HAND SURGERY
Changing Attitudes Toward Hand Allotransplantation Among North American Hand Surgeons Anthony A. Bertrand, MD, Subhro Sen, MD, Leo R. Otake, MD, PhD, and Gordon K. Lee, MD, FACS Objectives: Although more than 70 hand transplants have been performed worldwide, the appropriate clinical indications for this operation are still being determined. Cost and patient exposure to the challenges of lifelong immunosuppression for what is a quality of life-improving (but not life-saving) operation are the focus of the ongoing discussion. A study performed in 2007 showed that surgeons’ opinions on the issue varied widely. Recently, more information has been made available regarding long-term patient outcomes, and significant improvements in immunotherapy protocols have been reported. In light of this, we sought to examine changing attitudes regarding hand allotransplantation and its indications by surveying hand surgeons. Methods: An email-based survey was sent to members of the American Society for Surgery of the Hand. Demographic information and practice profiles were identified, followed by their risk assessment of hand allotransplants and endorsement of performing the operation in different clinical scenarios. Additional questions focused on the appropriate indications for hand allotransplantation, as well as the procedure’s associated ethical and financial implications. Results: A total of 385 surgeons responded to the survey (14% response rate). The majority (82%) considered hand transplantation to be a high-risk operation (as opposed to 27% in hand replantation), with 78% citing lifelong immunosuppression as the primary factor impacting their overall risk assessment. The most commonly accepted indication for hand vascularized composite allotransplantation was loss of bilateral hands (80% in favor). Dominant hand loss (with an intact contralateral hand) was a far less frequently accepted indication (36% in favor). Patient adherence to immunosuppressive regimens (51%) and expectations of functional/aesthetic outcome (38%) were the most frequently chosen top psychosocial issues that must be addressed by the surgical/medical teams involved in the operation. Conclusions: Our study’s results demonstrate increasing overall support for hand allotransplantation and increasing acceptance of today’s immunosuppressive regimens compared to prior literature. Bilateral hand loss remains the primary agreed-upon indication for transplantation. Despite increasing acceptance in the surgical community, the dangers of chronic immunosuppression, cost and patient adherence continue to be the primary concerns hindering its broader acceptance. Key Words: hand transplantation, immunosuppression, amputation (Ann Plast Surg 2014;72: S56YS60)
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mputation of the hands or upper limbs dramatically affects a patient’s activities of daily living, navigation of their physical environment, and engagement in social and professional activities. Restoration of these basic abilities can potentially have a profound impact on a patient’s psyche and quality of life.1,2 There are reconstructive options available; however, these procedures are often limited by poor functional and aesthetic outcomes, autologous tissue loss with possible donor-site morbidity, and the potential necessity of
Received August 5, 2013, and accepted for publication, after revision, December 29, 2013. From the Stanford Hospital and Clinics, Stanford University, Stanford, CA. Conflicts of interest and sources of funding: none declared. Reprints: Gordon K. Lee, MD, FACS, 770 Welch Road, 4th Floor, Palo Alto, CA 94304. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7201-S056 DOI: 10.1097/SAP.0000000000000147
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multiple revision operations.3 Despite significant advancements in prosthetic technology, many upper limb amputees reject this option, citing discomfort, appearance, and/or the absence of sensory feedback.1 Therefore, vascularized composite allotransplantation (VCA), with an unparalleled potential to restore ‘‘like with like,’’ holds tremendous reconstructive promise, and has become an area of growing interest for many reconstructive surgeons worldwide. More than 150 composite tissue allotransplants have been performed to date. Hand is the most common type of VCAVmore than 70 transplants have been performed in 51 recipients.4Y6 First attempted in Ecuador in 1964, the reinvigoration of hand VCA began in 1998, with the advantages of modern microvascular techniques and immunosuppressive drugs. Since this time, the technical feasibility of the operation itself has been confirmed.7 Most patients have been successfully maintained on immunosuppressive protocols similar to those developed for solid organ transplantation (SOT). There have been strong differences in opinion within the medical community regarding the appropriateness of VCA for hand amputee patients. The discussion has primarily centered on the postoperative risks and overall cost-benefit balance.4,6,8,9 Unlike SOT, hand transplantation requires that patients remain on lifelong immunosuppression for the sake of restoring function, sensation, and appearance, thereby improving overall quality of life. This drug regimen usually consists of antibody-based lymphocyte-depletion induction, followed by triple-drug maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids.8,10,11 Initially, dosing was similar to or slightly higher than in patients with solid organ transplants, believed to be due to the heightened immunogenicity caused by the presence of multiple tissue types, and in particular, skin.8,12 Many expressed concern that patients are at considerable risk for infectious or metabolic complications, nephrotoxicity, and even malignancy. Indeed, metabolic complications have been reported in 69% of hand recipients thus far, and the majority has experienced some form of opportunistic infection.10,12,13 Critics also cite the challenge of resource utilization: estimates place the cost of limb transplantation at approximately $500,000 for a single patient (including lifetime immunosuppression).13 This alone can be prohibitive in the absence of outside funding, save for the most wealthy and motivated. Therefore, hand allotransplantation has previously been viewed as an experimental, although scientifically fascinating, endeavor. In recent years, however, the field of hand VCA has benefitted from a preponderance of favorable data regarding patient outcomes, as well as substantial advancement in immunotherapy protocols. Patients have demonstrated significant functional improvement over time, including intrinsic and extrinsic muscle recovery ref lected by significant improvements in Hand Transplant Scoring System and Disabilities of the Arm Shoulder and Hand surveys, as well as tactile sensibility and protective sensation. Many can now perform activities of daily living that were previously unattainable.4 Approximately 75% of all patients have reported an improvement in their overall quality of life, and going back to work has been a consistent feature for most.1,10 Although the majority (85%) of recipients have experienced at least 1 episode of acute rejection at 1 year, all of these cases were effectively treated without significant patient morbidity or graft loss.5,7,8,12,14 Also, the incidence of chronic rejection in the few patients who have surpassed the 10-year follow-up mark are Annals of Plastic Surgery
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exceedingly low when compared to SOT.3,8 There have been at least 10 instances of graft loss internationally; however, almost all cases are attributed to an inappropriate cessation of immunosuppressive regimens. Although complications related to immunosuppression have occurred, almost all have been treatable and non-life threatening. The single case of postoperative death was seen in the patient who received the first face and bilateral hand transplant. Also, recent development of novel cell-based therapies has facilitated induction of at least transient chimerism and the experimental application of steroid-free, single-agent regimens.3,6,8,10 Breakthroughs like these are forging promising pathways toward fewer complications and improved medication adherence, and are making headway in the medical community. A previous survey performed by Mathes et al in 2007 demonstrated somewhat conf licting, but overall support for hand allotransplantation among hand surgeons. Seventy-one percent agreed with performing the operation in ‘‘properly-selected’’ patients, yet only 15% were in overall agreement (given the immunosuppression options available at the time).9 However, many of the aforementioned scientific advancements have been made since this time. Additionally, more long-term follow-up data have been made available. In light of this, we sought to examine changing attitudes regarding hand allotransplantation and its indications, focusing on actively practicing hand surgeons.
