J Cancer Res Clin Oncol (2013) 139:389–394 DOI 10.1007/s00432-012-1337-5
ORIGINAL PAPER
Surgical outcome and prognostic factors after treatment of osteoradionecrosis of the jaws Thomas Mu¨cke • Janett Koschinski • Andrea Rau • Denys J. Loeffelbein • Herbert Deppe • David A. Mitchell Anastasios Kanatas • Klaus-Dietrich Wolff
•
Received: 10 August 2012 / Accepted: 9 October 2012 / Published online: 30 October 2012 Ó Springer-Verlag Berlin Heidelberg 2012
Abstract Purpose This prospective study attempts to identify prognostic factors for outcome in patients Classes 2 and 3 osteoradionecrosis (ORN) treated using individualized methods. Methods From 2005 to 2010, patients with Classes 2 and 3 osteoradionecrosis of the jaws were treated by the same surgical team using standard protocols. The patients were evaluated prospectively and followed up for a minimum of 12 months after completion of treatment. Two examinations were performed at least six months apart. Results A total of 94 patients were assessed. Local debridement was performed in 33 patients (35.1 %), a rim resection with the application of a reconstruction plate was performed in 35 patients (37.2 %), and continuity resection in 26 patients (27.7 %). Postoperative wound infections locally or at the neck were detected in 69 patients (70.2 %), failure to eradicate radionecrosis occurred in 50 patients (53.2 %). The location of the primary tumor (p = 0.023) and radiation dose (p = 0.049), were associated with a
T. Mu¨cke J. Koschinski A. Rau D. J. Loeffelbein H. Deppe K.-D. Wolff Department of Oral and Maxillofacial Surgery, Technische Universita¨t Mu¨nchen, Klinikum Rechts der Isar, Munich, Germany T. Mu¨cke (&) Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar der Technischen Universita¨t Mu¨nchen, Ismaninger Str. 22, 81675 Munich, Germany e-mail:
[email protected] D. A. Mitchell A. Kanatas Department of Oral and Maxillofacial Surgery, Oral and Facial Specialties Department, Mid Yorkshire Hospitals NHS Trust, Aberford Road, West Yorks WF1 4DG, UK
significant risk of development of ORN. Prognostic factors for failure of treatment were the extent of initial osteoradionecrosis (p = 0.049) surgical treatment (p \ 0.0001), number of debridements (p \ 0.0001), type of microvascular free flap with (p \ 0.0001), and grossly infected ORN (p \ 0.0001). Conclusions Several factors affect the outcome of treatment of ORN. We confirm many of the intuitive factors influence outcome of treatment and add evidence that complete removal of affected bone and watertight well vascularized coverage is the most useful treatment strategy. Keywords Osteoradionecrosis Treatment Outcomes Microvascular
Introduction Osteoradionecrosis (ORN) of the jaws is defined as exposed irradiated bone that fails to heal over a period of 3 months without evidence of persisting or recurrent tumor (London et al. 1998; Marx 1983; Marx and Johnson 1987; PitakArnnop et al. 2008). Although radiotherapy techniques have modified in recent years (Mu¨cke et al. 2011), the occurrence of ORN remains an important complication of this treatment. The bone affected by ORN shows a hypocellular, hypovascular, and locally hypoxic appearance on histopathological examination (Marx and Johnson 1987). ORN may occur many years after radiotherapy and is complicated in its treatment by the associated poor wound healing (Marx and Johnson 1987; Jacobson et al. 2010). The necrotic region often shows an infection with complex microbial flora. Functional impairments of chewing, mobility, and speech (Mu¨cke et al. 2011) are complications of advanced ORN especially when associated with pathological fracture.
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Patients suffering from ORN of the jaws present with non-healing mucosal necrosis, chronic exposure of necrotic bone, ulceration, and pain. Associated symptoms include swelling, trismus, paresthesia or anesthesia, nonunion, orocutaneous fistula, or pathologic fracture (Jacobson et al. 2010). Long-term effects of irradiation are irreversible. Conservative treatment strategies such as antiseptic mouth rinses or antibiotics are part of every treatment plan. Drug therapy with pentoxifylline and tocopherol has become popular in some areas in an attempt to avoid surgery. Surgery of varying degrees is the most important option in prolonged exposure of bone with progressive infections and pathological fractures (Marx 1983; Marx and Johnson 1987). The aim of this study was to compare the outcome of different surgical approaches in ORN stages 2 and 3 and to identify predictors of treatment failure.
