Laryngeal Transplantation: Ethical Considerations SCOTT STROME,
MD, AND MARSHALL
On February 10, 1969, Kluyskens performed a partial laryngeal transp1antation.l Although initial graft viability and function proved such an operation to be feasible, secondary failure due to cancer recurrence highlighted the inherent conflict between “acceptable risk,” both to the individual and society, and “potential benefit.” When considering the potential for laryngeal transplantation today, the dilemma that otolaryngologists and society as a whole must confront still revolves around these fundamental issues. Recent advances in immunosuppression, graft preservation techniques, and an understanding of the cellular mechanisms of allograft rejection have diminished the risk of this therapeutic modality and warrant reconsideration of the ethics of laryngeal transplantation in the context of current scientific knowledge. A prerequisite for any type of ethical analysis of laryngeal transplantation is a statement of purpose. The goals of this procedure are the restoration of near-normal speech, deglutition, and cosmesis with a minimal risk of aspiration. In order to attain these benefits, the patient accepts significant risks, including a potentially increased probability of cancer recurrence, graft rejection, and the inherent morbidity of chronic immunosuppression. If we are to conclude that this procedure is ethical, it is first necessary to ascertain that such goals cannot be achieved by currently available surgical or medical techniques with less patient risk. There are several operative techniques for voice restoration in the post-laryngectomy pa-
From the Joint Center for Otolaryngology, Brigham & Women’s Hospital, Beth Israel Hospital, and the Surgical Research Laboratories of the Harvard Medical School, Boston, MA. Supported by the Brigham Surgical Group Foundation. Address reprint requests to Marshall Strome, MD, 333 Longwood Ave, Boston, MA 02115. Copyright 0 1992 by W.B. Saunders Company 0196-0709/92/l 302-0002$5.00/O American
Journal
of Otolaryngology,
STROME, MD, MS, FACS
tient. Besides the electronic larynx, all of the surgical procedures are designed to facilitate esophageal speech by altering the source and site of air introduced into the esophagus.’ Two procedures that have achieved popularity are the Blom-Singer tracheal-esophageal puncture and the myomucosal shunt. Although detailed analysis of these two techniques is beyond the scope of this discussion, it is important to evaluate their efficacy. The Blom-Singer tracheal-esophageal puncture depends on the placement of a prosthesis from the trachea to the esophagus, either at the time of laryngeal resection or during a second procedure. Although initial reports suggested that normal voice could be restored in 90% of patients, long-term studies document a success rate ranging between 64% and 83%, with the higher value dependent on patient selection.3’4 Failure is primarily related to poor patient compliance, yet procedural complications, such as aspiration, atelectasis, and fistula closure, plague a relatively large number of patients.2-4 Strome designed the myomucosal shunt to augment esophageal speech without the need for a prosthesis. In the original six patients described, there was one failure, two patients required a prosthesis, and the remaining three achieved excellent results with the shunt alone. All of the patients without prosthesis experienced a minimal degree of fluid aspiration5 Follow-up data noted that shunt stenosis complicated a significant number of casess6 Thus, currently available surgical techniques offer effective voice restoration in 50% to 90% of selected patients. Associated aspiration and poor patient compliance in the context of a significant cosmetic defect, warrant the exploration of laryngeal transplantation as a potential solution to these problems. It is reasonable to assume that laryngeal transplantation would result in the restoration of near-normal speech, a patent airway devoid of the visible sigmata commonly associated Vol 13, No 2 (March-April),
1992: pp 75-77
75
76
with laryngectomy, and normal deglutition. Speech production is independent of graft reinnervation, as patients with recurrent laryngeal nerve dysfunction maintain an adequate voice, despite bilaterally paralyzed vocal chords. These assumptions were verified in Kluysken’s case report of a partial laryngeal transplantation from a 40-year-old-male cadaver into a 62-year-old man with laryngeal cancer. With the allograft in place, this patient was able to speak and eat normally and reported no problems with aspiration.’ Additionally, the recipient was not plagued by the continued requirement for a prosthesis, and did not have to be taught esophageal speech. Such data documents the significant advantages of laryngeal transplantation over currently available voice restoration techniques and suggests that in the hypothetical absence of associated patient risk, we would be ethically obligated to offer such therapy to our patients. At present, it is impossible to quantify the risk to the patient who would potentially undergo laryngeal transplantation. Based on data from heart and kidney transplantation, it is logical to assume that the primary causes of morbidity would be rejection, sequelae commonly associated with chronic immunosuppression, and cancer recurrence. On a global level, there are considerations of cost/benefit and whether a disease that primarily afflicts the elderly is meritorious of such expense. As such, because cost considerations are inherent to the entire field of transplantation, they will not be discussed. However, the potential for immunosuppressive-related disease is a necessary component of any ethical discussion concerning laryngeal transplantation, as it is the primary impediment to the initiation of human trials. Both acute and chronic rejection represent major sources of transplantation-related morbidity. Using a histoincompatible rat model, our research has led to identification of both the sequence and time course of cellular allograft rejection. Currently, we are attempting to define the dose-dependent effects of cyclosporine on the laryngeal graft. Such animal data will optimistically decrease the risk of rejection in humans. Because the larynx is a
STROME AND STROME
“nonvital” organ, even if rejection were to occur, accurate diagnosis with subsequent medical or surgical treatment should not significantly compromise patient survival. The availability of effective therapy, combined with the widespread acceptance of rejection as a complication of other types of organ transplantation, suggests that rejection not be used as an exclusion criteria for human laryngeal transplantation. Other side effects of chemical immunosuppression are not so easily dismissed. Cancer recurrence is the most significant foreseeable risk to which the laryngeal transplant recipient would be exposed, as a result of the recognized influence of immunosuppression on tumor cell growth. Kluysken’s original patient experienced new evidence of neoplastic disease at the tracheal stoma 8 months postoperatively.’ In an editorial review of the ethics of this case, Daly concluded that the return of this neoplastic disease was secondary to immunosuppression and that no further human laryngeal transplants should occur until this problem was solved.7 Although this conclusion may be valid, it is seemingly difficult to assess any potential increase in the incidence of cancer recurrence based on one case report. There is a well-described elevation in hematogenous malignancies in relation to chronic immunosuppression, yet documentation of an increase in laryngeal squamous cell carcinoma (XC) is absent. The most comprehensive data linking SCC with immunosuppression is derived from two separate studies performed on renal transplant patients in Australia/New Zealand and Cincinnati. Each showed a significant incidence of both new and recurrent SCC of the skin.as’ In the Australian trial, approximately 6% of 4,241 patients developed SCC of the skin, but exact immunosuppressive regimens and dosages were not specifiede8 Interestingly, the study performed in Cincinnati compared the incidence of SCC in patients on azathioprine versus cyclosporine. In the azathioprine group, greater than 20% of all skin and lip tumors were SCC, with 7.5% of these producing metastatic disease and 6.4% resulting in death. In contrast, only 16% of patients in the
LARYNGEAL
77
TRANSPLANTATION
cyclosporine group had lip/skin tumors, and there were no associated metastases or deaths.g There are obvious problems with using such data to calculate the potential association of laryngeal cancer recurrence with immunosuppression. Although the tumor cell type is analogous to that which commonly occurs in the larynx, the organ systems involved are different and, perhaps more importantly, age-matched controls are often not presented. Despite these flaws, there is a suggestion that the incidence of recurrent SCC may be increased in chemically immunosuppressed patients, and that certain drug regimens may be associated with a more benign form of neoplastic disease. In keeping with set standards for human experimentation, our laboratory is attempting to document the effect of cyclosporine on SCC growth in rats. The results of such experiments must precede human laryngeal transplantation. Optimistically, correlation of this laboratory data with individual values will allow each patient to determine what constitutes “acceptable risk.” In an attempt to quantify patient attitudes towards laryngectomy and voice preservation, McNeil interviewed 37 healthy firefighters and executives. They were asked whether they would choose radiation or laryngectomy as therapy for advanced laryngeal cancer. Subjects were informed that radiation results in a 30% to 40% 3year survival rate with voice preservation, whereas laryngectomy is associated with a 60% 3-year survival rate with loss of speech. Despite a higher associated mortality, 20% of those interviewed chose to undergo radiation therapy and retain their ability to speak.” Clinically, the options available to patients are not as sharply defined as those presented in this study. However, this data suggests that a group of patients exists who are willing to risk an increased probability of death in order to preserve speech. This patient population would serve as suitable candidates for the first human trials, if
