative treatment, only concurrent CRT was strongly associated with the formation of PCF, with a hazard ratio of 10.75 (p = 0.004). Patients in which surgery was extended to the pharynx had a significantly higher incidence of PCF (p = 0.005) than the other patients. Duration of vacuum drainage > 4 days was an independent risk factor for PCF (p = 0.012). Table II
Table II. Multivariate analysis of risk factors for pharyngocutaneous fistula (PCF). 95% CI for OR Variable
p Value
OR
Constant
0.002
0.001
Age
0.713
0.991
Lower
Upper
0.943
1.041
Surgery extended to the pharynx
0.005
8.337
1.929
36.020
Nasogastric feeding
0.119
3.047
0.750
12.381
Pharynx closure
0.567
0.447
0.028
7.075
Duration of vacuum drainage
0.012
5.156
1.425
18.648
1.647
0.355
7.633
Preoperative treatment
0.041
Preoperative RT only
0.524
Preoperative ICT
0.645
1.553
0.239
10.081
Preoperative concurrent CRT
0.004
10.751
2.127
54.335
Significant values are shown in bold type. CI, confidence interval; CRT, chemoradiotherapy; ICT, induction chemotherapy; OR, odds ratio; RT, radiotherapy.
Pharyngocutaneous fistula after salvage laryngectomy shows the predisposing factors associated with PCF (with hazard ratios) based on multivariate analysis.
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Discussion The rate of PCF formation among 151 patients following total laryngectomy in the present study was 13%, which is in agreement with earlier reports [1–6]. Organ-preserving RT or CRT for laryngeal carcinoma results in good locoregional control and survival comparable to that achieved with total laryngectomy and postoperative RT, with the added benefit of preserving the voice and swallowing function in a significant number of patients [7,8]. Despite such results, many patients still experience recurrent or persistent disease requiring salvage surgery, most frequently total laryngectomy. It has been suggested that radiation diminishes the healing capacity of tissues due to a dysfunctional fibroblast population, which results in hypovascularity and aggravation of atherosclerosis via induction of myointimal fibrosis [2]. Many researchers have suggested that patients who receive preoperative RT have a high incidence of PCF – up to 58% [2,9,10]. A meta-analysis of postlaryngectomy PCF showed that preoperative RT increased the risk of PCF formation, and that the severity and duration of fistulae were greater than those in patients that had not undergone preoperative RT [11]. In contrast, other studies report that there is no association between PCF formation and preoperative RT [1,5]. In the present study the incidence of PCF in the SL-RT patients was 10.7%, which was not significantly different from that in the patients that underwent PL (9.6%). ICT was also reported to increase the occurrence of postoperative wound complications in patients with advanced-stage head and neck carcinoma [18]. Whether or not the addition of ICT to RT is associated with a higher risk of postoperative complications than RT only in patients undergoing SL remains uncertain. Newman et al. reported a PCF rate of 11.5% in a group of 28 patients that received preoperative ICT and RT [12]. To reduce the additional risk of RT in the present study’s analysis only the patients that underwent SL due to failure of preoperative ICT were included. There was no significant difference in the frequency of PCF formation between the patients that received ICT and PL. In recent years the use of concurrent CRT for organ preservation in patients with advanced laryngeal carcinoma has been increasing. It has been suggested that the concurrent addition of chemotherapy multiplies the damaging effects of RT on normal tissue, which results in PCF formation that persists post SL [13]. Weber et al. reported that the incidence of post-
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laryngectomy PCF was higher in patients that underwent concurrent CRT (30%) than in those the received RT only (15%) [13]. It was reported that when PCF develops in patients that undergo salvage surgery the severity and duration of the fistulae are significantly greater, and they are more likely to require surgical intervention than when they occur in patients treated with PL. However, the reported rate of PCF formation in patients treated with salvage surgery varies in the literature; in all of the recent studies a statistically significantly higher PCF formation rate in SL patients than PL patients has been reported (Table III) [14–16]. To the best of our knowledge the literature has not included any studies from a single institute that compare complications associated with salvage surgery in patients that received preoperative ICT and concurrent CRT; therefore, the present study was designed and performed. The present findings show that the incidence of PCF in the SL-CRT patients (35.3%) was higher than that in the SL-RT patients (10.7%, OR = 1.6) and SL-ICT patients (16.7%, OR = 1.5); however, the difference was not significant. We think that the synergistic or additive effect of RT and chemotherapy increased the normal tissue damage and increased the risk of PCF 10.75-fold. In the present study surgery extended to the pharynx (laryngopharyngectomy) increased the risk of PCF 8.7-fold, as compared with PL, which is consistent with other reports [14,15]. We believe that the high risk of PCF observed in the present study was related to the tension on the suture lines at the conjunction of the neopharynx, as only patients that underwent primary closure of this large defective mucosal region were included. Delaying oral feeding to prevent fistula development is common practice among head and neck surgeons. At present, the efficacy of early oral feeding remains controversial. Early initiation of oral feeding is thought to play a role in the development of PCF; as such, nasogastric feeding for 7–14 days is considered safe practice [2,17]. In contrast, some retrospective studies did not observe an association between fistulae Table III. Comparison of PCF rates in patients that underwent PL and SL. Study
SL (%)
PL (%)
Tsou et al. (2010) [14]
58.3
21.4
Patel and Keni (2009) [15]
57
27
Sewnaik et al. (2012) [16]
50
This study
19.3
– 9.6
PCF, pharyngocutaneous fistula; PL, primary total laryngectomy/ laryngopharyngectomy; SL, salvage laryngectomy.
