AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI NE AN D SUR G E RY 3 5 ( 2 0 14 ) 27 6–2 7 7
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Letters to the Editor Is radiotherapy necessary for pleomorphic adenoma? To the Editor: I was very interested to read the article by Wallace et al. [1] outlining their experience on radiotherapy (RT) for pleomorphic adenoma (PA). Although this report reveals useful information, there are some areas for discussion on which I would like to expand. First, the investigators designed and implemented a retrospective cohort study comparing RT versus RT plus surgery. It can be implied that the predictor study variable was surgical intervention (ie, yes or no). Had the authors demonstrated statistical significance between the 2 groups of the cohort, it would have been able to conclude that “surgery as an adjunct to RT improves the clinical outcomes of RT”. If the study's purpose is to address the following question: “Among patients having PA removed, is RT effective in controlling the recurrence of PA after surgery?” (as in their conclusion), the investigators should enroll a cohort of subjects/patients who underwent surgery with versus without RT. The alternative, 1-tail hypothesis will be that recurrence is lower in the surgery plus RT group than in the surgery alone group. By this reason, bias of the general interpretation of the results will be minimized. Second, the study's results are indeed inconclusive. The authors covered most of the issues associated with tumor treatment outcome. However, any impact seems to be lost due to the inability to make any significant difference between the 2 groups of the cohort (RT versus RT plus surgery). The Kaplan-Meier survival curve does not represent any statistical significance of the comparison. It is known that many studies on oral and facial diseases have no statistical analyses, even though it is possible and informative to perform them. Many reports also lack basic univariate analyses, so that it is unclear to whom the results may be generalizable, or the analyses do not fully relate to the hypotheses or the study design [2]. Third, it is generally accepted that observational studies do not control the exposure (intervention). Causal interference made in this study type is complicated by the contamination of unknown or unmeasured confounding variables. The findings based on a small sample size should also be interpreted cautiously [3–5]. Besides, small studies or subgroups are often underpowered, namely suffering from “falsenegative or type II error”. To detect a 50% to 80% relative efficacy benefit of one treatment over another, sample size in controlled therapeutic trials should range from 50 to 200 [4].
Fourth, as the authors also reminded us, surgical excision is the treatment of choice for PA [6]. RT alone is not recommended for PA because it does not reduce recurrence rates, a recurrence-free interval and the size of safety margins needed intraoperatively. Irradiation can result in tissue ischemia/fibrosis, oral and dental tissue changes, osteoradionecrosis, and retardation of the facial nerve recovery [7–9]. Some studies have shown the radioresistance of PA [6]. Moreover, different surgical modalities contribute to different treatment outcome. Two meta-analyses revealed that enucleation and extracapsular dissection of PA of the parotid gland elicited 9 and 10 times higher rates of recurrence compared with superficial parotidectomy (SP), respectively [10,11]. In the Wallace et al's study, various surgical procedures were mixed together: 12 SP, 4 total parotidectomy and 1 enucleation. This may skew the analysis and study results. Fifth, the authors concluded that “Patients with pleomorphic adenoma who present with positive margins or multinodular recurrence benefit from treatment with adjuvant RT”. However, they did not present or analyze any data on multinodular recurrence. This also requires further explanation. Lastly, the authors cited that the study by Makeieff et al. [12] was conducted at “Le Centre Hospitalier Universitaire (Montpellier, France)”. In fact, “Le Centre Hospitalier Universitaire” can be literally translated into “the University Hospital Center” (“Le” for masculine words in French means “the” in English). The readers may misunderstand that “Le” is the hospital's name. The words “Le Centre Hospitalier Universitaire (Montpellier, France)” should be read as “the University Hospital Center of Montpellier, France”. Taken together, Wallace et al. [1] presented an excellent analysis and interesting information on RT for PA, but their study results need to be interpreted with caution. Outcome research requires more attention in this evidence-based era, as it would influence systematic reviews and meta-analysis in the future. REFERENCES
0196-0709/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
[1] Wallace AS, Morris CG, Kirwan JM, et al. Radiotherapy for pleomorphic adenoma. Am J Otolaryngol 2013;34:36–40. [2] Baccaglini L, Shuster JJ, Cheng J, et al. Design and statistical analysis of oral medicine studies: common pitfalls. Oral Dis 2010;16:233–41. [3] Thornton A, Lee P. Publication bias in meta-analysis: its causes and consequences. J Clin Epidemiol 2000;53:207–16.