MATERIALS AND METHODS In September 2012, a survey was developed to examine surgeons’ current attitudes toward the evolving field of hand VCA. Using Qualtrics, a Web-based survey was emailed to all members of the American Society for Surgery of the Hand (ASSH). The survey consisted of 34 questions, and participants were ensured that responses were blinded and anonymous. The survey obtained data regarding demographic information and practice profiles of the responding surgeons. Information was obtained as to the type of training respondents had received, years of experience, clinical experience with complex hand injuries, annual case numbers for free tissue transfers, digital replants, and hand replants. Furthermore, we queried respondents’ risk assessment of hand transplantation as compared to replantation. Respondents were also given the opportunity (using a check box design with a write-in option) to explain the primary factor(s) influencing this risk assessment, including immunosuppression risks, psychosocial/financial concerns, operative complexity, and others. Additional survey items sought to determine respondents’ opinions regarding the appropriate indications for hand allotransplantation. This was first posed in a Likert scale (1Y5), allowing graded endorsement (from strongly disagree to strongly agree) of hand transplantation in various clinical scenarios. Respondents were then allowed
Changing Hand Allotransplantation Attitudes
FIGURE 2. Responding ASSH members with varying years of practice experience.
to directly choose (or write in) the appropriate indications for hand allotransplantation. Lastly, we asked respondents to consider the organizational policies surrounding hand transplantation, information sharing, as well as the health systems currently in place to support its successful execution. Data were collected and analyzed using the Qualtrics Web software. Response percentages were calculated, and cross-tabulations were performed via in-software W2 tests to determine relationships between individual questions.
RESULTS Of the 2671 ASSH members contacted, we received 385 unique responses (14.4% response rate). Most had residency training in orthopedic surgery (65%) or plastic surgery (18%), with the remainder having trained in general surgery. Two hundred twenty-three (60%) subsequently completed a hand fellowship (Fig. 1). Respondents averaged 17 years in practice (Fig. 2). The group performed an average of 12 digital replantations per year, and report having performed approximately 46 in their career. Respondents performed an average of 11 total hand replantations, and the same number of free tissue transfers (ie, toe to thumb) in their career. Forty-nine percent perceived hand replantation to be a mediumrisk operation, and 27% perceived it to be a high-risk operation. In contrast, most of respondents assessed hand allotransplantation to be a high-risk operation (Table 1). When prompted to choose the primary factor affecting their risk assessment of hand allotransplantation, 78% of respondents reported complications associated with lifelong immunosuppression. The second most common answer was the psychological, social, and financial challenges associated with the operation. When presented with various clinical scenarios and given the option of performing hand transplantation (with immunosuppressive options available today), 17% agreed with and 60% disagreed with performing transplantation of the nondominant hand in a patient with intact contralateral hand function. Thirty percent endorsed dominant hand transplantation (with today’s immunosuppression and intact contralateral hand function) for patients who would gain tangible functional improvement. When asked about bilateral hand transplantation with the immunosuppressive agents available today, 56% were in TABLE 1. Risk Assessment of Hand Replantation Versus Hand Allotransplantation Hand Replantation Option
FIGURE 1. Percentage of responding ASSH members who identified as having completed residency training in orthopedic surgery, plastic surgery, general surgery, and those who have completed a hand fellowship. * 2014 Lippincott Williams & Wilkins
High risk Medium risk Low risk Cannot assess risk level
Hand CTA
Response
%
Response
%
104 189 77 15
27 49 20 4
316 54 4 11
82 14 1 3
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TABLE 2. Endorsement of Hand Allotransplantation as Treatment in Different Clinical Scenarios: Amputation of the Nondominant Hand, Dominant Hand, Bilateral Hands, and Bilateral Hands if Graft Tolerance Were Achieved Bilateral With Graft Nondominant, % Dominant, % Bilateral, % Tolerance, %
Option Strongly agree Agree Neither Disagree Strongly disagree
2 15 23 34 26
5 25 26 27 17
12 44 24 12 8
28 47 15 6 4
agreement. With the elimination of standard immunosuppressive agents, the percentage in agreement increased to 75%. Ten percent disagreed with performing the procedure in this setting, and 15% had no opinion (Table 2). When asked about their endorsement of performing hand transplantation in a patient who had previously received SOT and was accordingly immunosuppressed, 42% of respondents were in agreement and 28% disagreed. When allowed to choose the proper indications for hand allotransplantation directly, 80% chose amputation of bilateral hands, 36% chose amputation of the dominant hand. Seven percent believed that there were no proper indications for hand allotransplantation (Fig. 3). Seventy-nine percent of respondents believed 18 to 35 years would be the optimal age range for patients undergoing hand allotransplantation. Importantly, there was no statistically significant association between demographic variables (training type, years in practice, microsurgical experience, number of hand replants) and surgeons’ risk assessment of hand VCA (P 9 0.05 in all cases). When respondents were asked whether, over the course of their practice, their opinion on hand allotransplantation had ever changed, 20% reported having changed to now being in favor of hand allotransplantation. Only 5 respondents reported having changed their opinion such that they are now in disagreement with hand allotransplantation. Eighty percent of those who stated their opinion had changed reported having done so in the past 5 years (Table 3). Fifty percent of respondents believed that composite tissue allotransplants (including transplanted hands) should be classified and treated as an organ, not tissue. Seventy-three percent of respondents agreed that VCAs should be governed under the same organizations as solid organ transplants (United Network for Organ
