- Email: [email protected]
Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy's Versus Modified Carnoy's Solution
Accepted Manuscript Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy’s Versus Modified Carnoy’s Solution Jason E. Dashow, DDS, MD, John B. McHugh, MD, Thomas M. Braun, PhD, Sean P. Edwards, DDS, MD, Joseph I. Helman, DMD, Brent B. Ward, DDS, MD PII:
S0278-2391(15)00543-1
DOI:
10.1016/j.joms.2015.05.005
Reference:
YJOMS 56810
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 10 February 2015 Revised Date:
11 May 2015
Accepted Date: 12 May 2015
Please cite this article as: Dashow JE, McHugh JB, Braun TM, Edwards SP, Helman JI, Ward BB, Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy’s Versus Modified Carnoy’s Solution, Journal of Oral and Maxillofacial Surgery (2015), doi: 10.1016/j.joms.2015.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI PT
Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy’s Versus Modified Carnoy’s Solution
Jason E. Dashow DDS, MD 1 , John B. McHugh MD 2, Thomas M. Braun PhD 3, Sean P. Edwards DDS, MD 4, Joseph I. Helman DMD 5, Brent B. Ward DDS, MD 6
Resident, University of Michigan Department of Oral & Maxillofacial Surgery
SC
1 Chief
2 Associate
Professor, University of Michigan Departments of Pathology and Oral & Maxillofacial Surgery University of Michigan Department of Biostatistics
M AN U
3 Professor, 4 Associate
Professor, Residency Program Director, University of Michigan Department of Oral & Maxillofacial Surgery
5 Professor,
University of Michigan Department of Oral & Maxillofacial Surgery
6 Associate
TE D
Professor, Program Director - Oral/Head and Neck Oncologic and Microvascular Reconstructive Surgery, University of Michigan Department of Oral & Maxillofacial Surgery
AC C
EP
Corresponding Author: Jason E. Dashow, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109. Email: [email protected]. Telephone: 734-936-5950. Fax: 734-6156159.
ACCEPTED MANUSCRIPT
Abstract:
RI PT
Purpose: A variety of modalities have been suggested for treatment of keratocystic odontogenic tumor (KOT) including Carnoy’s and “modified Carnoy’s” (without chloroform) solution. The purpose of this study is to investigate the effect of Carnoy’s solution (CS) versus modified Carnoy’s solution (MC) as it relates to KOT recurrence rates when used in conjunction with simple enucleation and curettage (E&C) for treatment of KOT.
M AN U
SC
Materials and Methods: A retrospective cohort study of patients with pathological diagnosis of KOT treated with E&C and application of CS or MC by three surgeons at a single center between January 1996 and April 2014 was completed. Demographic, clinical, radiographic, and histological data was collected for each patient. All disease recurrences were confirmed by biopsy. The primary outcome variable of the study was time to recurrence with the predictor of CS versus MC. Other variables included in the analysis were gender, age, surgeon, and lesion location. Multivariate analysis including Wilcoxon test and chi-squared test of associations were completed.
EP
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Results: 210 patient charts were reviewed, 80 patients meeting final study criteria; 44 subjects in the CS arm and 36 subjects in the MC arm. Median age range was 47 (1089) in the CS group and 50 (14-72) in the MC group (p=.70). Females accounted for 43% (19/44) and 44% (16/36) of patients in the CS and MC arms respectively (p=.91). Lesions were found in the mandible in 59% (26/44) of patients treated with CS and 61% (22/36) of patients treated with MC (p=.85). Surgeon 1 treated 84% (37/44) and 58% (21/36) of patients in the CS and MC groups respectively (p=.01). The recurrence rate was 10% for CS arm and 35% for MC arm (p=.027; HR=6.9).
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Conclusions: In this retrospective study, recurrence of KOTs treated by E&C with application of CS is significantly lower than that of MC. The data provided could be considered by the FDA for a clinical trial of CS in patients with KOT.