laryngeal transplantation were shown to offer improved survival rates versus radiation therapy alone. The ethics of laryngeal transplantation are defined by a procedural risk benefit analysis in the context of patient values. As quantification of these parameters requires extrapolation from data flawed by a relative lack of specificity, ethical discussion remains limited by uncertainty. In this setting some would argue that human experimentation is not justified. However, the exploration of a new therapeutic modality is always associated with a certain degree of risk, and advances in patient care are based on this premise. After the criteria for human experimentation are satisfied, there appears to exist a defined patient population willing to trade a potentially diminished survival rate for an improved quality of life. In this subset of individuals, the potential to prolong life with preserved speech is seemingly enough to justify attempted laryngeal transplantation. REFERENCES 1. Kluyskens P, Ringoir S: Follow-up of a human larynx transplantation. Laryngoscope 80:1244-1250, 1970 2. Vincent M, Robbins A, Walsh M, et al: Evaluation of Blom-Singer voice prosthesis. Am J Roentgen01 143:745750,1984 3. Wetmore S, Krueger K, Wesson K, et al: Long-term results of the Blom-Singer speech rehabilitation procedure. Arch Otolaryngol Head Neck Surg 111:106-109, 1985 4. Hamaker R, Singer M, Blom E, et al: Primary voice restoration at laryngectomy. Arch Otolaryngol Head Neck Surg 111:X32-186, 1985 5. Strome M, Mustoe T, Kelly J: Voice rehabilitation following laryngectomy. Arch Otolaryngol Head Neck Surg 112:1168-1171, 1986 6. Strome M, Brasnu D, Laccourreye H: Further experience with the myomucosal tracheoesophageal shunt. Arch Otolaryngol Head Neck Surg 114:1303-1306, 1988 7. Daly J: Is laryngeal transplantation justifiable? Laryngoscope 80:1251-1255, 1970 8. Sheil A, Flavel S, Disney A, et al: Cancer incidence in renal transplant patients treated with Azathioprine or Cyclosporine. Transplant Proc 19:2214-2216, 1987 9. Penn I: Cancers following cyclosporine therapy. Transplant Proc 19:2211-2213, 1987 10. McNeil B, Weichselbaum R, Pauker S: Speech and survival. N Engl J Med 305:982-987, 1981
MD, AND MARSHALL
On February 10, 1969, Kluyskens performed a partial laryngeal transp1antation.l Although initial graft viability and function proved such an operation to be feasible, secondary failure due to cancer recurrence highlighted the inherent conflict between “acceptable risk,” both to the individual and society, and “potential benefit.” When considering the potential for laryngeal transplantation today, the dilemma that otolaryngologists and society as a whole must confront still revolves around these fundamental issues. Recent advances in immunosuppression, graft preservation techniques, and an understanding of the cellular mechanisms of allograft rejection have diminished the risk of this therapeutic modality and warrant reconsideration of the ethics of laryngeal transplantation in the context of current scientific knowledge. A prerequisite for any type of ethical analysis of laryngeal transplantation is a statement of purpose. The goals of this procedure are the restoration of near-normal speech, deglutition, and cosmesis with a minimal risk of aspiration. In order to attain these benefits, the patient accepts significant risks, including a potentially increased probability of cancer recurrence, graft rejection, and the inherent morbidity of chronic immunosuppression. If we are to conclude that this procedure is ethical, it is first necessary to ascertain that such goals cannot be achieved by currently available surgical or medical techniques with less patient risk. There are several operative techniques for voice restoration in the post-laryngectomy pa-
From the Joint Center for Otolaryngology, Brigham & Women’s Hospital, Beth Israel Hospital, and the Surgical Research Laboratories of the Harvard Medical School, Boston, MA. Supported by the Brigham Surgical Group Foundation. Address reprint requests to Marshall Strome, MD, 333 Longwood Ave, Boston, MA 02115. Copyright 0 1992 by W.B. Saunders Company 0196-0709/92/l 302-0002$5.00/O American
Journal
of Otolaryngology,
STROME, MD, MS, FACS