FIGURE 3. Indications for hand allotransplantation. S58
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TABLE 3. If Your Opinion on Hand Allotransplantation Has Changed, Over What Period Has This Occurred? Option In In In In In
the last the last the last the last the last
6 mo y 1Y5 y 5Y7 y 7Y10 y
Response
%
4 14 46 11 6
5 18 57 13 8
Sharing, Organ Procurement and Transplantation Network), and 75% believed that these organizations should develop guidelines to ensure patient safety and build public trust. Most of surgeons (93%) were supportive of maintaining outcome registries for hand VCAs and were also in favor of surgical centers and societies (91% and 81%, respectively), more clearly defining their specific indications and contraindications for performing the procedure. When asked about the primary barriers stopping hand transplantation from being performed more frequently, the most common answers were ‘‘risks associated with long-term immunosuppression’’ and ‘‘financial burden and/or cost effectiveness of treatment’’ (Fig. 4). Sixty-one percent of surgeons believe that advancements in robotic prosthetic technology will become a more viable option than hand allotransplantation within the next 15 years. Adherence to an immunosuppressive regimen and managing realistic expectations of functional and aesthetic outcome were the most frequently chosen psychosocial issues that surgeons believed should be addressed with patients (Fig. 5).
DISCUSSION Hand VCA has thus far been considered an experimental procedure by the surgical community, primarily due to (a) the need for indefinite high-dose immunosuppression, (b) uncertain long-term outcomes, and (c) a questionable cost-benefit balance.4,6,8,9 However, in recent years, the field has benefited from a preponderance of favorable data regarding many of these challenges. As mentioned previously, considerable advancements have been made in the development of novel immunomodulatory protocols, making single-agent therapy a possibility.6 Some patients have surpassed the 10-year follow-up mark, and overall graft survival outcomes have been satisfactory or superior to those of SOT.3,8 Significant improvement in function, sensation, and (importantly) quality of life has been reliably achieved.3,8 Despite these advancements, no position paper has been officially reviewed in recent years by the major hand societies. The last comprehensive data available regarding opinions of hand VCA come from a paper
FIGURE 4. Barriers facing more common practice of hand allotransplantation. * 2014 Lippincott Williams & Wilkins
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Changing Hand Allotransplantation Attitudes
FIGURE 5. Prioritized rank order list of patient psychosocial issues that should be assessed by physicians performing hand CTA.
by Mathes et al performed in 2007. Therefore, our study sought to examine if and how hand surgeons’ attitudes toward the field may have changed since this time, with particular attention given to the appropriate indications for the procedure. Although hand surgeons withheld broad approval of the practice, hand allotransplantation has gained significant acceptance when performed under certain circumstances. This is demonstrated by the fact that up to 56% of respondents endorsed performing hand VCA with today’s immunosuppressive agents (in the scenario of bilateral hand loss). Overall support decreased to 30% when unilateral dominant hand loss (with intact contralateral hand function) was consideredVin this case, 44% disagreed and 26% were undecided. If the necessity of immunosuppression was eliminated, agreement with dominant hand VCA increased back up to 59%. Only 17% endorsed unilateral nondominant hand allotransplantation, with 60% expressing disagreement and 23% remaining undecided. This represents more definitive support than the previous Mathes survey in 2007, wherein only 15% of respondents agreed with performing hand VCA in general with immunosuppression available at the time.9 The high variability in support for hand VCA between these different scenarios speaks to surgeons’ perception of a tenuous risk-benefit balance associated with the procedure. No significant association was found between demographic variables (ie, years in practice and microsurgical experience) and responses regarding hand transplantation. No statistically significant association was found between demographic variablesVthat is, type of training, years in practice, microsurgical experienceVand responses regarding hand transplantation. The reluctance on the part of hand surgeons to fully embrace VCA is explained by the fear of long-term complications that are part and parcel of conventional immunosuppression.10,14,15 Most of those surveyed (82%) consider hand VCA to be a high-risk endeavor, and 78% reported that immunosuppression-related complications were the primary factor affecting their risk assessment. Further, 89% of respondents identified this issue as one of the primary barriers facing hand VCA’s more common practice. Although concerns regarding immune complications (rejection, metabolic, infection) have impeded acceptance of hand VCA in the past,5,9,16,17 our data suggest that recent publication of encouraging immunologic and functional outcomes are beginning to sway surgeons’ risk-benefit assessment. Of the 385 members who responded to the survey, 79 (21%) report that they have changed their opinion on hand transplantationValmost all were now in favor. Eighty percent of those who had changed their minds reported having done so in the past 5 years. Improvement in immunosuppressive options and positive outcome data was frequently mentioned in many respondents’ optional write-in comments (data not shown). The financial burden and cost-effectiveness was mentioned as * 2014 Lippincott Williams & Wilkins