ACCEPTED MANUSCRIPT
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SC
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Introduction: Keratocystic odontogenic tumor (KOT) is a common jaw tumor, comprising 12-14% of all odontogenic cysts of the jaws. (1) KOT is locally destructive, has a high recurrence rate, and may be associated with increased morbidity secondary to multiple surgical procedures. (2) To date, no randomized controlled trials have been undertaken to establish which treatment modality provides the lowest recurrence rate. (1) Enucleation and curettage (E&C) with application of Carnoy’s solution (CS) has been prescribed as one treatment modality with the advantage of decreased recurrence over enucleation alone. Recent data reiterate that enucleation with CS provides the lowest recurrence (4.8%) from any of the conservative techniques. Resection provides the lowest recurrence rate overall (1.85%), yet causes the most morbidity for the patient. (3) In the United States, the FDA has banned the use of chloroform for compounding resulting in a number of surgeons adopting the use of “modified Carnoy’s” solution (MC) (without chloroform) for chemical cauterization in KOT treatment. The purpose of this study is to investigate the effect of CS versus MC as it relates to KOT recurrence rates when used in conjunction with E&C for treatment of KOT. The investigators hypothesize that chloroform compounding in CS significantly affects disease recurrence. The specific aim of this study is to ascertain whether retrospective data clarify the affect of chloroform in Carnoy’s, which could justify approaching the FDA for an exception to allow a randomized control trial comparing KOT recurrence rates using CS versus MC.
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EP
TE D
Materials and Methods: Study Design: To address the research purpose, once IRB approval was obtained, the investigators designed and implemented a retrospective cohort study. The study population was composed of all patients presenting to the University of Michigan Department of Oral & Maxillofacial Surgery for evaluation and management of KOT between January 1996 and April 2014. To be included in the study sample, patients had to have pathological diagnosis of KOT treated with E&C and a 3-minute application of CS or MC by one of three attending surgeons. Patients were excluded as study subjects if they had Gorlin’s syndrome, if they were treated by surgical means including marsupialization, E&C with peripheral ostectomy, or resection, or if they had less than 12 months of post-surgical follow-up. To decrease statistical bias, patients with recurrence were categorized as such and their subsequent treatment outcomes were excluded from the study, whereby multiple recurrences would not affect the analysis. Variables: The predictor variable for this study was CS versus MC. The outcome variable was time to recurrence. Age, gender, KOT location, and surgeon were other variables that were statistically evaluated. Data Collection: A mail survey was undertaken, followed by telephone calls to patients whose recurrence status was still unknown. Demographic, clinical, radiographic, and histological data were collected for each patient. All disease recurrences were confirmed by biopsy. Data Analyses: Patient characteristic differences between CS and MC were assessed with chi-squared tests (categorical) and Wilcoxon Rank Sum test (continuous). Time to recurrence was estimated using Kaplan-Meier methods and differences
ACCEPTED MANUSCRIPT
between CS and MC were assessed with a logrank test. Multivariate modeling of time to recurrence was done using Cox regression. Statistical significance was defined as a p-value less than 0.05. All analyses were done in the R statistical programming language.
M AN U
SC
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Results: The study population was composed of 210 subjects; 80 subjects met the inclusion criteria and comprise the final study sample. There were 44 subjects in the CS arm and 36 subjects in the MC arm. Patient characteristics are presented in Table 1. Median age range was 47 (10-89) in the CS group and 50 (14-72) in the MC group (p=.70). Females accounted for 43% (19/44) and 44% (16/36) of patients in the CS and MC arms, respectively (p=.91). Lesions were found in the mandible in 59% (26/44) of patients treated with CS and 61% (22/36) of patients treated with MC (p=.85). Surgeon 1 treated 84% (37/44) and 58% (21/36) of patient in the CS and MC groups respectively (p=.01). Table 2 summarizes the univariate association of the predictor variable and each patient characteristic with time to recurrence. Recurrence rates are significantly higher in patients treated with MC versus CS (hazard ratio=6.9; p=0.027) and tend to be lower in females versus males (hazard ratio=0.27; p=0.099) and older patients (hazard ratio=0.96; p=0.042). Table 3 summarizes the association of the predictor variable after controlling for any confounding effects of the patient characteristics. The association of the predictor variable becomes stronger, with an increased differential in recurrence rates between MC and CS (hazard ratio=13.11; p=0.020).