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maxilla for longer than 8 weeks without any change of the stage of disease became evident. Conservative treatment Antibiotics were given as a routine treatment in every patient. The regimen consisted of either clindamycin (600 mg, two times daily), penicillin (1.5 million international units three times per day), or amoxicillin/clavulanic acid (875/125 mg, twice daily) depending on previous antibiotic therapy and allergies. Antibiotic therapy was modified according to culture and sensitivity following appropriate sampling. Antiseptic mouth rinses with Hexetidine were performed three times a day, and additional rinsing was performed at least once daily by the surgical staff for the time of primary wound healing of the mucosa. Surgical treatment
Materials and methods Patients Subjects were recruited from 2005 to 2010. All patients had surgery and adjuvant radiation therapy for oral squamous cell carcinoma. All surgical procedures were performed by the same surgical team following the same surgical protocol. The patients were evaluated prospectively and investigated at least twice for at least 12 months after completion of the surgical treatments for ORN. The two examinations were at least six months apart. The time of ORN occurrence was defined in months from the mucosal breakdown and exposure of bone. Exclusion criteria were inadequate information or presence of confounding variables (e.g., corticosteroids in the medication, history of bisphosphonates, metastases within the gingiva or jaws). Diagnostics The diagnosis of ORN was clinical supplemented by imaging [digital panoramic tomograms, computed tomography (CT)]. The classification of Marx and Schwartz (Marx 1983; Schwartz and Kagan 2002) was used. Complete clinical data were collected and classified; areas of osteoradionecrosis were measured by panoramic tomograms and three-dimensional evaluation of the CT. Intention to treat conservatively or surgically was based on the symptoms of each patient. There was no randomization. Surgical treatment was performed if the patient reported pain and/or neurological deficits of the inferior alveolar nerve, if the maxillary sinus was exposed, if pathological fracture or non-healing exposed bone in mandible or
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The treatments of patients with ORN included sequestrectomy, surgical debridement, wound debridement, including marginal or segmental resection of the bone depending of the stage and extent of the disease. Wound closure was carried out without tension on the local (e.g., mucoperiosteal), regional (e.g., pectoralis major), or microvascular (e.g., fibular) flap after the resection. Interrupted sutures were performed with resorbable suture material (Vicryl 3-0, Ethicon, Norderstedt, Germany). Postoperative care After surgery, the patients were fed using a nasogastric tube for at least 10 days. The wounds were checked daily for signs of infection, wound breakdown, or recurrence of the disease. In cases of wound breakdown, the lesion was reassessed and either conservative or surgical therapy was performed depending on the extent of wound healing. Sutures and enteral feeding tube were routinely removed 10 days after surgery. Statistical analysis Descriptive statistics for quantitative variables are given as the mean ± standard deviation. If appropriate, medians and ranges were also computed. The data were analyzed with the ‘‘Statistical Package for the Social Sciences’’ (SPSS for Windows, release 17.0.0. 2009, SPSS Inc). Figures are generated with SPSS. Multiple logistic regression analysis was used to determine factors independently associated with the dependent variable—recurrence of ORN. Covariates in this model were treatment-dependent variables of inflammation (CRP, leukocytes, bacterial infection within the bone), extent of
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necrosis, location, type of treatment (either conservative or surgical) and surgical concept (local flap, reconstruction plate, microsurgical reconstruction), type of and duration of radiation treatment, applied antibiotics, pathological fracture, and number of debridements carried out. 95 % confidence intervals (95 % CI) for estimated odds ratios (OR) approximating the relative risk are also given. P values are two-sided and subject to a significance level of 0.05.