the second most commonly identified (73%) barrier preventing broader acceptance of hand VCA. This will likely remain a continued challenge in the years to come. Although single-agent regimens may significantly decrease cost over time, no significant reduction in cost estimates has yet been released. A thorough, individualized assessment of a patient’s clinical condition, psychosocial support, financial resources, and health care access is critical before consideration for VCA. Clarity regarding overall surgical indications, however, will become increasingly important as the procedure becomes more commonplace. Most of the surgeons (80%) considered amputation of bilateral hands to be a proper indication for considering VCA. There was less support for dominant hand amputation alone (36%) and nondominant hand (15%). Few surgeons considered thumb (3%) or multiple-digit (3%) amputation to be proper indications for allotransplantation, and 7% believed that there were no proper indications. These endorsement rates were overall similar to those in previous studies, including those reported by the Mathes group (bilateral hands 78%, dominant hand 32%, thumb 20%, multiple digits 17%, and no acceptable indications 17%).9,15 Patients ranging from 18 to 35 years were considered to be the optimal age range to undergo the operation by 79% of respondents, followed by 35 to 50 years (39%). Compared to prior reports, the current study delved much further into the organizational considerations associated with VCA. Surgeons were generally supportive of greater transparency and more structured regulation/reporting of vascularized composite allotransplants. Most of the surgeons (73%) believed that VCA should be governed under the United Network for Organ Sharing/ Organ Procurement and Transplantation Network (similar to solid organ transplants), and believed that these bodies should provide oversight and guidelines (75%) to ensure patient safety and secure public trust. The overwhelming majority also supported reporting of society and institution-specific indications (81% and 91%, respectively), as well as the maintenance of interinstitutional outcome registries (93%). As hand VCA becomes more widely performed in clinical practice, transitioning toward a more standardized method of reporting is likely to increase acceptance in the surgical community. Our study faces certain limitations. First, an email-based Web survey was used for data collection. Although it was useful in efficiently reaching and gathering practice information from a large number of surgeons (n = 385), a modest overall response rate was obtained. Nonrespondent bias is a possibility, as surgeons less interested in hand allotransplantation (and therefore less supportive) could have been less likely to respond. Finally, although every effort was made to ensure question validation, some variation in interpretation must be assumed. www.annalsplasticsurgery.com
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CONCLUSIONS The present study provides insight into surgeons’ changing attitudes toward hand allotransplantation, including its appropriate indications. Our survey results demonstrate increasing overall support for hand allotransplantation and acceptance of today’s immunosuppressive options. This is consistent with the recent availability of long-term patient outcome data with modern immunosuppression and advancements in immunosuppressive protocols. Bilateral hand loss remains the primary agreed-upon indication for transplantation. Dominant hand loss alone, however, received less support. Surgeons are interested in institutional transparency and further standardization of indications and patient outcomes. Complications associated with lifelong immunosuppression and the financial burden/cost-effectiveness of treatment remains the primary barriers preventing its more common practice. REFERENCES 1. Jensen SE, Butt Z, Bill A, et al. Quality of life considerations in upper limb transplantation: review and future directions. J Hand Surg Am. 2012;37:2126Y2135. 2. Llull R. An open proposal for clinical composite tissue allotransplantation. Transplant Proc. 1998;30:2692Y2696; discussion 2697-703. 3. Breidenbach WC, Gonzales NR, Kaufman CL, et al. Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant. J Hand Surg Am. 2008;33:1039Y1047. 4. Petruzzo P, Dubernard JM. The International Registry on Hand and Composite Tissue allotransplantation. Clin Transpl. 2011:247Y253. 5. Schneeberger S, Landin L, Jableki J, et al. Achievements and challenges in composite tissue allotransplantation. Transpl Int. 2011;24:760Y769.
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6. Shores JT, Imbriglia JE, Lee WP. The current state of hand transplantation. J Hand Surg Am. 2011;36:1862Y1867. 7. Azari KK, Imbriglia JE, Goitz RJ, et al. Technical aspects of the recipient operation in hand transplantation. J Reconstr Microsurg. 2012;28:27Y34. 8. Brandacher G, Lee WP, Schneeberger S. Minimizing immunosuppression in hand transplantation. Expert Rev Clin Immunol. 2012;8:673Y683; quiz 684. 9. Mathes DW, Schlenker R, Ploplys E, et al. A survey of north american hand surgeons on their current attitudes toward hand transplantation. J Hand Surg Am. 2009;34:808Y814. 10. Ravindra KV, Xu H, Bozulic LD, et al. The need for inducing tolerance in vascularized composite allotransplantation. Clin Dev Immunol. 2012; 2012:438078. 11. Schneeberger S, Gorantla VS, Brandacher G, et al. Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression. Ann Surg. 2013;257:345Y351. 12. Brandacher G, Gorantla VS, Lee WP. Hand allotransplantation. Semin Plast Surg. 2010;24:11Y17. 13. Agnew SP, Ko J, De la Garza M, et al. Limb transplantation and targeted reinnervation: a practical comparison. J Reconstr Microsurg. 2012;28:63Y68. 14. Pei G, Xiang D, Gu L, et al. A report of 15 hand allotransplantations in 12 patients and their outcomes in China. Transplantation. 2012;94:1052Y1059. 15. Hollenbeck ST, Erdmann D, Levin LS. Current indications for hand and face allotransplantation. Transplant Proc. 2009;41:495Y498. 16. Gordon CR, Siemionow M. Requirements for the development of a hand transplantation program. Ann Plast Surg. 2009;63:262Y273. 17. Wu S, Xu H, Ravindra K, et al. Composite tissue allotransplantation: past, present and futureVthe history and expanding applications of CTA as a new frontier in transplantation. Transplant Proc. 2009;41:463Y465.