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TE D
Discussion: The purpose of this study is to investigate the effect of CS versus MC as it relates to KOT recurrence rates when used in conjunction with E&C for treatment of KOT. The investigators hypothesize that chloroform compounding in Carnoy’s solution significantly affects disease recurrence. The specific aim of this study is to ascertain whether retrospective data clarify the affect of chloroform in Carnoy’s solution, which could justify approaching the FDA for an exception to allow a randomized control trial comparing KOT recurrence rates using CS versus MC. As shown in figure 1, our findings demonstrate 10% recurrence of KOT with CS versus 35% with MC, which is statistically significant at P=.027 and demonstrates a Hazard Ratio of 6.9. KOT is nearly 7 times more likely to recur when treated with MC, and, the hazard ratio for treatment remains large and continues to be statistically significant, regardless of what characteristics we adjust for. Furthermore, when time is considered, the significance of our results is increased. This is particularly important given that MC was followed for less time and CS had a longer time to recurrence, both suggesting we are likely underestimating recurrence for the MC group, which may be much higher over a similar follow up to the CS group and amplify the findings of the study. Given the present dearth of prospective data on this topic coupled with findings from the current study, we believe it necessary and justified to request the FDA consider a waiver to pursue a pilot randomized controlled trial to elucidate recurrence rates of KOT using CS versus MC.
ACCEPTED MANUSCRIPT
RI PT
Other variables considered in this the study, include age, gender, KOT location, and surgeon. These were found to be generally without statistical significance with the only significant difference between the treatment arms being that surgeon 1 was more likely to use CS than MC. We believe this result is secondary to a lack of availability of CS due to FDA ban during substantial times of practice for surgeons 2 and 3. Note that surgeons 2 and 3 were collapsed into a single group due to the small patient numbers for those surgeons relative to surgeon 1.
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M AN U
SC
Other studies have suggested the possibility to similar results but without the statistical rigor of the current study. In their systematic review of KOT recurrence, Johnson and colleagues demonstrated that, other than resection, CS, in almost all cases, augments every other treatment with enhanced recurrence control. (3) Blanas et al reported similar outcomes in the only other systematic review of KOT treatment and recurrence rates. (4). When combining data from the 2 studies, simple E&C with adjunctive measures (excluding CS) had recurrence rates of 27.8 and 30.8%, respectively, followed by marsupialization alone (18.2%). The use of CS reduced recurrence to 4.8% and resection to 1.85%. (3) Unfortunately, most studies that mention use of “Carnoy’s solution” as an adjunct to E&C do not further describe CS versus MC formulation. Chirapathomsakul and colleagues described one recurrence in 5 patients (20%), but did not disclose whether chloroform was included in the “Carnoy’s solution”. (5) In the only existing studies where use of the original formulation of CS (including chloroform) was documented, recurrence of KOT was remarkably low. Stoelinga and colleagues saw zero recurrences in 20 patients in one study and zero recurrences in 5 patients in a subsequent series. (3, 6) Voorsmit and colleagues experienced one recurrence in 40 patients (2.5%) in their study. (7)
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EP
It must be kept in mind that our study is a retrospective review; therefore, results should be interpreted with caution. Further, many patients are unaccounted for which may confound the results. These inherent weaknesses notwithstanding, we believe that simple E&C with MC, with a recurrence rate of 35% is unacceptably high. Current data for KOT recurrence rates is weak at best, with the most helpful series demonstrating zero out of 13 recurrences using E&C with peripheral ostectomy with MC, and 18% recurrence with ostectomy alone, in the same series. (8) The 940 KOTs analyzed in two separate systematic reviews by Johnson et al and Blanas et al between 1970 and 2010 certainly have helped make reasonable recommendations as to which management techniques can best minimize the chance of recurrence. (3, 4) That said, as noted by Johnson, because there are no randomized controlled trials available in the literature, a meta-analysis cannot be used to analyze the results. Further, there are no odds ratios or risk ratios supplied in any of the available studies, precluding calculation of an effect size for the different management options, including use of CS. (3) Once again, given the present lack of prospective data on KOT treatment and the findings presented herein, we believe it imperative to request FDA permission to conduct a randomized controlled trial to clarify recurrence rates of KOT using CS
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versus MC.