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI N E AN D SUR G E RY 3 5 ( 2 0 14 ) 27 6–2 7 7
[4] Alam M, Barzilai DA, Wrone DA. Power and sample size of therapeutic trials in procedural dermatology: how many patients are enough? Dermatol Surg 2005;31:201–5. [5] Petrisor BA, Keating J, Schemitsch E. Grading the evidence: levels of evidence and grades of recommendation. Injury 2006;37:321–7. [6] Zbären P, Vander Poorten V, Witt RL, et al. Pleomorphic adenoma of the parotid: formal parotidectomy or limited surgery? Am J Surg 2013;205:109–18. [7] Pitak-Arnnop P, Lupanalaploy S, Rojvanakarn M, et al. A mass at labial mucosa of the upper lip: pleomorphic adenoma. Thai J Oral Maxillofac Surg 2000;27:22–4, 46–53. [8] Pitak-Arnnop P, Dhanuthai K, Hemprich A, et al. Does pleomorphic adenoma really require total parotidectomy? Ann Surg Oncol 2011;18(Suppl 3):S248–9. [9] Pitak-Arnnop P, Dhanuthai K, Hemprich A, et al. Pleomorphic adenoma of the upper lip: some clinicopathological considerations. J Cutan Aesthet Surg 2012;5:51–2. [10] Witt RL. The significance of the margin in parotid surgery for pleomorphic adenoma. Laryngoscope 2002; 112:2141–54. [11] Witt RL, Rejto L. Pleomorphic adenoma: extracapsular dissection versus partial superficial parotidectomy with facial nerve dissection. Del Med J 2009;81:119–25. [12] Makeieff M, Pelliccia P, Letois F, et al. Recurrent pleomorphic adenoma: results of surgical treatment. Ann Surg Oncol 2010;17:3308–13.
Poramate Pitak-Arnnop MD, DDS, PGDipClinSc (OMS) 1 MSc, PhD, DSc Department of Oral and Maxillofacial Surgery Research Group for Clinical and Psychosocial Research Evidence-Based Surgery and Ethics in Oral and Maxillofacial Surgery, UKGM GmbH University Hospital of Marburg Faculty of Medicine Philipps University, Marburg, Germany E-mail address: [email protected] 1 Formerly, Department of Maxillofacial Surgery AP-HP, Pitié-Salpêtrière University Hospital, Faculty of Medicine University Paris 6 (Pierre et Marie Curie) Paris, France
As clearly stated in the paper, this is a retrospective outcome study evaluating the role of adjuvant radiotherapy (RT) after surgery for patients at high risk for local recurrence after surgery alone. We also included 2 patients with incompletely resectable pleomorphic adenoma (PA) who were treated with RT alone by default. The goal of the paper is not to compare the outcomes of definitive RT and RT following “adjuvant” surgery. Only 2 patients were treated with RT alone and they are not comparable to those suitable for attempted gross total resection. If one were to design a prospective randomized trial it would be to compare surgery alone versus surgery and adjuvant RT in patients thought to be at high risk for local recurrence after surgery alone. This would be impractical for several reasons. First, as stated in the “Discussion,” the local control rate after surgery alone for previously untreated PA exceeds 95% and very few patients would be eligible for such a trial. Indeed, we treated only 25 patients over 38 years, averaging less than 1 patient per year. Second, 20 of 25 patients had gross or microscopic residual disease and were at very high risk for local progression. One might think that if it was worthwhile operating on these patients initially, that it would be worth considering adjuvant RT to eradicate known or suspected residual diseases. Finally, Professor Pitak-Arnnop is correct in stating that we did not present data pertaining to the outcomes after salvage surgery alone for patients with multinodular recurrences after prior surgery. Although it is my impression that such patients have a very high risk of local recurrence after surgery alone, all of our patients received RT and we do not have data to address this question. Sincerely,
William M. Mendenhall MD Department of Radiation Oncology College of Medicine, University of Florida http://dx.doi.org/10.1016/j.amjoto.2013.10.002
http://dx.doi.org/10.1016/j.amjoto.2013.08.023 In response to Pormate Pitak-Arnnop's commentary, “Is radiotherapy necessary for pleomorphic adenoma?” To the Editor: I appreciate the observations of Professor Pitak-Arnnop, especially the tutorial pertaining to French grammar.