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Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Changing Attitudes Toward Hand Allotransplantation Among North American Hand Surgeons Anthony A. Bertrand, MD, Subhro Sen, MD, Leo R. Otake, MD, PhD, and Gordon K. Lee, MD, FACS Objectives: Although more than 70 hand transplants have been performed worldwide, the appropriate clinical indications for this operation are still being determined. Cost and patient exposure to the challenges of lifelong immunosuppression for what is a quality of life-improving (but not life-saving) operation are the focus of the ongoing discussion. A study performed in 2007 showed that surgeons’ opinions on the issue varied widely. Recently, more information has been made available regarding long-term patient outcomes, and significant improvements in immunotherapy protocols have been reported. In light of this, we sought to examine changing attitudes regarding hand allotransplantation and its indications by surveying hand surgeons. Methods: An email-based survey was sent to members of the American Society for Surgery of the Hand. Demographic information and practice profiles were identified, followed by their risk assessment of hand allotransplants and endorsement of performing the operation in different clinical scenarios. Additional questions focused on the appropriate indications for hand allotransplantation, as well as the procedure’s associated ethical and financial implications. Results: A total of 385 surgeons responded to the survey (14% response rate). The majority (82%) considered hand transplantation to be a high-risk operation (as opposed to 27% in hand replantation), with 78% citing lifelong immunosuppression as the primary factor impacting their overall risk assessment. The most commonly accepted indication for hand vascularized composite allotransplantation was loss of bilateral hands (80% in favor). Dominant hand loss (with an intact contralateral hand) was a far less frequently accepted indication (36% in favor). Patient adherence to immunosuppressive regimens (51%) and expectations of functional/aesthetic outcome (38%) were the most frequently chosen top psychosocial issues that must be addressed by the surgical/medical teams involved in the operation. Conclusions: Our study’s results demonstrate increasing overall support for hand allotransplantation and increasing acceptance of today’s immunosuppressive regimens compared to prior literature. Bilateral hand loss remains the primary agreed-upon indication for transplantation. Despite increasing acceptance in the surgical community, the dangers of chronic immunosuppression, cost and patient adherence continue to be the primary concerns hindering its broader acceptance. Key Words: hand transplantation, immunosuppression, amputation (Ann Plast Surg 2014;72: S56YS60)
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mputation of the hands or upper limbs dramatically affects a patient’s activities of daily living, navigation of their physical environment, and engagement in social and professional activities. Restoration of these basic abilities can potentially have a profound impact on a patient’s psyche and quality of life.1,2 There are reconstructive options available; however, these procedures are often limited by poor functional and aesthetic outcomes, autologous tissue loss with possible donor-site morbidity, and the potential necessity of
Received August 5, 2013, and accepted for publication, after revision, December 29, 2013. From the Stanford Hospital and Clinics, Stanford University, Stanford, CA. Conflicts of interest and sources of funding: none declared. Reprints: Gordon K. Lee, MD, FACS, 770 Welch Road, 4th Floor, Palo Alto, CA 94304. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7201-S056 DOI: 10.1097/SAP.0000000000000147
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multiple revision operations.3 Despite significant advancements in prosthetic technology, many upper limb amputees reject this option, citing discomfort, appearance, and/or the absence of sensory feedback.1 Therefore, vascularized composite allotransplantation (VCA), with an unparalleled potential to restore ‘‘like with like,’’ holds tremendous reconstructive promise, and has become an area of growing interest for many reconstructive surgeons worldwide. More than 150 composite tissue allotransplants have been performed to date. Hand is the most common type of VCAVmore than 70 transplants have been performed in 51 recipients.4Y6 First attempted in Ecuador in 1964, the reinvigoration of hand VCA began in 1998, with the advantages of modern microvascular techniques and immunosuppressive drugs. Since this time, the technical feasibility of the operation itself has been confirmed.7 Most patients have been successfully maintained on immunosuppressive protocols similar to those developed for solid organ transplantation (SOT). There have been strong differences in opinion within the medical community regarding the appropriateness of VCA for hand amputee patients. The discussion has primarily centered on the postoperative risks and overall cost-benefit balance.4,6,8,9 Unlike SOT, hand transplantation requires that patients remain on lifelong immunosuppression for the sake of restoring function, sensation, and appearance, thereby improving overall quality of life. This drug regimen usually consists of antibody-based lymphocyte-depletion induction, followed by triple-drug maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids.8,10,11 Initially, dosing was similar to or slightly higher than in patients with solid organ transplants, believed to be due to the heightened immunogenicity caused by the presence of multiple tissue types, and in particular, skin.8,12 Many expressed concern that patients are at considerable risk for infectious or metabolic complications, nephrotoxicity, and even malignancy. Indeed, metabolic complications have been reported in 69% of hand recipients thus far, and the majority has experienced some form of opportunistic infection.10,12,13 Critics also cite the challenge of resource utilization: estimates place the cost of limb transplantation at approximately $500,000 for a single patient (including lifetime immunosuppression).13 This alone can be prohibitive in the absence of outside funding, save for the most wealthy and motivated. Therefore, hand allotransplantation has previously been viewed as an experimental, although scientifically fascinating, endeavor. In recent years, however, the field of hand VCA has benefitted from a preponderance of favorable data regarding patient outcomes, as well as substantial advancement in immunotherapy protocols. Patients have demonstrated significant functional improvement over time, including intrinsic and extrinsic muscle recovery ref lected by significant improvements in Hand Transplant Scoring System and Disabilities of the Arm Shoulder and Hand surveys, as well as tactile sensibility and protective sensation. Many can now perform activities of daily living that were previously unattainable.4 Approximately 75% of all patients have reported an improvement in their overall quality of life, and going back to work has been a consistent feature for most.1,10 Although the majority (85%) of recipients have experienced at least 1 episode of acute rejection at 1 year, all of these cases were effectively treated without significant patient morbidity or graft loss.5,7,8,12,14 Also, the incidence of chronic rejection in the few patients who have surpassed the 10-year follow-up mark are Annals of Plastic Surgery
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exceedingly low when compared to SOT.3,8 There have been at least 10 instances of graft loss internationally; however, almost all cases are attributed to an inappropriate cessation of immunosuppressive regimens. Although complications related to immunosuppression have occurred, almost all have been treatable and non-life threatening. The single case of postoperative death was seen in the patient who received the first face and bilateral hand transplant. Also, recent development of novel cell-based therapies has facilitated induction of at least transient chimerism and the experimental application of steroid-free, single-agent regimens.3,6,8,10 Breakthroughs like these are forging promising pathways toward fewer complications and improved medication adherence, and are making headway in the medical community. A previous survey performed by Mathes et al in 2007 demonstrated somewhat conf licting, but overall support for hand allotransplantation among hand surgeons. Seventy-one percent agreed with performing the operation in ‘‘properly-selected’’ patients, yet only 15% were in overall agreement (given the immunosuppression options available at the time).9 However, many of the aforementioned scientific advancements have been made since this time. Additionally, more long-term follow-up data have been made available. In light of this, we sought to examine changing attitudes regarding hand allotransplantation and its indications, focusing on actively practicing hand surgeons.