References:
RI PT
1. Pitak-Arnnop P, Chaine A, Oprean N, Dhanuthai K, Bertrand JC, Bertolus C. Management of odontogenic keratocysts of the jaws: a ten-year experience with 120 consecutive lesions. J Craniomaxillofac Surg 2010;38:358-64.
SC
2. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 1. Clinical and early experimental evidence of aggressive behaviour. Oral Oncol 2002;38: 219-26.
M AN U
3. Johnson, N. Management and recurrence of keratocystic odontogenic tumor: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;116:271-276. 4. Blanas N, Freund B, Schwartz M, Furst IM. Systematic review of the treatment and prognosis of the odontogenic keratocyst. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:553-8.
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5. Chirapathomsakul D, Sastravaha P, Jansisyanont P. A review of odontogenic keratocysts and the behaviour of recurrences. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:5-9. 6. Stoelinga PJW, Bronkhorst FB. The incidence, multiple presentation and recurrence of aggressive cysts of the jaws. J Craniomaxillofac Surg 1988;16:184-95.
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7. Voorsmit RA, Stollinga PT, Van Hallst VJ. The management of keratocysts. J Maxillofac Surg 1981;9:228-36.
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8. Morgan TA, Burton CC, Qian F. A retrospective review of treatment of the odontogenic keratocyst. J Oral Maxillofac Surg 2005;63:635-9.
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Table 1: Patient Characteristics
Table 2: Univariate Model for Association
95% Conf Int Lower Upper Bound Bound
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Variable Treatment Arm (MC vs. CS)
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CS arm MC arm p-value for Characteristic (n=44) (n=36) difference Median Age (Range) 47 (10-89) 50 (14-72) 0.70* # Females (%) 19 (43) 16 (44) 0.91** # Mandibular (%) 26 (59) 22 (61) 0.85** # Treated with Surgeon 1 37 (84) 21 (58) 0.01** Median Year of Surgery 2003 2009 <0.001* (Range) (1999-2007) 2007-2011 * via Wilcoxon Rank Sum test; **via chi-squared test of association
Hazard Ratio
p-value
6.90
1.25
38.10
0.027
0.27
0.06
1.28
0.099
0.96
0.93
1.00
0.042
Surgeon (1 vs. 2)
1.84
0.49
6.88
0.363
Location (Mandible vs. Maxilla)
1.19
0.33
4.23
0.790
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Age
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Gender (Female vs. Male)
Table 3: Multivariate Model for Association
Variable Treatment Arm Gender Age Surgeon Location
Hazard Ratio 13.11 0.34 0.96 0.78 1.64
95% Conf Int Lower Upper Bound Bound 1.51 113.74 0.06 1.91 0.92 1.00 0.17 3.62 0.37 7.22
p-value 0.020 0.222 0.065 0.747 0.513
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Figure & Table Legends: Table 1: Treatment Arm Differences in Patient Characteristics: The table below summarizes the difference in patient characteristics between the two arms.
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Table 2: Univariate Association of Predictor Variable and Patient Characteristics with Recurrence Rates. MC hazard ratio of 6.90 noting increased recurrence in this group compared to CS.