277
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Letters to the Editor Is radiotherapy necessary for pleomorphic adenoma? To the Editor: I was very interested to read the article by Wallace et al. [1] outlining their experience on radiotherapy (RT) for pleomorphic adenoma (PA). Although this report reveals useful information, there are some areas for discussion on which I would like to expand. First, the investigators designed and implemented a retrospective cohort study comparing RT versus RT plus surgery. It can be implied that the predictor study variable was surgical intervention (ie, yes or no). Had the authors demonstrated statistical significance between the 2 groups of the cohort, it would have been able to conclude that “surgery as an adjunct to RT improves the clinical outcomes of RT”. If the study's purpose is to address the following question: “Among patients having PA removed, is RT effective in controlling the recurrence of PA after surgery?” (as in their conclusion), the investigators should enroll a cohort of subjects/patients who underwent surgery with versus without RT. The alternative, 1-tail hypothesis will be that recurrence is lower in the surgery plus RT group than in the surgery alone group. By this reason, bias of the general interpretation of the results will be minimized. Second, the study's results are indeed inconclusive. The authors covered most of the issues associated with tumor treatment outcome. However, any impact seems to be lost due to the inability to make any significant difference between the 2 groups of the cohort (RT versus RT plus surgery). The Kaplan-Meier survival curve does not represent any statistical significance of the comparison. It is known that many studies on oral and facial diseases have no statistical analyses, even though it is possible and informative to perform them. Many reports also lack basic univariate analyses, so that it is unclear to whom the results may be generalizable, or the analyses do not fully relate to the hypotheses or the study design [2]. Third, it is generally accepted that observational studies do not control the exposure (intervention). Causal interference made in this study type is complicated by the contamination of unknown or unmeasured confounding variables. The findings based on a small sample size should also be interpreted cautiously [3–5]. Besides, small studies or subgroups are often underpowered, namely suffering from “falsenegative or type II error”. To detect a 50% to 80% relative efficacy benefit of one treatment over another, sample size in controlled therapeutic trials should range from 50 to 200 [4].
Fourth, as the authors also reminded us, surgical excision is the treatment of choice for PA [6]. RT alone is not recommended for PA because it does not reduce recurrence rates, a recurrence-free interval and the size of safety margins needed intraoperatively. Irradiation can result in tissue ischemia/fibrosis, oral and dental tissue changes, osteoradionecrosis, and retardation of the facial nerve recovery [7–9]. Some studies have shown the radioresistance of PA [6]. Moreover, different surgical modalities contribute to different treatment outcome. Two meta-analyses revealed that enucleation and extracapsular dissection of PA of the parotid gland elicited 9 and 10 times higher rates of recurrence compared with superficial parotidectomy (SP), respectively [10,11]. In the Wallace et al's study, various surgical procedures were mixed together: 12 SP, 4 total parotidectomy and 1 enucleation. This may skew the analysis and study results. Fifth, the authors concluded that “Patients with pleomorphic adenoma who present with positive margins or multinodular recurrence benefit from treatment with adjuvant RT”. However, they did not present or analyze any data on multinodular recurrence. This also requires further explanation. Lastly, the authors cited that the study by Makeieff et al. [12] was conducted at “Le Centre Hospitalier Universitaire (Montpellier, France)”. In fact, “Le Centre Hospitalier Universitaire” can be literally translated into “the University Hospital Center” (“Le” for masculine words in French means “the” in English). The readers may misunderstand that “Le” is the hospital's name. The words “Le Centre Hospitalier Universitaire (Montpellier, France)” should be read as “the University Hospital Center of Montpellier, France”. Taken together, Wallace et al. [1] presented an excellent analysis and interesting information on RT for PA, but their study results need to be interpreted with caution. Outcome research requires more attention in this evidence-based era, as it would influence systematic reviews and meta-analysis in the future. REFERENCES
0196-0709/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
[1] Wallace AS, Morris CG, Kirwan JM, et al. Radiotherapy for pleomorphic adenoma. Am J Otolaryngol 2013;34:36–40. [2] Baccaglini L, Shuster JJ, Cheng J, et al. Design and statistical analysis of oral medicine studies: common pitfalls. Oral Dis 2010;16:233–41. [3] Thornton A, Lee P. Publication bias in meta-analysis: its causes and consequences. J Clin Epidemiol 2000;53:207–16.