Results Between 2005 and 2010, 94 patients with initial occurrence of ORN were treated surgically. The mean age was 63.8 ± 9.34 years [range 27–89], and 70 patients were men and 24 women. The location of tumor origin was at the floor of the mouth in 49 patients, the tongue in 33 cases, in the maxilla or the upper jaw in 12 cases. The mean dosage of irradiation therapy was 63.3 ± 7.9 (range 45–93.6) Gy. Simultaneous chemotherapy was applied with cisplatin and carboplatin in 45 patients. Patients were classified as stage 2 in 46 cases (48.9 %) and 48 patients as stage 3 (51.1 %). In 87 patients (92.5 %), ORN was located in the mandible, in 5 patients (5.3 %) in the upper jaw, and 2 patients (2.2 %) developed ORN in both jaws. The mean volume of bone destruction measured was 4.12 ± 2.54 cm3 in all patients. The mean measured CRP was 4.97 ± 6.62 mg/dl (range 0.1–30.4), and mean leukocytes concentration was 8.91 ± 7.91 mg/dl (range 2.26–16.36). Only 36 patients (36.2 %) were found with increased leukocytes count, whereas CRP was increased in 87 patients (92.6 %). An obvious bone infection confirmed by culture was detected in 75 patients (79.8 %), in 19 patients (20.2 %) no growth was found on culture. A minimal bone resection with local debridement was performed in 33 patients (35.1 %), a rim resection with the application of a reconstruction plate was performed in 35 patients (37.2 %), and continuity resection with preservation of the inferior alveolar nerve of the mandible was necessary in 26 patients (27.7 %). Primary wound closure was performed in 36 patients (38.3 %), pectoralis major flaps in 12 patients (12.8 %), and microvascular free flaps in 46 patients (48.9 %). Microvascular flaps applied were each 7 anterolateral thigh flaps and radial forearm flaps, fibular flaps in 20 patients (21.3 %), and iliac crest flap in 12 patients (12.8 %). In 11 patients (11.7 %), a complete failure of the applied flap was detected, comprising 4 patients (4.3 %) with local wound closure, 3 patients (3.2 %) with pectoralis major flaps, and 4 patients with microvascular bone flaps (4.3 %, 3 iliac crest flaps and 1 fibular flap). Microvascular free flap failure was therefore present in 8.7 % of patients treated by these flaps. Postoperative wound infections locally or at the neck were
391 Table 1 Overview of surgical treatment performed and number of recurrences of ORN in patients (n = 94) Characteristic
Number of patients n (%)
Number of surgeries 1
44 (46.8)
2 3
31 (32.9) 17 (18.1)
4
1 (1.1)
5
1 (1.1)
Extent of surgical therapy Marginal resection
33 (35.1)
Rim resection
35 (37.2)
Continuity resection
26 (27.7)
Presence of pathological fracture Yes
20 (21.3)
No
74 (78.7)
detected in 69 patients (70.2 %). Relapse of ORN was found in 50 patients (53.2 %) and were frequently found after marginal bone resection with primary wound closure. The distribution of recurrences is illustrated in Table 1.
Multivariate analysis In the multivariate analysis, the location of the primary tumor was associated with a significant risk of development of an ORN (p = 0.023, OR 0.177, 95 % CI 1.057–1.837). A significant influence of the radiation dose was found on the extent of osteoradionecrosis (p = 0.049, OR 0.051, 95 % CI 0.001–0.203). The lost of a free flap was associated with the development of postoperative infections (p = 0.031, OR 0.06, 95 % CI 0.021–0.218). The results of the multiple linear regression analyses are presented in Table 2. Factors influencing the failure of treatment of ORN are presented in Table 3. Prognostic factors for the development of recurrence were the extent of surgical treatment with better outcome in larger resections (p \ 0.0001), number of debridements performed (p \ 0.0001), type of microvascular free flap with better outcome for soft tissue flaps only (p \ 0.0001), and the presence of bacterial bone infection of the necrotic area (p \ 0.0001).
Discussion This study reveals the high complication and recurrence rate after treatment of ORN and identified the important prognostic factors related to failure of treatment in these
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Table 2 Results of multiple logistic regression analyses examining the effects of prognostic factors on the development of ORN in patients (n = 94) Variable
Odds ratio
95 % CI
p
Development of ORN Location of treated tumor
0.177
1.057–1.837
0.023*
Radiation dose Tumor extent
0.078 0.563
0.741–1.007 0.67–6.091
0.062 0.212
Extent of osteoradionecrosis Radiation dose
0.051
0.001–0.203
Radiation frequency
2.141
-0.834–5.117
0.155
0.049*
Infection
0.582
0.417–4.079
0.648
Recurrence
0.543
0.829–6.952
0.107
Recurrence
0.539
0.371–3.07
0.903
Lost of flap
1.152
0.047–4.306
0.488
Mandible fracture
Type of antibiotics
Lost of free flap Radiation dose
0.07
0.837–1.101
0.558
Type of free flap
0.566
0.792–7.923
0.122
Infection
0.06
0.021–0.218
0.031*
* p \ 0.05
Table 3 Results of multiple logistic regression analyses examining the effects of prognostic factors on the development of recurrence of ORN in patients (n = 94) Variable
Odds ratio
95 % CI
p
Radiation dose
0.035
0.961–1.104
0.4
Number of irradiation sessions
0.938
0.088–3.479
0.528
Number of debridements
0.702
12.62–198.115 \0.0001*
Extent of operation
0.303
1.583–5.182
\0.0001*
Type of free flap
0.156
1.462–2.699
\0.0001*
Extent of ORN in radiological diagnostics Infection
0.109
0.854–1.309
0.608
0.544
2.351–19.86
\0.0001*
Type of antibiotics
0.122
0.887–1.433
0.326
* p \ 0.05