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Table 3: Multivariate Model for Association of Predictor Variable with Recurrence Rates after Adjusting for Patient Characteristics. MC hazard ratio of 13.11 noting increased recurrence in this group compared to CS.
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Figure 1: Recurrence Rates by Treatment Arm: This plot displays the recurrence rates in the two arms (blue=CS; red=MC). The x-axis is truncated at seven years due to lack of substantial follow-up past that point.
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ACCEPTED MANUSCRIPT
S0278-2391(15)00543-1
DOI:
10.1016/j.joms.2015.05.005
Reference:
YJOMS 56810
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 10 February 2015 Revised Date:
11 May 2015
Accepted Date: 12 May 2015
Please cite this article as: Dashow JE, McHugh JB, Braun TM, Edwards SP, Helman JI, Ward BB, Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy’s Versus Modified Carnoy’s Solution, Journal of Oral and Maxillofacial Surgery (2015), doi: 10.1016/j.joms.2015.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI PT
Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy’s Versus Modified Carnoy’s Solution
Jason E. Dashow DDS, MD 1 , John B. McHugh MD 2, Thomas M. Braun PhD 3, Sean P. Edwards DDS, MD 4, Joseph I. Helman DMD 5, Brent B. Ward DDS, MD 6
Resident, University of Michigan Department of Oral & Maxillofacial Surgery
SC
1 Chief
2 Associate
Professor, University of Michigan Departments of Pathology and Oral & Maxillofacial Surgery University of Michigan Department of Biostatistics
M AN U
3 Professor, 4 Associate
Professor, Residency Program Director, University of Michigan Department of Oral & Maxillofacial Surgery
5 Professor,
University of Michigan Department of Oral & Maxillofacial Surgery
6 Associate
TE D
Professor, Program Director - Oral/Head and Neck Oncologic and Microvascular Reconstructive Surgery, University of Michigan Department of Oral & Maxillofacial Surgery
AC C
EP
Corresponding Author: Jason E. Dashow, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109. Email: [email protected]. Telephone: 734-936-5950. Fax: 734-6156159.
ACCEPTED MANUSCRIPT
Abstract:
RI PT
Purpose: A variety of modalities have been suggested for treatment of keratocystic odontogenic tumor (KOT) including Carnoy’s and “modified Carnoy’s” (without chloroform) solution. The purpose of this study is to investigate the effect of Carnoy’s solution (CS) versus modified Carnoy’s solution (MC) as it relates to KOT recurrence rates when used in conjunction with simple enucleation and curettage (E&C) for treatment of KOT.
M AN U
SC
Materials and Methods: A retrospective cohort study of patients with pathological diagnosis of KOT treated with E&C and application of CS or MC by three surgeons at a single center between January 1996 and April 2014 was completed. Demographic, clinical, radiographic, and histological data was collected for each patient. All disease recurrences were confirmed by biopsy. The primary outcome variable of the study was time to recurrence with the predictor of CS versus MC. Other variables included in the analysis were gender, age, surgeon, and lesion location. Multivariate analysis including Wilcoxon test and chi-squared test of associations were completed.
EP
TE D
Results: 210 patient charts were reviewed, 80 patients meeting final study criteria; 44 subjects in the CS arm and 36 subjects in the MC arm. Median age range was 47 (1089) in the CS group and 50 (14-72) in the MC group (p=.70). Females accounted for 43% (19/44) and 44% (16/36) of patients in the CS and MC arms respectively (p=.91). Lesions were found in the mandible in 59% (26/44) of patients treated with CS and 61% (22/36) of patients treated with MC (p=.85). Surgeon 1 treated 84% (37/44) and 58% (21/36) of patients in the CS and MC groups respectively (p=.01). The recurrence rate was 10% for CS arm and 35% for MC arm (p=.027; HR=6.9).