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI N E AN D SUR G E RY 3 5 ( 2 0 14 ) 27 6–2 7 7
[4] Alam M, Barzilai DA, Wrone DA. Power and sample size of therapeutic trials in procedural dermatology: how many patients are enough? Dermatol Surg 2005;31:201–5. [5] Petrisor BA, Keating J, Schemitsch E. Grading the evidence: levels of evidence and grades of recommendation. Injury 2006;37:321–7. [6] Zbären P, Vander Poorten V, Witt RL, et al. Pleomorphic adenoma of the parotid: formal parotidectomy or limited surgery? Am J Surg 2013;205:109–18. [7] Pitak-Arnnop P, Lupanalaploy S, Rojvanakarn M, et al. A mass at labial mucosa of the upper lip: pleomorphic adenoma. Thai J Oral Maxillofac Surg 2000;27:22–4, 46–53. [8] Pitak-Arnnop P, Dhanuthai K, Hemprich A, et al. Does pleomorphic adenoma really require total parotidectomy? Ann Surg Oncol 2011;18(Suppl 3):S248–9. [9] Pitak-Arnnop P, Dhanuthai K, Hemprich A, et al. Pleomorphic adenoma of the upper lip: some clinicopathological considerations. J Cutan Aesthet Surg 2012;5:51–2. [10] Witt RL. The significance of the margin in parotid surgery for pleomorphic adenoma. Laryngoscope 2002; 112:2141–54. [11] Witt RL, Rejto L. Pleomorphic adenoma: extracapsular dissection versus partial superficial parotidectomy with facial nerve dissection. Del Med J 2009;81:119–25. [12] Makeieff M, Pelliccia P, Letois F, et al. Recurrent pleomorphic adenoma: results of surgical treatment. Ann Surg Oncol 2010;17:3308–13.
Poramate Pitak-Arnnop MD, DDS, PGDipClinSc (OMS) 1 MSc, PhD, DSc Department of Oral and Maxillofacial Surgery Research Group for Clinical and Psychosocial Research Evidence-Based Surgery and Ethics in Oral and Maxillofacial Surgery, UKGM GmbH University Hospital of Marburg Faculty of Medicine Philipps University, Marburg, Germany E-mail address: [email protected] 1 Formerly, Department of Maxillofacial Surgery AP-HP, Pitié-Salpêtrière University Hospital, Faculty of Medicine University Paris 6 (Pierre et Marie Curie) Paris, France
As clearly stated in the paper, this is a retrospective outcome study evaluating the role of adjuvant radiotherapy (RT) after surgery for patients at high risk for local recurrence after surgery alone. We also included 2 patients with incompletely resectable pleomorphic adenoma (PA) who were treated with RT alone by default. The goal of the paper is not to compare the outcomes of definitive RT and RT following “adjuvant” surgery. Only 2 patients were treated with RT alone and they are not comparable to those suitable for attempted gross total resection. If one were to design a prospective randomized trial it would be to compare surgery alone versus surgery and adjuvant RT in patients thought to be at high risk for local recurrence after surgery alone. This would be impractical for several reasons. First, as stated in the “Discussion,” the local control rate after surgery alone for previously untreated PA exceeds 95% and very few patients would be eligible for such a trial. Indeed, we treated only 25 patients over 38 years, averaging less than 1 patient per year. Second, 20 of 25 patients had gross or microscopic residual disease and were at very high risk for local progression. One might think that if it was worthwhile operating on these patients initially, that it would be worth considering adjuvant RT to eradicate known or suspected residual diseases. Finally, Professor Pitak-Arnnop is correct in stating that we did not present data pertaining to the outcomes after salvage surgery alone for patients with multinodular recurrences after prior surgery. Although it is my impression that such patients have a very high risk of local recurrence after surgery alone, all of our patients received RT and we do not have data to address this question. Sincerely,
William M. Mendenhall MD Department of Radiation Oncology College of Medicine, University of Florida http://dx.doi.org/10.1016/j.amjoto.2013.10.002
http://dx.doi.org/10.1016/j.amjoto.2013.08.023 In response to Pormate Pitak-Arnnop's commentary, “Is radiotherapy necessary for pleomorphic adenoma?” To the Editor: I appreciate the observations of Professor Pitak-Arnnop, especially the tutorial pertaining to French grammar.
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