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and early oral feeding [3,6]. Medina and Khafif compared early oral intake with delayed feeding following total laryngectomy without pharyngectomy [18]. They noted that early oral feeding (48 h post total laryngectomy) did not increase the rate of fistula formation. Seven et al. evaluated the safety and efficacy of early oral feeding in a prospective study that compared oral intake with feeding via primary tracheoesophageal puncture. They concluded that initiation of oral feeding on postoperative day 1 was safe clinical practice [19]. In addition, use of a nasogastric tube causes local trauma and significantly increases stress to the pharyngeal suture line, which may contribute to fistula formation. It has also been reported that use of a nasogastric tube is associated with such disadvantages as gastroesophageal reflux, poor cosmetic appearance, and low quality of life. It was suggested that a nasogastric tube might induce damage to the pharyngeal mucosa primarily via acidic gastroesophageal reflux [6]. It is clear that use of a nasogastric tube for 1–2 weeks is uncomfortable for patients. Since patients are in psychological discomfort because of their cancer and losing their larynx, placement of a nasogastric tube creates an additional stress on their well-being. Instead of using a nasogastric tube, we have been initiating oral intake with water in the first 24 h following total laryngectomy since 1979. With or without a nasogastric tube, patients swallow their saliva and the pharynx is never totally at rest during the postoperative period. In the light of the present findings we believe that early water intake is not associated with the formation of PCF, and in fact may facilitate early restoration of normal swallowing function. In the present study, the incidence of PCF in patients that used a nasogastric tube intraoperatively was significantly higher than in those in which feeding was started orally, including patients that received preoperative RT alone and concurrent CRT. Since a higher incidence was reported for those who received prior radiotherapy alone or concurrent CRT, another question in our mind was the time of starting oral feeding. However, when the incidence of PCF formation was observed in the patients that received prior treatment, the incidence was not higher in patients in whom oral feeding was started after 24 h, when compared with later days. The present findings indicate that early oral feeding had no effect on the incidence of PCF in patients that received preoperative RT only or concurrent CRT. Simultaneous neck dissection was another possible predisposing factor for PCF taken into account, as suggested by previous reports [2]. Neck dissection might increase the risk of fistula formation because of burdening the postoperative recovery due to extensive surgical
intervention; however, in the present study no such correlation was observed, which is in agreement with other similar studies [1,4,20]. Preoperative tracheotomy has been considered by some to be a predisposing factor for PCF. Tracheotomy is frequently performed for more advanced tumors, sometimes in emergency situations due to dyspnea in heavily burdened patients. These reasons may possibly contribute to an increase in the rate of fistula formation. It had been thought that an increased risk of PCF was due to preoperative tracheotomy, whereas in the present study a similar relationship was not noted [1]. Although the postoperative Hb level was reported to be associated with an increase in the risk of fistula development in earlier studies [5,11], in the present study there was no significant difference in the incidence of PCF between the patients with an Hb level < 10 g/dl and > 10 g/dl. Additionally, despite a tendency for PCF in the patients that received blood transfusion in the present study, this was not strongly correlated. Duration of vacuum drainage was another associated risk factor for PCF in the present study. To the best of our knowledge the present study is the first to examine the effect of vacuum drainage on the formation of PCF. It can be assumed that the long-term vacuum drainage is a result of undiagnosed low-level saliva flow through the neopharynx; therefore, we think that when the contents of vacuum drainage continue to have a dirty appearance instead of hemorrhagic characteristics, surgeons should consider PCF. Conclusion Although the incidence of PCF following SL was higher than that following PL in the present study, preoperative concurrent CRT was most strongly associated with PCF formation. The other two primary factors associated with the occurrence of PCF were surgery extended to the pharynx and vacuum drainage duration > 4 days. When considering which organpreserving protocols to use, clinicians should be aware that unsuccessful preoperative concurrent CRT might cause severe complications following SL. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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