AC C
Conclusions: In this retrospective study, recurrence of KOTs treated by E&C with application of CS is significantly lower than that of MC. The data provided could be considered by the FDA for a clinical trial of CS in patients with KOT.
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Introduction: Keratocystic odontogenic tumor (KOT) is a common jaw tumor, comprising 12-14% of all odontogenic cysts of the jaws. (1) KOT is locally destructive, has a high recurrence rate, and may be associated with increased morbidity secondary to multiple surgical procedures. (2) To date, no randomized controlled trials have been undertaken to establish which treatment modality provides the lowest recurrence rate. (1) Enucleation and curettage (E&C) with application of Carnoy’s solution (CS) has been prescribed as one treatment modality with the advantage of decreased recurrence over enucleation alone. Recent data reiterate that enucleation with CS provides the lowest recurrence (4.8%) from any of the conservative techniques. Resection provides the lowest recurrence rate overall (1.85%), yet causes the most morbidity for the patient. (3) In the United States, the FDA has banned the use of chloroform for compounding resulting in a number of surgeons adopting the use of “modified Carnoy’s” solution (MC) (without chloroform) for chemical cauterization in KOT treatment. The purpose of this study is to investigate the effect of CS versus MC as it relates to KOT recurrence rates when used in conjunction with E&C for treatment of KOT. The investigators hypothesize that chloroform compounding in CS significantly affects disease recurrence. The specific aim of this study is to ascertain whether retrospective data clarify the affect of chloroform in Carnoy’s, which could justify approaching the FDA for an exception to allow a randomized control trial comparing KOT recurrence rates using CS versus MC.
AC C
EP
TE D
Materials and Methods: Study Design: To address the research purpose, once IRB approval was obtained, the investigators designed and implemented a retrospective cohort study. The study population was composed of all patients presenting to the University of Michigan Department of Oral & Maxillofacial Surgery for evaluation and management of KOT between January 1996 and April 2014. To be included in the study sample, patients had to have pathological diagnosis of KOT treated with E&C and a 3-minute application of CS or MC by one of three attending surgeons. Patients were excluded as study subjects if they had Gorlin’s syndrome, if they were treated by surgical means including marsupialization, E&C with peripheral ostectomy, or resection, or if they had less than 12 months of post-surgical follow-up. To decrease statistical bias, patients with recurrence were categorized as such and their subsequent treatment outcomes were excluded from the study, whereby multiple recurrences would not affect the analysis. Variables: The predictor variable for this study was CS versus MC. The outcome variable was time to recurrence. Age, gender, KOT location, and surgeon were other variables that were statistically evaluated. Data Collection: A mail survey was undertaken, followed by telephone calls to patients whose recurrence status was still unknown. Demographic, clinical, radiographic, and histological data were collected for each patient. All disease recurrences were confirmed by biopsy. Data Analyses: Patient characteristic differences between CS and MC were assessed with chi-squared tests (categorical) and Wilcoxon Rank Sum test (continuous). Time to recurrence was estimated using Kaplan-Meier methods and differences
ACCEPTED MANUSCRIPT
between CS and MC were assessed with a logrank test. Multivariate modeling of time to recurrence was done using Cox regression. Statistical significance was defined as a p-value less than 0.05. All analyses were done in the R statistical programming language.
M AN U
SC
RI PT
Results: The study population was composed of 210 subjects; 80 subjects met the inclusion criteria and comprise the final study sample. There were 44 subjects in the CS arm and 36 subjects in the MC arm. Patient characteristics are presented in Table 1. Median age range was 47 (10-89) in the CS group and 50 (14-72) in the MC group (p=.70). Females accounted for 43% (19/44) and 44% (16/36) of patients in the CS and MC arms, respectively (p=.91). Lesions were found in the mandible in 59% (26/44) of patients treated with CS and 61% (22/36) of patients treated with MC (p=.85). Surgeon 1 treated 84% (37/44) and 58% (21/36) of patient in the CS and MC groups respectively (p=.01). Table 2 summarizes the univariate association of the predictor variable and each patient characteristic with time to recurrence. Recurrence rates are significantly higher in patients treated with MC versus CS (hazard ratio=6.9; p=0.027) and tend to be lower in females versus males (hazard ratio=0.27; p=0.099) and older patients (hazard ratio=0.96; p=0.042). Table 3 summarizes the association of the predictor variable after controlling for any confounding effects of the patient characteristics. The association of the predictor variable becomes stronger, with an increased differential in recurrence rates between MC and CS (hazard ratio=13.11; p=0.020).