tient. Besides the electronic larynx, all of the surgical procedures are designed to facilitate esophageal speech by altering the source and site of air introduced into the esophagus.’ Two procedures that have achieved popularity are the Blom-Singer tracheal-esophageal puncture and the myomucosal shunt. Although detailed analysis of these two techniques is beyond the scope of this discussion, it is important to evaluate their efficacy. The Blom-Singer tracheal-esophageal puncture depends on the placement of a prosthesis from the trachea to the esophagus, either at the time of laryngeal resection or during a second procedure. Although initial reports suggested that normal voice could be restored in 90% of patients, long-term studies document a success rate ranging between 64% and 83%, with the higher value dependent on patient selection.3’4 Failure is primarily related to poor patient compliance, yet procedural complications, such as aspiration, atelectasis, and fistula closure, plague a relatively large number of patients.2-4 Strome designed the myomucosal shunt to augment esophageal speech without the need for a prosthesis. In the original six patients described, there was one failure, two patients required a prosthesis, and the remaining three achieved excellent results with the shunt alone. All of the patients without prosthesis experienced a minimal degree of fluid aspiration5 Follow-up data noted that shunt stenosis complicated a significant number of casess6 Thus, currently available surgical techniques offer effective voice restoration in 50% to 90% of selected patients. Associated aspiration and poor patient compliance in the context of a significant cosmetic defect, warrant the exploration of laryngeal transplantation as a potential solution to these problems. It is reasonable to assume that laryngeal transplantation would result in the restoration of near-normal speech, a patent airway devoid of the visible sigmata commonly associated Vol 13, No 2 (March-April),
1992: pp 75-77
75
76
with laryngectomy, and normal deglutition. Speech production is independent of graft reinnervation, as patients with recurrent laryngeal nerve dysfunction maintain an adequate voice, despite bilaterally paralyzed vocal chords. These assumptions were verified in Kluysken’s case report of a partial laryngeal transplantation from a 40-year-old-male cadaver into a 62-year-old man with laryngeal cancer. With the allograft in place, this patient was able to speak and eat normally and reported no problems with aspiration.’ Additionally, the recipient was not plagued by the continued requirement for a prosthesis, and did not have to be taught esophageal speech. Such data documents the significant advantages of laryngeal transplantation over currently available voice restoration techniques and suggests that in the hypothetical absence of associated patient risk, we would be ethically obligated to offer such therapy to our patients. At present, it is impossible to quantify the risk to the patient who would potentially undergo laryngeal transplantation. Based on data from heart and kidney transplantation, it is logical to assume that the primary causes of morbidity would be rejection, sequelae commonly associated with chronic immunosuppression, and cancer recurrence. On a global level, there are considerations of cost/benefit and whether a disease that primarily afflicts the elderly is meritorious of such expense. As such, because cost considerations are inherent to the entire field of transplantation, they will not be discussed. However, the potential for immunosuppressive-related disease is a necessary component of any ethical discussion concerning laryngeal transplantation, as it is the primary impediment to the initiation of human trials. Both acute and chronic rejection represent major sources of transplantation-related morbidity. Using a histoincompatible rat model, our research has led to identification of both the sequence and time course of cellular allograft rejection. Currently, we are attempting to define the dose-dependent effects of cyclosporine on the laryngeal graft. Such animal data will optimistically decrease the risk of rejection in humans. Because the larynx is a
STROME AND STROME
“nonvital” organ, even if rejection were to occur, accurate diagnosis with subsequent medical or surgical treatment should not significantly compromise patient survival. The availability of effective therapy, combined with the widespread acceptance of rejection as a complication of other types of organ transplantation, suggests that rejection not be used as an exclusion criteria for human laryngeal transplantation. Other side effects of chemical immunosuppression are not so easily dismissed. Cancer recurrence is the most significant foreseeable risk to which the laryngeal transplant recipient would be exposed, as a result of the recognized influence of immunosuppression on tumor cell growth. Kluysken’s original patient experienced new evidence of neoplastic disease at the tracheal stoma 8 months postoperatively.’ In an editorial review of the ethics of this case, Daly concluded that the return of this neoplastic disease was secondary to immunosuppression and that no further human laryngeal transplants should occur until this problem was solved.7 Although this conclusion may be valid, it is seemingly difficult to assess any potential increase in the incidence of cancer recurrence based on one case report. There is a well-described elevation in hematogenous malignancies in relation to chronic immunosuppression, yet documentation of an increase in laryngeal squamous cell carcinoma (XC) is absent. The most comprehensive data linking SCC with immunosuppression is derived from two separate studies performed on renal transplant patients in Australia/New Zealand and Cincinnati. Each showed a significant incidence of both new and recurrent SCC of the skin.as’ In the Australian trial, approximately 6% of 4,241 patients developed SCC of the skin, but exact immunosuppressive regimens and dosages were not specifiede8 Interestingly, the study performed in Cincinnati compared the incidence of SCC in patients on azathioprine versus cyclosporine. In the azathioprine group, greater than 20% of all skin and lip tumors were SCC, with 7.5% of these producing metastatic disease and 6.4% resulting in death. In contrast, only 16% of patients in the
LARYNGEAL
77
TRANSPLANTATION
cyclosporine group had lip/skin tumors, and there were no associated metastases or deaths.g There are obvious problems with using such data to calculate the potential association of laryngeal cancer recurrence with immunosuppression. Although the tumor cell type is analogous to that which commonly occurs in the larynx, the organ systems involved are different and, perhaps more importantly, age-matched controls are often not presented. Despite these flaws, there is a suggestion that the incidence of recurrent SCC may be increased in chemically immunosuppressed patients, and that certain drug regimens may be associated with a more benign form of neoplastic disease. In keeping with set standards for human experimentation, our laboratory is attempting to document the effect of cyclosporine on SCC growth in rats. The results of such experiments must precede human laryngeal transplantation. Optimistically, correlation of this laboratory data with individual values will allow each patient to determine what constitutes “acceptable risk.” In an attempt to quantify patient attitudes towards laryngectomy and voice preservation, McNeil interviewed 37 healthy firefighters and executives. They were asked whether they would choose radiation or laryngectomy as therapy for advanced laryngeal cancer. Subjects were informed that radiation results in a 30% to 40% 3year survival rate with voice preservation, whereas laryngectomy is associated with a 60% 3-year survival rate with loss of speech. Despite a higher associated mortality, 20% of those interviewed chose to undergo radiation therapy and retain their ability to speak.” Clinically, the options available to patients are not as sharply defined as those presented in this study. However, this data suggests that a group of patients exists who are willing to risk an increased probability of death in order to preserve speech. This patient population would serve as suitable candidates for the first human trials, if
laryngeal transplantation were shown to offer improved survival rates versus radiation therapy alone. The ethics of laryngeal transplantation are defined by a procedural risk benefit analysis in the context of patient values. As quantification of these parameters requires extrapolation from data flawed by a relative lack of specificity, ethical discussion remains limited by uncertainty. In this setting some would argue that human experimentation is not justified. However, the exploration of a new therapeutic modality is always associated with a certain degree of risk, and advances in patient care are based on this premise. After the criteria for human experimentation are satisfied, there appears to exist a defined patient population willing to trade a potentially diminished survival rate for an improved quality of life. In this subset of individuals, the potential to prolong life with preserved speech is seemingly enough to justify attempted laryngeal transplantation. REFERENCES 1. Kluyskens P, Ringoir S: Follow-up of a human larynx transplantation. Laryngoscope 80:1244-1250, 1970 2. Vincent M, Robbins A, Walsh M, et al: Evaluation of Blom-Singer voice prosthesis. Am J Roentgen01 143:745750,1984 3. Wetmore S, Krueger K, Wesson K, et al: Long-term results of the Blom-Singer speech rehabilitation procedure. Arch Otolaryngol Head Neck Surg 111:106-109, 1985 4. Hamaker R, Singer M, Blom E, et al: Primary voice restoration at laryngectomy. Arch Otolaryngol Head Neck Surg 111:X32-186, 1985 5. Strome M, Mustoe T, Kelly J: Voice rehabilitation following laryngectomy. Arch Otolaryngol Head Neck Surg 112:1168-1171, 1986 6. Strome M, Brasnu D, Laccourreye H: Further experience with the myomucosal tracheoesophageal shunt. Arch Otolaryngol Head Neck Surg 114:1303-1306, 1988 7. Daly J: Is laryngeal transplantation justifiable? Laryngoscope 80:1251-1255, 1970 8. Sheil A, Flavel S, Disney A, et al: Cancer incidence in renal transplant patients treated with Azathioprine or Cyclosporine. Transplant Proc 19:2214-2216, 1987 9. Penn I: Cancers following cyclosporine therapy. Transplant Proc 19:2211-2213, 1987 10. McNeil B, Weichselbaum R, Pauker S: Speech and survival. N Engl J Med 305:982-987, 1981