MATERIALS AND METHODS In September 2012, a survey was developed to examine surgeons’ current attitudes toward the evolving field of hand VCA. Using Qualtrics, a Web-based survey was emailed to all members of the American Society for Surgery of the Hand (ASSH). The survey consisted of 34 questions, and participants were ensured that responses were blinded and anonymous. The survey obtained data regarding demographic information and practice profiles of the responding surgeons. Information was obtained as to the type of training respondents had received, years of experience, clinical experience with complex hand injuries, annual case numbers for free tissue transfers, digital replants, and hand replants. Furthermore, we queried respondents’ risk assessment of hand transplantation as compared to replantation. Respondents were also given the opportunity (using a check box design with a write-in option) to explain the primary factor(s) influencing this risk assessment, including immunosuppression risks, psychosocial/financial concerns, operative complexity, and others. Additional survey items sought to determine respondents’ opinions regarding the appropriate indications for hand allotransplantation. This was first posed in a Likert scale (1Y5), allowing graded endorsement (from strongly disagree to strongly agree) of hand transplantation in various clinical scenarios. Respondents were then allowed
Changing Hand Allotransplantation Attitudes
FIGURE 2. Responding ASSH members with varying years of practice experience.
to directly choose (or write in) the appropriate indications for hand allotransplantation. Lastly, we asked respondents to consider the organizational policies surrounding hand transplantation, information sharing, as well as the health systems currently in place to support its successful execution. Data were collected and analyzed using the Qualtrics Web software. Response percentages were calculated, and cross-tabulations were performed via in-software W2 tests to determine relationships between individual questions.
RESULTS Of the 2671 ASSH members contacted, we received 385 unique responses (14.4% response rate). Most had residency training in orthopedic surgery (65%) or plastic surgery (18%), with the remainder having trained in general surgery. Two hundred twenty-three (60%) subsequently completed a hand fellowship (Fig. 1). Respondents averaged 17 years in practice (Fig. 2). The group performed an average of 12 digital replantations per year, and report having performed approximately 46 in their career. Respondents performed an average of 11 total hand replantations, and the same number of free tissue transfers (ie, toe to thumb) in their career. Forty-nine percent perceived hand replantation to be a mediumrisk operation, and 27% perceived it to be a high-risk operation. In contrast, most of respondents assessed hand allotransplantation to be a high-risk operation (Table 1). When prompted to choose the primary factor affecting their risk assessment of hand allotransplantation, 78% of respondents reported complications associated with lifelong immunosuppression. The second most common answer was the psychological, social, and financial challenges associated with the operation. When presented with various clinical scenarios and given the option of performing hand transplantation (with immunosuppressive options available today), 17% agreed with and 60% disagreed with performing transplantation of the nondominant hand in a patient with intact contralateral hand function. Thirty percent endorsed dominant hand transplantation (with today’s immunosuppression and intact contralateral hand function) for patients who would gain tangible functional improvement. When asked about bilateral hand transplantation with the immunosuppressive agents available today, 56% were in TABLE 1. Risk Assessment of Hand Replantation Versus Hand Allotransplantation Hand Replantation Option
FIGURE 1. Percentage of responding ASSH members who identified as having completed residency training in orthopedic surgery, plastic surgery, general surgery, and those who have completed a hand fellowship. * 2014 Lippincott Williams & Wilkins
High risk Medium risk Low risk Cannot assess risk level
Hand CTA
Response
%
Response
%
104 189 77 15
27 49 20 4
316 54 4 11
82 14 1 3
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TABLE 2. Endorsement of Hand Allotransplantation as Treatment in Different Clinical Scenarios: Amputation of the Nondominant Hand, Dominant Hand, Bilateral Hands, and Bilateral Hands if Graft Tolerance Were Achieved Bilateral With Graft Nondominant, % Dominant, % Bilateral, % Tolerance, %
Option Strongly agree Agree Neither Disagree Strongly disagree
2 15 23 34 26
5 25 26 27 17
12 44 24 12 8
28 47 15 6 4
agreement. With the elimination of standard immunosuppressive agents, the percentage in agreement increased to 75%. Ten percent disagreed with performing the procedure in this setting, and 15% had no opinion (Table 2). When asked about their endorsement of performing hand transplantation in a patient who had previously received SOT and was accordingly immunosuppressed, 42% of respondents were in agreement and 28% disagreed. When allowed to choose the proper indications for hand allotransplantation directly, 80% chose amputation of bilateral hands, 36% chose amputation of the dominant hand. Seven percent believed that there were no proper indications for hand allotransplantation (Fig. 3). Seventy-nine percent of respondents believed 18 to 35 years would be the optimal age range for patients undergoing hand allotransplantation. Importantly, there was no statistically significant association between demographic variables (training type, years in practice, microsurgical experience, number of hand replants) and surgeons’ risk assessment of hand VCA (P 9 0.05 in all cases). When respondents were asked whether, over the course of their practice, their opinion on hand allotransplantation had ever changed, 20% reported having changed to now being in favor of hand allotransplantation. Only 5 respondents reported having changed their opinion such that they are now in disagreement with hand allotransplantation. Eighty percent of those who stated their opinion had changed reported having done so in the past 5 years (Table 3). Fifty percent of respondents believed that composite tissue allotransplants (including transplanted hands) should be classified and treated as an organ, not tissue. Seventy-three percent of respondents agreed that VCAs should be governed under the same organizations as solid organ transplants (United Network for Organ