AC C
EP
TE D
Discussion: The purpose of this study is to investigate the effect of CS versus MC as it relates to KOT recurrence rates when used in conjunction with E&C for treatment of KOT. The investigators hypothesize that chloroform compounding in Carnoy’s solution significantly affects disease recurrence. The specific aim of this study is to ascertain whether retrospective data clarify the affect of chloroform in Carnoy’s solution, which could justify approaching the FDA for an exception to allow a randomized control trial comparing KOT recurrence rates using CS versus MC. As shown in figure 1, our findings demonstrate 10% recurrence of KOT with CS versus 35% with MC, which is statistically significant at P=.027 and demonstrates a Hazard Ratio of 6.9. KOT is nearly 7 times more likely to recur when treated with MC, and, the hazard ratio for treatment remains large and continues to be statistically significant, regardless of what characteristics we adjust for. Furthermore, when time is considered, the significance of our results is increased. This is particularly important given that MC was followed for less time and CS had a longer time to recurrence, both suggesting we are likely underestimating recurrence for the MC group, which may be much higher over a similar follow up to the CS group and amplify the findings of the study. Given the present dearth of prospective data on this topic coupled with findings from the current study, we believe it necessary and justified to request the FDA consider a waiver to pursue a pilot randomized controlled trial to elucidate recurrence rates of KOT using CS versus MC.
ACCEPTED MANUSCRIPT
RI PT
Other variables considered in this the study, include age, gender, KOT location, and surgeon. These were found to be generally without statistical significance with the only significant difference between the treatment arms being that surgeon 1 was more likely to use CS than MC. We believe this result is secondary to a lack of availability of CS due to FDA ban during substantial times of practice for surgeons 2 and 3. Note that surgeons 2 and 3 were collapsed into a single group due to the small patient numbers for those surgeons relative to surgeon 1.
TE D
M AN U
SC
Other studies have suggested the possibility to similar results but without the statistical rigor of the current study. In their systematic review of KOT recurrence, Johnson and colleagues demonstrated that, other than resection, CS, in almost all cases, augments every other treatment with enhanced recurrence control. (3) Blanas et al reported similar outcomes in the only other systematic review of KOT treatment and recurrence rates. (4). When combining data from the 2 studies, simple E&C with adjunctive measures (excluding CS) had recurrence rates of 27.8 and 30.8%, respectively, followed by marsupialization alone (18.2%). The use of CS reduced recurrence to 4.8% and resection to 1.85%. (3) Unfortunately, most studies that mention use of “Carnoy’s solution” as an adjunct to E&C do not further describe CS versus MC formulation. Chirapathomsakul and colleagues described one recurrence in 5 patients (20%), but did not disclose whether chloroform was included in the “Carnoy’s solution”. (5) In the only existing studies where use of the original formulation of CS (including chloroform) was documented, recurrence of KOT was remarkably low. Stoelinga and colleagues saw zero recurrences in 20 patients in one study and zero recurrences in 5 patients in a subsequent series. (3, 6) Voorsmit and colleagues experienced one recurrence in 40 patients (2.5%) in their study. (7)
AC C
EP
It must be kept in mind that our study is a retrospective review; therefore, results should be interpreted with caution. Further, many patients are unaccounted for which may confound the results. These inherent weaknesses notwithstanding, we believe that simple E&C with MC, with a recurrence rate of 35% is unacceptably high. Current data for KOT recurrence rates is weak at best, with the most helpful series demonstrating zero out of 13 recurrences using E&C with peripheral ostectomy with MC, and 18% recurrence with ostectomy alone, in the same series. (8) The 940 KOTs analyzed in two separate systematic reviews by Johnson et al and Blanas et al between 1970 and 2010 certainly have helped make reasonable recommendations as to which management techniques can best minimize the chance of recurrence. (3, 4) That said, as noted by Johnson, because there are no randomized controlled trials available in the literature, a meta-analysis cannot be used to analyze the results. Further, there are no odds ratios or risk ratios supplied in any of the available studies, precluding calculation of an effect size for the different management options, including use of CS. (3) Once again, given the present lack of prospective data on KOT treatment and the findings presented herein, we believe it imperative to request FDA permission to conduct a randomized controlled trial to clarify recurrence rates of KOT using CS
ACCEPTED MANUSCRIPT
versus MC.