patients. Many of these factors are intuitive or have been previously demonstrated. Failure of treatment occurred more often with the higher the number of debridements, the more extensive the destruction of affected bone, in patients with obvious bone infection, and if bony microvascular flaps were used for reconstruction compared to soft tissue free flaps only although the latter may simply be a manifestation of the complexity of the pathology being treated. In the critical evaluation of treatment of ORN, it is difficult to find studies which identify valid prognostic
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factors. Most studies represent an institutional experience with the presentation of management of ORN performed in relatively small cohorts. The largest series was published by Oh et al. analyzing their outcome and concluded that radical resection of necrotic and infected bone is the most valuable treatment in terms of successful outcome (Oh et al. 2009). The concept of wide radical resection of the affected bone with immediate reconstruction has gained wide acceptance in the literature and seems the therapy of choice in advanced ORN of the jaws, especially the mandible and associated with pathological fracture (Schwartz and Kagan 2002; Oh et al. 2009; Celik et al. 2002; Curi and Dib 1997; Curi 2007; Hirsch et al. 2008; Shaha et al. 1997; Wei et al. 2003). Many authors reported a positive effect on the quality of life of these patients regarding the reduction in pain and improvement of form and function (Celik et al. 2002; Curi and Dib 1997; Curi 2007; Koka et al. 1990). In this study, microvascular free flap reconstruction was also frequently performed after occurrence of extensive ORN of the mandible, although in this study the application of soft tissue microvascular free flaps showed superior results compared with free flaps containing bone. We are aware we may not be comparing like with like. Although the fibular free flap was described as a very safe and reliable option for reconstruction, the failure and complication rate varies between 12 and 20 % (Curi 2007; Hirsch et al. 2008; Chang et al. 2001) flap loss and 21–43 % (Hirsch et al. 2008; Gal et al. 2003) overall complications. The complication rate in this study was 8.7 % free flap losses, which is marginally lower than reported in the literature. In contrast, the overall complication rate was 70.2 % comprising postoperative wound infections and wound healing disturbances is much higher, but this is probably due to the prospective nature of this study. Nearly all the other studies were performed retrospectively, with a few exceptions (Annane et al. 2004; Wang et al. 2009). The complication rate in ORN patients is recognized to be high and can be quantified by imaging techniques in the preoperative planning of microvascular reconstructions (Buchbinder and St Hilaire 2006; Lell et al. 2005). The overall condition of these patients is generally poor and is accepted as requiring a high degree of surgical expertise and discretion in individual selection of treatment for each patient (Mu¨cke et al. 2011; Bengtson et al. 1993; Bourget et al. 2011; Schultze-Mosgau et al. 2002). The risk of developing ORN persists for years after completion of radiotherapy, and a reduced healing capacity of within the oral cavity is a permanent problem (Schultze-Mosgau et al. 2002; Epstein et al. 1997). Many risk factors have been discussed in the literature, but little evidence has been given. The tumor site was found to be of significance in this study as well as in other studies (Beumer et al. 1984; Guttenberg 1974; Kluth et al. 1988; Sanger et al. 1993).
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Although additional risk factors like tooth extractions, denture irritation, or other surgery in the mouth have been described (Kluth et al. 1988), the etiology can be spontaneous (Sanger et al. 1993). In the present prospective study, ORN occurred spontaneously and nearly all patients were screened for potential dental problems before radiation. This concept is well described (Oh et al. 2009; Beumer et al. 1984). The reconstructive method is a very challenging problem in the management of the disease. In Classes 2 and 3 ORN, the use of microvascular free flaps provides safe results with a high quality outcome of reconstruction (Schwartz and Kagan 2002; Celik et al. 2002; Curi and Dib 1997; Curi 2007; Hirsch et al. 2008; Shaha et al. 1997; Wei et al. 2003) in suitably experienced hands. Although the use of bony flaps like free fibular or iliac crest flaps is perfect for full rehabilitation of these patients, these are more demanding procedures and as shown here may not be as successful as soft tissue only flaps. The soft tissue free flaps in this study showed no failure in the postoperative course and led to complete wound closure. After application of these flaps, no recurrence of ORN was observed. In contrast, local wound closure after wound debridement, demonstrated a high rate of failure. The use of free flaps, representing provides an improved blood supply to the region of reconstruction, promoting its healing with subsequent enhancement of the viability of the remaining bone that might be partially involved with ORN (Baker 1983). The use of soft tissue flaps alone has the disadvantage that a secondary procedure is necessary for obtaining bone and dental restoration (Baker 1983). Reconstruction using bony free flaps result in good functional results, but the risk of complications associated with these flaps is higher than soft tissue flaps, but lower than local debridement followed by local wound closure only. The choice of flap and management should be selected with the individual patient circumstance in mind.
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