FIGURE 3. Indications for hand allotransplantation. S58
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TABLE 3. If Your Opinion on Hand Allotransplantation Has Changed, Over What Period Has This Occurred? Option In In In In In
the last the last the last the last the last
6 mo y 1Y5 y 5Y7 y 7Y10 y
Response
%
4 14 46 11 6
5 18 57 13 8
Sharing, Organ Procurement and Transplantation Network), and 75% believed that these organizations should develop guidelines to ensure patient safety and build public trust. Most of surgeons (93%) were supportive of maintaining outcome registries for hand VCAs and were also in favor of surgical centers and societies (91% and 81%, respectively), more clearly defining their specific indications and contraindications for performing the procedure. When asked about the primary barriers stopping hand transplantation from being performed more frequently, the most common answers were ‘‘risks associated with long-term immunosuppression’’ and ‘‘financial burden and/or cost effectiveness of treatment’’ (Fig. 4). Sixty-one percent of surgeons believe that advancements in robotic prosthetic technology will become a more viable option than hand allotransplantation within the next 15 years. Adherence to an immunosuppressive regimen and managing realistic expectations of functional and aesthetic outcome were the most frequently chosen psychosocial issues that surgeons believed should be addressed with patients (Fig. 5).
DISCUSSION Hand VCA has thus far been considered an experimental procedure by the surgical community, primarily due to (a) the need for indefinite high-dose immunosuppression, (b) uncertain long-term outcomes, and (c) a questionable cost-benefit balance.4,6,8,9 However, in recent years, the field has benefited from a preponderance of favorable data regarding many of these challenges. As mentioned previously, considerable advancements have been made in the development of novel immunomodulatory protocols, making single-agent therapy a possibility.6 Some patients have surpassed the 10-year follow-up mark, and overall graft survival outcomes have been satisfactory or superior to those of SOT.3,8 Significant improvement in function, sensation, and (importantly) quality of life has been reliably achieved.3,8 Despite these advancements, no position paper has been officially reviewed in recent years by the major hand societies. The last comprehensive data available regarding opinions of hand VCA come from a paper
FIGURE 4. Barriers facing more common practice of hand allotransplantation. * 2014 Lippincott Williams & Wilkins
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Changing Hand Allotransplantation Attitudes
FIGURE 5. Prioritized rank order list of patient psychosocial issues that should be assessed by physicians performing hand CTA.
by Mathes et al performed in 2007. Therefore, our study sought to examine if and how hand surgeons’ attitudes toward the field may have changed since this time, with particular attention given to the appropriate indications for the procedure. Although hand surgeons withheld broad approval of the practice, hand allotransplantation has gained significant acceptance when performed under certain circumstances. This is demonstrated by the fact that up to 56% of respondents endorsed performing hand VCA with today’s immunosuppressive agents (in the scenario of bilateral hand loss). Overall support decreased to 30% when unilateral dominant hand loss (with intact contralateral hand function) was consideredVin this case, 44% disagreed and 26% were undecided. If the necessity of immunosuppression was eliminated, agreement with dominant hand VCA increased back up to 59%. Only 17% endorsed unilateral nondominant hand allotransplantation, with 60% expressing disagreement and 23% remaining undecided. This represents more definitive support than the previous Mathes survey in 2007, wherein only 15% of respondents agreed with performing hand VCA in general with immunosuppression available at the time.9 The high variability in support for hand VCA between these different scenarios speaks to surgeons’ perception of a tenuous risk-benefit balance associated with the procedure. No significant association was found between demographic variables (ie, years in practice and microsurgical experience) and responses regarding hand transplantation. No statistically significant association was found between demographic variablesVthat is, type of training, years in practice, microsurgical experienceVand responses regarding hand transplantation. The reluctance on the part of hand surgeons to fully embrace VCA is explained by the fear of long-term complications that are part and parcel of conventional immunosuppression.10,14,15 Most of those surveyed (82%) consider hand VCA to be a high-risk endeavor, and 78% reported that immunosuppression-related complications were the primary factor affecting their risk assessment. Further, 89% of respondents identified this issue as one of the primary barriers facing hand VCA’s more common practice. Although concerns regarding immune complications (rejection, metabolic, infection) have impeded acceptance of hand VCA in the past,5,9,16,17 our data suggest that recent publication of encouraging immunologic and functional outcomes are beginning to sway surgeons’ risk-benefit assessment. Of the 385 members who responded to the survey, 79 (21%) report that they have changed their opinion on hand transplantationValmost all were now in favor. Eighty percent of those who had changed their minds reported having done so in the past 5 years. Improvement in immunosuppressive options and positive outcome data was frequently mentioned in many respondents’ optional write-in comments (data not shown). The financial burden and cost-effectiveness was mentioned as * 2014 Lippincott Williams & Wilkins