References:
RI PT
1. Pitak-Arnnop P, Chaine A, Oprean N, Dhanuthai K, Bertrand JC, Bertolus C. Management of odontogenic keratocysts of the jaws: a ten-year experience with 120 consecutive lesions. J Craniomaxillofac Surg 2010;38:358-64.
SC
2. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 1. Clinical and early experimental evidence of aggressive behaviour. Oral Oncol 2002;38: 219-26.
M AN U
3. Johnson, N. Management and recurrence of keratocystic odontogenic tumor: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;116:271-276. 4. Blanas N, Freund B, Schwartz M, Furst IM. Systematic review of the treatment and prognosis of the odontogenic keratocyst. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:553-8.
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Table 1: Patient Characteristics
Table 2: Univariate Model for Association
95% Conf Int Lower Upper Bound Bound
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Variable Treatment Arm (MC vs. CS)
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CS arm MC arm p-value for Characteristic (n=44) (n=36) difference Median Age (Range) 47 (10-89) 50 (14-72) 0.70* # Females (%) 19 (43) 16 (44) 0.91** # Mandibular (%) 26 (59) 22 (61) 0.85** # Treated with Surgeon 1 37 (84) 21 (58) 0.01** Median Year of Surgery 2003 2009 <0.001* (Range) (1999-2007) 2007-2011 * via Wilcoxon Rank Sum test; **via chi-squared test of association
Hazard Ratio
p-value
6.90
1.25
38.10
0.027
0.27
0.06
1.28
0.099
0.96
0.93
1.00
0.042
Surgeon (1 vs. 2)
1.84
0.49
6.88
0.363
Location (Mandible vs. Maxilla)
1.19
0.33
4.23
0.790
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Age
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Gender (Female vs. Male)
Table 3: Multivariate Model for Association
Variable Treatment Arm Gender Age Surgeon Location
Hazard Ratio 13.11 0.34 0.96 0.78 1.64
95% Conf Int Lower Upper Bound Bound 1.51 113.74 0.06 1.91 0.92 1.00 0.17 3.62 0.37 7.22
p-value 0.020 0.222 0.065 0.747 0.513
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Figure & Table Legends: Table 1: Treatment Arm Differences in Patient Characteristics: The table below summarizes the difference in patient characteristics between the two arms.
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Table 2: Univariate Association of Predictor Variable and Patient Characteristics with Recurrence Rates. MC hazard ratio of 6.90 noting increased recurrence in this group compared to CS.
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Table 3: Multivariate Model for Association of Predictor Variable with Recurrence Rates after Adjusting for Patient Characteristics. MC hazard ratio of 13.11 noting increased recurrence in this group compared to CS.
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Figure 1: Recurrence Rates by Treatment Arm: This plot displays the recurrence rates in the two arms (blue=CS; red=MC). The x-axis is truncated at seven years due to lack of substantial follow-up past that point.
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M AN U
SC
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