the second most commonly identified (73%) barrier preventing broader acceptance of hand VCA. This will likely remain a continued challenge in the years to come. Although single-agent regimens may significantly decrease cost over time, no significant reduction in cost estimates has yet been released. A thorough, individualized assessment of a patient’s clinical condition, psychosocial support, financial resources, and health care access is critical before consideration for VCA. Clarity regarding overall surgical indications, however, will become increasingly important as the procedure becomes more commonplace. Most of the surgeons (80%) considered amputation of bilateral hands to be a proper indication for considering VCA. There was less support for dominant hand amputation alone (36%) and nondominant hand (15%). Few surgeons considered thumb (3%) or multiple-digit (3%) amputation to be proper indications for allotransplantation, and 7% believed that there were no proper indications. These endorsement rates were overall similar to those in previous studies, including those reported by the Mathes group (bilateral hands 78%, dominant hand 32%, thumb 20%, multiple digits 17%, and no acceptable indications 17%).9,15 Patients ranging from 18 to 35 years were considered to be the optimal age range to undergo the operation by 79% of respondents, followed by 35 to 50 years (39%). Compared to prior reports, the current study delved much further into the organizational considerations associated with VCA. Surgeons were generally supportive of greater transparency and more structured regulation/reporting of vascularized composite allotransplants. Most of the surgeons (73%) believed that VCA should be governed under the United Network for Organ Sharing/ Organ Procurement and Transplantation Network (similar to solid organ transplants), and believed that these bodies should provide oversight and guidelines (75%) to ensure patient safety and secure public trust. The overwhelming majority also supported reporting of society and institution-specific indications (81% and 91%, respectively), as well as the maintenance of interinstitutional outcome registries (93%). As hand VCA becomes more widely performed in clinical practice, transitioning toward a more standardized method of reporting is likely to increase acceptance in the surgical community. Our study faces certain limitations. First, an email-based Web survey was used for data collection. Although it was useful in efficiently reaching and gathering practice information from a large number of surgeons (n = 385), a modest overall response rate was obtained. Nonrespondent bias is a possibility, as surgeons less interested in hand allotransplantation (and therefore less supportive) could have been less likely to respond. Finally, although every effort was made to ensure question validation, some variation in interpretation must be assumed. www.annalsplasticsurgery.com
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CONCLUSIONS The present study provides insight into surgeons’ changing attitudes toward hand allotransplantation, including its appropriate indications. Our survey results demonstrate increasing overall support for hand allotransplantation and acceptance of today’s immunosuppressive options. This is consistent with the recent availability of long-term patient outcome data with modern immunosuppression and advancements in immunosuppressive protocols. Bilateral hand loss remains the primary agreed-upon indication for transplantation. Dominant hand loss alone, however, received less support. Surgeons are interested in institutional transparency and further standardization of indications and patient outcomes. Complications associated with lifelong immunosuppression and the financial burden/cost-effectiveness of treatment remains the primary barriers preventing its more common practice. REFERENCES 1. Jensen SE, Butt Z, Bill A, et al. Quality of life considerations in upper limb transplantation: review and future directions. J Hand Surg Am. 2012;37:2126Y2135. 2. Llull R. An open proposal for clinical composite tissue allotransplantation. Transplant Proc. 1998;30:2692Y2696; discussion 2697-703. 3. Breidenbach WC, Gonzales NR, Kaufman CL, et al. Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant. J Hand Surg Am. 2008;33:1039Y1047. 4. Petruzzo P, Dubernard JM. The International Registry on Hand and Composite Tissue allotransplantation. Clin Transpl. 2011:247Y253. 5. Schneeberger S, Landin L, Jableki J, et al. Achievements and challenges in composite tissue allotransplantation. Transpl Int. 2011;24:760Y769.
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6. Shores JT, Imbriglia JE, Lee WP. The current state of hand transplantation. J Hand Surg Am. 2011;36:1862Y1867. 7. Azari KK, Imbriglia JE, Goitz RJ, et al. Technical aspects of the recipient operation in hand transplantation. J Reconstr Microsurg. 2012;28:27Y34. 8. Brandacher G, Lee WP, Schneeberger S. Minimizing immunosuppression in hand transplantation. Expert Rev Clin Immunol. 2012;8:673Y683; quiz 684. 9. Mathes DW, Schlenker R, Ploplys E, et al. A survey of north american hand surgeons on their current attitudes toward hand transplantation. J Hand Surg Am. 2009;34:808Y814. 10. Ravindra KV, Xu H, Bozulic LD, et al. The need for inducing tolerance in vascularized composite allotransplantation. Clin Dev Immunol. 2012; 2012:438078. 11. Schneeberger S, Gorantla VS, Brandacher G, et al. Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression. Ann Surg. 2013;257:345Y351. 12. Brandacher G, Gorantla VS, Lee WP. Hand allotransplantation. Semin Plast Surg. 2010;24:11Y17. 13. Agnew SP, Ko J, De la Garza M, et al. Limb transplantation and targeted reinnervation: a practical comparison. J Reconstr Microsurg. 2012;28:63Y68. 14. Pei G, Xiang D, Gu L, et al. A report of 15 hand allotransplantations in 12 patients and their outcomes in China. Transplantation. 2012;94:1052Y1059. 15. Hollenbeck ST, Erdmann D, Levin LS. Current indications for hand and face allotransplantation. Transplant Proc. 2009;41:495Y498. 16. Gordon CR, Siemionow M. Requirements for the development of a hand transplantation program. Ann Plast Surg. 2009;63:262Y273. 17. Wu S, Xu H, Ravindra K, et al. Composite tissue allotransplantation: past, present and futureVthe history and expanding applications of CTA as a new frontier in transplantation. Transplant Proc. 2009;41:463Y465.
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